C Ovid 19 Treatment Guidelines

COVID-19 Treatment Guidelines
Coronavirus Disease 2019 (COVID-19)

Treatment Guidelines
Credit NIAID-RML
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Visit https://www.covid19treatmentguidelines.nih.gov/ to access the most up-to-date guideline.
How to Cite the COVID-19 Treatment Guidelines:

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of
Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [insert date].
The COVID-19 Treatment Guidelines Panel regularly updates the recommendations in these guidelines as new information
on the management of COVID-19 becomes available. The most recent version of the guidelines can be found on the
COVID-19 Treatment Guidelines website (https://www.covid19treatmentguidelines.nih.gov/).

Table of Contents
What’s New in the Guidelines................................................................................................... 5
Guidelines Development........................................................................................................... 8
Overview
Overview of COVID-19........................................................................................................ 11
Testing for SARS-CoV-2 Infection....................................................................................... 16
Prevention of SARS-CoV-2 Infection.................................................................................. 23
Clinical Spectrum of SARS-CoV-2 Infection....................................................................... 33
Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of
COVID-19 When There Are Logistical or Supply Constraints............................................. 43
Clinical Management of Adults
Clinical Management of Adults Summary........................................................................... 46
General Management of Nonhospitalized Patients With Acute COVID-19........................ 51
Therapeutic Management of Nonhospitalized Adults With COVID-19............................... 58
Therapeutic Management of Hospitalized Adults With COVID-19..................................... 68
Clinical Management of Children
Clinical Management of Children Summary....................................................................... 80
Special Considerations in Children..................................................................................... 86
Therapeutic Management of Nonhospitalized Children with COVID-19............................ 97
Therapeutic Management of Hospitalized Children with COVID-19................................. 106
Therapeutic Management of Hospitalized Pediatric Patients With Multisystem
Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem
Inflammatory Syndrome in Adults [MIS-A])....................................................................... 116
Critical Care for Adults
Care of Critically Ill Adults With COVID-19 (Summary Recommendations)...................... 126
Introduction to Critical Care Management of Adults With COVID-19............................... 128
Hemodynamics for Adults................................................................................................ 135
Oxygenation and Ventilation for Adults............................................................................. 139
Pharmacologic Interventions for Critically Ill Patients....................................................... 148
Extracorporeal Membrane Oxygenation for Adults.......................................................... 150
Critical Care for Children
Introduction to Critical Care Management of Children With COVID-19............................ 152
Hemodynamic Considerations for Children...................................................................... 156
Oxygenation and Ventilation for Children......................................................................... 161
Extracorporeal Membrane Oxygenation for Children....................................................... 170
Antiviral Therapy
Antiviral Drugs That Are Approved, Authorized, or Under Evaluation for the Treatment
COVID-19 Treatment Guidelines 2

of COVID-19 (Summary Recommendations).................................................................... 173
Remdesivir........................................................................................................................ 175
Table 4a. Remdesivir: Selected Clinical Data.............................................................. 179
Ritonavir-Boosted Nirmatrelvir (Paxlovid)......................................................................... 187
Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid)
and Concomitant Medications.................................................................................... 192
Molnupiravir...................................................................................................................... 198
Interferons......................................................................................................................... 202
Table 4b. Interferons: Selected Clinical Data .............................................................. 204
Ivermectin......................................................................................................................... 210
Table 4c. Ivermectin: Selected Clinical Data............................................................... 214
Table 4d. Characteristics of Antiviral Agents.................................................................... 226
Anti-SARS-CoV-2 Antibody Products
Anti-SARS-CoV-2 Antibody Products (Summary Recommendations)............................. 232
Anti-SARS-CoV-2 Monoclonal Antibodies........................................................................ 234
Table 5a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data.............. 246
COVID-19 Convalescent Plasma...................................................................................... 250
Table 5b. COVID-19 Convalescent Plasma: Selected Clinical Data............................ 258
Immunoglobulins: SARS-CoV-2-Specific......................................................................... 265
Table 5c. Characteristics of SARS-CoV-2 Antibody-Based Products.............................. 266
Cell-Based Therapy Under Evaluation for the Treatment of COVID-19.............................. 271
Immunomodulators
Immunomodulators Under Evaluation for the Treatment of COVID-19 (Summary
Recommendations)........................................................................................................... 274
Corticosteroids.................................................................................................................. 275
Table 6a. Systemic Corticosteroids: Selected Clinical Data........................................ 283
Table 6b. Inhaled Corticosteroids: Selected Clinical Data........................................... 293
Interleukin-6 Inhibitors...................................................................................................... 297
Table 6c. Interleukin-6 Inhibitors: Selected Clinical Data............................................ 303
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s Tyrosine Kinase Inhibitors......... 311
Table 6d: Kinase Inhibitors: Selected Clinical Data..................................................... 318
Colchicine......................................................................................................................... 325
Fluvoxamine...................................................................................................................... 331
Table 6e. Fluvoxamine: Selected Clinical Data............................................................ 334
Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors...................................... 337
Table 6f. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors:
Selected Clinical Data................................................................................................. 340
Immunoglobulins: Non-SARS-CoV-2-Specific................................................................. 344
Interleukin-1 Inhibitors...................................................................................................... 346

Table 6g. Characteristics of Immunomodulators.............................................................. 352
Antithrombotic Therapy in Patients with COVID-19............................................................ 364
Table 7a. Antithrombotic Therapy: Selected Clinical Data................................................ 377
Table 7b. Antiplatelet Therapy: Selected Clinical Data..................................................... 384
Supplements
Supplements (Summary Recommendations)................................................................... 388
Vitamin C........................................................................................................................... 389
Vitamin D........................................................................................................................... 393
Zinc................................................................................................................................... 395
Considerations for Using Concomitant Medications in Patients With COVID-19.............. 399
Special Populations
Special Considerations in People Who Are Immunocompromised.................................. 401
Special Considerations in Adults and Children With Cancer............................................ 417
Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell
Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients............... 427
Special Considerations in People With HIV...................................................................... 437
Influenza and COVID-19................................................................................................... 445
Special Considerations in Pregnancy............................................................................... 450
Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Members............................. 455
Appendix A, Table 2. Panel on COVID-19 Treatment Guidelines Financial Disclosure
for Companies Related to COVID-19 Treatment or Diagnostics......................................... 457

What’s New in the Guidelines
Last Updated: August 8, 2022
The Coronavirus Disease 2019 (COVID-19) Treatment Guidelines is published in an electronic format
that can be updated in step with the rapid pace and growing volume of information regarding the
treatment of COVID-19.
The COVID-19 Treatment Guidelines Panel (the Panel) is committed to updating this document to
ensure that health care providers, patients, and policy experts have the most recent information regarding
the optimal management of COVID-19 (see the Panel Roster for a list of Panel members).
New Guidelines sections and recommendations and updates to existing Guidelines sections are
developed by working groups of Panel members. All recommendations included in the Guidelines are
endorsed by a majority of Panel members (see Guidelines Development for additional details on the
development process).
Major revisions to the Guidelines within the past month are as follows:
August 8, 2022
Special Considerations in People Who Are Immunocompromised
Individuals who are immunocompromised may have a higher risk of progressing to severe disease or
death from COVID-19 than the general population. The Panel added a new section to the Guidelines to
discuss some unique considerations for the prevention and management of COVID-19 in these patients.
This section covers methods of preventing SARS-CoV-2 infection, including vaccinating patients and
their close contacts against COVID-19 and using tixagevimab plus cilgavimab (Evusheld) as pre-
exposure prophylaxis (PrEP). It also discusses considerations for clinicians who manage patients with
COVID-19 who are immunocompromised. Key considerations include consulting with specialists before
stopping or reducing doses of immunosuppressive drugs, promptly initiating antiviral drugs or anti-
SARS-CoV-2 monoclonal antibodies in patients with mild to moderate disease, managing concomitant
medications and drug-drug interactions, and monitoring for secondary infections.
Clinical Management of Children

The Panel added 3 new sections to the Guidelines that focus on the therapeutic management of
COVID-19 in children. Because there are currently no results available from clinical trials that evaluated
the treatment of COVID-19 in children, and because data from observational studies are limited, the
Panel’s recommendations for children are based largely on safety and efficacy data from clinical trials
in adults. The recommendations take the child’s risk of disease progression into consideration; this risk
assessment is based on the limited available data for children with COVID-19.
The new sections include:
• Clinical Management of Children Summary
• This section provides an overview of the Panel’s recommendations for the therapeutic
management of children with COVID-19 or multisystem inflammatory syndrome in children
(MIS-C).

• Therapeutic Management of Nonhospitalized Children With COVID-19
• The recommendations in this section are stratified by age and risk for disease progression based
on underlying conditions. This section also includes a discussion on the risk factors for severe
COVID-19 in children based on their vaccination status.
• Therapeutic Management of Hospitalized Children With COVID-19
• This section provides the Panel’s recommendations for children who are hospitalized
for COVID-19. The recommendations are stratified by disease severity, similar to the
recommendations for hospitalized adults.
The Panel also revised Special Considerations in Children to include recent epidemiologic data on
COVID-19 and information on the risk factors for severe COVID-19 in children.
Clinical Spectrum of SARS-CoV-2 Infection

This section includes information regarding breakthrough SARS-CoV-2 infections in people who are
vaccinated against COVID-19. It also includes updated epidemiologic and clinical information on
persistent symptoms and other conditions after acute COVID-19.
Prevention of SARS-CoV-2 Infection

The Panel updated this section to include 2 new revisions to the Food and Drug Administration (FDA)
Emergency Use Authorization (EUA) for tixagevimab plus cilgavimab (Evusheld). The updates include
a warning about the potential risk of cross-hypersensitivity between COVID-19 vaccines and Evusheld
and a new recommendation for repeat dosing of tixagevimab 300 mg plus cilgavimab 300 mg every 6
months (BIIb), as authorized by the updated EUA.
Therapeutic Management of Nonhospitalized Adults With COVID-19

The Panel briefly discusses the recent case reports of viral rebound, with or without recurrence of
symptoms, after a course of ritonavir-boosted nirmatrelvir (Paxlovid) has been completed. To date, these
rebounds have not been associated with progression to severe COVID-19. The Panel notes that longer
treatment courses of ritonavir-boosted nirmatrelvir are not authorized based on the current EUA, and
there are insufficient data on the efficacy of administering a second course.
This update also includes a review of recent observational data showing that corticosteroids confer no
benefits and may potentially cause harm in patients with COVID-19 who do not require supplemental
oxygen. The Panel stresses that the use of corticosteroids in nonhospitalized patients with COVID-19 is
not recommended (AIIb).
Therapeutic Management of Hospitalized Adults With COVID-19

The Panel revised this section based on recent clinical trial data on the use of remdesivir or baricitinib
in hospitalized patients with COVID-19. The Panel’s recommendations are categorized by a patient’s
disease severity and specific clinical scenario. The Panel also updated the rationale for these
recommendations.
Key updates to this section include:
• For patients who are hospitalized for reasons other than COVID-19 and who are found to have
mild to moderate COVID-19 and a high risk of disease progression, the Panel recommends
following its recommendations for treating nonhospitalized patients with COVID-19.
• For patients who require oxygen supplementation through a high-flow nasal cannula

or noninvasive ventilation (NIV), the Panel recommends the use of a combination of 2
immunomodulators (either dexamethasone plus baricitinib [AI] or dexamethasone plus
tocilizumab [BIIa]). If baricitinib, tofacitinib, tocilizumab, or sarilumab cannot be obtained, the
Panel recommends starting dexamethasone while waiting for an additional immunomodulator to
be acquired.
• For patients who require mechanical ventilation or extracorporeal membrane oxygenation
(ECMO) and who have not initiated 1 of the recommended immunomodulator combinations,
the Panel recommends promptly starting either dexamethasone plus baricitinib (BIIa) or
dexamethasone plus tocilizumab (BIIa). If the second immunomodulator is not available,
dexamethasone should be started while waiting for the second agent.
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s Tyrosine Kinase Inhibitors
This section references the recent approval of baricitinib by the FDA for the treatment of COVID-19 in
hospitalized adults who require supplemental oxygen, NIV, mechanical ventilation, or ECMO. Minor
revisions have been made to the Panel’s rationale for the use of kinase inhibitors for the treatment of
COVID-19. A new clinical data table summarizes the results of key randomized controlled trials.
Minor Updates to the Guidelines

Minor updates were made to the following Guidelines sections:
• Testing for SARS-CoV-2 Infection
• Remdesivir

Guidelines Development
Last Updated: April 29, 2022
The COVID-19 Treatment Guidelines were developed to provide clinicians with guidance on how
to care for patients with COVID-19. Because clinical information about the optimal management of
COVID-19 is evolving quickly, these Guidelines are updated frequently to reflect newly published data
and other authoritative information.
Panel Composition
Members of the COVID-19 Treatment Guidelines Panel (the Panel) are appointed by the Panel co-chairs
based on their clinical experience and expertise in patient management, translational and clinical
science, and/or the development of treatment guidelines. Panel members include representatives from
federal agencies, health care organizations, academic organizations, and professional societies. Federal
agencies and professional societies represented on the Panel include:
• American Association of Critical-Care Nurses
• American Association for Respiratory Care
• American College of Chest Physicians
• American College of Clinical Pharmacy
• American College of Emergency Physicians
• American College of Obstetricians and Gynecologists
• American Society of Hematology
• American Thoracic Society
• Biomedical Advanced Research and Development Authority
• Centers for Disease Control and Prevention
• Department of Defense
• Department of Veterans Affairs
• Food and Drug Administration
• Infectious Diseases Society of America
• National Institutes of Health
• Pediatric Infectious Diseases Society
• Society of Critical Care Medicine
• Society of Infectious Diseases Pharmacists
The inclusion of representatives from professional societies does not imply that their societies have
endorsed all elements of these Guidelines.
The names, affiliations, and financial disclosures of the Panel members and ex officio members, as well
as members of the Guidelines support team, are provided in the Panel Roster and Financial Disclosure
sections of the Guidelines.

Development of the Guidelines
Each section of the Guidelines is developed by a working group of Panel members with expertise in the
area addressed in the section. Each working group is responsible for identifying relevant information and
published scientific literature and for conducting a systematic, comprehensive review of that information
and literature. The working groups propose updates to the Guidelines based on the latest published
research findings and clinical information.
New Guidelines sections and recommendations are reviewed and voted on by the voting members of the
Panel. To be included in the Guidelines, a recommendation statement must be endorsed by a majority
of voting members; this applies to recommendations for and against treatments and cases where there
is insufficient evidence to recommend either for or against treatments. Updates to existing sections that
do not affect the rated recommendations are approved by Panel co-chairs without a Panel vote. Panel
members are required to keep all Panel deliberations and unpublished data that are evaluated during the
development of the Guidelines confidential.
Method of Synthesizing Data and Formulating Recommendations

The working groups critically review and synthesize the available data to develop recommendations.
During this process, the Panel evaluates the data, including the source of the data, the type of study (e.g.,
randomized controlled trial, prospective or retrospective cohort study, case series, in vitro study), the
quality and suitability of the methods, the number of participants, and the effect sizes observed.
The recommendations in these Guidelines are based on scientific evidence and expert opinion. Each
recommendation includes 2 ratings: an uppercase letter (A, B, or C) that indicates the strength of the
recommendation and a Roman numeral with or without a lowercase letter (I, IIa, IIb, or III) that
indicates the quality of the evidence that supports the recommendation.
Table 1. Recommendation Rating Scheme
Strength of Recommendation Quality of Evidence for Recommendation
A: Strong recommendation for the statement I: One or more randomized trials without major
B: Moderate recommendation for the statement limitations
C: Weak recommendation for the statement IIa: Other randomized trials or subgroup analyses of
randomized trials
IIb: Nonrandomized trials or observational cohort studies
III: Expert opinion
To develop the recommendations in these Guidelines, the Panel uses data from the rapidly growing
body of research on COVID-19. The Panel also relies heavily on experience with other diseases,
supplemented with the members’ evolving clinical experience with COVID-19.
In general, the recommendations in these Guidelines fall into the following categories:
• The Panel recommends using [blank] for the treatment of COVID-19 (rating).
Recommendations in this category are based on evidence that the potential benefits of using this
intervention outweigh the potential risks.
• There is insufficient evidence for the Panel to recommend either for or against the use of
[blank] for the treatment of COVID-19 (no rating). This statement is used when there are
currently not enough data to support a recommendation, or the available data are conflicting.
• The Panel recommends against the use of [blank] for the treatment of COVID-19, except

in a clinical trial (rating). This recommendation is used for an intervention that has not clearly
demonstrated efficacy in the treatment of COVID-19 and/or has potential safety concerns. More
clinical trials are needed to further define the role of the intervention in treating COVID-19.
• The Panel recommends against the use of [blank] for the treatment of COVID-19 (rating).
This recommendation is used in cases where the available data clearly show a safety concern and/
or the data show no benefit to using this intervention for the treatment of COVID-19.
Evolving Knowledge on Treatments for COVID-19

Remdesivir, an antiviral agent, is currently the only drug that is approved by the Food and Drug
Administration for the treatment of COVID-19. An array of drugs that are approved for other indications
and multiple investigational agents are being studied for the treatment of COVID-19 in clinical trials
around the globe. These trials can be accessed at ClinicalTrials.gov. In addition, providers can access
and prescribe investigational drugs or agents that are approved or licensed for other indications through
various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug
applications, compassionate use or expanded access programs with drug manufacturers, and/or off-label
use.
Whenever possible, the Panel recommends that promising, unapproved, or unlicensed treatments for
COVID-19 be studied in well-designed, controlled clinical trials. This recommendation also applies
to drugs that have been approved or licensed for indications other than the treatment of COVID-19.
The Panel recognizes the critical importance of clinical research in generating evidence to address
unanswered questions regarding the safety and efficacy of potential treatments for COVID-19. However,
the Panel also realizes that many patients and providers who cannot access these potential treatments via
clinical trials still seek guidance about whether to use them.
New data on the treatment of COVID-19 are emerging at a rapid pace. Some of these data are being
published in peer-reviewed journals, but some can be found in manuscripts that have not yet been peer
reviewed or in press releases. The Panel continuously reviews the available data and assesses their
scientific rigor and validity. These sources of data and the clinical experiences of the Panel members
are used to determine whether new recommendations or changes to the current recommendations are
warranted.
Finally, it is important to stress that the rated treatment recommendations in these Guidelines should
not be considered mandates. The choice of what to do or not to do for an individual patient is ultimately
decided by the patient and their provider.

Overview of COVID-19
Epidemiology
The COVID-19 pandemic has exploded since cases were first reported in China in December 2019. As
of April 15, 2022, more than 503 million cases of COVID-19—caused by SARS-CoV-2 infection—have
been reported globally, including more than 6.2 million deaths.1
Individuals of all ages are at risk for SARS-CoV-2 infection and severe disease. However, the
probability of serious COVID-19 disease is higher in people aged ≥60 years, those living in a nursing
home or long-term care facility, and those with chronic medical conditions. In an analysis of more than
1.3 million laboratory-confirmed cases of COVID-19 that were reported in the United States between
January and May 2020, 14% of patients required hospitalization, 2% were admitted to the intensive care
unit, and 5% died.2 The percentage of patients who died was 12 times higher among those with reported
medical conditions (19.5%) than among those without medical conditions (1.6%), and the percentage
of patients who were hospitalized was 6 times higher among those with reported medical conditions
(45.4%) than among those without medical conditions (7.6%). Mortality was highest in patients aged
>70 years, regardless of the presence of chronic medical conditions. Data on comorbid health conditions
among patients with COVID-19 indicate that 32% had cardiovascular disease, 30% had diabetes, and
18% had chronic lung disease. Other conditions that may lead to a high risk for severe COVID-19
include cancer, kidney disease, liver disease (especially in patients with cirrhosis), obesity, sickle cell
disease, and other immunocompromising conditions. Transplant recipients and pregnant people are also
at a higher risk of severe COVID-19.3-10
Data from the United States suggest that racial and ethnic minorities experience higher rates of
COVID-19, subsequent hospitalization, and death.11-15 However, surveillance data that include race and
ethnicity are not available for most reported cases of COVID-19 in the United States.4,16 Factors that
contribute to the increased burden of COVID-19 in these populations may include over-representation
in work environments that confer higher risks of exposure to COVID-19, economic inequality (which
limits people’s ability to protect themselves against COVID-19 exposure), neighborhood disadvantage,17
and a lack of access to health care.16 Structural inequalities in society contribute to health disparities for
racial and ethnic minority groups, including higher rates of comorbid conditions (e.g., cardiac disease,
diabetes, hypertension, obesity, pulmonary diseases), which further increase the risk of developing
severe COVID-19.15
SARS-CoV-2 Variants
Like other RNA viruses, SARS-CoV-2 is constantly evolving through random mutations. New mutations
can potentially increase or decrease infectiousness and virulence. In addition, mutations can increase
the virus’ ability to evade adaptive immune responses from past SARS-CoV-2 infection or vaccination.
This viral evolution may increase the risk of reinfection or decrease the efficacy of vaccines.18 There is
evidence that some SARS-CoV-2 variants have reduced susceptibility to plasma from people who were
previously infected or immunized, as well as to certain monoclonal antibodies (mAbs) that are being
considered for prevention and treatment.19-21
Since December 2020, the World Health Organization (WHO) has assigned Greek letter designations to
several identified variants. A SARS-CoV-2 variant designated as a variant of concern (VOC) displays
certain characteristics, such as increased transmissibility or virulence. In addition, vaccines and

therapeutics may have decreased effectiveness against VOCs, and the mutations found in these variants
may interfere with the targets of diagnostic tests. The variant of interest (VOI) designation has been
used for important variants that are not fully characterized; however, organizations do not use the same
variant designations, and they may define their variant designations differently.22,23 In September 2021,
the Centers for Disease Control and Prevention (CDC) added a new designation for variants: variant
being monitored (VBM). This refers to variants for which data indicate a potential or clear impact on
approved or authorized medical countermeasures or variants associated with more severe disease or
increased transmission rates. However, these variants are either no longer detected or are circulating at
very low levels in the United States; therefore, they do not pose a significant and imminent risk to public
health in the United States.
The Omicron (B.1.1.529) variant was designated a VOC in November 2021 and rapidly became the
dominant variant across the globe. More recently, the Omicron subvariants BA.1, BA.1.1, and BA.2
have emerged. The Omicron VOC is more transmissible than other variants and is not susceptible to
some of the anti-SARS-CoV-2 mAbs that have been developed for treatment and prevention.20,21,24 The
Omicron VOC has surpassed Delta (B.1.617.2) as the dominant variant in the United States; the Delta
variant was first identified in India and was the dominant variant in July 2021.
Earlier variants include the Alpha (B.1.1.7) variant, which was first seen in the United Kingdom and
has been shown to be highly infectious and possibly more virulent than previously reported variants;25-
27
the Beta (B.1.351) variant, which was originally identified in South Africa; and the Gamma (P.1)
variant, which was identified in Manaus, Brazil. The Beta and Gamma variants demonstrated reduced
susceptibility to select anti-SARS-CoV-2 mAbs used for treatment and prevention. Although the
Alpha, Beta, and Gamma variants were previously designated as VOCs, they have largely disappeared
worldwide. For a detailed discussion on the susceptibility of certain VOCs, VOIs, and VBMs to
available anti-SARS-CoV-2 mAbs, please see Anti-SARS-CoV-2 Monoclonal Antibodies.
Data on the emergence, transmission, and clinical relevance of these new variants are rapidly evolving;
this is especially true for research on how variants might affect transmission rates, disease progression,
vaccine development, and the efficacy of current therapeutics. Because the research on variants is
moving quickly and the classification of the different variants may change over time, websites such as
the CDC COVID Data Tracker and CoVariants.org provide regular updates on the data for SARS-CoV-2
variants. The COVID-19 Treatment Guidelines Panel reviews emerging data on these variants, paying
particular attention to research on the impacts of these variants on testing, prevention, and treatment.
Clinical Presentation
The estimated incubation period for COVID-19 is up to 14 days from the time of exposure, with a
median incubation period of 4 to 5 days.6,28,29 The spectrum of illness can range from asymptomatic
infection to severe pneumonia with acute respiratory distress syndrome and death. Among 72,314 people
with COVID-19 in China, 81% of cases were reported to be mild (defined in this study as no pneumonia
or mild pneumonia), 14% were severe (defined as dyspnea, respiratory frequency ≥30 breaths/min,
oxygen saturation ≤93%, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen
[PaO2/FiO2] <300 mm Hg, and/or lung infiltrates >50% within 24 to 48 hours), and 5% were critical
(defined as respiratory failure, septic shock, and/or multiple organ dysfunction syndrome or failure).30 In
a report on more than 370,000 confirmed COVID-19 cases with reported symptoms in the United States,
70% of patients experienced fever, cough, or shortness of breath; 36% had muscle aches; and 34%
reported headaches.2 Other reported symptoms have included, but are not limited to, diarrhea, dizziness,
rhinorrhea, anosmia, dysgeusia, sore throat, abdominal pain, anorexia, and vomiting.
The abnormalities seen in chest X-rays of patients with COVID-19 vary, but bilateral multifocal

opacities are the most common. The abnormalities seen in computed tomography of the chest also
vary, but the most common are bilateral peripheral ground-glass opacities, with areas of consolidation
developing later in the clinical course of COVID-19.31 Imaging may be normal early in infection and can
be abnormal in the absence of symptoms.
Common laboratory findings in patients with COVID-19 include leukopenia and lymphopenia. Other
laboratory abnormalities have included elevated levels of aminotransferase, C-reactive protein, D-dimer,
ferritin, and lactate dehydrogenase.
Although COVID-19 is primarily a pulmonary disease, emerging data suggest that it also leads to
cardiac,32,33 dermatologic,34 hematologic,35 hepatic,36 neurologic,37,38 renal,39,40 and other complications.
Thromboembolic events also occur in patients with COVID-19, with the highest risk occurring in
critically ill patients.41
The long-term sequelae of COVID-19 survivors are currently unknown. Persistent symptoms after
recovery from acute COVID-19 have been described (see Clinical Spectrum of SARS-CoV-2 Infection).
Lastly, SARS-CoV-2 infection has been associated with a potentially severe inflammatory syndrome
in children (multisystem inflammatory syndrome in children, or MIS-C).42,43 Please see Special
Considerations in Children for more information.
References
1. Johns Hopkins University and Medicine. COVID-19 dashboard. 2021. Available at:
https://coronavirus.jhu.edu/map.html. Accessed February 15, 2022.
2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States,
January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(24):759-765. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32555134.
3. Cai Q, Chen F, Wang T, et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China.
Diabetes Care. 2020;43(7):1392-1398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409502.
4. Centers for Disease Control and Prevention. COVID Data Tracker. 2022. Available at:
https://covid.cdc.gov/covid-data-tracker/#datatracker-home. Accessed April 15, 2022.
5. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with
laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1–30, 2020. MMWR Morb
Mortal Wkly Rep. 2020;69(15):458-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298251.
6. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med.
2020;382(18):1708-1720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.
7. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in
patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.
8. Palaiodimos L, Kokkinidis DG, Li W, et al. Severe obesity, increasing age and male sex are independently
associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with
COVID-19 in the Bronx, New York. Metabolism. 2020;108:154262. Available at:
9. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age
with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3,
2020. MMWR Morb Mortal Wkly Rep. 2020;69(44):1641-1647. Available at:
10. Centers for Disease Control and Prevention. COVID-19: people with certain medical conditions. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html. Accessed April 13, 2022.

11. Azar KMJ, Shen Z, Romanelli RJ, et al. Disparities in outcomes among COVID-19 patients in a large health
care system in California. Health Aff (Millwood). 2020;39(7):1253-1262. Available at:
12. Gold JAW, Wong KK, Szablewski CM, et al. Characteristics and clinical outcomes of adult patients
hospitalized with COVID-19—Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69(18):545-550.
13. Gross CP, Essien UR, Pasha S, et al. Racial and ethnic disparities in population-level COVID-19 mortality. J
Gen Intern Med. 2020;35(10):3097-3099. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32754782.
14. Nayak A, Islam SJ, Mehta A, et al. Impact of social vulnerability on COVID-19 incidence and outcomes in the
United States. medRxiv. 2020;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511437.
15. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and mortality among black patients and white
patients with COVID-19. N Engl J Med. 2020;382(26):2534-2543. Available at:
16. Centers for Disease Control and Prevention. Health equity considerations and racial and ethnic minority
groups. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-
ethnicity.html. Accessed February 15, 2022.
17. Kind AJH, Buckingham WR. Making neighborhood-disadvantage metrics accessible - the neighborhood atlas.
N Engl J Med. 2018;378(26):2456-2458. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29949490.
18. Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 variants of concern in the United States—challenges and
opportunities. JAMA. 2021;325(11):1037-1038. Available at:
19. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature.
20. Cameroni E, Bowen JE, Rosen LE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron
antigenic shift. Nature. 2022;602(7898):664-670. Available at:
21. Liu L, Iketani S, Guo Y, et al. Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.
Nature. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35016198.
22. World Health Organization. Tracking SARS-CoV-2 variants. 2022. Available at:
https://www.who.int/en/activities/tracking-SARS-CoV-2-variants. Accessed April 13, 2022.
23. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Accessed April
13, 2022.
24. Centers for Disease Control and Prevention. Omicron variant: what you need to know. 2022. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/variants/omicron-variant.html. Accessed April 13, 2022.
25. Leung K, Shum MH, Leung GM, Lam TT, Wu JT. Early transmissibility assessment of the N501Y mutant
strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. 2021;26(1).
26. Davies NG, Barnard RC, Jarvis CI, et al. Report: continued spread of VOC 202012/01 in England. 2020.
Available at: https://cmmid.github.io/topics/covid19/reports/uk-novel-variant/2020_12_31_Transmissibility_
and_severity_of_VOC_202012_01_in_England_update_1.pdf.
27. Murugan NA, Javali PS, Pandian CJ, et al. Computational investigation of increased virulence and
pathogenesis of SARS-CoV-2 lineage B.1.1.7. bioRxiv. 2021;Preprint. Available at:
https://www.biorxiv.org/content/10.1101/2021.01.25.428190v1.
28. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected
pneumonia. N Engl J Med. 2020;382(13):1199-1207. Available at:

29. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from
publicly reported confirmed cases: estimation and application. Ann Intern Med. 2020;172(9):577-582.
30. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019
(COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease
Control and Prevention. JAMA. 2020;323(13):1239-1242. Available at:
31. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan,
China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434. Available at:
32. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular
system. Circulation. 2020;142(1):68-78. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32293910.
33. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular
system: a review. JAMA Cardiol. 2020;5(7):831-840. Available at:
34. Sachdeva M, Gianotti R, Shah M, et al. Cutaneous manifestations of COVID-19: report of three cases and a
review of literature. J Dermatol Sci. 2020;98(2):75-81. Available at:
35. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune
biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019
(COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021-1028. Available at:
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COVID-19. J Clin Exp Hepatol. 2020;10(3):263-265. Available at:
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39. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia.
J Am Soc Nephrol. 2020;31(6):1157-1165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32345702.
40. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with
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in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. Available at:

Testing for SARS-CoV-2 Infection
Summary Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using either a nucleic acid amplification test
(NAAT) or an antigen test with a sample collected from the upper respiratory tract (e.g., nasopharyngeal, nasal mid-
turbinate, anterior nasal) to diagnose acute SARS-CoV-2 infection (AIII).
• A NAAT should not be repeated in an asymptomatic person (with the exception of health care workers) within 90 days
of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-CoV-2 (AIII).
• SARS-CoV-2 reinfection has been reported in people after an initial diagnosis of the infection; therefore, clinicians
should consider using a NAAT for those who have recovered from a previous infection and who present with
symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis (BIII).
• The Panel recommends against diagnosing acute SARS-CoV-2 infection solely on the basis of serologic (i.e.,
antibody) test results (AIII).
• There is insufficient evidence for the Panel to recommend either for or against the use of SARS-CoV-2 serologic
testing to assess for immunity or to guide clinical decisions about using COVID-19 vaccines or anti-SARS-CoV-2
monoclonal antibodies.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or
subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion
Diagnostic Testing for SARS-CoV-2 Infection

Everyone who has symptoms that are consistent with COVID-19 and people with known high-risk
exposures to SARS-CoV-2 should be tested for SARS-CoV-2 infection. Such testing should employ
either a nucleic acid amplification test (NAAT) or an antigen test to detect SARS-CoV-2. Testing may
also be used for screening and determining the length of a patient’s isolation period.1
A number of diagnostic tests for SARS-CoV-2 infection (e.g., NAATs, antigen tests) have received
Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA),2 but no
diagnostic test has been approved by the FDA. Diagnostic tests have been authorized for use by trained
personnel in several settings, including lab facilities. They can also be used in point-of-care settings,
where the test is performed by trained personnel at or near the place where the specimen was collected.
Point-of-care settings include physician offices, pharmacies, long-term care facilities, and school clinics.
Antigen tests can be self-administered, and most can be used in point-of-care settings, allowing results to
be available within minutes. Some NAATs can also be self-administered at home or in other non-health
care locations and shipped to a laboratory for testing.
Although nasopharyngeal specimens remain the recommended samples for SARS-CoV-2 diagnostic
testing, nasal (anterior nares or mid-turbinate) or oropharyngeal swabs are acceptable alternatives.3
Lower respiratory tract samples have a higher yield than upper respiratory tract samples, but they
are often not obtained because of concerns about aerosolization of the virus during sample collection
procedures. Some of the tests that have received EUAs can also be performed on saliva specimens, but
the quality of saliva specimens can be highly variable. Studies are currently evaluating the use of other
sample types, including stool samples.

Nucleic Acid Amplification Testing for SARS-CoV-2 Infection
Reverse transcription polymerase chain reaction (RT-PCR)-based diagnostic tests (which detect
viral nucleic acids) are considered the gold standard for detecting current SARS-CoV-2 infection.
More recently, NAATs have included isothermal amplification platforms (e.g., nicking endonuclease
amplification reaction [NEAR], loop-mediated isothermal amplification [LAMP], transcription-mediated
amplification [TMA]).4 Some NAATs have also received EUAs for use in different settings, such as
in laboratory facilities and point-of-care settings. Laboratory-based NAATs generally have higher
sensitivity than point-of-care tests.4
Clinically, there may be a window period of up to 5 days after exposure before viral nucleic acids can
be detected. Diagnostically, some NAATs may produce false negative results if a mutation occurs in
the part of the virus’s genome that is assessed by that test.5 The FDA monitors the potential effects of
SARS-CoV-2 genetic variations on NAAT results and issues updates when specific variations could
affect the performance of NAATs that have received EUAs. Generally, false negative results are more
likely to occur when using NAATs that rely on only 1 genetic target. Therefore, a single negative test
result does not exclude the possibility of SARS-CoV-2 infection in people who have a high likelihood of
infection based on their exposure history and/or their clinical presentation.6
Many commercial NAATs that use RT-PCR rely on multiple targets to detect the virus, such that even if
a mutation impacts 1 of the targets, the other RT-PCR targets will still work.7 NAATs that use multiple
targets are less likely to be impacted by an increased prevalence of genetic variants. In fact, because
each of these tests target multiple locations on the virus’ genome, they can be helpful in identifying new
genetic variants before they become widespread in the population. For example, the Alpha (B.1.1.7)
variant and the BA.1 subvariant of the Omicron (B.1.1.529) variant, both of which have been associated
with increased transmission, carry many mutations, including a double deletion at positions 69 and 70
on the spike protein gene (S-gene). This mutation appears to impact the detection of the S-gene but does
not impact other genetic targets in certain NAATs. If COVID-19 is still suspected after a patient receives
a negative test result, clinicians should consider repeating testing; ideally, they should use a NAAT with
different genetic targets.5
SARS-CoV-2 poses several diagnostic challenges, including the potential for discordant viral shedding
between the upper and lower respiratory tract. However, due to the high specificity of NAATs, a positive
result on a NAAT of an upper respiratory tract sample from a patient with recent onset of SARS-CoV-
2-compatible symptoms is sufficient to diagnose COVID-19. In patients with COVID-19, severe acute
respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), lower respiratory tract
specimens have a higher viral load and thus a higher yield than upper respiratory tract specimens.8-14
Nucleic Acid Amplification Testing for Individuals With a Previous Positive SARS-CoV-2 Test
Result
NAATs can detect SARS-CoV-2 RNA in specimens obtained weeks to months after the onset of
COVID-19 symptoms.15,16 However, the likelihood of recovering replication-competent virus >10 days
from the onset of symptoms in those with mild disease and >20 days in those with severe disease is
very low.17,18 Furthermore, both virologic studies and contact tracing of high-risk contacts show a low
risk for SARS-CoV-2 transmission after these intervals.19,20 Based on these results, the Centers for
Disease Control and Prevention (CDC) does not recommend repeating NAATs in asymptomatic persons
within 90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure
to SARS-CoV-2.21 An exception to this is for health care workers who meet the specific criteria found
in CDC guidance.22 If there are concerns that an immunocompromised health care worker may still be
infectious >20 days from the onset of SARS-CoV-2 infection, consulting local employee health services

about return-to-work testing policies is advised.
SARS-CoV-2 reinfection has been reported in people after an initial diagnosis of infection; therefore,
clinicians should consider using a NAAT for those who have recovered from a previous infection and
who present with symptoms that are compatible with SARS-CoV-2 infection if there is no alternative
diagnosis (BIII). However, a negative result on an initial NAAT followed by a positive result on
a subsequent test does not necessarily mean a person has been reinfected, as this can occur due to
intermittent detection of viral RNA.15 When the results for an initial and a subsequent test are positive,
comparative viral sequence data from both tests are needed to distinguish between the persistent
presence of viral fragments and reinfection. In the absence of viral sequence data, the cycle threshold
(Ct) value from a positive NAAT result may provide information about whether a newly detected
infection is related to the persistence of viral fragments or to reinfection. The Ct value is the number of
PCR cycles at which the nucleic acid target in the sample becomes detectable. In general, the Ct value
is inversely related to the SARS-CoV-2 viral load. Because the clinical utility of Ct values is an area of
active investigation, an expert should be consulted if these values are used to guide clinical decisions.
Antigen Testing for SARS-CoV-2 Infection

Antigen-based diagnostic tests (which detect viral antigens) are less sensitive than laboratory-based
NAATs, but they have a similarly high specificity. Antigen tests perform best early in the course of
symptomatic SARS-CoV-2 infection, when the viral load is thought to be highest. Early data suggest
that antigen tests can detect the Omicron variant, but they may have lower sensitivity to this variant
compared to earlier variants.23 Advantages of antigen tests include their low cost and rapid turnaround
time. The availability of immediate results makes them an attractive option for point-of-care testing in
high-risk congregate settings (e.g., long-term care facilities, schools, dormitories, correctional facilities)
and community settings, where preventing transmission is critical.
Increasingly, data are available to guide the use of antigen tests as screening tests to detect or exclude
SARS-CoV-2 infection in asymptomatic persons, or to determine whether a person who was previously
confirmed to have SARS-CoV-2 infection is still infectious. The CDC has developed an antigen testing
algorithm for persons in congregate living settings and community settings who have symptoms of
COVID-19, those who are asymptomatic and have a close contact with COVID-19, and those who are
asymptomatic and have no known exposure to a person with COVID-19.24 The CDC testing algorithm
recommends performing additional confirmatory testing with a laboratory-based NAAT when a
person who is strongly suspected of having SARS-CoV-2 infection (i.e., a person who is symptomatic)
receives a negative result and when a person in a congregate living setting is asymptomatic but receives
a positive result. People in congregate living settings who test positive for SARS-CoV-2 infection
may need to be isolated as a group; therefore, correct identification of these individuals is especially
important in this setting. People who are asymptomatic and have no known exposure to a person with
COVID-19 should also undergo additional testing with a NAAT if they receive a positive result on an
initial test.24
Antigen tests can yield false positive results for a variety of reasons, including:
• Incomplete adherence to the instructions for antigen test performance (e.g., reading the results
outside the specified time interval, storing test cartridges/cards inappropriately);
• Test interference due to human antibodies (e.g., rheumatoid factor or other nonspecific antibodies);
and
• Use in communities that have a low prevalence of SARS-CoV-2 infection.

Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection
Unlike NAATs and antigen tests for SARS-CoV-2 that detect the presence of the virus, serologic or
antibody tests can detect recent or prior SARS-CoV-2 infection. Because it may take 21 days or longer
after symptom onset for seroconversion to occur (i.e., the development of detectable immunoglobulin
[Ig] M and/or IgG antibodies to SARS-CoV-2),25-30 the Panel does not recommend using serologic
testing as the sole basis for diagnosing acute SARS-CoV-2 infection (AIII). Because NAATs and antigen
tests for SARS-CoV-2 occasionally yield false negative results, serologic tests have been used in some
settings as an additional diagnostic test for patients who are strongly suspected to have SARS-CoV-2
infection. Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4
weeks after symptom onset maximizes the sensitivity and specificity to detect past infection.
No serologic tests for SARS-CoV-2 are approved by the FDA; some, but not all, commercially available
serologic tests for SARS-CoV-2 have received EUAs from the FDA.31 Several professional societies and
federal agencies, including the Infectious Diseases Society of America, the CDC, and the FDA, provide
guidance on the use of serologic testing for SARS-CoV-2.
Several factors should be considered when using serologic tests, including:
• Important performance characteristics of many of the commercially available serologic tests have
not been fully characterized, including the sensitivity and specificity of these tests (i.e., the rates of
true positive and true negative results). Only serologic assays that have FDA EUAs should be used
in public health or clinical settings. Formal comparisons of serologic tests are in progress.
• Two types of serologic tests have received EUAs from the FDA. The first type are antibody tests
that detect the presence of binding antibodies, which bind to a pathogen (e.g., a virus). The second
type detects neutralizing antibodies from recent or prior SARS-CoV-2 infection. It is unknown
whether either type of test is more clinically useful than the other.
• Serologic assays may detect IgM, IgG, or IgA antibodies, or certain combinations of these
antibodies. Some assays may also detect total antibodies. Serologic assays that detect IgG and total
antibodies have a higher specificity to detect past infection than assays that detect IgM and/or IgA
antibodies or a combination of IgM and IgG antibodies.
• False positive test results may occur due to cross-reactivity from pre-existing antibodies to other
coronaviruses.
Serologic Testing and Immunity to SARS-CoV-2 Infection

The FDA has issued EUAs for more than 80 SARS-CoV-2 serologic tests since the start of the pandemic.
However, these tests are not currently authorized for routine use in making individual medical decisions.31
SARS-CoV-2 serologic tests are authorized for detecting antibodies, but their ability to predict protective
immunity has not been validated. The majority of these tests are not standardized. Furthermore, as
SARS-CoV-2 is not a well-conserved virus, mutations in the receptor binding domain of the virus could
lead to decreased binding affinity between antibodies and SARS-CoV-2-specific antigens.
There is currently insufficient evidence for the Panel to recommend either for or against the use
of SARS-CoV-2 serologic testing to assess for immunity or to guide clinical decisions about using
COVID-19 vaccines or anti-SARS-CoV-2 monoclonal antibodies.
If a serologic test is performed, the result should be interpreted with caution. First, it remains unclear
how long SARS-CoV-2 antibodies persist following either infection or vaccination. A negative serologic
test result also does not preclude prior SARS-CoV-2 infection or vaccination against COVID-19.
Second, some people who are infected with SARS-CoV-2 or who are vaccinated against COVID-19 may

not develop measurable antibodies (e.g., those who are immunocompromised). It is presumed that those
who do not have measurable antibodies after vaccination are at higher risk of SARS-CoV-2 infection
than those who have measurable antibodies. Third, because nucleocapsid proteins are not a constituent
of the vaccines that are currently approved by the FDA, available through EUAs, or in late-stage clinical
trials, serologic tests that detect antibodies by recognizing nucleocapsid proteins should be used to
distinguish between antibody responses to natural infection and vaccine-induced antibody responses to
the SARS-CoV-2 spike protein antigen.
In communities that have a low prevalence of SARS-CoV-2 infection, the proportion of positive test
results that are false positives may be quite high. In these situations, performing confirmatory testing
with a different antibody assay can substantially reduce the number of false positives. Ideally, the
confirmatory testing should be performed with an assay that uses a different antigenic target (e.g., the
nucleocapsid phosphoprotein if the first assay targeted the spike protein).
Assuming that the test is reliable, serologic tests that identify recent or prior SARS-CoV-2 infection may
be used to:
• Determine who may be eligible to donate convalescent plasma;
• Define multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory
syndrome in adults (MIS-A); or
• Estimate the proportion of the population that has been exposed to SARS-CoV-2.
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30. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease
2019. Clin Infect Dis. 2020;71(16):2027-2034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32221519.
31. Food and Drug Administration. EUA authorized serology test performance. 2021. Available at: https://www.
fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/
eua-authorized-serology-test-performance. Accessed June 16, 2022.

Prevention of SARS-CoV-2 Infection
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination as soon as possible
for everyone who is eligible according to the Centers for Disease Control and Prevention’s Advisory Committee on
Immunization Practices (AI).
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg (Evusheld) administered as 2
consecutive 3-mL intramuscular (IM) injections (BIIb) as SARS-CoV-2 pre-exposure prophylaxis (PrEP) for adults
and adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection, who have not been
recently exposed to an individual with SARS-CoV-2 infection, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune response to COVID-19
vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of severe adverse
reactions to a COVID-19 vaccine or any of its components.
• The Panel recommends repeat dosing of tixagevimab 300 mg plus cilgavimab 300 mg administered as IM injections
every 6 months (BIIb).
• The Food and Drug Administration Emergency Use Authorization states that individuals who received tixagevimab
150 mg plus cilgavimab 150 mg should be given a second dose as soon as possible.
• If the initial dose was administered ≤3 months prior, the second dose should be tixagevimab 150 mg plus
cilgavimab 150 mg.
• If the initial dose was administered >3 months prior, the second dose should be tixagevimab 300 mg plus
cilgavimab 300 mg.
• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not be used in unvaccinated
individuals for whom COVID-19 vaccination is recommended.
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab for
post-exposure prophylaxis (PEP), as the Omicron variant and its subvariants, which are not susceptible to these
agents, are currently the dominant SARS-CoV-2 variants circulating in the United States (AIII).
General Prevention Measures

Transmission of SARS-CoV-2 is thought to occur primarily through exposure to respiratory droplets.
Exposure can occur when someone inhales droplets or particles that contain the virus (with the greatest
risk of transmission occurring within 6 feet of an infectious source) or touches their mucous membranes
with hands that have been contaminated with the virus. Exhaled droplets or particles can also deposit the
virus onto exposed mucous membranes.1
Less commonly, airborne transmission of small droplets and particles of SARS-CoV-2 to people farther
than 6 feet away can occur; in rare cases, people passing through a room that was previously occupied
by an infectious person may become infected. SARS-CoV-2 infection via airborne transmission of small
particles tends to occur after prolonged exposure (i.e., >15 minutes) to an infectious person who is in an
enclosed space with poor ventilation.1
The risk of SARS-CoV-2 transmission can be reduced by covering coughs and sneezes and maintaining
a distance of at least 6 feet from others. When consistent distancing is not possible, face coverings

may reduce the spread of infectious droplets from individuals with SARS-CoV-2 infection to others.
Frequent handwashing also effectively reduces the risk of infection.2 Health care providers should follow
the Centers for Disease Control and Prevention (CDC) recommendations for infection control and the
appropriate use of personal protective equipment.3
Vaccines
Vaccination is the most effective way to prevent SARS-CoV-2 infection. The COVID-19 Treatment
Guidelines Panel (the Panel) recommends COVID-19 vaccination as soon as possible for everyone who
is eligible according to the CDC’s Advisory Committee on Immunization Practices (AI). Three vaccines
are authorized or approved for use in the United States to prevent COVID-19. For primary and booster
vaccinations, the mRNA vaccines (i.e., BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) are
preferable to the Ad26.COV2.S (Johnson & Johnson/Janssen) vaccine due to its risk of serious adverse
events.4 A primary series of COVID-19 vaccinations is recommended for everyone aged ≥6 months in
the United States. Certain groups of people should receive additional doses at specified intervals after
the primary series of vaccinations. The type and dose of vaccine and the timing of these additional doses
depend on the recipient’s age and underlying medical conditions. The CDC regularly updates the clinical
considerations for use of the COVID-19 vaccines that are currently approved by the Food and Drug
Administration (FDA) or authorized for use in the United States.5
Adverse Events
COVID-19 vaccines are safe and effective. Local and systemic adverse events are relatively common
with these vaccines. Most of the adverse events that occurred during vaccine trials were mild or moderate
in severity (i.e., they did not prevent vaccinated people from engaging in daily activities) and resolved
after 1 or 2 days. There have been a few reports of severe allergic reactions following COVID-19
vaccination, including rare reports of patients who experienced anaphylaxis after receiving an mRNA
vaccine.6,7
Reports have suggested that there is an increased risk of thrombosis with thrombocytopenia syndrome
(TTS) in adults who have received the Ad26.COV2.S vaccine7 and, rarely, the mRNA-1273 vaccine.8
TTS is a rare but serious condition that causes blood clots in large blood vessels and low platelet levels.
Women aged 30 to 49 years should be aware of the increased risk of TTS. The American Society
of Hematology and the American Heart Association/American Stroke Association Stroke Council
leadership have published considerations that are relevant to the diagnosis and treatment of TTS that
occurs in people who receive the Ad26.COV2.S vaccine.9,10 These considerations include information
on administering a nonheparin anticoagulant and intravenous immunoglobulin to these patients. Given
the rarity of this syndrome and the unique treatment required, consider consulting a hematologist when
treating these patients.
Myocarditis and pericarditis after COVID-19 vaccination are rare, and most of the reported cases were
very mild and self-limiting.11 These conditions have occurred most often in male adolescents, young
adults, and people who have received mRNA vaccines.
Guillain-Barré syndrome (GBS) in people who received the Ad26.COV2.S vaccine is rare.11 GBS is a
neurologic disorder that causes muscle weakness and sometimes paralysis. Most people with GBS fully
recover, but some have permanent nerve damage. Onset typically occurs about 2 weeks after vaccination.
GBS has mostly been reported in men aged ≥50 years.
The CDC provides regular updates on selected adverse events of COVID-19 vaccines on its website.

Vaccination in Pregnant or Lactating People
Pregnant and lactating individuals were not included in the initial COVID-19 vaccine trials. However, the
CDC, the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-
Fetal Medicine recommend vaccination for pregnant and lactating people based on the accumulated safety
and efficacy data on the use of these vaccines in pregnant people, as well as the increased risk of severe
disease in pregnant individuals with COVID-19.12-17 These organizations also recommend vaccination
for people who are trying to become pregnant or who may become pregnant in the future. The ACOG
publication includes a guide for clinicians on counseling pregnant patients about COVID-19 vaccination.18
Pre-Exposure Prophylaxis
Anti-SARS-CoV-2 Monoclonal Antibodies
Vaccination remains the most effective way to prevent SARS-CoV-2 infection and should be considered
the first line of prevention. However, some individuals cannot or may not mount an adequate protective
response to COVID-19 vaccines. Others may not have been fully vaccinated because they have a history of
severe adverse reactions to a COVID-19 vaccine or its components.
On the basis of results from PROVENT, a large randomized controlled trial conducted when the major
circulating SARS-CoV-2 variants were Alpha, Beta, Delta, and Epsilon,19 the FDA issued an Emergency
Use Authorization (EUA) for the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus
cilgavimab (Evusheld).20 The EUA allows these anti-SARS-CoV-2 mAbs to be used as pre-exposure
prophylaxis (PrEP) for certain individuals who are immunocompromised and therefore may have
inadequate responses to COVID-19 vaccines or are unable to be fully vaccinated due to a history of severe
adverse reactions to a COVID-19 vaccine. A modification in the fragment crystallizable (Fc) region gives
these anti-SARS-CoV-2 mAbs prolonged half-lives, resulting in potential protection from SARS-CoV-2
infection for up to 6 months, depending on the variant.
The PROVENT trial used tixagevimab 150 mg plus cilgavimab 150 mg, which was the dose initially
authorized by the FDA. However, in vitro data showed that some subvariants of the Omicron variant had
decreased susceptibility to tixagevimab plus cilgavimab. Because of these findings, in February 2022, the
FDA revised the EUA to authorize the use of an increased dose of tixagevimab 300 mg plus cilgavimab 300
mg.20-23 For patients who previously received a dose of tixagevimab 150 mg plus cilgavimab 150 mg, the
FDA EUA suggested administering an second dose; the specific dose depends on the amount of time that has
passed since the initial dose (see below). On June 30, 2022, the FDA further revised the EUA to authorize
repeated doses of tixagevimab 300 mg plus cilgavimab 300 mg to be administered every 6 months.
When prescribing tixagevimab plus cilgavimab for SARS-CoV-2 PrEP, clinicians should be aware of the
following:
• Tixagevimab plus cilgavimab is authorized for use as PrEP in a population that was not well
represented in the PROVENT trial (i.e., a very small proportion of the participants were
immunocompromised).
• There are no clinical trial efficacy data on the use of tixagevimab 300 mg plus cilgavimab 300 mg
for the prevention of symptomatic COVID-19, and there are no data for any repeated dose at any
defined interval, including for the authorized schedule of repeat dosing every 6 months proposed
in the latest EUA. This dose and the strategy of repeating the dose every 6 months are based on
pharmacokinetic/pharmacodynamic (PK/PD) modeling data.24 Substantial uncertainty in the PK/PD
model remains.
• The tixagevimab 150 mg plus cilgavimab 150 mg dose initially authorized by the FDA may not be
sufficient to prevent cases of COVID-19 caused by the Omicron BA.1 and BA.1.1 subvariants. No

clinical data and only limited PK/PD data guide the administration of repeat doses of tixagevimab
plus cilgavimab in those who were previously treated with tixagevimab 150 mg plus cilgavimab
150 mg. Simulations based on population PK models suggest that administering an additional
dose of tixagevimab 150 mg plus cilgavimab 150 mg ≤3 months after the initial dose will allow
a patient to achieve drug concentrations approximating those observed in people who received
tixagevimab 300 mg plus cilgavimab 300 mg as their initial dose. For patients who initially
received tixagevimab 150 mg plus cilgavimab 150 mg >3 months ago, the simulations suggest that
a repeat dose of tixagevimab 300 mg plus cilgavimab 300 mg is necessary.
• Observational data reported after the emergence of the Omicron variant suggested an association
between the receipt of tixagevimab plus cilgavimab and a decreased incidence of COVID-19,
although these studies were not definitive.25,26
• Safety data on the use of tixagevimab 300 mg plus cilgavimab 300 mg primarily come from
TACKLE, a Phase 3 clinical trial that evaluated single doses of tixagevimab plus cilgavimab for
the treatment of patients with mild to moderate COVID-19.24
Recommendations
Factoring in the limitations outlined above:
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg administered as
2 consecutive 3-mL intramuscular (IM) injections (BIIb) as SARS-CoV-2 PrEP for adults and
adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection, who
have not been recently exposed to an individual with SARS-CoV-2 infection, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune
response to COVID-19 vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of
severe adverse reactions to a COVID-19 vaccine or any of its components.
• The Panel recommends repeat dosing of tixagevimab 300 mg plus cilgavimab 300 mg
administered as IM injections every 6 months (BIIb), as allowed by the most recent revision
of the FDA EUA. Repeat doses should be timed from the most recent dose of tixagevimab plus
cilgavimab.
• The FDA EUA states that individuals who received tixagevimab 150 mg plus cilgavimab 150 mg
should be given a second dose as soon as possible.
• If the initial dose was administered ≤3 months prior, the second dose should be tixagevimab
150 mg plus cilgavimab 150 mg.
• If the initial dose was administered >3 months prior, the second dose should be tixagevimab
300 mg plus cilgavimab 300 mg.
• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not
be used in unvaccinated individuals for whom COVID-19 vaccination is recommended.
Additional Considerations
• Evusheld contains the ingredient polysorbate 80, which is structurally related to polyethylene
glycol.20 COVID-19 vaccines approved or authorized by the FDA contain either polysorbate 80
or polyethylene glycol. There is a theoretical risk of cross-hypersensitivity between Evusheld
and COVID-19 vaccines. Before administering Evusheld to individuals with a history of severe
hypersensitivity reactions to a COVID-19 vaccine, consultation with an allergist/immunologist
should be considered.
• Individuals who qualify as having moderate to severe immunocompromising conditions under the

FDA EUA for tixagevimab plus cilgavimab are those who:
• Are receiving active treatment for solid tumors and hematologic malignancies.
• Received a solid organ transplant and are receiving immunosuppressive therapy.
• Received chimeric antigen receptor T cell therapy or a hematopoietic stem cell transplant (and
are within 2 years of transplantation or are receiving immunosuppressive therapy).
• Have a moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-
Aldrich syndrome).
• Have advanced or untreated HIV infection (defined as people with HIV and CD4 T
lymphocyte cell counts <200 cells/mm3, a history of an AIDS-defining illness without immune
reconstitution, or clinical manifestations of symptomatic HIV).
• Are receiving active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or
equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites,
transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified
as severely immunosuppressive, tumor-necrosis blockers, or other immunosuppressive or
immunomodulatory biologic agents (e.g., B cell-depleting agents).
• The strength of the Panel’s recommendation for tixagevimab 300 mg plus cilgavimab 300 mg is
based partly on PK/PD modeling for the Omicron BA.1 and BA.1.1 subvariants and partly on the
fact that the BA.2 subvariant has been shown to retain near-full susceptibility to tixagevimab plus
cilgavimab in vitro.27
• Because no clinical trial efficacy data are available for tixagevimab 300 mg plus cilgavimab 300
mg, and there are uncertainties about the extent and duration of protection against the dominant
circulating Omicron subvariants, high-risk individuals who receive PrEP should continue to use
other measures to protect themselves from infection.
• If supplies of tixagevimab plus cilgavimab are limited, priority for use as PrEP should be given to
those who are at the highest risk for severe COVID-19.
• If a person has received a COVID-19 vaccine, tixagevimab plus cilgavimab should be
administered at least 2 weeks after vaccination.
Clinical Trial Data for Tixagevimab Plus Cilgavimab
PROVENT is an ongoing, Phase 3, double-blind, randomized, placebo-controlled trial that evaluated
the use of tixagevimab plus cilgavimab for SARS-CoV-2 PrEP.19,20 The study enrolled adults aged ≥18
years who had not received a COVID-19 vaccine and who were at increased risk of severe SARS-CoV-2
infection (e.g., those aged ≥60 years or those who had a prespecified comorbidity) or who had an
increased risk of acquiring SARS-CoV-2 infection due to their occupation or living situation. The study
excluded those with a history of confirmed SARS-CoV-2 infection or who had a positive SARS-CoV-2
antibody result at screening.
The analyzed population included participants who received a negative reverse transcription polymerase
chain reaction (RT-PCR) result at baseline. Participants received either tixagevimab 150 mg plus
cilgavimab 150 mg (administered as 2 consecutive IM injections; n = 3,460) or placebo (administered
as 2 IM injections; n = 1,737). The primary endpoint was symptomatic SARS-CoV-2 infection and a
positive RT-PCR result during the 183 days of follow-up.
Once COVID-19 vaccines became available, participants could choose to be unblinded and receive the
vaccine during the study. Only the primary endpoints that occurred prior to unblinding or vaccine receipt
were included in the analysis, resulting in a median follow-up of 83 days. Baseline characteristics were
well balanced between the arms. Prior to unblinding or vaccination, RT-PCR-confirmed symptomatic
SARS-CoV-2 infection was reported for 8 participants (0.2%) in the tixagevimab plus cilgavimab arm

and 17 participants (1.0%) in the placebo arm, representing a 77% reduction in the incidence of infection
in the tixagevimab plus cilgavimab arm (95% CI, 46% to 90%; P < 0.001). A post hoc analysis after
a median follow-up period of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8% to
91.4%) for symptomatic infection in the tixagevimab plus cilgavimab arm. Five cases of COVID-19 were
considered to be severe or critical, and 2 COVID-19-related deaths were reported. All of these events
occurred in participants who received placebo.
Adverse events were reported for 35.3% of participants in the tixagevimab plus cilgavimab arm and
34.2% of participants in the placebo arm. Serious adverse events were reported for 1% of participants
in each arm; 1 participant in the tixagevimab plus cilgavimab arm had an anaphylactic reaction that
was resolved with epinephrine therapy. The incidence of adverse events was similar in both study arms;
most events were mild (62%) or moderate (32%). Rare, serious cardiac adverse events occurred in 0.7%
of participants in the tixagevimab plus cilgavimab arm and in 0.3% of participants in the placebo arm.
All participants who experienced a cardiac event had cardiac risk factors or a history of cardiac disease
at baseline. There was no clear temporal pattern between these serious cardiac adverse events and
administration of the anti-SARS-CoV-2 mAbs.20
TACKLE was a Phase 3 trial that evaluated the use of tixagevimab plus cilgavimab for the treatment of
nonhospitalized patients with mild to moderate COVID-19. In this study, 452 high-risk adults aged ≥18
years received a single IM dose of tixagevimab 300 mg plus cilgavimab 300 mg and had a follow-up visit
within 183 days (the median follow-up period was 84 days). Adverse events were reported for 29% of
patients in the tixagevimab plus cilgavimab arm and for 36% of patients in the placebo arm; the majority
of events were mild to moderate in severity. Serious cardiac adverse events were reported for 4 patients;
3 had received tixagevimab plus cilgavimab and 1 had received placebo. All events occurred in patients
who had cardiac risk factors or a history of cardiovascular disease.20
Other Drugs for Pre-Exposure Prophylaxis

• The Panel recommends against the use of any oral drugs for SARS-CoV-2 PrEP, except in a
clinical trial (AIII).
Clinical trials are investigating several agents, including emtricitabine plus tenofovir alafenamide or
tenofovir disoproxil fumarate; hydroxychloroquine; ivermectin; and supplements such as zinc, vitamin C,
and vitamin D. Please see ClinicalTrials.gov for the latest information.
Hydroxychloroquine, given at different doses and durations, has been studied in randomized controlled
trials to assess whether it could prevent SARS-CoV-2 infection in those at risk of being exposed to
infected individuals, such as health care workers. One study reported no evidence of a benefit of
hydroxychloroquine, and it was ultimately halted due to futility before it reached its target enrollment.28
In another hydroxychloroquine study, which also did not meet its target enrollment and was stopped
early, the majority of the potential transmission events were not confirmed by virologic testing.29 Neither
study demonstrated any evidence of a reduction in the rate of acquiring infection. Both studies reported
an increased frequency of mild adverse events in the treatment group.
Post-Exposure Prophylaxis
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab plus
imdevimab for post-exposure prophylaxis (PEP), as the Omicron variant and its subvariants, which
are not susceptible to these agents, are currently the dominant SARS-CoV-2 variants circulating in
the United States (AIII).

Vaccination remains a highly effective way to prevent SARS-CoV-2 infection. However, despite the
widespread availability of COVID-19 vaccines, some individuals are not fully vaccinated or cannot mount
an adequate response to the vaccine. Some of these individuals, if infected, are at high risk of progressing
to serious COVID-19. Bamlanivimab plus etesevimab and casirivimab plus imdevimab have previously
received FDA EUAs for PEP; however, the Omicron variant and its subvariants are currently the dominant
SARS-CoV-2 variants circulating in the United States. The Panel recommends against the use of these anti-
SARS-CoV-2 mAbs because the Omicron variant and its subvariants are not susceptible to them (AIII).
Chloroquine and Hydroxychloroquine

• The Panel recommends against the use of hydroxychloroquine for SARS-CoV-2 PEP (AI).
Both chloroquine and hydroxychloroquine have in vitro activity against SARS-CoV and SARS-CoV-
2.30,31 A small cohort study without a control group suggested that hydroxychloroquine might reduce the
risk of SARS-CoV-2 transmission to close contacts.32 There have been several large trials to determine
whether hydroxychloroquine can reduce the risk of infection after exposure to individuals infected with
SARS-CoV-2. These studies used different dose schedules and targeted different at-risk populations. In
addition, some studies were unable to confirm infection using molecular or antigen tests. None of these
studies demonstrated any evidence of efficacy for hydroxychloroquine, and all showed a higher risk of
generally mild adverse events in those who received the drug.33-35
Other Drugs for Post-Exposure Prophylaxis

• The Panel recommends against the use of other drugs for SARS-CoV-2 PEP, except in a clinical
trial (AIII).
A number of other agents (e.g., ivermectin, hyperimmune gamma globulin, COVID-19 convalescent
plasma, interferons, tenofovir with or without emtricitabine, vitamin D) are currently being investigated for
SARS-CoV-2 PEP. The latest clinical trials for SARS-CoV-2 PEP can be found at ClinicalTrials.gov.
High concentrations of ivermectin have been shown to inhibit SARS-CoV-2 replication in vitro.36,37
Population data indicated that countrywide, mass-use of prophylactic chemotherapy for parasitic infections,
including the use of ivermectin, was associated with a lower incidence of COVID-19.38 At this time, few
clinical trials have evaluated the safety and efficacy of using ivermectin for SARS-CoV-2 PrEP or PEP.36,37
In a descriptive, uncontrolled, interventional study of 33 contacts of patients with laboratory-confirmed
SARS-CoV-2 infection, no cases of SARS-CoV-2 infection were identified within 21 days of initiating
ivermectin for PEP.39 In a small case-control study in SARS-CoV-2-exposed health care workers, 186
participants who became infected were matched with 186 uninfected controls. Of those who received
ivermectin after exposure to SARS-CoV-2, 38 were in the infected group and 77 were in the uninfected
group, which led the investigators to conclude that ivermectin reduced the incidence of SARS-CoV-2
infection.40
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exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med.
29. Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis
for coronavirus disease 2019 (COVID-19) in healthcare workers: a randomized trial. Clin Infect Dis.
2021;72(11):e835-e843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33068425.
30. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of
hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin
Infect Dis. 2020;71(15):732-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150618.
31. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection
and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
32. Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for COVID-19 be considered as an outbreak
response strategy in long-term care hospitals? Int J Antimicrob Agents. 2020;55(6):105988. Available at:
33. Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as postexposure prophylaxis to
prevent severe acute respiratory syndrome coronavirus 2 infection: a randomized trial. Ann Intern Med.
34. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure
prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525. Available at:
35. Mitja O, Corbacho-Monne M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for
prevention of COVID-19. N Engl J Med. 2021;384(5):417-427. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33289973.
36. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the

replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at: https://www.ncbi.nlm.nih.
gov/pubmed/32251768.
37. Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children
in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. Available at:
38. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic
administration of ivermectin. Int J Antimicrob Agents. 2021;57(1):106248. Available at:
39. Aguirre Chang G, Trujillo Figueredo AN. COVID-19: post-exposure prophylaxis with ivermectin in contacts.
At homes, places of work, nursing homes, prisons, and others. ResearchGate. 2020;Preprint. Available at:
https://www.researchgate.net/publication/344781515_COVID-19_POST-EXPOSURE_PROPHYLAXIS_
WITH_IVERMECTIN_IN_CONTACTS.
40. Behera P, Patro BK, Singh AK, et al. Role of ivermectin in the prevention of SARS-CoV-2 infection among
healthcare workers in India: a matched case-control study. PLoS One. 2021;16(2):e0247163. Available at:

Clinical Spectrum of SARS-CoV-2 Infection
Patients with SARS-CoV-2 infection can experience a range of clinical manifestations, from no
symptoms to critical illness. In general, adults with SARS-CoV-2 infection can be grouped into the
following severity of illness categories; however, the criteria for each category may overlap or vary
across clinical guidelines and clinical trials, and a patient’s clinical status may change over time.
• Asymptomatic or presymptomatic infection: Individuals who test positive for SARS-CoV-2 using
a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test) but who have no
symptoms that are consistent with COVID-19.
• Mild illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g.,
fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste
and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging.
• Moderate illness: Individuals who show evidence of lower respiratory disease during clinical
assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level.
• Severe illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial
pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30
breaths/min, or lung infiltrates >50%.
• Critical illness: Individuals who have respiratory failure, septic shock, and/or multiple organ
dysfunction.
Patients with certain underlying comorbidities are at a higher risk of progressing to severe COVID-19.
These comorbidities include being aged ≥65 years; having cancer, cardiovascular disease, chronic
kidney disease, chronic liver disease, chronic lung disease, diabetes, advanced or untreated HIV
infection, or obesity; being pregnant; being a cigarette smoker; being a transplant recipient; and
receiving immunosuppressive therapy.1 Health care providers should monitor such patients closely until
clinical recovery is achieved.
Initial evaluation for patients may include chest imaging (e.g., X-ray, ultrasound or computed
tomography scan) and electrocardiogram. Laboratory testing should include a complete blood count
with differential and a metabolic profile, including liver and renal function tests. Although inflammatory
markers such as C-reactive protein (CRP), D-dimer, and ferritin are not routinely measured as part of
standard care, results from such measurements may have prognostic value.2-4
The definitions for the severity of illness categories listed above also apply to pregnant patients.
However, the threshold for certain interventions is different for pregnant patients and nonpregnant
patients. For example, oxygen supplementation is recommended for pregnant patients when SpO2 falls
below 95% on room air at sea level to accommodate physiologic changes in oxygen demand during
pregnancy and to ensure adequate oxygen delivery to the fetus.5 If laboratory parameters are used for
monitoring pregnant patients and making decisions about interventions, clinicians should be aware that
normal physiologic changes during pregnancy can alter several laboratory values. In general, leukocyte
cell count increases throughout gestation and delivery and peaks during the immediate postpartum
period. This increase is mainly due to neutrophilia.6 D-dimer and CRP levels also increase during
pregnancy and are often higher in pregnant patients than nonpregnant patients.7 Detailed information on
treating COVID-19 in pregnant patients can be found in Special Considerations in Pregnancy and in the
pregnancy considerations subsections in the Guidelines.

In pediatric patients, radiographic abnormalities are common and, for the most part, should not be
the only criteria used to determine the severity of illness. The normal values for respiratory rate also
vary with age in children; therefore, hypoxemia should be the primary criterion used to define severe
COVID-19, especially in younger children. In a small number of children and in some young adults,
SARS-CoV-2 infection may be followed by a severe inflammatory condition called multisystem
inflammatory syndrome in children (MIS-C).8,9 This syndrome is discussed in detail in Special
Considerations in Children.
Asymptomatic or Presymptomatic Infection

Asymptomatic SARS-CoV-2 infection can occur, although the percentage of patients who remain truly
asymptomatic throughout the course of infection is variable and incompletely defined. It is unclear what
percentage of individuals who present with asymptomatic infection progress to clinical disease. Some
asymptomatic individuals have been reported to have objective radiographic findings consistent with
COVID-19 pneumonia.10,11
Mild Illness
Patients with mild illness may exhibit a variety of signs and symptoms (e.g., fever, cough, sore throat,
malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell). They do not
have shortness of breath, dyspnea on exertion, or abnormal imaging. Most patients who are mildly
ill can be managed in an ambulatory setting or at home through telemedicine or telephone visits. No
imaging or specific laboratory evaluations are routinely indicated in otherwise healthy patients with
mild COVID-19. Older patients and those with underlying comorbidities are at higher risk of disease
progression; therefore, health care providers should monitor these patients closely until clinical
recovery is achieved. See Therapeutic Management of Nonhospitalized Adults With COVID-19 for
recommendations regarding SARS-CoV-2-specific therapy.
Moderate Illness
Moderate illness is defined as evidence of lower respiratory disease during clinical assessment or
imaging, with SpO2 ≥94% on room air at sea level. Given that pulmonary disease can progress rapidly in
patients with COVID-19, patients with moderate disease should be closely monitored. See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for recommendations regarding SARS-CoV-2-
specific therapy. If bacterial pneumonia is suspected, administer empiric antibiotic treatment, re-evaluate
the patient daily, and de-escalate or stop antibiotics if further testing indicates the patient does not have a
bacterial infection.
Severe Illness
Patients with COVID-19 are considered to have severe illness if they have SpO2 <94% on room air at
sea level, PaO2/FiO2 <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%. These
patients may experience rapid clinical deterioration. Oxygen therapy should be administered immediately
using a nasal cannula or a high-flow oxygen device. See Therapeutic Management of Hospitalized Adults
With COVID-19 for recommendations regarding SARS-CoV-2-specific therapy. If bacterial pneumonia
or sepsis is suspected, administer empiric antibiotics, re-evaluate the patient daily, and de-escalate or stop
antibiotics if further testing indicates the patient does not have a bacterial infection.
Critical Illness
SARS-CoV-2 infection can cause acute respiratory distress syndrome, virus-induced distributive (septic)
shock, cardiac shock, an exaggerated inflammatory response, thrombotic disease, and exacerbation of

underlying comorbidities.
Successful clinical management of a patient with COVID-19, as with any patient in the intensive care
unit (ICU), includes treating both the medical condition that initially resulted in ICU admission as well as
other comorbidities and nosocomial complications. For more information, see Critical Care for Adults.
Infectious Complications in Patients With COVID-19

Some patients with COVID-19 may have additional infections when they present for care or that
develop during the course of treatment. These coinfections may complicate treatment and recovery.
Older patients or those with certain comorbidities or immunocompromising conditions may be at
higher risk for these infections. The use of immunomodulators such as dexamethasone, interleukin-6
inhibitors (e.g., tocilizumab, sarilumab), or Janus kinase inhibitors (e.g., baricitinib, tofacitinib) to treat
COVID-19 may also be a risk factor for infectious complications; however, when these therapies are
used appropriately, the benefits outweigh the risks.
Infectious complications in patients with COVID-19 can be categorized as follows:
• Coinfections at presentation: Although most individuals present with only SARS-CoV-2 infection,
concomitant viral infections, including influenza and other respiratory viruses, have been
reported.12 Community-acquired bacterial pneumonia has also been reported, but it is uncommon,
with a prevalence that ranges from 0% to 6% of people with SARS-CoV-2 infection.12,13
Antibacterial therapy is generally not recommended unless additional evidence for bacterial
pneumonia is present (e.g., leukocytosis, the presence of a focal infiltrate on imaging).
• Reactivation of latent infections: There are case reports of underlying chronic hepatitis B
virus and latent tuberculosis infections reactivating in patients with COVID-19 who receive
immunomodulators as treatment,14-16 although the data are currently limited. Reactivation of herpes
simplex virus and varicella zoster virus infections have also been reported.17 Cases of severe and
disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment
with tocilizumab and corticosteroids.18,19 Many clinicians would initiate empiric treatment (e.g.,
with the antiparasitic drug ivermectin), with or without serologic testing, in patients who are from
areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).20
• Nosocomial infections: Hospitalized patients with COVID-19 may acquire common nosocomial
infections, such as hospital-acquired pneumonia (including ventilator-associated pneumonia),
line-related bacteremia or fungemia, catheter-associated urinary tract infection, and Clostridioides
difficile–associated diarrhea. Early diagnosis and treatment of these infections are important for
improving outcomes in these patients.
• Opportunistic fungal infections: Invasive fungal infections, including aspergillosis and
mucormycosis, have been reported in hospitalized patients with COVID-19.21-24 Although these
infections are relatively rare, they can be fatal, and they may be seen more commonly in patients
who are immunocompromised or receiving mechanical ventilation. The majority of mucormycosis
cases have been reported in India and are associated with diabetes mellitus or the use of
corticosteroids.25,26 The approach for managing these fungal infections should be the same as the
approach for managing invasive fungal infections in other settings.
SARS-CoV-2 Reinfection and Breakthrough Infection

As seen with other viral infections, reinfection after recovery from prior infection has been reported for
SARS-CoV-2.27 Reinfection may occur as initial immune responses to the primary infection wane over
time. The true prevalence of reinfection is not known and likely varies depending on the circulating

variants. A national database study in Qatar estimated that previous infection prevented reinfection
with the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants of concern (VOC) with 90%,
86%, and 92% effectiveness, respectively, whereas protection against reinfection with the Omicron
(B.1.1.529) VOC was about 56% effective.28 Furthermore, an investigation of Omicron infection after
Delta infection in 4 U.S. states identified 10 cases of reinfection occurring <90 days after a symptomatic
infection (1 reinfection required hospitalization).29 The majority of reinfection cases (70%) occurred in
people who were unvaccinated. Fewer patients were symptomatic during reinfection than during initial
infection. Among patients who were symptomatic, the median duration of symptoms was shorter with
reinfection than with the initial infection.
Breakthrough SARS-CoV-2 infections (i.e., infection in people who completed the primary vaccine
series) have been reported.30 Breakthrough SARS-CoV-2 infection appears to be less likely to lead to
severe illness than infection in people who are unvaccinated. An analysis of electronic health record
data from a large U.S. sample of 664,722 patients seen from December 2020 to September 2021 found
that full vaccination was associated with a 28% reduced risk for a breakthrough infection.31 That study
also found that the time to breakthrough infection was shorter for patients with immunocompromising
conditions (i.e., people with HIV or solid organ or bone marrow transplant recipients) than for those
with no immunocompromising conditions. For information on diagnostic testing in the setting of
suspected reinfection, see Testing for SARS-CoV-2 Infection. In addition, guidelines for the diagnosis
and evaluation of suspected SARS-CoV-2 reinfection or breakthrough infection are provided by the
Centers for Disease Control and Prevention (CDC).
Although data are limited, no evidence suggests that the treatment of suspected or documented
SARS-CoV-2 reinfection or breakthrough infection should be different from the treatment used during
the initial infection, as outlined in Therapeutic Management of Nonhospitalized Adults With COVID-19
and Therapeutic Management of Hospitalized Adults With COVID-19.
Persistent Symptoms and Other Conditions After Acute COVID-19

Some patients may experience persistent symptoms or other conditions after acute COVID-19.
Adult and pediatric data on the incidence, natural history, and etiology of these symptoms and organ
dysfunction are emerging. However, reports on these data have several limitations, including differing
case definitions. In addition, many reports only included patients who attended post-COVID-19 clinics,
and the studies often lack comparator groups. No specific treatments for persistent effects of COVID-19
have been shown to be effective, although general management strategies have been proposed, including
interim guidance from CDC, the American Academy of Physical Medicine and Rehabilitation, and the
United Kingdom’s COVID-19 rapid guideline.
The nomenclature for this phenomenon is evolving, and no clinical terminology has been established.
It has been referred to as post-COVID-19 condition, post-COVID syndrome, post-acute sequelae of
SARS-CoV-2, or, colloquially, “long COVID,” and affected patients have been referred to as “long
haulers.” MIS-C and multisystem inflammatory syndrome in adults (MIS-A) are serious, postinfectious
complications of acute COVID-19. For more information on these syndromes, see Therapeutic
Management of Hospitalized Pediatric Patients With Multisystem Inflammatory Syndrome in Children
(MIS-C) (With Discussion on Multisystem Inflammatory Syndrome in Adults [MIS-A]).
The CDC has defined post-COVID-19 conditions as new, returning, or ongoing symptoms that people
experience ≥4 weeks after being infected with SARS-CoV-2.32 In October 2021, the World Health
Organization published a clinical case definition that described the post-COVID-19 clinical condition
as usually occurring 3 months after the onset of COVID-19 with symptoms that last for ≥2 months and

cannot be explained by an alternative diagnosis.33
Persistent Symptoms
The prevalence of persistent post-COVID-19 clinical signs and symptoms remains unclear. In a
systematic review of 25 observational cohort studies, prevalence varied widely (from 5% to 80%) and
likely reflected differences in study population, case definition, and data resources.34 Another large,
systematic review found similar prevalence of post-COVID-19 symptoms 6 months after initial infection
between studies from high-income or low- and middle-income countries and between studies in which
>60% or <60% of the patients were hospitalized.35
A prospective study conducted at the University of Washington investigated mostly outpatients with
laboratory-confirmed SARS-CoV-2 infection (150 participants had mild illness, 11 had no symptoms,
and 11 had moderate or severe disease that required hospitalization).36 Participants completed a
follow-up questionnaire 3 months to 9 months after illness onset; 33% of outpatients and 31% of
hospitalized patients reported ≥1 persistent symptom. Persistent symptoms were reported by 27% of the
patients aged 18 to 39 years, 30% of those aged 40 to 64 years, and 43% of those aged ≥65 years.
In these and other studies, the most commonly reported nonneurologic, persistent symptoms included
fatigue or muscle weakness, joint pain, chest pain, palpitations, shortness of breath, and cough.35-42 From
January 2020 to April 2021, CDC conducted an internet-based survey of 3,135 noninstitutionalized
adults who self-reported receiving either a positive or negative SARS-CoV-2 test result.43 The study
found that fatigue, shortness of breath, and cough were commonly reported symptoms lasting >4 weeks
after onset. The prevalence of these symptoms among participants with a positive test result versus the
prevalence among participants with a negative test result was 22.5% versus 12% for fatigue, 15.5%
versus 5.2% for shortness of breath, and 14.5% versus 4.9% for cough.
Some of the reported symptoms overlap with post-intensive care syndrome symptoms that have been
described for patients without COVID-19. Prolonged symptoms and disabilities after COVID-19 have
also been reported in patients with milder illness, including outpatients.44,45
Patients who had breakthrough infection after COVID-19 vaccination are less likely to report symptoms
that persist ≥28 days than patients with SARS-CoV-2 infection who are unvaccinated.46,47 The COVID
Symptom Study, conducted from December 2020 to July 2021, included participants who used a mobile
application to report symptoms after breakthrough infections or reinfection.46 The investigators found
that the odds of reporting symptoms for ≥28 days was reduced by about half among participants who
received 2 vaccine doses, when compared with participants who received 1 or 0 vaccine doses.
A study of electronic health record data from 59 health care organizations, primarily in the United
States, compared the records of people who did not receive any vaccine doses with records of people
who received 2 vaccine doses.48 In the 6 months after infection, those who received 2 vaccine doses had
a lower risk for some, but not all, long-COVID outcomes, such as fatigue, muscle weakness, loss of
sense of smell, or hair loss.
Cardiopulmonary Injury
A U.S. Department of Veterans Affairs (VA) study of a national health care database compared 153,760
veterans who survived the first 30 days of COVID-19 to contemporary and historical control cohorts
that had no evidence of SARS-CoV-2 infection.49 When compared with the control cohorts, patients
with a history of COVID-19 had a greater incidence of postacute cardiovascular outcomes (e.g.,
cerebrovascular disorder, dysrhythmia, inflammatory heart disease, ischemic heart disease, heart failure,
thromboembolic disease) at 12 months.

A prospective study of pulmonary function examined longitudinal data from the adult Copenhagen
General Population Study and found that pulmonary function declined faster (median 5.6 months) for
the 107 patients with mostly mild COVID-19 than for a matched sample from the general population.50
Neuropsychiatric Impairment
Neuropsychiatric impairments have been reported among patients who have recovered from acute
COVID-19. Reported persistent neurologic symptoms include headaches, vision changes, hearing loss,
impaired mobility, numbness in extremities, restless legs syndrome, tremors, memory loss, cognitive
impairment, sleep difficulties, concentration problems, mood changes, and loss of sense of smell or
taste.51-54
One study in the United Kingdom administered cognitive tests to 84,285 participants who had recovered
from suspected or confirmed SARS-CoV-2 infection. These participants had worse performances across
multiple domains than would be expected for people with the same ages and demographic profiles; this
effect was observed even among those who had not been hospitalized.55 However, the study authors did
not report when the tests were administered in relation to the diagnosis of COVID-19.
A retrospective cohort study examined the electronic health records of 273,618 patients from 59 health
care organizations, primarily in the United States.56 The study reported that cognitive dysfunction
(defined using International Classification of Diseases 10th Revision codes) 3 to 6 months after
diagnosis was worse for people with COVID-19 than for people with influenza. Other studies have
reported high rates of anxiety and depression among patients who evaluated their psychiatric distress
using self-report scales.42,57 Reports also show that patients aged ≤60 years experienced more psychiatric
symptoms than patients aged >60 years.41,42
Metabolic Perturbations
There have been reports of new-onset diabetes after COVID-19.58 A study of a VA national health care
database analyzed the records of 181,280 people who survived the first 30 days of COVID-19 and
compared them to a contemporary control cohort that had no evidence of SARS-CoV-2 infection. People
with a history of COVID-19 had a 40% greater risk of diabetes 12 months after infection than people
in the control cohort.59 A CDC study of people aged <18 years reported that those with a history of
COVID-19 had an increased risk of diabetes >30 days after SARS-CoV-2 infection when compared with
the risk of those with no history of infection.60
Research on persistent symptoms and other conditions after COVID-19 is ongoing, including the
National Institutes of Health’s RECOVER initiative, which aims to better characterize the prevalence,
characteristics, and pathophysiology of post-acute sequelae of SARS-CoV-2 and inform potential
therapeutic strategies.
Considerations in Pregnant People

Minimal data are available on differences or unique characteristics of post-acute sequelae of
SARS-CoV-2 among pregnant patients. Persistent symptoms after acute COVID-19 have been reported
in pregnant people. In a prospective cohort study of predominantly (95%) outpatient pregnant and
recently pregnant patients with SARS-CoV-2, 25% of 594 patients had persistent symptoms ≥8 weeks
after symptom onset.61 The most commonly reported persistent symptoms among this cohort were
fatigue, shortness of breath, and loss of sense of smell or taste. For pregnant patients and their children,
as well as for all patients affected by post-acute sequelae of SARS-CoV-2, more research is needed to
understand any unique long-term effects of COVID-19. The RECOVER initiative plans to enroll and
longitudinally follow pregnant patients and their offspring to better understand any long-term effects of

COVID-19.
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32. Centers for Disease Control and Prevention. Long COVID or post-COVID conditions. 2022. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html. Accessed June 2, 2022.

33. Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a
Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/34951953.
34. Cabrera Martimbianco AL, Pacheco RL, Bagattini AM, Riera R. Frequency, signs and symptoms, and criteria
adopted for long COVID-19: a systematic review. Int J Clin Pract. 2021;75(10):e14357. Available at:
35. Groff D, Sun A, Ssentongo AE, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2
infection: a systematic review. JAMA Netw Open. 2021;4(10):e2128568. Available at:
36. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA
Netw Open. 2021;4(2):e210830. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33606031.
37. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital:
a cohort study. Lancet. 2021;397(10270):220-232. Available at:
38. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and
independent of severity of initial infection. PLoS One. 2020;15(11):e0240784. Available at:
39. Carfi A, Bernabei R, Landi F, Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms
in patients after acute COVID-19. JAMA. 2020;324(6):603-605. Available at:
40. Peluso MJ, Kelly JD, Lu S, et al. Persistence, magnitude, and patterns of postacute symptoms and quality of
life following onset of SARS-CoV-2 infection: cohort description and approaches for measurement. Open
Forum Infect Dis. 2022;9(2):ofab640. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35106317.
41. Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of
COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2021;93(2):1013-1022. Available at:
42. Cai X, Hu X, Ekumi IO, et al. Psychological distress and its correlates among COVID-19 survivors during
early convalescence across age groups. Am J Geriatr Psychiatry. 2020;28(10):1030-1039. Available at:
43. Wanga V, Chevinsky JR, Dimitrov LV, et al. Long-term symptoms among adults tested for SARS-CoV-2—
United States, January 2020–April 2021. MMWR Morb Mortal Wkly Rep. 2021;70(36):1235-1241. Available
44. Rawal G, Yadav S, Kumar R. Post-intensive care syndrome: an overview. J Transl Int Med. 2017;5(2):90-92.
45. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health
among outpatients with COVID-19 in a multistate health care systems network—United States, March–June
46. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2
infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-
control study. Lancet Infect Dis. 2022;22(1):43-55. Available at:
47. Kuodi P, Gorelik Y, Zayyad H, et al. Association between vaccination status and reported incidence of
post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and
November 2021. medRxiv. 2022;Preprint. Available at:
48. Taquet M, Dercon Q, Harrison PJ. Six-month sequelae of post-vaccination SARS-CoV-2 infection: a

retrospective cohort study of 10,024 breakthrough infections. Brain Behav Immun. 2022;103:154-162.
49. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med.
50. Iversen KK, Afzal S, Ahlstrom MG, et al. Lung function decline in relation to COVID-19 in the
general population: a matched cohort study with prepandemic assessment of lung function. J Infect Dis.
51. Lu Y, Li X, Geng D, et al. Cerebral micro-structural changes in COVID-19 patients—an MRI-based 3-month
follow-up study. EClinicalMedicine. 2020;25:100484. Available at:
52. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of
COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12(1):69.
53. Lechien JR, Chiesa-Estomba CM, Beckers E, et al. Prevalence and 6-month recovery of olfactory dysfunction:
a multicentre study of 1363 COVID-19 patients. J Intern Med. 2021;290(2):451-461. Available at:
54. Weinstock LB, Brook JB, Walters AS, et al. Restless legs syndrome is associated with long-COVID in women.
J Clin Sleep Med. 2022;18(5):1413-1418. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35484639.
55. Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from
COVID-19. EClinicalMedicine. 2021;39:101044. Available at:
56. Taquet M, Dercon Q, Luciano S, et al. Incidence, co-occurrence, and evolution of long-COVID features: a
6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med. 2021;18(9):e1003773.
57. Mazza MG, De Lorenzo R, Conte C, et al. Anxiety and depression in COVID-19 survivors: role of
inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594-600. Available at:
58. Banerjee M, Pal R, Dutta S. Risk of incident diabetes post-COVID-19: a systematic review and meta-analysis.
Prim Care Diabetes. 2022;Published online ahead of print. Available at:
59. Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes
Endocrinol. 2022;10(5):311-321. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35325624.
60. Barrett CE, Koyama AK, Alvarez P, et al. Risk for newly diagnosed diabetes >30 days after SARS-CoV-2
infection among persons aged <18 Years—United States, March 1, 2020–June 28, 2021. MMWR Morb Mortal
Wkly Rep. 2022;71(2):59-65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35025851.
61. Afshar Y, Gaw SL, Flaherman VJ, et al. Clinical presentation of coronavirus disease 2019 (COVID-19) in
pregnant and recently pregnant people. Obstet Gynecol. 2020;136(6):1117-1125. Available at:

Prioritization of Anti-SARS-CoV-2 Therapies for
the Treatment and Prevention of COVID-19
When There Are Logistical or Supply Constraints
Last Updated: May 13, 2022
The prioritization guidance in this section should be used only when logistical or supply constraints limit
the availability of therapies. When there are no supply or logistical constraints, the COVID-19 Treatment
Guidelines Panel (the Panel) recommends that therapies for the prevention or treatment of SARS-CoV-2
be prescribed for any eligible individual as recommended in these Guidelines.
At times during the pandemic, increased cases of COVID-19 and the emergence of new variants of
concern have resulted in logistical or supply constraints that made offering recommended therapies to all
eligible patients impossible. In these situations, prioritization of therapy for those who will benefit the
most becomes necessary. This section provides guidance on which individuals might receive the greatest
benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention when access is limited.
The Panel has recommended several therapeutic agents for the treatment and prevention of SARS-CoV-2
infection in individuals who are at high risk for progression to severe COVID-19. These anti-SARS-
CoV-2 therapeutics have the greatest proven clinical benefit for nonhospitalized patients who have risk
factors for progression to severe COVID-19. The risks for progression are substantially higher for those
who are not vaccinated or who are vaccinated but not expected to mount an adequate immune response
to the vaccine.
The Food and Drug Administration provides a broad list of medical conditions or other factors as criteria
for use of anti-SARS-CoV-2 agents as treatment or pre-exposure prophylaxis (PrEP).
When it becomes necessary to triage patients for receipt of anti-SARS-CoV-2 therapies or preventive
strategies, the Panel suggests prioritizing:
• Treatment of COVID-19 in unvaccinated or incompletely vaccinated individuals with clinical risk
factors for severe illness and vaccinated individuals who are not expected to mount an adequate
immune response (see Immunocompromising Conditions below)
• Use of tixagevimab plus cilgavimab (Evusheld) as PrEP for individuals who are severely
immunocompromised over those who are moderately immunocompromised (see
Immunocompromising Conditions below)
Prioritization Strategies When There Are Logistical or Supply Constraints

When logistical or supply constraints limit the availability of anti-SARS-CoV-2 monoclonal antibodies
(mAbs) or small-molecule antiviral agents, the Panel recommends that clinicians prioritize their use
for patients at highest risk of clinical progression. Providers should use their clinical judgment when
prioritizing the use of anti-SARS-CoV-2 mAbs for treatment.
Prioritization schemes should consider how to equitably distribute scarce resources to populations that
include individuals who may have less knowledge of or access to these therapies. The availability and
distribution of recommended therapies should be monitored to ensure that access to products is equitable.
Patient Prioritization for Treatment

The prioritization table below should be used only when logistical or supply constraints limit the

availability of therapies. When there are no supply or logistical constraints, the Panel recommends that
therapies for the prevention or treatment of anti-SARS-CoV-2 be prescribed for any eligible individual as
recommended in these Guidelines.
The Panel prioritized the following risk groups for anti-SARS-CoV-2 mAbs and antiviral therapy based on
4 key elements: age, vaccination status, immune status, and clinical risk factors. The groups are listed by
tier in descending order of priority.
For a list of risk factors, see the Centers for Disease Control and Prevention (CDC) webpage Underlying
Medical Conditions Associated With Higher Risk for Severe COVID-19.
Tier Risk Group

1 • Immunocompromised individuals not expected to mount an adequate immune response to COVID-19
vaccination or SARS-CoV-2 infection due to their underlying conditions, regardless of vaccine status (see
Immunocompromising Conditions below); or
• Unvaccinated individuals at the highest risk of severe disease (anyone aged ≥75 years or anyone aged ≥65
years with additional risk factors).
2 • Unvaccinated individuals not included in Tier 1 who are at risk of severe disease (anyone aged ≥65 years or
anyone aged <65 years with clinical risk factors)
3 • Vaccinated individuals at high risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years
with clinical risk factors)
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients within this tier in this situation should be prioritized for treatment.
4 • Vaccinated individuals at risk of severe disease (anyone aged ≥65 years or anyone aged <65 years with
clinical risk factors)
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients within this tier in this situation should be prioritized for treatment.
Patient Prioritization for Pre-Exposure Prophylaxis

Tixagevimab plus cilgavimab is authorized for use as SARS-CoV-2 PrEP for individuals who have
moderate to severe immunocompromising conditions that may result in an inadequate immune response
to COVID-19 vaccination. Unlike anti-SARS-CoV-2 agents used for treatment, tixagevimab plus
cilgavimab is not authorized for use in unvaccinated individuals unless full vaccination is not possible
due to a history of severe allergic reaction to the COVID-19 vaccine. Generally, unless they are also
immunocompromised, individuals who qualify for PrEP because of vaccine allergy or contraindication are
less likely to suffer severe consequences from SARS-CoV-2 infection than individuals who are moderately
to severely immunocompromised.
Immunocompromising Conditions
The CDC website COVID-19 Vaccines for People Who Are Moderately or Severely Immunocompromised
provides a list of moderate or severe immunocompromising conditions.1
If, because of logistical constraints or supply limitations, anti-SARS-CoV-2 therapies cannot be provided
to all individuals who are moderately to severely immunocompromised, the Panel suggests prioritizing
their use for patients who are least likely to mount an adequate response to COVID-19 vaccination
or SARS-CoV-2 infection and who are at risk for severe outcomes, including (but not limited to) the
following populations:
• Patients who are within 1 year of receiving B cell-depleting therapies (e.g., rituximab, ocrelizumab,
ofatumumab, alemtuzumab)

• Patients receiving Bruton’s tyrosine kinase inhibitors
• Chimeric antigen receptor T cell recipients
• Post-hematopoietic cell transplant recipients who have chronic graft-versus-host disease or who
are taking immunosuppressive medications for another indication
• Patients with hematologic malignancies who are on active therapy
• Lung transplant recipients
• Patients who are within 1 year of receiving a solid organ transplant (other than lung transplant)
• Solid organ transplant recipients who had recent treatment with T cell- or B cell-depleting agents
for acute rejection
• Patients with severe combined immunodeficiencies
• Patients with advanced or untreated HIV
If supplies are extremely limited, the Panel suggests prioritizing patients who are more severely
immunocompromised and who have additional risk factors for severe disease (as discussed below).
Clinical Risk Factors

Some of the most important risk factors for severe COVID-19 include age (risk increases with each
decade after age 50),2 cancer, cardiovascular disease, chronic kidney disease, chronic lung disease,
diabetes, immunocompromising conditions or receipt of immunosuppressive medications, obesity (i.e.,
body mass index ≥30), and pregnancy. For a complete list of risk factors, including information on the
relative risk of severe disease, see the CDC webpage Underlying Medical Conditions Associated With
Higher Risk for Severe COVID-19. Of note, the likelihood of developing severe COVID-19 increases
when a person has multiple comorbidities.3
Although the data on risk factors for severe COVID-19 in children are limited, there is substantial
overlap between risk factors in children and those identified in adults. Children aged <1 year or
children with obesity, moderate to severe immunosuppression, or complex chronic disease and medical
complexity and dependence on respiratory technology are at substantially increased risk of severe
disease.4
References
1. Centers for Disease Control and Prevention. COVID-19 vaccines for people who are moderately or
severely immunocompromised. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
recommendations/immuno.html. Accessed May 9, 2022.
2. Centers for Disease Control and Prevention. COVID-19 risks and vaccine information for older adults. 2021.
Available at: https://www.cdc.gov/aging/covid19/covid19-older-adults.html. Accessed December 22, 2021.
3. Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk factors associated with in-hospital mortality in a U.S.
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
4. Kompaniyets L, Agathis NT, Nelson JM, et al. Underlying medical conditions associated with severe
COVID-19 illness among children. JAMA Netw Open. 2021;4(6):e2111182. Available at:

Clinical Management of Adults Summary
Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course, the
disease is primarily driven by the replication of SARS-CoV-2. Later in the clinical course, the disease
appears to be driven by a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to
tissue damage. Based on this understanding, therapies that directly target SARS-CoV-2 are anticipated to
have the greatest effect early in the course of the disease, while immunosuppressive/anti-inflammatory
therapies are likely to be more beneficial in the later stages of COVID-19.
The clinical spectrum of SARS-CoV-2 infection includes asymptomatic or presymptomatic infection and
mild, moderate, severe, and critical illness. Table 2a provides guidance for clinicians on the therapeutic
management of nonhospitalized adult patients. This includes patients who do not require hospitalization
or supplemental oxygen and those who have been discharged from an emergency department or a
hospital. Table 2c provides guidance on the therapeutic management of hospitalized adult patients
according to their disease severity and oxygen requirements.

Table 2a. Therapeutic Management of Nonhospitalized Adults With COVID-19
Patient Disposition Panel’s Recommendations

For All Patients:
• All patients should be offered symptomatic management (AIII).
• The Panel recommends against the use of dexamethasonea or other
systemic corticosteroids in the absence of another indication (AIIb).
For Patients Who Are at High Risk of Progressing to Severe COVID-19b
Preferred Therapies. Listed in order of preference:
Does Not Require Hospitalization or
Supplemental Oxygen • Ritonavir-boosted nirmatrelvir (Paxlovid)c,d (AIIa)
• Remdesivird,e (BIIa)
Alternative Therapies. For use ONLY when neither of the preferred therapies
are available, feasible to use, or clinically appropriate. Listed in alphabetical
order
• Bebtelovimabf (CIII)
• Molnupiravird,g (CIIa)
Discharged from Hospital Inpatient
The Panel recommends against continuing the use of remdesivir (AIIa),
Setting in Stable Condition and Does Not
dexamethasonea (AIIa), or baricitinib (AIIa) after hospital discharge.
Require Supplemental Oxygen
Discharged from Hospital Inpatient Setting
and Requires Supplemental Oxygen There is insufficient evidence to recommend either for or against the
For those who are stable enough for continued use of remdesivir or dexamethasone.
discharge but still require oxygen h
The Panel recommends using dexamethasone 6 mg PO once daily for the
Discharged from ED Despite New or duration of supplemental oxygen (dexamethasone use should not exceed
Increasing Need for Supplemental Oxygen 10 days) with careful monitoring for AEs (BIII).
When hospital resources are limited, Because remdesivir is recommended for patients with similar oxygen needs
inpatient admission is not possible, and who are hospitalized,j clinicians may consider using it in this setting. As
close follow-up is ensured i remdesivir requires IV infusions for up to 5 consecutive days, there may be
logistical constraints to administering remdesivir in the outpatient setting.
Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup
analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion
a
T here is currently a lack of safety and efficacy data on the use of dexamethasone in outpatients with COVID-19. Using
systemic glucocorticoids in this setting may cause harm.
b
For a list of risk factors, see the CDC webpage Underlying Medical Conditions Associated With Higher Risk for Severe
COVID-19.
c
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions. Clinicians should carefully review a patient’s
concomitant medications and evaluate potential drug-drug interactions. See Drug-Drug Interactions Between Ritonavir-
Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications for more information.
d
If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the health care
provider’s discretion.
e
Administration of remdesivir requires 3 consecutive days of IV infusion.
f
Bebtelovimab is active in vitro against all circulating Omicron (B.1.1.529) subvariants, but there are no clinical efficacy
data from placebo-controlled trials that evaluated the use of bebtelovimab in patients who are at high risk of progressing
to severe COVID-19. Therefore, bebtelovimab should be used only when the preferred treatment options are not
available, feasible to use, or clinically appropriate.
g
Molnupiravir has lower efficacy than the preferred treatment options. Therefore, it should be used only when the

preferred options are not available, feasible to use, or clinically appropriate.
h
These individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse services, or
in-person visits.
i
Provide an advanced level of home care, including supplemental oxygen (whether patients are receiving oxygen for the
first time or are increasing their baseline oxygen requirements), pulse oximetry, laboratory monitoring, and close follow-
up through telehealth, visiting nurse services, or in-person visits.
j
See Therapeutic Management of Hospitalized Adults With COVID-19.
Key: AE = adverse event; CDC = Centers for Disease Control and Prevention; ED = emergency department; IV =
intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PO = orally

Table 2c. Therapeutic Management of Hospitalized Adults With COVID-19 Based on Disease Severity
Recommendations for Antiviral or Immunomodulator Therapy Recommendations for Anticoagulant

Disease Severity
Clinical Scenario Recommendation Therapy
Patients with mild to moderate See Therapeutic Management of Nonhospitalized Adults With COVID-19. For patients without an indication for
Hospitalized for
COVID-19 who are at high therapeutic anticoagulation:
Reasons Other
risk of progressing to severe • Prophylactic dose of heparin,
Than COVID-19
COVID-19a unless contraindicated (AI); (BIII) for
Hospitalized All patients The Panel recommends against the use of dexamethasone (AIIa) or pregnant patients
but Does Not other systemic corticosteroids (AIII) for the treatment of COVID-19.b
Require Oxygen Patients who are at high risk of Remdesivirc (BIII)
Supplementation progressing to severe COVID-19 a
Patients who require minimal Remdesivire (BIIa) For nonpregnant patients with D-dimer
conventional oxygen levels above the ULN who do not have
Hospitalized Most patients Use dexamethasone plus remdesivire (BIIa). If remdesivir cannot be an increased bleeding risk:
and Requires obtained, use dexamethasone (BI). • Therapeutic dose of heparing (CIIa)
Conventional Patients who are receiving Add PO baricitinibf or IV tocilizumabf to 1 of the options above (BIIa). For other patients:
Oxygend dexamethasone and who have • Prophylactic dose of heparin,
rapidly increasing oxygen needs unless contraindicated (AI); (BIII) for
and systemic inflammation pregnant patients
Most patients Promptly start 1 of the following, if not already initiated: For patients without an indication for
• Dexamethasone plus PO baricitinibf (AI) therapeutic anticoagulation:
Hospitalized and • Dexamethasone plus IV tocilizumab (BIIa) f • Prophylactic dose of heparin,
Requires HFNC unless contraindicated (AI); (BIII) for
If baricitinib, tofacitinib, tocilizumab, or sarilumab cannot be obtained: pregnant patients
Oxygen or NIV
• Dexamethasoneh (AI)
For patients who are started on a
Add remdesivir to 1 of the options above in certain patients (CIIa).i therapeutic dose of heparin in a non-
Most patients Promptly start 1 of the following, if not already initiated: ICU setting and then transferred to the
• Dexamethasone plus PO baricitinib (BIIa)
f ICU, the Panel recommends switching
Hospitalized and
• Dexamethasone plus IV tocilizumab (BIIa) f to a prophylactic dose of heparin,
Requires MV or
unless there is another indication for
ECMO If baricitinib, tofacitinib, tocilizumab, or sarilumab cannot be obtained: therapeutic anticoagulation (BIII).

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb =
Nonrandomized trials or observational cohort studies; III = Expert opinion

a
F or a list of risk factors, see the CDC webpage Underlying Medical Conditions Associated With Higher Risk for Severe
COVID-19.
b
Corticosteroids that are prescribed for an underlying condition should be continued.
c
Evidence suggests that the benefit of remdesivir is greatest when the drug is given early in the course of COVID-19 (e.g.,
within 10 days of symptom onset).
d
Conventional oxygen refers to oxygen supplementation that is not HFNC oxygen, NIV, MV, or ECMO.
e
If these patients progress to requiring HFNC oxygen, NIV, MV, or ECMO, the full course of remdesivir should still be
completed.
f
If PO baricitinib and IV tocilizumab are not available or not feasible to use, PO tofacitinib can be used instead of PO
baricitinib (BIIa), and IV sarilumab can be used instead of IV tocilizumab (BIIa).
g
Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 include a platelet count <50 x
109/L, Hgb <8 g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required an ED visit or
hospitalization, a history of a bleeding disorder, or an inherited or active acquired bleeding disorder.
h
If a JAK inhibitor or an anti-IL-6 receptor mAb is not readily available, start dexamethasone while waiting for the
additional immunomodulator to be acquired. If neither of the other immunomodulators can be obtained, use
dexamethasone alone.
i
Clinicians may consider adding remdesivir to 1 of the recommended immunomodulator combinations in patients who
require HFNC oxygen or NIV, including immunocompromised patients. The Panel recommends against the use of
remdesivir without immunomodulators in these patients (AIIa).
Key: CDC = Centers for Disease Control and Prevention; ECMO = extracorporeal membrane oxygenation; ED =
emergency department; HFNC = high-flow nasal cannula; Hgb = hemoglobin; ICU = intensive care unit; IL = interleukin;
IV = intravenous; JAK = Janus kinase; mAb = monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive
ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; PO = oral; ULN = upper limit of normal

General Management of Nonhospitalized
Patients With Acute COVID-19
Last Updated: December 16, 2021
• Management of nonhospitalized patients with acute COVID-19 should include providing supportive care, considering
the use of COVID-19-specific therapy for patients who have a high risk for disease progression, taking steps to reduce
the risk of SARS-CoV-2 transmission (including isolating the patient), and advising patients on when to contact a
health care provider and seek an in-person evaluation (AIII).
• When possible, patients with symptoms of COVID-19 should be triaged via telehealth visits to determine whether they
require COVID-19-specific therapy and in-person care (AIII).
• Patients with dyspnea should be referred for an in-person evaluation by a health care provider and should be followed
closely during the initial days after the onset of dyspnea to assess for worsening respiratory status (AIII).
• Management plans should be based on a patient’s vital signs, physical exam findings, risk factors for progression to
severe illness, and the availability of health care resources (AIII).
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for specific recommendations on using
pharmacologic therapy in nonhospitalized patients.
Introduction
This section of the Guidelines is intended to provide information to health care providers who are
caring for nonhospitalized patients with COVID-19. The COVID-19 Treatment Guidelines Panel’s (the
Panel) recommendations for pharmacologic management can be found in Therapeutic Management of
Nonhospitalized Adults With COVID-19. The Panel recognizes that the distinction between outpatient
and inpatient care may be less clear during the COVID-19 pandemic. Patients with COVID-19 may
receive care outside traditional ambulatory care or hospital settings if there is a shortage of hospital beds,
staff, or resources. Settings such as field hospitals and ambulatory surgical centers and programs such as
Acute Hospital Care at Home have been implemented to alleviate hospital bed and staffing shortages.1
Patients may enter an Acute Hospital Care at Home program from either an emergency department (ED)
or an inpatient hospital setting. Health care providers should use their judgment when deciding whether
the guidance offered in this section applies to individual patients.
This section focuses on the evaluation and management of:
• Adults with COVID-19 in an ambulatory care setting;
• Adults with COVID-19 following discharge from the ED; and
• Adults with COVID-19 following inpatient discharge.
Outpatient evaluation and management in each of these settings may include some or all of the
following: telemedicine, remote monitoring, in-person visits, and home visits by nurses or other health
care providers.
Managing Patients With COVID-19 in an Ambulatory Care Setting

Approximately 80% of patients with COVID-19 have mild illness that does not warrant medical
intervention or hospitalization.2 Most patients with mild COVID-19 (defined as the absence of viral

pneumonia and hypoxemia) can be managed in an ambulatory care setting or at home. Patients with
moderate COVID-19 (those with viral pneumonia but without hypoxemia) or severe COVID-19 (those
with dyspnea, hypoxemia, or lung infiltrates >50%) need in-person evaluation and close monitoring, as
pulmonary disease can progress rapidly and require hospitalization.3
Health care providers should identify patients who may be at high risk for progression to severe
COVID-19; these patients may be candidates for anti-SARS-CoV-2 monoclonal antibody treatment (see
Figure 1 in Therapeutic Management of Nonhospitalized Adults with COVID-19). When managing
outpatients with COVID-19, clinicians should provide supportive care, take steps to reduce the risk of
SARS-CoV-2 transmission (e.g., wear a mask, isolate the patient),4,5 evaluate the need for COVID-19-
specific therapy, and advise patients on when to seek in-person evaluation.6 Supportive care includes
managing symptoms (as described below), ensuring that patients are receiving the proper nutrition, and
paying attention to the risks of social isolation, particularly in older adults.7 Other unique aspects of care
for geriatric patients with COVID-19 include considerations related to cognitive impairment, frailty,
fall risk, and polypharmacy. Older patients and those with chronic medical conditions have a higher
risk for hospitalization and death; however, SARS-CoV-2 infection may cause severe disease and death
in patients of any age, even in the absence of any risk factors. The decision to monitor a patient in the
outpatient setting should be made on a case-by-case basis.
Assessing the Need for In-Person Evaluation

When possible, patients with symptoms of COVID-19 should be triaged via telehealth visits to
determine whether they require COVID-19-specific therapy and in-person care (AIII). Outpatient
management may include the use of patient self-assessment tools. During initial triage, clinic staff
should determine which patients are eligible to receive supportive care at home and which patients
warrant an in-person evaluation.8 Local emergency medical services, if called by the patient, may also
be of help in deciding whether an in-person evaluation is indicated. Patient management plans should be
based on the patient’s vital signs, physical exam findings, risk factors for progression to severe illness,
and the availability of health care resources (AIII).
All patients with dyspnea, oxygen saturation (SpO2) ≤94% on room air at sea level (if this information
is available), or symptoms that suggest higher acuity (e.g., chest pain or tightness, dizziness, confusion
or other mental status changes) should be referred for an in-person evaluation by a health care provider
(AIII). The criteria used to determine the appropriate clinical setting for an in-person evaluation may vary
by location and institution; it may also change over time as new data and treatment options emerge. There
should be a low threshold for in-person evaluation of older persons and those with medical conditions that
are associated with a risk of progression to severe COVID-19. The individual who performs the initial
triage should use their clinical judgement to determine whether a patient requires ambulance transport.
There are unique considerations for residents of nursing homes and other long-term care facilities who
develop acute COVID-19. Decisions about transferring these patients for an in-person evaluation should
be a collaborative effort between the resident (or their health care decision maker), a hospital-based
specialist (e.g., an emergency physician or geriatrician), and the clinical manager of the facility.9
In some settings where clinical evaluation is challenged by geography, health care provider home visits
may be used to evaluate patients.10 Patients who are homeless should be provided with housing where
they can adequately self-isolate. Providers should be aware of the potential adverse effects of prolonged
social isolation, including depression and anxiety.7 All outpatients should receive instructions regarding
self-care, isolation, and follow-up, and should be advised to contact a health care provider or a local ED
for any worsening symptoms.11,12 Guidance for implementing home care and isolation of outpatients with
COVID-19 is provided by the U.S. Centers for Disease Control and Prevention.

Clinical Considerations When Managing Patients in an Ambulatory Care Setting
Persons who have symptoms that are compatible with COVID-19 should undergo diagnostic
SARS-CoV-2 testing (see Prevention of SARS-CoV-2 Infection). Patients with SARS-CoV-2 infection
may be asymptomatic or experience symptoms that are indistinguishable from other acute viral or
bacterial infections (e.g., fever, cough, sore throat, malaise, muscle pain, headache, gastrointestinal
symptoms). It is important to consider other possible etiologies of symptoms, including other respiratory
viral infections (e.g., influenza), community-acquired pneumonia, congestive heart failure, asthma or
chronic obstructive pulmonary disease exacerbations, and streptococcal pharyngitis.
In most adult patients, if dyspnea develops, it tends to occur between 4 and 8 days after symptom
onset, although it can also occur after 10 days.13 While mild dyspnea is common, worsening dyspnea
and severe chest pain/tightness suggest the development or progression of pulmonary involvement. In
studies of patients who developed acute respiratory distress syndrome, progression occurred a median of
2.5 days after the onset of dyspnea.14-16 Adult outpatients with dyspnea should be followed closely with
telehealth or in-person monitoring, particularly during the first few days following the onset of dyspnea,
to monitor for worsening respiratory status (AIII).
If an adult patient has access to a pulse oximeter at home, SpO2 measurements can be used to help
assess overall clinical status. Patients should be advised to use pulse oximeters on warm fingers rather
than cold fingers for better accuracy. Patients should inform their health care provider if the value
is repeatedly below 95% on room air at sea level. Pulse oximetry may not accurately detect occult
hypoxemia, especially in Black patients.3,17,18 Additionally, SpO2 readings obtained through a mobile
phone application may not be accurate enough for clinical use.19-21 Importantly, oximetry should only be
interpreted within the context of a patient’s entire clinical presentation (i.e., results should be disregarded
if a patient is complaining of increasing dyspnea).
Counseling Regarding the Need for Follow-Up

Health care providers should identify patients who are at high risk for disease progression. These
patients may be candidates for anti-SARS-CoV-2 monoclonal antibody treatments, and clinicians
should ensure that these patients receive adequate medical follow-up. The frequency and duration of
follow-up will depend on the risk for severe disease, the severity of symptoms, and the patient’s ability
to self-report worsening symptoms. Health care providers should determine whether a patient has access
to a phone, computer, or tablet for telehealth; whether they have adequate transportation for clinic visits;
and whether they have regular access to food. The clinician should also confirm that the patient has a
caregiver who can assist with daily activities if needed.
All patients and/or their family members or caregivers should be counseled about the warning symptoms
that should prompt re-evaluation through a telehealth visit or an in-person evaluation in an ambulatory
care setting or ED. These symptoms include new onset of dyspnea; worsening dyspnea (particularly
if dyspnea occurs while resting or if it interferes with daily activities); dizziness; and mental status
changes, such as confusion. Patients should be educated about the time course of these symptoms and
the possible respiratory decline that may occur, on average, 1 week after the onset of illness.
Managing Adults With COVID-19 Following Discharge from the Emergency

Department
There are no fixed criteria for admitting patients with COVID-19 to the hospital; criteria may vary
by region and hospital facilities. Patients with severe disease are typically admitted to the hospital,
but some patients with severe disease may not be admitted due to a high prevalence of infection and
limited hospital resources. In addition, patients who could receive appropriate care at home but are

unable to be adequately managed in their usual residential setting are candidates for temporary shelter
in supervised facilities, such as a COVID-19 alternative care facility.22 For example, patients who are
living in multigenerational households or who are homeless may not be able to self-isolate and should
be provided resources such as dedicated housing units or hotel rooms, when available. Unfortunately,
dedicated residential care facilities for COVID-19 patients are not widely available, and community-
based solutions for self-care and isolation should be explored.
Treatment with an anti-SARS-CoV-2 monoclonal antibody is recommended for patients with mild to
moderate COVID-19 who are not on supplemental oxygen and who have been discharged from the
ED but who are at high risk for clinical progression (see Therapeutic Management of Nonhospitalized
Adults With COVID-19).
In the cases where institutional resources (e.g., inpatient beds, staff members) are scarce, it may
be necessary to discharge an adult patient and provide an advanced level of home care, including
supplemental oxygen (if indicated), pulse oximetry, and close follow-up. Although early discharge
of those with severe disease is not generally recommended by the Panel, it is recognized that these
management strategies are sometimes necessary. In these situations, some institutions are providing
frequent telemedicine follow-up visits for these patients or providing a hotline that allows patients to
speak with a clinician when necessary. Home resources should be assessed before a patient is discharged
from the ED; outpatients should have a caregiver and access to a device that is suitable for telehealth.
Patients and/or their family members or caregivers should be counseled about the warning symptoms
that should prompt re-evaluation by a health care provider. Special consideration may be given to
using certain therapeutics (e.g., dexamethasone) in this setting. For more information, see Therapeutic
Management of Nonhospitalized Adults With COVID-19.
Anticoagulants and antiplatelet therapy should not be initiated in the ED for the prevention of venous
thromboembolism (VTE) or arterial thrombosis if the patient is not being admitted to the hospital, unless
the patient has other indications for the therapy or is participating in a clinical trial (AIII). For more
information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to
ambulate, and activity should be increased according to the patient’s tolerance.
Managing Adults With COVID-19 Following Hospital Discharge

Most patients who are discharged from the hospital setting should have a follow-up visit with a health
care provider soon after discharge. Whether an in-person or a telehealth visit is most appropriate
depends on the clinical and social situation. In some cases, adult patients are deemed to be stable
for discharge from the inpatient setting even though they still require supplemental oxygen. Special
consideration may be given to using certain therapeutics (e.g., dexamethasone) in this setting. For more
information, see Therapeutic Management of Nonhospitalized Adults With COVID-19. When possible,
these individuals should receive oximetry monitoring and close follow-up through telehealth visits,
visiting nurse services, or in-person clinic visits.
Hospitalized patients with COVID-19 should not be routinely discharged while receiving VTE
prophylaxis, unless they have another indication or are participating in a clinical trial (AIII). For more
information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to
ambulate, and activity should be increased according to the patient’s tolerance.
Considerations in Pregnancy
Managing pregnant outpatients with COVID-19 is similar to managing nonpregnant patients (see
Special Considerations in Pregnancy). Clinicians should offer supportive care, take steps to reduce the

risk of SARS-CoV-2 transmission, and provide guidance on when to seek an in-person evaluation. The
American College of Obstetricians and Gynecologists (ACOG) has developed an algorithm to aid the
practitioner in evaluating and managing pregnant outpatients with laboratory-confirmed or suspected
COVID-19.23 ACOG has also published recommendations on how to use telehealth for prenatal care and
how to modify routine prenatal care when necessary to decrease the risk of SARS-CoV-2 transmission to
patients, caregivers, and staff.
In pregnant patients, SpO2 should be maintained at 95% or above on room air at sea level; therefore,
the threshold for monitoring pregnant patients in an inpatient setting may be lower than in nonpregnant
patients.24 In general, there are no changes to fetal monitoring recommendations in the outpatient setting,
and fetal management should be similar to the fetal management used for other pregnant patients with
medical illness.25 However, these monitoring strategies can be discussed on a case-by-case basis with
an obstetrician. Pregnant and lactating patients should be given the opportunity to participate in clinical
trials of outpatients with COVID-19 to help inform decision-making in this population.
Considerations in Children
Children and adolescents with acute COVID-19 are less likely than adults to require medical
intervention or hospitalization, and most can be managed in an ambulatory care setting or at home.
In general, the need for ED evaluation or hospitalization should be based on the patient’s vital signs,
physical exam findings (e.g., dyspnea), and risk factors for progression to severe illness. Certain
groups, including young infants, children with risk factors, and those with presentations that overlap
with multisystem inflammatory syndrome in children (MIS-C), may require hospitalization for more
intensive monitoring. However, this should be determined on a case-by-case basis.
Most children with mild or moderate COVID-19, even those with risk factors, will not progress to more
severe illness and will recover without specific therapy (see Special Considerations in Children). There
is insufficient evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2
monoclonal antibody products in nonhospitalized children with COVID-19 who have risk factors for
severe disease. The available efficacy data for adults suggests that anti-SARS-CoV-2 monoclonal
antibody products may be considered for use in children who meet the Food and Drug Administration
Emergency Use Authorization (EUA) criteria, especially those who have more than 1 risk factor. The
decision to use these products in children should be made on a case-by-case basis in consultation with a
pediatric infectious disease specialist. The risk factors that predict progression to severe disease in adults
can be used to determine the risk of progression in children aged ≥16 years.
In general, pediatric patients should not continue receiving remdesivir, dexamethasone, or other
COVID-19-directed therapies following discharge from an ED or an inpatient setting. Clinicians should
refer to Special Considerations in Children for more information on the management of children with
COVID-19.
References
1. Centers for Medicare & Medicaid Services. CMS announces comprehensive strategy to enhance hospital
capacity amid COVID-19 surge. 2020. Available at: https://www.cms.gov/newsroom/press-releases/cms-
announces-comprehensive-strategy-enhance-hospital-capacity-amid-covid-19-surge. Accessed December 13,
2021.
2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States,
January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69. Available at:
https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6924e2-H.pdf.
3. Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with

confirmed coronavirus disease (COVID-19). 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/
hcp/clinical-guidance-management-patients.html. Accessed December 13, 2021.
4. Centers for Disease Control and Prevention. COVID-19: how to protect yourself & others. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed December 13,
2021.
5. Centers for Disease Control and Prevention. COVID-19: if you are sick or caring for someone. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/. Accessed December 13, 2021.
6. Cheng A, Caruso D, McDougall C. Outpatient management of COVID-19: rapid evidence review. Am Fam
Physician. 2020;102(8):478-486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33064422.
7. Morrow-Howell N, Galucia N, Swinford E. Recovering from the COVID-19 pandemic: a focus on older
adults. J Aging Soc Policy. 2020;32(4-5):526-535. Available at:
8. Centers for Disease Control and Prevention. Coronavirus self-checker. 2021. Available at: https://www.cdc.
gov/coronavirus/2019-ncov/symptoms-testing/coronavirus-self-checker.html. Accessed December 13, 2021.
9. Burkett E, Carpenter CR, Hullick C, Arendts G, Ouslander JG. It’s time: delivering optimal emergency care of
residents of aged care facilities in the era of COVID-19. Emerg Med Australas. 2021;33(1):131-137. Available
10. Close RM, Stone MJ. Contact tracing for native americans in rural Arizona. N Engl J Med. 2020;383(3):e15.
11. Centers for Disease Control and Prevention. COVID-19: what to do if you are sick. 2020. Available at: https://
www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/steps-when-sick.html. Accessed December 13, 2021.
12. Centers for Disease Control and Prevention. COVID-19: isolate if you are sick. 2021. Available at: https://
www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/isolation.html. Accessed December 13, 2021.
13. Cohen PA, Hall LE, John JN, Rapoport AB. The early natural history of SARS-CoV-2 infection: clinical
observations from an urban, ambulatory COVID-19 clinic. Mayo Clin Proc. 2020;95(6):1124-1126. Available
14. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-
infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. Available at:
15. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in
Washington state. JAMA. 2020;323(16):1612-1614. Available at:
16. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia
in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-
17. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home. Potential pitfalls
and practical guidance. Ann Am Thorac Soc. 2020;17(9):1040-1046. Available at:
18. Sjoding MW, Dickson RP, Iwashyna TJ, Gay SE, Valley TS. Racial bias in pulse oximetry measurement. N
Engl J Med. 2020;383(25):2477-2478. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33326721.
19. Modi A, Kiroukas R, Scott JB. Accuracy of smartphone pulse oximeters in patients visiting an outpatient
pulmonary function lab for a 6-minute walk test. Respir Care. 2019;64(Suppl 10). Available at:
http://rc.rcjournal.com/content/64/Suppl_10/3238714.
20. Tarassenko L, Greenhalgh T. Question: should smartphone apps be used clinically as oximeters? Answer: no.
2020. Available at: https://www.cebm.net/covid-19/question-should-smartphone-apps-be-used-as-oximeters-
answer-no/. Accessed December 13, 2021.

21. Jordan TB, Meyers CL, Schrading WA, Donnelly JP. The utility of iPhone oximetry apps: a comparison with
standard pulse oximetry measurement in the emergency department. Am J Emerg Med. 2020;38(5):925-928.
22. Meyer GS, Blanchfield BB, Bohmer RMJ, Mountford MB, Vanderwagen WC. Alternative care sites for the
COVID-19 pandemic: the early U.S. and U.K. experience. NEJM Catalyst. 2020. Available at:
https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0224.
23. The American College of Obstetricians and Gynecologists. Outpatient assessment and management for
pregnant women with suspected or confirmed novel coronavirus (COVID-19). 2020. Available at:
https://www.smfm.org/covid19/. Accessed December 13, 2021.
24. The American College of Obstetricians and Gynecologists. COVID-19 FAQs for obstetrician-gynecologists,
obstetrics. 2020. Available at: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-
gyns-obstetrics. Accessed December 13, 2021.
COVID_pos_preg_patients_4-30-20_final.pdf.

Therapeutic Management of Nonhospitalized
Adults With COVID-19
Several therapeutic options are now available to treat nonhospitalized adults with mild to moderate COVID-19
who are at high risk of disease progression. Several factors affect the selection of the best treatment option
for a specific patient. These factors include the clinical efficacy and availability of the treatment option, the
feasibility of administering parenteral medications (i.e., remdesivir), the potential for significant drug-drug
interactions (e.g., those associated with the use of ritonavir-boosted nirmatrelvir [Paxlovid]), and the regional
prevalence of variants of concern (e.g., the regional prevalence of the Omicron BA.2 subvariant may affect
which anti-SARS-CoV-2 monoclonal antibodies [mAbs] can be used for treatment).
Table 2a outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for using these
therapeutic interventions outside the hospital inpatient setting.
Table 2a. Therapeutic Management of Nonhospitalized Adults With COVID-19
Patient Disposition Panel’s Recommendations

For All Patients:
• All patients should be offered symptomatic management (AIII).
• The Panel recommends against the use of dexamethasonea or other
systemic corticosteroids in the absence of another indication (AIIb).
For Patients Who Are at High Risk of Progressing to Severe COVID-19b
Preferred therapies. Listed in order of preference:
Does Not Require Hospitalization or
Supplemental Oxygen • Ritonavir-boosted nirmatrelvir (Paxlovid)c,d (AIIa)
• Remdesivird,e (BIIa)
Alternative therapies. For use ONLY when neither of the preferred therapies
are available, feasible to use, or clinically appropriate. Listed in alphabetical
order:
• Bebtelovimabf (CIII)
• Molnupiravird,g (CIIa)
Discharged From Hospital Inpatient
The Panel recommends against continuing the use of remdesivir (AIIa),
Setting in Stable Condition and Does Not
dexamethasonea (AIIa), or baricitinib (AIIa) after hospital discharge.
Discharged From Hospital Inpatient Setting
and Requires Supplemental Oxygen There is insufficient evidence to recommend either for or against the
For those who are stable enough for continued use of remdesivir or dexamethasone.
discharge but still require oxygen h
The Panel recommends using dexamethasone 6 mg PO once daily for the

Discharged From ED Despite New or duration of supplemental oxygen (dexamethasone use should not exceed
Increasing Need for Supplemental Oxygen 10 days) with careful monitoring for AEs (BIII).
When hospital resources are limited, Because remdesivir is recommended for patients with similar oxygen needs
inpatient admission is not possible, and who are hospitalized,j clinicians may consider using it in this setting. As
close follow-up is ensured i remdesivir requires IV infusions for up to 5 consecutive days, there may be
logistical constraints to administering remdesivir in the outpatient setting.

a
T here is currently a lack of safety and efficacy data on the use of dexamethasone in outpatients with COVID-19. Using
systemic glucocorticoids in this setting may cause harm.
b
COVID-19.
c
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions. Clinicians should carefully review a patient’s
concomitant medications and evaluate potential drug-drug interactions. See Drug-Drug Interactions Between Ritonavir-
Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications for more information.
d
If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the health care
provider’s discretion.
e
Administration of remdesivir requires 3 consecutive days of IV infusion.
f
Bebtelovimab is active in vitro against all circulating Omicron subvariants, but there are no clinical efficacy data from
placebo-controlled trials that evaluated the use of bebtelovimab in patients who are at high risk of progressing to severe
COVID-19. Therefore, bebtelovimab should be used only when the preferred treatment options are not available, feasible
to use, or clinically appropriate.
g
Molnupiravir has lower efficacy than the preferred treatment options. Therefore, it should be used only when the
preferred options are not available, feasible to use, or clinically appropriate.
h
These individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse services, or
in-person visits.
i
Provide an advanced level of home care, including supplemental oxygen (whether patients are receiving oxygen for the
first time or are increasing their baseline oxygen requirements), pulse oximetry, laboratory monitoring, and close follow-
up through telehealth, visiting nurse services, or in-person visits.
j
See Therapeutic Management of Hospitalized Adults With COVID-19.
Key: AE = adverse event; CDC = Centers for Disease Control and Prevention; ED = emergency department; IV =
intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PO = orally
Patient Prioritization for Treatment

When there are no logistical or supply constraints, the Panel recommends prescribing therapies for
the treatment of COVID-19 for any eligible individual as recommended in these Guidelines. During
surges in cases of SARS-CoV-2 infection, logistical or supply constraints may make it impossible to
offer available therapeutics to all the nonhospitalized patients who are eligible to receive them. In these
situations, the Panel recommends prioritizing the treatment of patients who are at the highest risk of
clinical progression (see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention
of COVID-19 When There Are Logistical or Supply Constraints).
Table 2b. Dosing Regimens for the Drugs Listed in Table 2a
Drug Name Dosing Regimen Time From Symptom Onseta
eGFR ≥60 mL/min: ≤5 days
• Nirmatrelvir 300 mg with RTV 100 mg PO twice daily for 5 days
eGFR ≥30 to <60 mL/min:
Ritonavir-
Boosted • Nirmatrelvir 150 mg with RTV 100 mg PO twice daily for 5 days
Nirmatrelvir eGFR <30 mL/min:
(Paxlovid)
• Not recommended
Severe Hepatic Impairment (Child-Pugh Class C):
• Not recommended
RDV 200 mg IV on Day 1, followed by RDV 100 mg IV once daily on ≤7 days
Days 2 and 3.b,c Each infusion should be administered over 30–120
Remdesivir
minutes. Patients should be observed for ≥1 hour after infusion as
clinically appropriate.

Table 2b. Dosing Regimens for the Drugs Listed in Table 2a, continued
Drug Name Dosing Regimen Time From Symptom Onseta
BEB 175 mg as a single IV injection, administered over ≥30 seconds. ≤7 days
Bebtelovimab
Patients should be observed for ≥1 hour after injection.
Molnupiravir Molnupiravir 800 mg PO twice daily for 5 days ≤5 days
a
Per EUA criteria or clinical trial entry criteria.
b
See the Remdesivir section for a discussion of RDV use in patients with renal impairment.
c
If RDV is administered to patients who have a new or increasing need for supplemental oxygen but who are discharged
from the ED because hospital resources are limited and inpatient admission is not possible, the total duration of therapy
is ≤5 days.
Key: BEB = bebtelovimab; ED = emergency department; eGFR = estimated glomerular filtration rate; EUA = Emergency
Use Authorization; IV = intravenous; PO = orally; RDV = remdesivir; RTV = ritonavir
Symptom Management
Symptomatic treatment includes using over-the-counter antipyretics, analgesics, or antitussives for fever,
headache, myalgias, and cough. Patients with dyspnea may benefit from resting in the prone position
rather than the supine position.1 Health care providers should consider educating patients about breathing
exercises, as severe breathlessness may cause anxiety.2 Patients should be advised to drink fluids
regularly to avoid dehydration. Rest is recommended as needed during the acute phase of COVID-19, and
ambulation and other forms of activity should be increased according to the patient’s tolerance. Patients
should be educated about the variability in time to symptom resolution and complete recovery.
Rationale for the Use of Specific Agents Listed in Table 2a

The Panel’s recommendations for the therapeutics that are used to treat nonhospitalized patients with
mild to moderate COVID-19 who are at risk of clinical progression are based on the results of clinical
trials for the antiviral drugs (ritonavir-boosted nirmatrelvir, remdesivir, and molnupiravir) and on
laboratory assessments of the activity of the anti-SARS-CoV-2 mAb bebtelovimab.
Several factors affect the selection of the best treatment option for a specific patient. These factors
include the clinical efficacy of the treatment option against circulating variants, the availability of the
treatment option, the feasibility of administering parenteral medications (i.e., remdesivir, bebtelovimab),
and the potential for significant drug-drug interactions (i.e., the interactions associated with using
ritonavir-boosted nirmatrelvir).
The Panel recommends ritonavir-boosted nirmatrelvir and remdesivir as preferred therapy options
because Phase 3 randomized placebo-controlled trials have reported high clinical efficacies for these
agents in patients with COVID-19.3,4 The Panel favors the use of ritonavir-boosted nirmatrelvir in most
high-risk, nonhospitalized patients with mild to moderate COVID-19. If ritonavir-boosted nirmatrelvir
is not available or cannot be used because of drug-drug interactions, the Panel recommends using
remdesivir as the second option.
The Panel recommends bebtelovimab and molnupiravir as alternative therapy options. These drugs
should ONLY be used when neither of the preferred treatment options are available, feasible to
use, or clinically appropriate. The Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for bebtelovimab based on in vitro data that showed that bebtelovimab has activity
against all circulating Omicron subvariants and clinical efficacy data from a small, Phase 2 clinical trial
in individuals with mild to moderate COVID-19 who were at low risk of disease progression.5 However,
there are no Phase 3 clinical trial data for bebtelovimab. Molnupiravir had lower clinical efficacy in

Phase 3 clinical trials than the preferred treatment options.
The Panel previously recommended the anti-SARS-CoV-2 mAb sotrovimab as a treatment option for
certain nonhospitalized patients with COVID-19. However, sotrovimab, which is active against the
Omicron BA.1 and BA.1.1 subvariants, has substantially decreased in vitro activity against the Omicron
BA.2 subvariant.6-8 The distribution of sotrovimab has been paused, and the Panel no longer recommends
using sotrovimab to treat COVID-19.
There are currently no clinical trial data that directly compare the clinical efficacies of the 4
recommended therapies, and there are no data on the use of combinations of antiviral agents and/
or anti-SARS-CoV-2 mAbs for the treatment of COVID-19. The rationale for each of the Panel’s
recommendations is discussed below.
Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that
plays an essential role in viral replication by cleaving the 2 viral polyproteins.9 It has demonstrated
antiviral activity against all coronaviruses that are known to infect humans.10 Nirmatrelvir is packaged
with ritonavir (as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic
boosting agent. Ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic range.
Recommendations
• The Panel recommends using nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally (PO)
twice daily for 5 days in those aged ≥12 years and weighing ≥40 kg; treatment should be initiated
as soon as possible and within 5 days of symptom onset (AIIa).
• Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due to
the ritonavir component of the combination.
• Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medications and herbal supplements, to
evaluate potential drug-drug interactions.
• A quick reference guide is also provided in Drug-Drug Interactions Between Ritonavir-Boosted
Nirmatrelvir (Paxlovid) and Concomitant Medications. The FDA EUA fact sheet for ritonavir-
boosted nirmatrelvir, the Liverpool COVID-19 Drug Interactions website, and guidance from
the Ontario COVID-19 Science Advisory Table should also be utilized to identify and manage
drug-drug interactions.
In the EPIC-HR trial, ritonavir-boosted nirmatrelvir reduced the risk of hospitalization or death by 88%
compared to placebo in nonhospitalized adults with laboratory-confirmed SARS-CoV-2 infection.3,11 This
efficacy is comparable to the efficacies reported in similar patient populations for remdesivir (87% relative
reduction)4 and greater than the efficacy reported for molnupiravir in this setting (30% relative reduction).12
Ritonavir-boosted nirmatrelvir is expected to be active against all Omicron subvariants, although
clinical efficacy data are lacking.13-15 Because ritonavir-boosted nirmatrelvir has the potential for
significant drug-drug interactions with concomitant medications, this regimen may not be a safe choice
for all patients (see Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir [Paxlovid] and
Concomitant Medications). However, because ritonavir-boosted nirmatrelvir is the only highly effective
oral antiviral available for the treatment of COVID-19, drug-drug interactions that can be safely managed
should not preclude the use of this medication.
Case reports and results from the EPIC-HR trial have described SARS-CoV-2 viral rebound and the
recurrence of COVID-19 symptoms in some patients who have completed treatment with ritonavir-
boosted nirmatrelvir.16,17 Viral and symptomatic rebound can also occur in the absence of treatment with

ritonavir-boosted nirmatrelvir.18 The frequency, mechanism, and clinical implications of these events
are unclear. To date, recurrence of symptoms following the use of ritonavir-boosted nirmatrelvir has not
been associated with progression to severe COVID-19.18-20 Longer treatment courses of ritonavir-boosted
nirmatrelvir are not authorized based on the current EUA, and there are insufficient data on the efficacy
of administering a second course.20
The EPIC-HR trial excluded pregnant and lactating individuals. Ritonavir has been used extensively
during pregnancy in people with HIV, which suggests that it has an acceptable safety profile during
pregnancy. Based on the mechanisms of action for both nirmatrelvir and ritonavir and the available
animal data, the Panel recommends ritonavir-boosted nirmatrelvir for pregnant patients because the
potential benefits likely outweigh the risks.
Remdesivir
Remdesivir is currently approved by the FDA for use in hospitalized patients with COVID-19 and in
nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression.
Remdesivir has been studied in nonhospitalized patients with mild to moderate COVID-19 who were
at high risk of progressing to severe disease. The PINETREE trial showed that 3 consecutive days of
intravenous (IV) remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death
compared to placebo.4 Remdesivir is expected to be active against the Omicron variant, although in vitro
and in vivo data are currently limited.15 See Remdesivir for more information.
Recommendations
• The Panel recommends using remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg
IV once daily on Days 2 and 3 in those aged ≥12 years and weighing ≥40 kg; treatment should be
initiated as soon as possible and within 7 days of symptom onset (BIIa).
• Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for
at least 1 hour after infusion as clinically appropriate.
Because remdesivir requires IV infusions for 3 consecutive days, there may be logistical constraints to
administering remdesivir in many settings. However, it is an option if ritonavir-boosted nirmatrelvir is
not available.
The Panel recommends using remdesivir, dexamethasone, or both drugs together in hospitalized
patients who require supplemental oxygen (see Therapeutic Management of Hospitalized Adults With
COVID-19). When remdesivir is used in this setting, it is administered as a once-daily IV infusion for 5
days. There are rare instances when hospital resources are limited and admission to an inpatient unit is
not possible for patients who need to initiate supplemental oxygen in the emergency department (ED)
or who have increasing supplemental oxygen requirements. In these cases, patients may be discharged
from the ED with close monitoring and are often prescribed dexamethasone for up to 10 days. Since
remdesivir is often recommended for hospitalized patients with COVID-19 who have similar oxygen
needs, clinicians can consider using it in this setting. However, it should be noted that the data on using
remdesivir in this situation are limited and administering IV infusions for up to 5 consecutive days can
be difficult in the outpatient setting.
Bebtelovimab
Bebtelovimab is a recombinant neutralizing human mAb that binds to the spike protein of SARS-CoV-2.
In vitro data suggest that bebtelovimab has activity against a broad range of SARS-CoV-2 variants,
including the Omicron variant and its BA.1, BA.1.1, and BA.2 subvariants.7,21 However, to date, the
clinical trial data for bebtelovimab come from a single Phase 2 randomized placebo-controlled trial in

patients with COVID-19 who were at low risk of progressing to severe disease. The trial showed no
unexpected safety events, and patients who received bebtelovimab had more rapid viral decay than those
who received the placebo.
Recommendations
• The Panel recommends using bebtelovimab 175 mg IV in those aged ≥12 years ONLY when
ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to use, or
clinically appropriate; treatment should be initiated as soon as possible and within 7 days of
symptom onset (CIII).
• Bebtelovimab should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for
at least 1 hour after infusion.
Although there are insufficient data on hospitalization and mortality outcomes for patients with
COVID-19 who were at high risk of disease progression and who received bebtelovimab, this agent
has a mechanism of action that is similar to other anti-SARS-CoV-2 mAbs that have been shown to
reduce rates of hospitalization or death among high-risk patients in Phase 3 trials. Therefore, the in vitro
data and Phase 2 clinical trial data for bebtelovimab, coupled with the clinical efficacy data for other
anti-SARS-CoV-2 mAbs, support the use of bebtelovimab in high-risk patients with COVID-19 when
preferred treatment options are not available, feasible to use, or clinically appropriate.
Molnupiravir
Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad
antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results
in viral mutations and lethal mutagenesis.22,23
Molnupiravir has potent antiviral activity against SARS-CoV-2.23 As a mutagenic ribonucleoside
antiviral agent, there is a theoretical risk that molnupiravir will be metabolized by the human host cell
and incorporated into the host DNA, leading to mutations. Molnupiravir has been evaluated in 2 in
vivo rodent mutagenicity assays. One study produced equivocal results; in the other study, there was
no evidence for mutagenicity. The FDA concluded that, based on the available genotoxicity data and
the 5-day duration of treatment, molnupiravir has a low risk for genotoxicity.24 In addition, there have
been concerns about the potential effects of molnupiravir on SARS-CoV-2 mutation rates; the FDA is
requiring the manufacturer to establish a process to monitor genomic databases for the emergence of
SARS-CoV-2 variants.
Molnupiravir is expected to be active against the Omicron variant, although in vitro and in vivo data are
currently limited.15
Recommendation
• The Panel recommends using molnupiravir 800 mg PO twice daily for 5 days in those aged ≥18
years ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available,
feasible to use, or clinically appropriate (CIIa).
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to
placebo in nonhospitalized patients with COVID-19.12,24 Even though the different treatment options
have not been directly compared in clinical trials, the Panel recommends using molnupiravir only when
ritonavir-boosted nirmatrelvir and remdesivir are not available or cannot be used, because molnupiravir
has lower efficacy than the other options.
The FDA EUA states that molnupiravir is not recommended for use in pregnant patients due to concerns

about the instances of fetal toxicity observed during animal studies. However, when other therapies are
not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease
may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly if they
are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should
document that a discussion of the risks and benefits occurred and that the patient chose this therapy.
People who engage in sexual activity that may result in conception should use effective contraception
during and following treatment with molnupiravir.
Dexamethasone
For Nonhospitalized Patients With Mild to Moderate COVID-19
The Panel recommends against the use of dexamethasone or other systemic glucocorticoids to
treat outpatients with mild to moderate COVID-19 who do not require hospitalization or supplemental
oxygen (AIIb). However, patients who are receiving dexamethasone or another corticosteroid for
other indications should continue therapy for their underlying conditions as directed by their health care
providers (AIII).
Medicare and FDA data show a significant increase in the number of prescriptions for systemic
corticosteroids among nonhospitalized patients with COVID-1925 despite a lack of safety and efficacy
data on the use of systemic corticosteroids in this setting. Systemic glucocorticoids may cause
harm in nonhospitalized patients with COVID-19. Results from 1 randomized controlled trial and 1
observational cohort study did not demonstrate a clinical benefit of dexamethasone among hospitalized
patients who did not require supplemental oxygen,26 and dexamethasone may potentially cause harm in
these patients.27 In the RECOVERY trial, the use of dexamethasone had no effect on mortality among
hospitalized patients with COVID-19 who did not require supplemental oxygen (rate ratio 1.19; 95% CI,
0.91–1.55).26 A large observational study of patients at Veterans Affairs hospitals reported no survival
benefit for dexamethasone among patients with COVID-19 who did not require supplemental oxygen.
Instead, these patients had an increased risk of 90-day mortality (HR 1.76; 95% CI, 1.47–2.12).27
However, hospitalized patients with COVID-19 are likely to have an increased risk of mortality
compared to nonhospitalized patients, which is a limitation of observational trial data.
See Table 6a for more information on the clinical trials that evaluated the use of corticosteroids,
including dexamethasone.
For Patients Who Are Discharged From the Hospital and Do Not Require Supplemental Oxygen
During the RECOVERY trial, dexamethasone was stopped at the time of hospital discharge. For
hospitalized patients with COVID-19 who do not require supplemental oxygen after discharge, the Panel
recommends against the continuation of dexamethasone (AIIa).
For Patients Who Are Discharged From the Hospital and Require Supplemental Oxygen
In some cases, adult patients are deemed to be stable enough to be discharged from the inpatient
setting even though they still require supplemental oxygen. This practice was likely uncommon during
the RECOVERY trial; therefore, there is insufficient evidence for the Panel to recommend either
for or against the continued use of dexamethasone after hospital discharge in patients who require
supplemental oxygen. The use of corticosteroids can lead to adverse events (e.g., hyperglycemia,
neuropsychiatric symptoms, secondary infections), which may be difficult to detect and monitor in an
outpatient setting. If a patient continues to receive corticosteroids after discharge, consider continuing
corticosteroids for the duration of supplemental oxygen. However, the total duration of corticosteroid
use should not exceed 10 days (including days during hospitalization). Only patients who showed good
tolerance to this therapy prior to discharge should continue to receive corticosteroids after discharge.

These patients should receive oximetry monitoring and close follow-up through telehealth, visiting nurse
services, or in-person visits.
For Patients Who Require Hospitalization and Supplemental Oxygen but Were Discharged From
the Emergency Department Due to Scarce Resources
In rare cases, patients with COVID-19 who require supplemental oxygen and hospital admission may
need to be discharged from the ED due to scarce resources (e.g., in cases where hospital beds or staff
are not available). For these patients, the Panel recommends using dexamethasone 6 mg PO once daily
for the duration of supplemental oxygen (dexamethasone use should not exceed 10 days) with careful
monitoring for adverse events (BIII). These patients should receive oximetry monitoring and close
follow-up through telehealth, visiting nurse services, or in-person visits.
Other Agents That Have Been Studied or Are Under Investigation

• The Panel recommends against the use of chloroquine or hydroxychloroquine with or without
azithromycin (AI), lopinavir/ritonavir, and other HIV protease inhibitors (AIII) for the
outpatient treatment of COVID-19.
• The Panel recommends against the use of antibacterial therapy (e.g., azithromycin,
doxycycline) for the outpatient treatment of COVID-19 in the absence of another indication (AIII).
• Other agents have undergone or are currently undergoing investigation in the outpatient setting.
For more information, please refer to the sections of the Guidelines that address:
• Antiviral agents, such as ivermectin
• Convalescent plasma
• Immunomodulators, such as colchicine, fluvoxamine, and inhaled corticosteroids
• Supplements, such as vitamin C, vitamin D, and zinc
• The Panel recommends against the use of anticoagulants and antiplatelet therapy for the
prevention of venous thromboembolism or arterial thrombosis unless the patient has other
indications for the therapy or is participating in a clinical trial (AIIa). For more information, see
Antithrombotic Therapy in Patients With COVID-19.
• Health care providers should provide information about ongoing clinical trials of investigational
therapies to eligible outpatients with COVID-19 so they can make informed decisions about
participation (AIII).
Concomitant Medication Management

In general, a patient’s usual medication and/or supplement regimen should be continued after the diagnosis
of COVID-19 (see Considerations for Using Concomitant Medications in Patients With COVID-19).
Angiotensin-converting enzyme inhibitors, statin therapy, nonsteroidal anti-inflammatory drugs,
and oral, inhaled, and intranasal corticosteroids that are prescribed for comorbid conditions should be
continued as directed (AIII). Patients should be advised to avoid the use of nebulized medications in the
presence of others to avoid potential aerosolization of SARS-CoV-2.28 In patients with HIV, antiretroviral
therapy should not be switched or adjusted for the purpose of preventing or treating SARS-CoV-2
infection (AIII). For more information, see Special Considerations in People With HIV.
When a patient is receiving an immunomodulating medication, the prescribing clinician should
be consulted about the risks and benefits that are associated with a temporary dose reduction or
discontinuation. These risks and benefits will depend on the medication’s indication and the severity of
the underlying condition.

Use of Concomitant Medications With Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Ritonavir-boosted nirmatrelvir has the potential for significant and complex drug-drug interactions
with concomitant medications, primarily due to the ritonavir component of the combination.
Boosting with ritonavir, a strong CYP3A inhibitor, is required to increase the exposure of nirmatrelvir
to a concentration that is effective against SARS-CoV-2. However, ritonavir may also increase
concentrations of certain concomitant medications, thereby increasing the potential for serious and
sometimes life-threatening drug toxicities. Additionally, ritonavir is an inhibitor, inducer, and substrate
of various other drug-metabolizing enzymes and/or drug transporters.
Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medicines, herbal supplements, and recreational
drugs. Clinicians should refer to resources such as the Liverpool COVID-19 Drug Interactions
website, Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant
Medications, and the FDA EUA fact sheet for ritonavir-boosted nirmatrelvir for guidance regarding
potential drug-drug interactions.
References
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department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-
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Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of
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3. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with
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4. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in
outpatients. N Engl J Med. 2022;386(4):305-315. Available at:
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bebtelovimab. 2022. Available at: https://www.fda.gov/media/156152/download.
6. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of
sotrovimab. 2022. Available at: https://www.fda.gov/media/149534/download.
8. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron
subvariant BA.2. N Engl J Med. 2022;386(15):1475-1477. Available at:
9. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory
syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule
chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/26878082.
10. Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for
the treatment of COVID-19. Science. 2021;374(6575):1586-1593. Available at:
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2022. Available at: https://www.fda.gov/media/155050/download.

12. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of COVID-19 in
nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. Available at:
13. Greasley SE, Noell S, Plotnikova O, et al. Structural basis for the in vitro efficacy of nirmatrelvir against
SARS-CoV-2 variants. J Biol Chem. 2022:101972. Available at:
14. Rai DK, Yurgelonis I, McMonagle P, et al. Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of
SARS-CoV-2 variants of concern. bioRxiv. 2022;Preprint. Available at:
15. Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against
SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252. Available at:
16. Charness M, Gupta K, Stack G, et al. Rapid relapse of symptomatic Omicron SARS-CoV-2 infection
following early suppression with nirmatrelvir/ritonavir. Research Square. 2022;Preprint. Available at:
https://www.researchsquare.com/article/rs-1588371/v2.
17. Food and Drug Administration. Emergency use authorization (EUA) for Paxlovid (nirmatrelvir tablets
co-packaged with ritonavir tablets): Center for Drug Evaluation and Research (CDER) review. 2021. Available
at: https://www.fda.gov/media/155194/download.
18. Soares H, Baniecki ML, Cardin R, et al. Viral load rebound in placebo and nirmatrelvir-ritonavir treated
COVID-19 patients is not associated with recurrence of severe disease or mutations. Res Sq. 2022;Preprint.
Available at: https://www.researchsquare.com/article/rs-1720472/v1.
19. Ranganath N, O’Horo JC, Challener DW, et al. Rebound phenomenon after nirmatrelvir/ritonavir treatment of
coronavirus disease-2019 in high-risk persons. Clin Infect Dis. 2022. Available at:
20. Centers for Disease Control and Prevention. COVID-19 rebound after Paxlovid treatment. 2022. Available at:
https://emergency.cdc.gov/han/2022/han00467.asp. Accessed June 16, 2022.
21. Westendorf K, Zentelis S, Wang L, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2
variants. Cell Rep. 2022;39(7):110812. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35568025/.
22. Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol. 2021;28(9):740-746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34381216.
23. Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis
but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. Available at:
molnupiravir. 2022. Available at: https://www.fda.gov/media/155054/download.
25. Bradley MC, Perez-Vilar S, Chillarige Y, et al. Systemic corticosteroid use for COVID-19 in US outpatient
settings From April 2020 to August 2021. JAMA. 2022;327(20):2015-2018. Available at:
26. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with
27. Crothers K, DeFaccio R, Tate J, et al. Dexamethasone in hospitalised COVID-19 patients not on intensive
respiratory support. Eur Respir J. 2022;60(1):2102532. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/34824060.
28. Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19
pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.

Therapeutic Management of Hospitalized Adults With
COVID-19
Table 2c. Therapeutic Management of Hospitalized Adults With COVID-19 Based on Disease Severity
Recommendations for Antiviral or Immunomodulator Therapy Recommendations for Anticoagulant

Disease Severity
Clinical Scenario Recommendation Therapy
Patients with mild to moderate See Therapeutic Management of Nonhospitalized Adults With COVID-19. For patients without an indication for
Hospitalized for
COVID-19 who are at high therapeutic anticoagulation:
Reasons Other
risk of progressing to severe • Prophylactic dose of heparin,
Than COVID-19
COVID-19a unless contraindicated (AI); (BIII) for
Hospitalized All patients The Panel recommends against the use of dexamethasone (AIIa) or pregnant patients
but Does Not other systemic corticosteroids (AIII) for the treatment of COVID-19.b
Require Oxygen Patients who are at high risk of Remdesivirc (BIII)
Supplementation progressing to severe COVID-19a
Patients who require minimal Remdesivire (BIIa) For nonpregnant patients with D-dimer
conventional oxygen levels above the ULN who do not have
Hospitalized Most patients Use dexamethasone plus remdesivire (BIIa). If remdesivir cannot be an increased bleeding risk:
and Requires obtained, use dexamethasone (BI). • Therapeutic dose of heparing (CIIa)
Conventional Patients who are receiving Add PO baricitinibf or IV tocilizumabf to 1 of the options above (BIIa). For other patients:
Oxygend dexamethasone and who have • Prophylactic dose of heparin,
rapidly increasing oxygen needs unless contraindicated (AI); (BIII) for
and systemic inflammation pregnant patients
Most patients Promptly start 1 of the following, if not already initiated: For patients without an indication for
• Dexamethasone plus PO baricitinibf (AI) therapeutic anticoagulation:
Hospitalized and • Dexamethasone plus IV tocilizumabf (BIIa) • Prophylactic dose of heparin,
Requires HFNC unless contraindicated (AI); (BIII) for
If baricitinib, tofacitinib, tocilizumab, or sarilumab cannot be obtained: pregnant patients
Oxygen or NIV
For patients who are started on a
Add remdesivir to 1 of the options above in certain patients (CIIa).i therapeutic dose of heparin in a non-
Most patients Promptly start 1 of the following, if not already initiated: ICU setting and then transferred to the
• Dexamethasone plus PO baricitinib (BIIa)
f ICU, the Panel recommends switching
Hospitalized and
• Dexamethasone plus IV tocilizumab (BIIa) f to a prophylactic dose of heparin,
Requires MV or
unless there is another indication for
ECMO If baricitinib, tofacitinib, tocilizumab, or sarilumab cannot be obtained: therapeutic anticoagulation (BIII).

a
COVID-19.
b
Corticosteroids that are prescribed for an underlying condition should be continued.
c
Evidence suggests that the benefit of remdesivir is greatest when the drug is given early in the course of COVID-19 (e.g.,
within 10 days of symptom onset).
d
Conventional oxygen refers to oxygen supplementation that is not HFNC oxygen, NIV, MV, or ECMO.
e
If these patients progress to requiring HFNC oxygen, NIV, MV, or ECMO, the full course of remdesivir should still be
completed.
f
If PO baricitinib and IV tocilizumab are not available or not feasible to use, PO tofacitinib can be used instead of PO
baricitinib (BIIa), and IV sarilumab can be used instead of IV tocilizumab (BIIa).
g
Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 include a platelet count <50 x
109/L, Hgb <8 g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required an ED visit or
hospitalization, a history of a bleeding disorder, or an inherited or active acquired bleeding disorder.
h
If a JAK inhibitor or an anti-IL-6 receptor mAb is not readily available, start dexamethasone while waiting for the
additional immunomodulator to be acquired. If neither of the other immunomodulators can be obtained, use
dexamethasone alone.
i
Clinicians may consider adding remdesivir to 1 of the recommended immunomodulator combinations in patients who
require HFNC oxygen or NIV, including immunocompromised patients. The Panel recommends against the use of
remdesivir without immunomodulators in these patients (AIIa).
Key: CDC = Centers for Disease Control and Prevention; ECMO = extracorporeal membrane oxygenation; ED =
emergency department; HFNC = high-flow nasal cannula; Hgb = hemoglobin; ICU = intensive care unit; IL = interleukin;
IV = intravenous; JAK = Janus kinase; mAb = monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive
ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; PO = oral; ULN = upper limit of normal
Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course,
the disease is primarily driven by the replication of SARS-CoV-2. Later in the clinical course, the
disease appears to be also driven by a dysregulated immune/inflammatory response to SARS-CoV-2
infection that may lead to further tissue damage and thrombosis. Based on this understanding, therapies
that directly target SARS-CoV-2 are anticipated to have the greatest effect early in the course of the
disease, whereas immunosuppressive, anti-inflammatory, and antithrombotic therapies are likely to be
more beneficial after COVID-19 has progressed to stages characterized by hypoxemia and endothelial
dysfunction.
Below is a summary of the rationale for the COVID-19 Treatment Guidelines Panel’s (the Panel)
recommendations on the therapeutic management of hospitalized patients with COVID-19. For dosing
information for each of the recommended drugs, please refer to Table 2d below. For detailed information
regarding the therapies and evidence from clinical trials that support the Panel’s recommendations,
please refer to the specific drug pages and clinical data tables.
Patients Who Are Hospitalized for Reasons Other Than COVID-19 and Who Do Not
Hospitalized patients with COVID-19 who do not require supplemental oxygen are a heterogeneous
population. Some patients may be hospitalized for reasons other than COVID-19 but may also have mild
to moderate COVID-19 (see Clinical Spectrum of SARS-CoV-2 Infection). In these cases, patients who
are at high risk of progressing to severe COVID-19 may benefit from antiviral therapy.

Remdesivir has been approved by the Food and Drug Administration (FDA) for the treatment of
COVID-19 in adult and pediatric patients aged ≥12 years and weighing ≥40 kg, and several other
therapies have received FDA Emergency Use Authorizations for use in patients with mild to moderate
COVID-19 who are at high risk of progressing to severe disease. These therapies can be used in
hospitalized patients who qualify for therapy if they were admitted to the hospital for a diagnosis
other than COVID-19. The Panel’s recommendations for these patients are the same as those for
nonhospitalized patients (see Therapeutic Management of Nonhospitalized Adults With COVID-19).
Patients Who Are Hospitalized for COVID-19 and Who Do Not Require
Supplemental Oxygen
Recommendations
• The Panel recommends using remdesivir for the treatment of COVID-19 in patients who do not
require supplemental oxygen and who are at high risk of progressing to severe disease (BIII).
• Remdesivir should be administered for 5 days or until hospital discharge, whichever comes first.
The rationale for using remdesivir in this population is based on several lines of evidence. In a trial
conducted predominantly among hospitalized patients with COVID-19 who were not receiving
supplemental oxygen at enrollment, a 5-day course of remdesivir was associated with greater clinical
improvement, when compared with standard of care.1 Evidence from the PINETREE trial also suggests
that early therapy reduces the risk of progression, although that study was performed in high-risk,
unvaccinated, nonhospitalized patients with ≤7 days of symptoms.
Other studies have not shown a clinical benefit of remdesivir in this group of hospitalized patients with
COVID-19. In ACTT-1, remdesivir showed no significant benefit in hospitalized patients with mild to
moderate disease. However, only 13% of the study population did not require supplemental oxygen.
In the large Solidarity trial, the use of remdesivir was not associated with a survival benefit among
the subset of hospitalized patients who did not require supplemental oxygen. See Table 4a for more
information.
The aggregate data on using remdesivir to treat this population show a faster time to recovery in patients
who received remdesivir but no clear evidence of a survival benefit. Given the impact on reducing
progression, the Panel finds that the available data support a recommendation for using remdesivir in
hospitalized patients with COVID-19 who are at risk of progressing to severe disease. For information
on medical conditions that confer high risk, see the Centers for Disease Control and Prevention webpage
People With Certain Medical Conditions.
Recommendation
• The Panel recommends against the use of dexamethasone (AIIa) or other systemic
corticosteroids (AIII) for the treatment of COVID-19 in patients who do not require supplemental
oxygen.
In the RECOVERY trial, no survival benefit was observed for dexamethasone among the subset of
patients with COVID-19 who did not require supplemental oxygen at enrollment.2 In an observational
cohort study of U.S. veterans, the use of dexamethasone was associated with higher mortality in
hospitalized patients with COVID-19 who did not require supplemental oxygen.3
There are no data to support the use of other systemic corticosteroids in hospitalized patients with
COVID-19. However, patients who are receiving corticosteroid treatment for an underlying condition
should continue to receive corticosteroids. See Table 6a for more information.

Patients Who Require Conventional Oxygen
Patients with COVID-19 who require conventional oxygen (i.e., those who do not require high-flow
nasal cannula [HFNC] oxygen, noninvasive ventilation [NIV], or mechanical ventilation) are a
heterogeneous population. Although the oxygen requirement qualifies all these patients as having severe
disease, some of these patients will improve after a short period with or without treatment; others will
develop progressive disease. There is no consensus on which clinical or laboratory parameters should be
used to determine a patient’s risk of progression and guide therapy.
Recommendation
• For patients with COVID-19 who only require minimal conventional oxygen, the Panel
recommends using remdesivir without dexamethasone (BIIa).
In these patients, the hyperinflammatory state for which corticosteroids might be most beneficial
may not yet be present or fully developed. In a subgroup analysis during the ACTT-1 trial, remdesivir
significantly reduced the time to clinical recovery and significantly reduced mortality among the subset
of patients who were receiving conventional oxygen at enrollment.4 Evidence from ACTT-1 suggests
that remdesivir will have its greatest benefit when administered early in the clinical course of COVID-19
(e.g., within 10 days of symptom onset). See Table 4a for more information.
Recommendations
• For most patients with COVID-19 who require conventional oxygen, the Panel recommends using
dexamethasone plus remdesivir (BIIa).
• If dexamethasone is not available, an equivalent dose of another corticosteroid (e.g., prednisone,
methylprednisolone, or hydrocortisone) may be used (BIII).
The results of several studies suggest that the use of remdesivir plus dexamethasone improves clinical
outcomes among hospitalized patients with COVID-19. In the CATCO trial, in which 87% of patients
received corticosteroids and 54% were on conventional oxygen, remdesivir significantly reduced the
need for mechanical ventilation among the subset of patients who did not require mechanical ventilation
at enrollment, when compared with standard of care.5 In the Solidarity trial, in which approximately
two-thirds of the patients received corticosteroids, remdesivir significantly reduced mortality among the
subset of patients who were receiving conventional or HFNC oxygen at enrollment.6 See Table 4a for
more information.
Recommendation
• If remdesivir is not available, the Panel recommends using dexamethasone alone in patients with
COVID-19 who require conventional oxygen (BI).
In the RECOVERY trial, dexamethasone significantly reduced mortality among the subset of patients
who were receiving oxygen (defined as receiving oxygen supplementation but not mechanical
ventilation or extracorporeal membrane oxygenation [ECMO]) at enrollment.2 Remdesivir was
administered to <1% of the study participants. Results for patients who were only receiving conventional
oxygen at enrollment were not available. See Table 6a for more information.
Recommendation
• The Panel recommends adding a second immunomodulatory drug (e.g., baricitinib or
tocilizumab) to dexamethasone in patients who have rapidly increasing oxygen needs and
systemic inflammation (BIIa).

Several large randomized trials evaluated the use of interleukin (IL)-6 inhibitors (e.g., tocilizumab,
sarilumab) or Janus kinase (JAK) inhibitors (e.g., baricitinib, tofacitinib) with or without corticosteroids
in patients with COVID-19.7-11 These studies included some patients who required conventional oxygen
only, as well as those with increasing oxygen needs and/or elevated levels of inflammatory markers.
Subgroup analyses in these trials have not clearly defined which patients in this heterogeneous group
are most likely to benefit from adding another immunomodulator to their corticosteroid regimens.
Nonetheless, some trials suggest that adding a second immunomodulator to dexamethasone provides
benefits to patients who require conventional oxygen, especially those with rapidly increasing oxygen
requirements and systemic inflammation. Because there are no studies that directly compare the use
of baricitinib and tocilizumab as treatments for COVID-19, the Panel has insufficient evidence to
recommend 1 drug over the other.
Use of Anticoagulants
• The Panel recommends using a therapeutic dose of heparin for nonpregnant patients with
D-dimer levels above the upper limit of normal who require conventional oxygen and who do not
have an increased bleeding risk (CIIa).
• Patients who do not meet the criteria for therapeutic heparin noted above, including pregnant
individuals, should receive a prophylactic dose of heparin, unless this drug is contraindicated
(AI); (BIII) for pregnant patients.
The Panel’s recommendations for the use of heparin are based on data from 3 open-label randomized
controlled trials that compared the use of therapeutic doses of heparin to prophylactic or intermediate
doses of heparin in hospitalized patients who did not require intensive care unit (ICU)-level care.
The multiplatform ATTACC/ACTIV-4a/REMAP-CAP trial reported more organ support-free days
for patients in the therapeutic heparin arm than in the usual care arm, but there was no difference
between the arms in mortality or length of hospitalization.12 The RAPID trial compared a therapeutic
dose of heparin to a prophylactic dose in hospitalized patients with moderate COVID-19. There was
no statistically significant difference between the arms in the occurrence of the primary endpoint
(which was a composite endpoint of ICU admission and initiation of NIV or mechanical ventilation),
but the therapeutic dose of heparin reduced 28-day mortality.13 In the HEP-COVID trial, venous
thromboembolism (VTE), arterial thromboembolism, and death by Day 30 occurred significantly
less frequently in patients who received a therapeutic dose of heparin than in those who received a
prophylactic dose of heparin, but there was no difference in mortality by Day 30 between the arms.14
Patients Who Require High-Flow Nasal Cannula Oxygen or Noninvasive Ventilation

In these patients, systemic inflammation contributes to hypoxemia as the predominant clinical feature,
and patients benefit from a second immunomodulator in addition to dexamethasone. There is no
consensus on which clinical or laboratory parameters reliably predict the risk of death or progression to
mechanical ventilation.
The available evidence suggests that the benefits of adding baricitinib or tocilizumab to dexamethasone
treatment outweigh the potential risks in patients with COVID-19 who require HFNC oxygen, NIV,
mechanical ventilation, or ECMO. Although the combination of dexamethasone and secondary
immunomodulating medications may increase the risk of opportunistic infections or the risk of
reactivating latent infections, there are insufficient data to make recommendations about initiating
prophylaxis against these infections.

Recommendations
• For most patients, the Panel recommends using 1 of the following combinations of
immunomodulators:
• Dexamethasone plus oral (PO) baricitinib (AI); or
• Dexamethasone plus intravenous (IV) tocilizumab (BIIa)
Several large randomized controlled trials have demonstrated that these patients benefit from combining
dexamethasone with an additional immunomodulator, such as an IL-6 inhibitor (e.g., tocilizumab,
sarilumab) or a JAK inhibitor (e.g., baricitinib, tofacitinib). See Table 6c and Table 6d for more
information.
The use of baricitinib plus dexamethasone was associated with a survival benefit among hospitalized
patients with COVID-19 in the RECOVERY trial. The treatment effect was most pronounced among
patients who were receiving HFNC oxygen or NIV.11 The COV-BARRIER trial also demonstrated a
survival benefit of baricitinib that was most pronounced among patients who were receiving HFNC
oxygen or NIV.10 Data from the ACTT-29 and ACTT-415 trials support the overall safety of baricitinib
and the potential for a clinical benefit, but neither trial studied baricitinib in combination with
dexamethasone as the standard of care.
In the REMAP-CAP trial, the use of tocilizumab in combination with corticosteroids reduced
in-hospital mortality in patients with rapid respiratory decompensation who were admitted to the ICU.16
Similar results were reported during the RECOVERY trial.7 However, patients were only selected for
randomization into the tocilizumab arm during the RECOVERY trial if they had oxygen saturation
<92% on room air and C-reactive protein levels ≥75 mg/L. These factors put them at higher risk of
clinical progression. Both REMAP-CAP and RECOVERY evaluated the efficacy of adding tocilizumab
to standard care; in both cases, standard care included dexamethasone therapy. Other randomized trials
that have evaluated the use of tocilizumab have demonstrated mixed results, including a lack of benefit
when tocilizumab was administered without dexamethasone as part of standard care.
Combinations of 3 immunomodulators (e.g., dexamethasone plus baricitinib plus tocilizumab) have not
been studied in clinical trials. Although some patients in the baricitinib arm of the RECOVERY trial also
received tocilizumab, data from the study are insufficient to issue a recommendation. When both agents
are used, a potential for additive risk of secondary infections remains.11
In summary, the clinical trials data cited above informed the Panel’s recommendations for adding a
second immunomodulator to dexamethasone in hospitalized patients who require HFNC oxygen or NIV.
The quality of the evidence and the totality of the data support a stronger recommendation for baricitinib
than tocilizumab. See Table 6c and Table 6d for more information.
Recommendation
• If PO baricitinib and IV tocilizumab are not available or not feasible to use, PO tofacitinib can
be used instead of PO baricitinib (BIIa), and IV sarilumab can be used instead of IV tocilizumab
(BIIa).
When neither baricitinib nor tocilizumab is available or feasible to use, the JAK inhibitor tofacitinib
or the IL-6 inhibitor sarilumab may be used as alternative agents for baricitinib or tocilizumab,
respectively. Tofacitinib decreased the risk for respiratory failure or death in the STOP-COVID trial,17
and sarilumab reduced mortality and the duration of organ support to the same degree as tocilizumab in
the REMAP-CAP trial.8

Recommendation
• The Panel recommends using dexamethasone alone if baricitinib, tofacitinib, tocilizumab, or
sarilumab cannot be obtained (AI).
Significant effort should be made to obtain baricitinib, tofacitinib, tocilizumab, or sarilumab.
Dexamethasone should be initiated immediately, without waiting until the second immunomodulator can
be acquired. Dexamethasone was used as a single-agent immunomodulatory strategy in the RECOVERY
trial and demonstrated a survival benefit among patients who required supplemental oxygen.2 At the
time of the trial, the treatment effect for dexamethasone could not be evaluated separately for those who
required conventional oxygen and those who required HFNC oxygen or NIV (see Corticosteroids).
Recommendation
• For hospitalized patients who require HFNC oxygen or NIV and have certain medical conditions,
the Panel recommends adding remdesivir to 1 of the recommended immunomodulator
combinations (CIIa).
Although clinical trial data have not established a clear benefit of using remdesivir in patients who
require HFNC oxygen or NIV, the Panel’s recommendation reflects the balance of 2 factors. First, given
that these patients are routinely treated with 2 immunomodulators to prevent or mitigate inflammatory-
mediated injury, these treatments may impair the patient’s antiviral response, and directly treating the
virus with remdesivir may help improve outcomes. In this context, some Panel members would add
remdesivir to treatments for immunocompromised patients who require HFNC oxygen or NIV. In
addition, clinicians may extend the course of remdesivir beyond 5 days in this population based on
clinical response. In the Solidarity trial, remdesivir had a modest but statistically significant effect on
reducing the risk of death or progression to mechanical ventilation; however, these effects could not be
evaluated separately for patients who required conventional oxygen supplementation and those who
required HFNC oxygen or NIV.18 See Table 4a for more information.
Recommendation
• The Panel recommends against the use of remdesivir without immunomodulators in hospitalized
patients who require HFNC oxygen or NIV (AIIa).
In the ACTT-1 trial, hospitalized patients with COVID-19 received remdesivir or placebo without
immunomodulators. In the subgroup of 193 patients who required high-flow oxygen or NIV at
enrollment, there was no difference in time to recovery between patients in the remdesivir arm and
patients in the placebo arm (recovery rate ratio 1.09; 95% CI, 0.76–1.57). A post hoc analysis did not
show a survival benefit for remdesivir at Day 29 (HR 1.02; 95% CI, 0.54–1.91).4
The Panel recommends against using remdesivir without immunomodulators in patients who require
HFNC oxygen or NIV because there is uncertainty regarding whether using remdesivir by itself confers
a clinical benefit in this subgroup. Patients who are taking remdesivir and then progress to requiring
HFNC oxygen or NIV should complete the course of remdesivir. If these patients are not already
receiving 1 of the recommended immunomodulator combinations as part of their treatment, they should
initiate immunomodulatory therapy.
• For patients without an indication for therapeutic anticoagulation, the Panel recommends using a
prophylactic dose of heparin as VTE prophylaxis, unless a contraindication exists (AI); (BIII)
for pregnant patients.

• For patients who are started on a therapeutic dose of heparin in a non-ICU setting for the
management of COVID-19 and then transferred to the ICU, the Panel recommends switching from
the therapeutic dose to a prophylactic dose of heparin, unless VTE is confirmed (BIII).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg once
daily) or a therapeutic dose of anticoagulation for VTE prophylaxis, except in a clinical trial
(BI).
The INSPIRATION trial compared the use of intermediate doses of anticoagulation to prophylactic doses
in adults who were admitted to the ICU with COVID-19. There was no difference between the arms in
the incidence of VTE, the incidence of arterial thrombosis, the need for ECMO, or all-cause mortality.19
The multiplatform randomized controlled trial REMAP-CAP/ACTIV-4a/ATTACC compared the
effectiveness of a therapeutic dose of heparin to standard care in critically ill patients with COVID-19.
The study did not show an increase in the number of organ support-free days or the probability of
survival to hospital discharge among patients who received therapeutic doses of anticoagulation.20 See
Antithrombotic Therapy in Patients With COVID-19 for more information.
Patients Who Require Mechanical Ventilation or Extracorporeal Membrane

Oxygenation
Recommendation
• The Panel recommends initiating dexamethasone plus PO baricitinib (BIIa) or dexamethasone
plus IV tocilizumab (BIIa) if not already initiated in patients with COVID-19 who require
mechanical ventilation or ECMO.
Clinical trials that have evaluated combining IL-6 inhibitors and JAK inhibitors with corticosteroids
for the treatment of patients with COVID-19 provide the most robust evidence for the Panel’s
recommendations.
Clinical trials of tocilizumab have reported an overall survival benefit in patients with hypoxemia and
signs of systemic inflammation (RECOVERY)7 and in patients who are critically ill and require organ
support (REMAP-CAP).16 Although these studies included patients who were receiving mechanical
ventilation at randomization, the studies were not specifically powered to assess the effectiveness of IL-6
inhibitors in these patients. Other studies of tocilizumab in critically ill patients did not find a survival
benefit, although the time between initiation of organ support in the ICU and study enrollment differed
across the studies (see Table 6c).21,22 The use of corticosteroids also varied across the studies.
An extension of the COV-BARRIER trial compared the efficacy of baricitinib to placebo in 101
critically ill patients with COVID-19. The study reported significant reductions in mortality (relative
reduction of 46% at 28 days and 44% at 60 days) and no major adverse events among patients who
received baricitinib.23 Systematic reviews of JAK inhibitors confirm the efficacy of using baricitinib in
hospitalized patients with COVID-19 who require oxygen support. There is a lower certainty of evidence
for patients who were receiving mechanical ventilation or ECMO, and baricitinib may have modestly
attenuated efficacy in this group.24 Baricitinib or tocilizumab should only be administered in combination
with dexamethasone or another corticosteroid.
Regarding the use of tofacitinib and sarilumab if baricitinib and tocilizumab are not available or feasible
to use, please refer to the rationale for patients who require HFNC oxygen or NIV.
Recommendation
• The Panel recommends using dexamethasone alone for the treatment of patients with COVID-19

who require mechanical ventilation or ECMO if baricitinib, tofacitinib, tocilizumab, or sarilumab
cannot be obtained (AI).
Dexamethasone was shown to reduce mortality in critically ill patients with COVID-19 in a meta-
analysis that aggregated 7 randomized trials and included data on 1,703 critically ill patients. The
largest trial in the meta-analysis was the RECOVERY trial, which included a subgroup of patients who
were receiving mechanical ventilation (see Corticosteroids and Table 6a).2 However, as noted above,
subsequent studies of immunomodulator therapy suggest that using a combination of dexamethasone
and another immunomodulator is more effective in patients with COVID-19 who require mechanical
ventilation or ECMO.
Considerations for the Use of Remdesivir

Remdesivir is most effective against COVID-19 in patients who are earlier in the course of the disease
and who do not require mechanical ventilation or ECMO. However, in the Solidarity trial, among
patients who were receiving mechanical ventilation or ECMO, there was a trend toward an increase in
mortality for patients treated with remdesivir.6 For patients who started on remdesivir and progressed to
requiring mechanical ventilation or ECMO, the Panel suggests continuing remdesivir until the treatment
course is completed.
Subgroup analyses from 2 randomized trials suggest there is no clinical benefit to using a combination
of remdesivir and dexamethasone in patients who are receiving mechanical ventilation or ECMO.5,15
The data are inconclusive on whether corticosteroid therapy may delay viral clearance in patients with
COVID-19.25-29 Given the conflicting results from observational studies and the lack of clinical trial data,
some Panel members would add remdesivir to dexamethasone and a second immunomodulator only in
patients who have recently been placed on mechanical ventilation.
• The Panel recommends using a prophylactic dose of heparin as VTE prophylaxis, unless a
contraindication exists (AI); (BIII) for pregnant patients.
• For patients who are started on a therapeutic dose of heparin in a non-ICU setting for the
management of COVID-19 and then transferred to the ICU, the Panel recommends switching
from the therapeutic dose to a prophylactic dose of heparin, unless there is another indication for
therapeutic anticoagulation (BIII).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg daily)
and a therapeutic dose of anticoagulation for VTE prophylaxis in critically ill patients with
COVID-19, except in a clinical trial (BI).
Patients who required mechanical ventilation or ECMO were included in the multiplatform
REMAP-CAP/ACTIV-4a/ATTACC and INSPIRATION trials that studied therapeutic doses and
intermediate doses of heparin, respectively.19,20 Because these studies reported no benefits to using
intermediate or therapeutic doses of heparin, the recommendations for using prophylactic doses of
heparin in hospitalized patients who require mechanical ventilation or ECMO are the same as those for
patients who require HFNC oxygen or NIV.

Table 2d. Dosing Regimens for the Drugs Recommended in Table 2c
The drugs in this table are listed in alphabetical order.
Drug Name Dosing Regimen Comments
Baricitinib BAR dose is dependent on eGFR; • eGFR ≥60 mL/min/1.73 m2: BAR 4 mg PO once daily
duration of therapy is up to 14 days • eGFR 30 to <60 mL/min/1.73 m2: BAR 2 mg PO once daily
or until hospital discharge (whichever
comes first). • eGFR 15 to <30 mL/min/1.73 m2: BAR 1 mg PO once daily
• eGFR <15 mL/min/1.73 m2: BAR is not recommended.
Dexamethasone DEX 6 mg IV or PO once daily for up • If DEX is not available, an equivalent dose of another
to 10 days or until hospital discharge corticosteroid may be used.
(whichever comes first) • For more information, see Corticosteroids.
Heparin Therapeutic dose of SUBQ LMWH or • Administer for 14 days or until hospital discharge
IV UFH (whichever comes first) unless there is a diagnosis of VTE
or another indication for therapeutic anticoagulation.
Prophylactic dose of SUBQ LMWH or • Administer for the duration of the hospital stay.
SUBQ UFH
Remdesivir RDV 200 mg IV once, then RDV 100 • If the patient is hospitalized for reasons other than
mg IV once daily for 4 days or until COVID-19, the treatment duration is 3 days (see
hospital discharge (whichever comes Therapeutic Management of Nonhospitalized Adults With
first) COVID-19).
• If the patient progresses to more severe illness, complete
the course of RDV.
• For a discussion on using RDV in patients with renal
insufficiency, see Remdesivir.
Sarilumab Use the single-dose, prefilled syringe • Use if BAR or tocilizumab is not available or not feasible to
(not the prefilled pen) for SUBQ use (BIIa).
injection. Reconstitute sarilumab • In the United States, the currently approved route of
400 mg in 100 cc 0.9% NaCl and administration for sarilumab is SUBQ injection. In the
administer as an IV infusion over 1 REMAP-CAP trial, the SUBQ formulation was used to
hour. prepare the IV infusion.
Tocilizumab Tocilizumab 8 mg/kg actual body • In clinical trials, a third of the participants received a
weight (up to 800 mg) administered second dose of tocilizumab 8 hours after the first dose if
as a single IV dose no clinical improvement was observed.
Tofacitinib Tofacitinib 10 mg PO twice daily • Use if BAR or tocilizumab is not available or not feasible to
for up to 14 days or until hospital use (BIIa).
discharge (whichever comes first) • eGFR <60 mL/min/1.73 m2: tofacitinib 5 mg PO twice daily
Key: BAR = baricitinib; DEX = dexamethasone; eGFR = estimated glomerular filtration rate; IV = intravenous; LMWH
= low-molecular-weight heparin; NaCl = sodium chloride; PO = oral; RDV = remdesivir; SUBQ = subcutaneous; UFH =
unfractionated heparin; VTE = venous thromboembolism
References
1. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in
patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at:
2. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients
with COVID-19. N Engl J Med. 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32678530.

3. Crothers K, DeFaccio R, Tate J, et al. Dexamethasone in hospitalised COVID-19 patients not on intensive
respiratory support. Eur Respir J. 2022;60(1):2102532. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/34824060.
4. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J
Med. 2020;383(19):1813-1826. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.
5. Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada:
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COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet.
7. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645.
8. REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically
ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized
clinical trial. medRxiv. 2021;Preprint. Available at:
9. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N
10. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised
adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled
Phase 3 trial. Lancet Respir Med. 2021;9(12):1407-1418. Available at:
11. RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet.
2022;400(10349):359-368. Available at: https://pubmed.ncbi.nlm.nih.gov/35908569.
12. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic
anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802.
13. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin
on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with COVID-19
admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. Available at:
14. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard
prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with
COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620.
15. Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with
COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med.
2022;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35617986.
16. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill
17. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N
18. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim

WHO Solidarity trial results. N Engl J Med. 2021;384(6):497-511. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33264556.
19. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose
prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or
mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized
clinical trial. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.
20. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic
anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med. 2021;385(9):777-789.
21. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N
22. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe
COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at:
23. Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for
the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or
extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir
24. Zhang X, Shang L, Fan G, et al. The efficacy and safety of janus kinase inhibitors for patients with
COVID-19: a living systematic review and meta-analysis. Front Med (Lausanne). 2021;8:800492. Available
25. Chen Y, Li L. Influence of corticosteroid dose on viral shedding duration in patients with COVID-19. Clin
Infect Dis. 2021;72(7):1298-1300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32588884.
26. Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients
with COVID-19. Clin Infect Dis. 2021;72(7):1297-1298. Available at:
27. Ding C, Feng X, Chen Y, et al. Effect of corticosteroid therapy on the duration of SARS-CoV-2 clearance in
patients with mild COVID-19: a retrospective cohort study. Infect Dis Ther. 2020;9(4):943-952. Available at:
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29. Spagnuolo V, Guffanti M, Galli L, et al. Viral clearance after early corticosteroid treatment in patients with
moderate or severe COVID-19. Sci Rep. 2020;10(1):21291. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33277573.

Clinical Management of Children Summary
Data from the Centers for Disease Control and Prevention demonstrate a lower incidence of
SARS-CoV-2 infection, severe disease, and death in children compared with adults.1-4 Although only a
small percentage of children with COVID-19 will require medical attention, the percentage of intensive
care unit admissions among hospitalized children is comparable to the percentage among hospitalized
adults with COVID-19.5-16
Risk factors for severe COVID-19 have been identified through observational studies and meta-analyses
primarily conducted before the availability of COVID-19 vaccines. Risk factors include having ≥1
severe comorbid conditions, such as medical complexity with respiratory technology dependence, a
neurologic condition resulting in impaired mucociliary clearance, obesity (particularly severe obesity),
severe underlying cardiac or pulmonary disease, or severely immunocompromised status. However,
pediatric data on risk factors for severe COVID-19 are generally more limited and provide lower
certainty than data for adults.
In general, COVID-19 has similar clinical manifestations and disease stages in children and adults,
including an early phase driven by viral replication and a late phase that appears to be driven by a
dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. Respiratory
complications in young children that can occur during the early clinical phase include croup and
bronchiolitis. In addition, a small number of children who have recovered from acute SARS-CoV-2
infection develop multisystem inflammatory syndrome in children (MIS-C) 2 to 6 weeks after infection.
MIS-C is a postinfectious inflammatory condition that can lead to severe organ dysfunction, which is in
contrast to COVID-19, the acute, primarily respiratory illness due to infection with SARS-CoV-2.
There are no results available from clinical trials that evaluated treatments for COVID-19 in children,
and data from observational studies are limited. Applying adult data from COVID-19 trials to children is
a unique challenge because most children experience a mild course of illness with COVID-19. Relative
to adults, children with COVID-19 have substantially lower mortality and less need for hospitalization.
Because of these differences in epidemiology and disease severity, the effect sizes for children are
likely to be smaller than those observed in adults; therefore, to produce a beneficial outcome, the
number needed to treat is higher. Collectively, these factors influence the risk versus benefit balance for
pharmacologic therapies in children.
In the absence of sufficient clinical trial data on the treatment of children with COVID-19, the
COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the therapeutic management
of children are based largely on adult safety and efficacy data from clinical trials, the child’s risk of
disease progression, and expert opinion. In general, the older the child and the more severe the disease,
the more reasonable it is to follow treatment recommendations for adult patients with COVID-19.
The Panel’s recommendations for the management of children with COVID-19 or MIS-C are
summarized in the tables below. Table 3a provides recommendations for the therapeutic management
of nonhospitalized children with COVID-19. The Panel’s recommendations are stratified by age (per
the Food and Drug Administration Emergency Use Authorizations) and risk level. See Therapeutic
Management of Nonhospitalized Children With COVID-19 for more information. Table 3b includes a
framework to help clinicians evaluate the risk for severe COVID-19 based on patient conditions and
COVID-19 vaccination status.

The recommendations for hospitalized children in Table 3c are stratified by disease severity. See
Therapeutic Management of Hospitalized Children With COVID-19 for more information. Table
3d summarizes the recommendations for the therapeutic management of MIS-C. For the rationale
behind these recommendations and supporting data, see Therapeutic Management of Hospitalized
Pediatric Patients With Multisystem Inflammatory Syndrome in Children (MIS-C) (With Discussion on
Multisystem Inflammatory Syndrome in Adults [MIS-A]).
Table 3a. Therapeutic Management of Nonhospitalized Children With COVID-19
Panel’s Recommendations
Patient Disposition
Aged 12–17 years Aged <12 years
Symptomatic, Regardless of • Provide supportive care (AIII). • Provide supportive care (AIII).
Risk Factors
• Use 1 of the following options (listed • Ritonavir-boosted nirmatrelvir is
in order of preference):c not authorized by the FDA for use in
• Ritonavir-boosted nirmatrelvir children aged <12 years.
(Paxlovid) within 5 days of • There is insufficient evidence to
symptom onset (BIII) recommend either for or against
High Riska,b routine use of remdesivir. Consider
• Remdesivir within 7 days of
symptom onset (CIII) treatment based on age and other risk
factors.
• There is insufficient evidence to
recommend either for or against the
use of bebtelovimab.d
• There is insufficient evidence to • There is insufficient evidence to
recommend either for or against the recommend either for or against
Intermediate Riskb,e use of any antiviral therapy. Consider routine use of remdesivir.
treatment based on age and other risk
factors.
• Manage with supportive care alone • Manage with supportive care alone
Low Riskb,f
(BIII). (BIII).
a
Molnupiravir is not authorized by the FDA for use in children aged <18 years and should not be used.
b
See Table 3b for the Panel’s framework for assessing the risk of progression to severe COVID-19 based on patient
conditions and COVID-19 vaccination status.
c
Initiate treatment as soon as possible after symptom onset.
d
Bebtelovimab is the only anti-SARS-CoV-2 mAb active against the current dominant circulating Omicron subvariants. In
nonhospitalized adults, bebtelovimab may be used as an alternative therapy when none of the preferred therapies (i.e.,
ritonavir-boosted nirmatrelvir, remdesivir) are available, feasible to use, or clinically appropriate.
e
The relative risk of severe COVID-19 for intermediate-risk patients is lower than the risk for high-risk patients but higher
than the risk for low-risk patients.
f
Low-risk patients include those with comorbid conditions that have a weak or unknown association with severe
COVID-19. Patients with no comorbidities are included in this group.
Key: FDA = Food and Drug Administration; mAb = monoclonal antibody; the Panel = the COVID-19 Treatment Guidelines
Panel

Table 3b. The Panel’s Framework for Assessing the Risk of Progression to Severe COVID-19
Based on Patient Conditions and COVID-19 Vaccination Status
Risk Level by Vaccination Statusa

Conditions
Unvaccinated Primary Series Up to Date
Strong or Consistent Association With Progression to Severe COVID-19
• Moderately or severely immunocompromised
(see Special Considerations in People Who High
Are Immunocompromised)
• Obesity (BMI ≥95th percentile for age),
especially severe obesity (BMI ≥120% of 95th
percentile for age)b
• Medical complexity with dependence on
respiratory technologyc
• Severe neurologic, genetic, metabolic, or
other disability that results in impaired
airway clearance or limitations in self care or High Intermediate
activities of daily living
• Severe asthma or other severe chronic lung
disease requiring ≥2 inhaled or ≥1 systemic
medications daily
• Severe congenital or acquired cardiac disease
• Multiple moderate to severe chronic diseases
Moderate or Inconsistent Association With Progression to Severe COVID-19
• Aged <1 year
• Prematurity in children aged ≤2 years
• Sickle cell disease
Intermediate
• Diabetes mellitus (poorly controlled)
• Nonsevere cardiac, neurologic, or metabolic
diseased
Weak or Unknown Association With Progression to Severe COVID-19
• Mild asthma
• Overweight Low
• Diabetes mellitus (well controlled)
a
Unvaccinated = individuals who are not eligible for COVID-19 vaccination or are <2 weeks from the final dose of
the primary series. Vaccinated with primary series = individuals who completed the primary series of 2 or 3 doses
(the current CDC term is “fully vaccinated”) and are >2 weeks after the final dose of the primary series but have not
received a booster, if they are eligible for a booster. Children aged <5 years are not currently eligible for booster doses.
Vaccinated and up to date = individuals who received the recommended booster dose(s) if eligible or have completed
the primary series but are not yet eligible for a booster. See the CDC for more information.
b
The degree of risk conferred by obesity in younger children is less clear than it is in older adolescents.
c
Includes tracheostomy or NIV.
d
Data for this group are particularly limited.
Key: BMI = body mass index; CDC = Centers for Disease Control and Prevention; NIV = noninvasive ventilation; the Panel
= the COVID-19 Treatment Guidelines Panel

Table 3c. Therapeutic Management of Hospitalized Children With COVID-19
Disease Severity Panel’s Recommendations

For children aged ≥12 years admitted for COVID-19, use prophylactic
Hospitalized for COVID-19
anticoagulation unless contraindicated (BIII).
For children admitted for COVID-19 who are at the highest risk of
progression to severe COVID-19,a consider using remdesivirb for
children aged 12–17 years (CIII). There is insufficient evidence for using
Does Not Require Supplemental Oxygen remdesivir in children aged 28 days to <12 years.
For children admitted for reasons other than COVID-19 who have mild to
moderate COVID-19 and are at the highest risk of progression,a refer to
Therapeutic Management of Nonhospitalized Children With COVID-19.
Use 1 of the following options:
• Remdesivirb (BIII)
Requires Conventional Oxygenc
• Dexamethasone plus remdesivirb for children with increasing oxygen
needs, particularly adolescents (BIII)
• Dexamethasone (BIII)
Requires Oxygen Through High-Flow • Dexamethasone plus remdesivirb (BIII)
Device or NIVd For children who do not have rapid (e.g., within 24 hours) improvement in
oxygenation after initiation of dexamethasone, baricitinibe or tocilizumab
can be considered for children aged 12–17 years (BIII) and for children
aged 2–11 years (CIII).
Dexamethasonef (AIII)
For children who do not have rapid (e.g., within 24 hours) improvement in
Requires MV or ECMOf oxygenation after initiation of dexamethasone, baricitinibe or tocilizumab
may be considered for children aged 12–17 years (BIII) and for children
a
F or example, for children who are severely immunocompromised regardless of COVID-19 vaccination status and those
who are unvaccinated and have additional risk factors for progression (see Therapeutic Management of Nonhospitalized
Children With COVID-19).
b
The clinical benefit of remdesivir is greatest if it is initiated within 10 days of symptom onset. Remdesivir should be
given for 5 days or until hospital discharge, whichever comes first.
c
Conventional oxygen refers to oxygen supplementation that is not high-flow oxygen, NIV, MV, or ECMO.
d
Patients who are receiving NIV or MV at baseline and require a substantial increase in baseline support should be treated
per the recommendations for patients requiring new NIV or MV.
e
Tofacitinib is an alternative if baricitinib is not available (BIII).
f
For children who started receiving remdesivir before admission to the ICU, the remdesivir should be continued to
complete the treatment course.
Key: ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; MV = mechanical ventilation; NIV =
noninvasive ventilation

Table 3d. Therapeutic Management of Hospitalized Pediatric Patients With MIS-C
Patient Condition Panel’s Recommendations

Initial treatment for MIS-C includes both immunomodulatory and antithrombotic therapy.
Initial Immunomodulatory Therapy:
• IVIG 2 g/kg IBW/dose (up to a maximum total dose of 100 g)a IV plus low-to-moderate
dose methylprednisolone (1–2 mg/kg/day) IVa or another glucocorticoid at an equivalent
dosea (AIIb).
• The Panel recommends against the routine use of IVIG monotherapy for the treatment of
MIS-C unless glucocorticoid use is contraindicated (AIIb).
Intensification Immunomodulatory Therapy:
• For children with refractory MIS-C who do not improve within 24 hours of initial
immunomodulatory therapy, start one of the following (listed in alphabetical order) (AIII):
• High-dose anakinra 5–10 mg/kg IV or SUBQ daily (BIIb), or
• Higher-dose glucocorticoid (e.g., methylprednisolone 10–30 mg/kg/day IV or
equivalent glucocorticoid) (BIIb),b or
MIS-C
• Infliximabc 5–10 mg/kg IV for 1 dose (BIIb).
Antithrombotic Treatment:
• Low-dose aspirin (3–5 mg/kg/day, up to maximum daily dose of 81 mg) PO for all
patients without risk factors for bleeding (AIII), AND
• Anticoagulation for patients who fall under 1 of the following clinical scenarios:
• Therapeutic anticoagulation for patients with large CAAs according to the American
Heart Association guidelines for Kawasaki disease (AIII).
• Therapeutic anticoagulation for patients with moderate to severe LV dysfunction who
have no risk factors for bleeding (AIII).
• For patients with MIS-C who do not have large CAAs or moderate to severe LV
dysfunction, consider prophylactic or therapeutic anticoagulation on an individual
basis, taking into consideration risk factors for thrombosis. See Table 3e for additional
information.
a
uration of therapy may vary. For more information, see Therapeutic Management of Hospitalized Pediatric Patients
D
With Multisystem Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory
Syndrome in Adults [MIS-A]).
b
In certain patients with severe illness, intensification therapy may include dual therapy with higher-dose glucocorticoids
and infliximab or anakinra. Anakinra and infliximab should not be given in combination.
c
Infliximab should not be used in patients with macrophage activation syndrome.
Key: CAA = coronary artery aneurysm; IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LV
= left ventricular; MIS-C = multisystem inflammatory syndrome in children; PO = oral; SUBQ = subcutaneously
References
1. Centers for Disease Control and Prevention. COVID-19 weekly cases and deaths per 100,000
population by age, race/ethnicity, and sex. 2022. Available at: https://covid.cdc.gov/covid-data-
tracker/#demographicsovertime. Accessed July 26, 2022.
2. Centers for Disease Control and Prevention. Demographic trends of COVID-19 cases and deaths in the US
reported to CDC. 2022. Available at: https://covid.cdc.gov/covid-data-tracker/#demographics. Accessed July

26, 2022.
3. Centers for Disease Control and Prevention. COVID-NET laboratory-confirmed COVID-19 hospitalizations.
2022. Available at: https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalization-network. Accessed July
26, 2022.
4. Centers for Disease Control and Prevention. Provisional COVID-19 deaths: focus on ages 0–18 years. 2022.
Available at: https://data.cdc.gov/NCHS/Provisional-COVID-19-Deaths-Focus-on-Ages-0-18-Yea/nr4s-juj3.
Accessed July 26, 2022.
5. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics.
2020;145(6):e20200702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179660.
6. CDC COVID-19 Response Team. Coronavirus disease 2019 in children—United States, February 12–April 2,
7. Cui X, Zhang T, Zheng J, et al. Children with coronavirus disease 2019: a review of demographic, clinical,
laboratory, and imaging features in pediatric patients. J Med Virol. 2020;92(9):1501-1510. Available at:
8. Livingston E, Bucher K. Coronavirus disease 2019 (COVID-19) in Italy. JAMA. 2020;323(14):1335. Available
9. Tagarro A, Epalza C, Santos M, et al. Screening and severity of coronavirus disease 2019 (COVID-19) in
children in Madrid, Spain. JAMA Pediatr. 2020;Published online ahead of print. Available at:
10. DeBiasi RL, Song X, Delaney M, et al. Severe coronavirus disease-2019 in children and young adults in the
Washington, DC, metropolitan region. J Pediatr. 2020;223:199-203. Available at:
11. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically
ill children and adolescents with coronavirus disease 2019 at a tertiary care medical center in New York City. J
Pediatr. 2020;223:14-19. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
12. Swann OV, Holden KA, Turtle L, et al. Clinical characteristics of children and young people admitted to
hospital with COVID-19 in United Kingdom: prospective multicentre observational cohort study. BMJ.
2020;370:m3249. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32960186.
13. Gotzinger F, Santiago-Garcia B, Noguera-Julian A, et al. COVID-19 in children and adolescents in Europe: a
multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020;4(9):653-661. Available at:
14. Shi DS, Whitaker M, Marks KJ, et al. Hospitalizations of children aged 5–11 years with laboratory-confirmed
COVID-19—COVID-NET, 14 states, March 2020–February 2022. MMWR Morb Mortal Wkly Rep.
15. Siegel DA, Reses HE, Cool AJ, et al. Trends in COVID-19 cases, emergency department visits, and hospital
admissions among children and adolescents aged 0–17 years—United States, August 2020–August 2021.
MMWR Morb Mortal Wkly Rep. 2021;70(36):1249-1254. Available at:
16. Marks KJ, Whitaker M, Anglin O, et al. Hospitalizations of children and adolescents with laboratory-
confirmed COVID-19—COVID-NET, 14 states, July 2021–January 2022. MMWR Morb Mortal Wkly Rep.

Special Considerations in Children
Key Considerations
• SARS-CoV-2 infection is generally milder in children than in adults, and a substantial proportion of children with the
infection are asymptomatic.
• Most nonhospitalized children with COVID-19 will not require any specific therapy.
• Observational studies describe associations between severe COVID-19 and the presence of ≥1 comorbid conditions,
including cardiac disease, neurologic disorders, prematurity (in young infants), diabetes, obesity (particularly severe
obesity), chronic lung disease, feeding tube dependence, and immunocompromised status. Age (<1 year and 10–14
years) and non-White race/ethnicity are also associated with severe disease.
• Most children hospitalized for severe COVID-19 have not been fully vaccinated or are not eligible for COVID-19
vaccination.
• Data on the pathogenesis and clinical spectrum of SARS-CoV-2 infection are more limited for children than for adults.
• Vertical transmission of SARS-CoV-2 appears to be rare, but suspected or probable cases of vertical transmission
have been described.
• A small subset of children and young adults with SARS-CoV-2 infection may develop multisystem inflammatory
syndrome in children (MIS-C). Many patients with MIS-C require intensive care management. The majority of children
with MIS-C do not have underlying comorbid conditions.
• Data on the prevalence of post-COVID conditions in children are limited but suggest that younger children may have
fewer persistent symptoms than older children and adults.

This section provides an overview of the epidemiology and clinical spectrum of disease, including
COVID-19, multisystem inflammatory syndrome in children (MIS-C), and post-COVID conditions.
This section also includes information on risk factors for severe COVID-19, vertical transmission,
and infants born to a birth parent with SARS-CoV-2 infection. Throughout this section, COVID-19
refers to the acute, primarily respiratory illness due to infection with SARS-CoV-2. MIS-C refers to the
postinfectious inflammatory condition.
For information on the prevention, treatment, and management of severe complications of COVID-19 in
children, see:
• Prevention of SARS-CoV-2 Infection
• Therapeutic Management of Hospitalized Children With COVID-19
• Therapeutic Management of Hospitalized Pediatric Patients With Multisystem Inflammatory
Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory Syndrome in
Adults [MIS-A])
• Introduction to Critical Care Management of Children With COVID-19
Epidemiology
Data from the Centers for Disease Control and Prevention (CDC) demonstrate that SARS-CoV-2
infection and severe disease and death due to COVID-19 occur less often in children than in adults.1-4

However, the true burden of pediatric SARS-CoV-2 infection remains unclear, as children with mild
symptoms are seldom systematically tested, and contact tracing and seroprevalence studies are not
generally conducted. Seroprevalence data have suggested that, as of mid-2021, most children did not
have evidence of prior SARS-CoV-2 infection. However, among children and adolescents, the estimated
number of SARS-CoV-2 infections that occurred through May 2021 was 4.7 to 8.9 times greater than
the number of COVID-19 cases.5 In a report from the CDC, by February 2022, approximately 75% of
children and adolescents had serologic evidence of prior SARS-CoV-2 infection.6
Data on the pathogenesis and disease severity of SARS-CoV-2 infection in children are increasing
but are still limited compared to the adult data. Although only a small percentage of children with
COVID-19 will require medical attention, the percentage of intensive care unit (ICU) admissions among
hospitalized children is comparable to that for hospitalized adults with COVID-19.7-18
Children from some racial and ethnic groups experience disproportionate rates of COVID-19-related
hospitalization, which may be a result of barriers to accessing health care and economic and structural
inequities. From 2020 to 2021, Black/African American children with COVID-19 in the United States
were 2 times more likely to be hospitalized and 5 times more likely to be admitted to the ICU than
White children.19
A U.S. study of children with COVID-19 who were hospitalized between April and September 2020
reported an association between race/ethnicity and disease severity.20 In a large United Kingdom study,
admission to critical care was independently associated with hospitalized children who self-reported as
being of Black ethnicity.14 A study in England reported that children who identified as Asian were more
likely than children who identified as White to be hospitalized for COVID-19 and to be admitted to an
ICU.21 The study also found that children who identified as Black or as mixed or other races/ethnicities
had significantly more hospitalizations than children who identified as White.
Clinical Manifestations of COVID-19

The signs and symptoms of SARS-CoV-2 infection in symptomatic children may be similar to those
in adults; however, a greater proportion of children may be asymptomatic or have only mild illness
when compared with adults. Although the true incidence of asymptomatic SARS-CoV-2 infection is
unknown, a small study reported that 45% of children who underwent surveillance testing at the time
of hospitalization for a non-COVID-19 indication had asymptomatic infection.22 The most common
signs and symptoms of COVID-19 in hospitalized children are fever, nausea/vomiting, cough, shortness
of breath, and upper respiratory symptoms.14,23 The signs and symptoms of COVID-19 may overlap
significantly with those of influenza and other respiratory and enteric viral infections. Critical disease,
including respiratory failure, acute respiratory distress syndrome, and, less commonly, shock, may occur
in children with COVID-19.24,25 The overall incidence of SARS-CoV-2 infection and, by extension,
COVID-19-related hospitalizations among children has increased substantially with the emergence of
recent variants of concern (VOCs), particularly Omicron.18,26
Risk Factors for Severe COVID-19

Risk factors for severe COVID-19 identified by observational studies and meta-analyses include
having ≥1 comorbidities, such as cardiac disease, neurologic disorders, prematurity (in young infants),
diabetes, obesity (particularly severe obesity), chronic lung disease, feeding tube dependence, and
immunocompromised status. Demographic factors, such as age (<1 year and 10–14 years) and
non-White race/ethnicity, have also been associated with severe disease. However, many studies did not
assess the relative severity of underlying medical conditions.
Many published studies reported an increased relative risk of severe disease in children with

comorbidities, but the absolute risk of severe COVID-19 among children remains low. However,
protocolized admissions for certain populations (e.g., febrile young infants) may confound the
association between comorbid conditions and severe COVID-19. Most children who have been
hospitalized for severe COVID-19 have not been fully vaccinated—many were not eligible for
COVID-19 vaccination because of their age. The CDC has additional information on the underlying
conditions that are risk factors for severe COVID-19.
The children most likely to benefit from treatment are nonhospitalized patients with mild to moderate
COVID-19 who are at the highest risk for severe COVID-19 (e.g., those with severe comorbidities). For
a description of children considered at high risk for severe COVID-19 and the COVID-19 Treatment
Guidelines Panel’s (the Panel) recommendations for their treatment, see Therapeutic Management of
Hospitalized Children With COVID-19.
Age
Among all children, infants and adolescents have the highest risk of COVID-19-related ICU admission
or death. From March 2020 to mid-August 2021, U.S. children aged <5 years had the highest cumulative
COVID-19-related hospitalization rates, followed closely by adolescents.27 Children aged 5 to 11 years
had the lowest hospitalization rates. From July to August 2021, when the Delta variant was the dominant
VOC, 25% of 713 children admitted to 6 U.S. hospitals were aged <1 year, 17% were aged 1 to 4 years,
20% were aged 5 to 11 years, and 38% were aged 12 to 17 years.28 From March 2020 to mid-June 2021,
26.5% of 3,116 U.S. children hospitalized for COVID-19 were admitted to an ICU.27
An individual patient data meta-analysis reported that patients aged <1 year and those aged 10 to 14
years had the highest risks of ICU admission and death among hospitalized children with COVID-19.29
Another meta-analysis reported that neonates, but not infants aged 1 to 3 months, had an increased risk
of severe COVID-19 compared with other pediatric age groups.30 When Omicron was the dominant
circulating VOC, hospitalization rates among children and adolescents were higher than when the Delta
VOC was dominant, and they were highest for children aged <5 years.26,31 However, the proportion of
hospitalized children requiring ICU admission was significantly lower when the Omicron VOC was
dominant.
Comorbidities
Several chronic conditions are prevalent in hospitalized children with COVID-19. When the Delta
variant was the dominant VOC in the United States, 68% of hospitalized children had ≥1 underlying
medical condition, such as obesity (32%), asthma or reactive airway disease (16%), or feeding tube
dependence (8%). Obesity was present in approximately a third of hospitalized children aged 5 to 11
years, 60% of whom had a body mass index (BMI) ≥120% of the 95th percentile. For adolescents, 61%
had obesity; of those patients, 61% had a BMI ≥120% of the 95th percentile.28
Meta-analyses and observational studies identified risk factors for ICU admission, mechanical
ventilation, or death among hospitalized children with COVID-19.30,32,33 These risk factors included
prematurity in young infants, obesity, diabetes, chronic lung disease, cardiac disease, neurologic disease,
and immunocompromising conditions. Another study found that having a complex chronic condition
that affected ≥2 body systems or having a progressive chronic condition or continuous dependence on
technology for ≥6 months (e.g., dialysis, tracheostomy with ventilator assistance) was significantly
associated with an increased risk of moderate or severe COVID-19.34 The study also found that having
more severe chronic disease (e.g., active cancer treated within the previous 3 months or asthma with
hospitalization within the previous 12 months), when compared with less severe conditions, increased
the risk of critical COVID-19 or death. The CDC has additional information on the underlying

conditions that are risk factors for severe COVID-19.
Having multiple comorbidities increases the risk of severe COVID-19 in children. A meta-analysis of
data from children hospitalized with COVID-19 found that the risk of ICU admission was greater for
children with 1 chronic condition than for those with no comorbid conditions, and the risk increased
substantially as the number of comorbidities increased.29
COVID-19 Vaccination Status

the first line of prevention. Most children hospitalized for COVID-19 were not fully vaccinated or were
not eligible to receive COVID-19 vaccination because of their age.16,18,28,35 With the wider availability
of COVID-19 vaccines for younger children, the number of COVID-19 cases among children may
decrease over time.
Mortality
Death from COVID-19 is uncommon in children. Risk factors for death include having chronic
conditions, such as neurologic or cardiac disease, and having multiple comorbidities. Among children
aged <21 years in the United States, deaths associated with COVID-19 have been higher for children
aged 10 to 20 years, especially for young adults aged 18 to 20 years, and for those who identify as
Hispanic, Black, or American Indian/Alaskan Native.36,37
A systematic review and meta-analysis reported that neurologic or cardiac comorbidities were associated
with the greatest increase in risk of death among hospitalized children with COVID-19.29 In the same
study, an individual patient data meta-analysis reported that the risk of COVID-19-related death was
greater for children with 1 chronic condition than for those with no comorbid conditions, and the risk
increased substantially as the number of comorbidities increased.
Vertical Transmission and Infants Born to People With SARS-CoV-2 Infection

A systematic review and meta-analysis reported that confirmed vertical transmission of SARS-CoV-2
appears to be rare, and severe maternal COVID-19 has been associated with SARS-CoV-2 infection
in babies.38 In two large, combined cohorts of pregnant individuals from the United States and United
Kingdom, SARS-CoV-2 infection was reported in 1.8% and 2% of the babies born to people with
SARS-CoV-2 infection.39
Case reports have described intrauterine fetal demise during the third trimester of pregnancy in
individuals with mild COVID-19 due to infection with the Delta VOC.40,41 These individuals had
evidence of placental SARS-CoV-2 infection, placental malperfusion, and placental inflammation. One
case report described a person with asymptomatic SARS-CoV-2 infection and severe preeclampsia who
gave birth at 25 weeks of gestation by emergency cesarean delivery. The neonate died on Day 4, and
evidence of SARS-CoV-2 infection was found in placental tissues and in the infant’s lungs and vascular
endothelium at autopsy.42 Evidence of placental SARS-CoV-2 infection was reported in 5 stillbirths and
for 1 live-born neonate in Sweden.43
A systematic review of neonatal SARS-CoV-2 infections reported that 70% were due to postpartum
transmission, and 30% were due to vertical transmission from an infected birth parent.44 Another
systematic review reported that newborn infants rooming-in with the birth parent did not have an
increased risk of SARS-CoV-2 transmission when compared with newborns who were isolated from the
birth parent.45
Detection of SARS-CoV-2 RNA in the breast milk of individuals with confirmed cases of COVID-19 is

very uncommon.46 Currently, there is no evidence of SARS-CoV-2 transmission through breast milk.47
Breast milk from people with SARS-CoV-2 infection can contain antibodies to SARS-CoV-2.48,49
Multisystem Inflammatory Syndrome in Children

A small subset of children and young adults with SARS-CoV-2 infection, including those with
asymptomatic infection, may develop MIS-C. This syndrome is also called pediatric multisystem
inflammatory syndrome—temporally associated with SARS-CoV-2 (PMIS-TS). Although the case
definitions for these syndromes differ slightly, they are likely the same disease. The syndrome was first
described in Europe, where previously healthy children with severe inflammation and Kawasaki disease-
like features were identified as having current or recent infection with SARS-CoV-2.
The clinical spectrum of MIS-C has been described in the United States and is similar to that described
for PMIS-TS. MIS-C is consistent with a postinfectious inflammatory syndrome related to SARS-CoV-
2.50,51 Most patients with MIS-C have serologic evidence of previous SARS-CoV-2 infection, but only
a minority have had a positive reverse transcription polymerase chain reaction (RT-PCR) result for
SARS-CoV-2 at presentation.52,53
The peak population-based incidence of MIS-C lags about 4 weeks behind the peak of acute pediatric
COVID-19-related hospitalizations. Emerging data suggests that adults may develop a similar syndrome,
multisystem inflammatory syndrome in adults (MIS-A), although it is not clear if this postinfectious
complication is similar to MIS-C.52-54 Published data that characterize the condition are limited.
Although risk factors for the development of MIS-C have not been established, an analysis of MIS-C
cases in the United States found that ICU admission was more likely for patients aged 6 to 12 years
than for younger children, and it was more likely for children who identified as non-Hispanic Black
than for those who identified as non-Hispanic White.55 Unlike most children who present with severe
COVID-19, the majority of children who present with MIS-C do not seem to have common underlying
comorbid conditions other than obesity.55 In addition, children whose deaths were related to MIS-C were
less likely to have underlying medical conditions than children who died of COVID-19.37
Emerging evidence suggests that COVID-19 vaccination protects against the development of MIS-C.56,57
The development of MIS-C after COVID-19 vaccination is very rare.56,58
Clinical Manifestations of Multisystem Inflammatory Syndrome in Children

The current CDC case definition for MIS-C is an individual aged <21 years who:
• Presents with fever,a laboratory evidence of inflammation,b and evidence of clinically severe
illness requiring hospitalization, with multisystem (i.e., >2) organ involvement (cardiac, renal,
respiratory, hematologic, gastrointestinal, dermatologic, or neurological); and
• Has no alternative plausible diagnoses; and
• Is positive for current or recent SARS-CoV-2 infection by RT-PCR, antigen test, or serology
results; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms.59
a
Fever >38.0°C for ≥24 hours or report of subjective fever lasting ≥24 hours
b
Including, but not limited to, ≥1 of the following: elevated levels of C-reactive protein, fibrinogen, procalcitonin, D-dimer,
ferritin, lactic acid dehydrogenase, or interleukin (IL)-6; an elevated erythrocyte sedimentation rate or neutrophil count;
or a reduced lymphocyte count or albumin level
Distinguishing MIS-C from other febrile illnesses in the community setting remains challenging, but
the presence of persistent fever, multisystem manifestations, and laboratory abnormalities could help
early recognition.60 The clinical spectrum of hospitalized cases has included younger children with

mucocutaneous manifestations that overlap with Kawasaki disease, older children with more multiorgan
involvement and shock, and patients with respiratory manifestations that overlap with COVID-19.
Patients with MIS-C are often critically ill, and up to 80% of children require ICU admission.61 Most
patients with MIS-C have markers of cardiac injury or dysfunction, including elevated levels of
troponin and brain natriuretic protein; higher levels of these markers are associated with ICU admission,
myocardial dysfunction, and shock.55 In these cases, echocardiographic findings may include impaired
left ventricular function, coronary artery dilations, and, rarely, coronary artery aneurysms. The reported
mortality in the United States for hospitalized children with MIS-C is 1% to 2%. Longitudinal studies to
examine the long-term sequelae of MIS-C are currently ongoing.
The pathogenesis of MIS-C is still being elucidated and may include distinct humoral immune
responses, innate immune activation, or a superantigen effect. Differences between MIS-C and typical
Kawasaki disease have been demonstrated in terms of epidemiology, cytopenias, cytokine expression,
and elevation of inflammatory markers. Immunologic profiling has also shown differences in cytokine
expression (tumor necrosis factor alpha and IL-10) between MIS-C and COVID-19 in children.62-64
For the Panel’s recommendations on the treatment of MIS-C, see Therapeutic Management of
Hospitalized Pediatric Patients With Multisystem Inflammatory Syndrome in Children (MIS-C) (With
Discussion on Multisystem Inflammatory Syndrome in Adults [MIS-A]).
Post-COVID Conditions
Persistent symptoms after COVID-19 have been described in adults and are an active area of research in
children, although data on the incidence of post-COVID sequelae in children are limited and somewhat
conflicting (see Clinical Spectrum of SARS-CoV-2 Infection).65-67 Cardiac imaging studies have
described myocardial injury in young athletes who had only mild disease;68 additional studies are needed
to identify long-term cardiac sequelae.
The reported clinical manifestations and duration of post-COVID conditions in children are highly
variable.69 Not all studies included controls without SARS-CoV-2 infection, which makes determining
the true incidence a challenge. The incidence of post-COVID symptoms appears to increase with age.
The most common symptoms reported include persistent fatigue, headache, shortness of breath, sleep
disturbances, and altered sense of smell.
Among children, health care utilization increases following COVID-19. A Norwegian study of 10,279
children with and 275,859 without SARS-CoV-2 infection reported that primary care visits for children
aged 6 to 15 years increased for up to 3 months after a positive SARS-CoV-2 test result when compared
with controls.66,70 For preschool-age children, visits increased for up to 6 months.
In a study of 6,804 adolescents in England, 30% of the 3,065 participants who tested positive for
SARS-CoV-2 infection reported ≥3 symptoms at a 3-month follow-up visit.71 Common symptoms
included tiredness (39%), headache (23%), and shortness of breath (23%). In the same study, only 16%
of the 3,739 participants who tested negative for SARS-CoV-2 infection reported ≥3 symptoms at the
3-month follow-up visit.
A study in Denmark examined persistent symptoms among 16,836 children with and 16,620 children
without SARS-CoV-2 infection. The number of children with SARS-CoV-2 infection who reported
symptoms that persisted for >4 weeks increased as age increased. Among the preschool-age children,
more children in the control arm than in the SARS-CoV-2 arm reported experiencing symptoms that
persisted for >4 weeks.72

Additional research is needed to define the incidence, spectrum, and severity of post-COVID conditions
in children and to identify optimal strategies for prevention, diagnosis, and treatment of those conditions.
References
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18. Marks KJ, Whitaker M, Anglin O, et al. Hospitalizations of children and adolescents with laboratory-
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22. Poline J, Gaschignard J, Leblanc C, et al. Systematic severe acute respiratory syndrome coronavirus
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23. Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged <18 years
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25. Bhalala US, Gist KM, Tripathi S, et al. Characterization and outcomes of hospitalized children with
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27. Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations associated with COVID-19 among children and
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28. Wanga V, Gerdes ME, Shi DS, et al. Characteristics and clinical outcomes of children and adolescents aged
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29. Harwood R, Yan H, Talawila Da Camara N, et al. Which children and young people are at higher risk of
severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: a
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30. Choi JH, Choi SH, Yun KW. Risk factors for severe COVID-19 in children: a systematic review and meta-
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31. Dorabawila V, Hoefer D, Bauer UE, et al. Risk of infection and hospitalization among vaccinated and
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34. Forrest CB, Burrows EK, Mejias A, et al. Severity of acute COVID-19 in children <18 years old March 2020
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35. Olson SM, Newhams MM, Halasa NB, et al. Effectiveness of BNT162b2 vaccine against critical COVID-19
in adolescents. N Engl J Med. 2022;386(8):713-723. Available at:
36. Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2-associated deaths among persons aged <21 years—
United States, February 12–July 31, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(37):1324-1329. Available
37. McCormick DW, Richardson LC, Young PR, et al. Deaths in children and adolescents associated with
COVID-19 and MIS-C in the United States. Pediatrics. 2021;148(5):e2021052273. Available at:
38. Allotey J, Chatterjee S, Kew T, et al. SARS-CoV-2 positivity in offspring and timing of mother-to-child
transmission: living systematic review and meta-analysis. BMJ. 2022;376:e067696. Available at:
39. Mullins E, Hudak ML, Banerjee J, et al. Pregnancy and neonatal outcomes of COVID-19: coreporting
of common outcomes from PAN-COVID and AAP-SONPM registries. Ultrasound Obstet Gynecol.
40. Shook LL, Brigida S, Regan J, et al. SARS-CoV-2 placentitis associated with B.1.617.2 (Delta) variant and
fetal distress or demise. J Infect Dis. 2022;225(5):754-758. Available at:
41. Guan M, Johannesen E, Tang CY, et al. Intrauterine fetal demise in the third trimester of pregnancy associated
with mild infection with the SARS-CoV-2 Delta variant without protection from vaccination. J Infect Dis.
42. Reagan-Steiner S, Bhatnagar J, Martines RB, et al. Detection of SARS-CoV-2 in neonatal autopsy tissues and
placenta. Emerg Infect Dis. 2022;28(3):510-517. Available at:
43. Zaigham M, Gisselsson D, Sand A, et al. Clinical-pathological features in placentas of pregnancies with
SARS-CoV-2 infection and adverse outcome: case series with and without congenital transmission. BJOG.
44. Raschetti R, Vivanti AJ, Vauloup-Fellous C, et al. Synthesis and systematic review of reported neonatal
SARS-CoV-2 infections. Nat Commun. 2020;11(1):5164. Available at:
45. Walker KF, O’Donoghue K, Grace N, et al. Maternal transmission of SARS-CoV-2 to the neonate, and
possible routes for such transmission: a systematic review and critical analysis. BJOG. 2020;127(11):1324-
46. Kumar J, Meena J, Yadav A, Kumar P. SARS-CoV-2 detection in human milk: a systematic review. J Matern

Fetal Neonatal Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/
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47. Centeno-Tablante E, Medina-Rivera M, Finkelstein JL, et al. Transmission of SARS-CoV-2 through breast
milk and breastfeeding: a living systematic review. Ann N Y Acad Sci. 2021;1484(1):32-54. Available at:
48. Bauerl C, Randazzo W, Sanchez G, et al. SARS-CoV-2 RNA and antibody detection in breast milk from a
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49. Duncombe CJ, McCulloch DJ, Shuey KD, et al. Dynamics of breast milk antibody titer in the six months
following SARS-CoV-2 infection. J Clin Virol. 2021;142:104916. Available at:
50. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in
children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at:
51. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269. Available at:
52. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York
State. N Engl J Med. 2020;383(4):347-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32598830.
53. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and
adolescents. N Engl J Med. 2020;383(4):334-346. Available at:
54. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults
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55. Abrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe outcomes in multisystem
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56. Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA
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Therapeutic Management of Nonhospitalized
Children With COVID-19
This section outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for
the therapeutic management of nonhospitalized children (i.e., pediatric patients aged <18 years) with
mild to moderate COVID-19. These recommendations are also for children who have mild to moderate
COVID-19 and are hospitalized for reasons other than COVID-19. For patients aged <18 years, see
Therapeutic Management of Nonhospitalized Adults With COVID-19. Throughout this section, the term
“COVID-19” refers to the acute, primarily respiratory illness due to infection with SARS-CoV-2, which
is in contrast to multisystem inflammatory syndrome in children (MIS-C), a postinfectious inflammatory
condition.
Treatment Considerations for Children With COVID-19

Currently, no results from pediatric clinical trials that evaluated the treatment of COVID-19 have been
published. Data evaluating the use of pharmacologic therapy in children with COVID-19 are limited
largely to descriptive reports.1,2 Therefore, more high-quality randomized trials, observational studies,
and pharmacokinetic studies are urgently needed. Whenever possible, clinical trials of therapeutics and
multicenter observational cohorts should enroll children with COVID-19.
Published guidance documents on the treatment of COVID-19 in children have been mostly extrapolated
from recommendations for adults with COVID-19, recommendations for children with other viral
infections, and expert opinion.3-5 Applying adult data from COVID-19 trials to children is a unique
challenge because most children experience a mild course of illness with COVID-19. Relative to adults,
children with COVID-19 have substantially lower mortality and less need for hospitalization. Because
of these differences in epidemiology and disease severity, the effect sizes for children are likely to be
smaller than those observed in adults; therefore, to produce a beneficial outcome, the number needed
to treat is higher. Collectively, these factors influence the risk versus benefit balance for pharmacologic
therapies in children.
Other challenges are the uncertainty about which comorbid conditions place children at the highest
risk of severe COVID-19 and the uncertainty about the absolute magnitude of the increased risk from
those comorbid conditions. For children with COVID-19, the number and severity of their comorbid
conditions influence decisions about pharmacologic treatment. For more information on risk factors for
children with COVID-19, see Special Considerations in Children.
Recommendations
In the absence of sufficient clinical trial data on the treatment of children with COVID-19, the Panel’s
recommendations for the therapeutic management of nonhospitalized children are based largely on adult
safety and efficacy data from clinical trials (see Table 3a). No pediatric comparative studies have been
published; therefore, all quality of evidence ratings for the Panel’s recommendations in this section are
based on expert opinion (i.e., a III rating).
The majority of children with mild to moderate COVID-19 will not progress to more severe illness;
therefore, the Panel recommends managing these patients with supportive care alone (AIII). The risks
and benefits of therapy should be assessed based on COVID-19 disease severity, age, vaccination status,

and the presence of underlying medical conditions that may place the patient at high risk of severe
COVID-19. For the Panel’s framework for assessing the risk of progression to severe COVID-19 based
on patient conditions and vaccination status, see Table 3b.
Table 3a. Therapeutic Management of Nonhospitalized Children With COVID-19
See Table 3b for the Panel’s framework for assessing the risk of progression to severe COVID-19 based
on patient conditions and vaccination status.
Panel’s Recommendations
Patient Disposition
Aged 12–17 years Aged <12 years
Symptomatic, Regardless of • Provide supportive care (AIII). • Provide supportive care (AIII).
Risk Factors
• Use 1 of the following options (listed • Ritonavir-boosted nirmatrelvir is
in order of preference):c not authorized by the FDA for use in
• Ritonavir-boosted nirmatrelvir children aged <12 years.
(Paxlovid) within 5 days of • There is insufficient evidence to
symptom onset (BIII) recommend either for or against
High Riska,b routine use of remdesivir. Consider
• Remdesivir within 7 days of
symptom onset (CIII) treatment based on age and other risk
factors.
• There is insufficient evidence to
recommend either for or against the
use of bebtelovimab.d
• There is insufficient evidence to • There is insufficient evidence to
recommend either for or against the recommend either for or against
Intermediate Riskb,e use of any antiviral therapy. Consider routine use of remdesivir.
treatment based on age and other risk
factors.
• Manage with supportive care alone • Manage with supportive care alone
Low Riskb,f
(BIII). (BIII).
a
Molnupiravir is not authorized by the FDA for use in children aged <18 years and should not be used.
b
See Table 3b for the Panel’s framework for assessing the risk of progression to severe COVID-19 based on patient
conditions and COVID-19 vaccination status.
c
Initiate treatment as soon as possible after symptom onset.
d
Bebtelovimab is the only anti-SARS-CoV-2 mAb active against the current dominant circulating Omicron subvariants. In
nonhospitalized adults, bebtelovimab may be used as an alternative therapy when none of the preferred therapies (i.e.,
ritonavir-boosted nirmatrelvir, remdesivir) are available, feasible to use, or clinically appropriate.
e
The relative risk of severe COVID-19 for intermediate-risk patients is lower than the risk for high-risk patients but higher
than the risk for low-risk patients.
f
Low-risk patients include those with comorbid conditions that have a weak or unknown association with severe
COVID-19. Patients with no comorbidities are included in this group.
Key: FDA = Food and Drug Administration; mAb = monoclonal antibody; the Panel = the COVID-19 Treatment Guidelines
Panel

Table 3b. The Panel’s Framework for Assessing the Risk of Progression to Severe COVID-19
Based on Patient Conditions and COVID-19 Vaccination Status
Risk Level by Vaccination Statusa

Conditions
Unvaccinated Primary Series Up to Date
Strong or Consistent Association With Progression to Severe COVID-19
• Moderately or severely immunocompromised
(see Special Considerations in People Who High
Are Immunocompromised)
• Obesity (BMI ≥95th percentile for age),
especially severe obesity (BMI ≥120% of 95th
percentile for age)b
• Medical complexity with dependence on
respiratory technologyc
• Severe neurologic, genetic, metabolic, or
other disability that results in impaired
airway clearance or limitations in self care or High Intermediate
activities of daily living
• Severe asthma or other severe chronic lung
disease requiring ≥2 inhaled or ≥1 systemic
medications daily
• Severe congenital or acquired cardiac disease
• Multiple moderate to severe chronic diseases
Moderate or Inconsistent Association With Progression to Severe COVID-19
• Aged <1 year
• Prematurity in children aged ≤2 years
• Sickle cell disease
Intermediate
• Diabetes mellitus (poorly controlled)
• Nonsevere cardiac, neurologic, or metabolic
diseased
Weak or Unknown Association With Progression to Severe COVID-19
• Mild asthma
• Overweight Low
• Diabetes mellitus (well controlled)
a
Unvaccinated = individuals who are not eligible for COVID-19 vaccination or are <2 weeks from the final dose of
the primary series. Vaccinated with primary series = individuals who completed the primary series of 2 or 3 doses
(the current CDC term is “fully vaccinated”) and are >2 weeks after the final dose of the primary series but have not
received a booster, if they are eligible for a booster. Children aged <5 years are not currently eligible for booster doses.
Vaccinated and up to date = individuals who received the recommended booster dose(s) if eligible or have completed
the primary series but are not yet eligible for a booster. See the CDC for more information.
b
The degree of risk conferred by obesity in younger children is less clear than it is in older adolescents.
c
Includes tracheostomy or NIV.
d
Data for this group are particularly limited.
Key: BMI = body mass index; CDC = Centers for Disease Control and Prevention; NIV = noninvasive ventilation; the Panel
= the COVID-19 Treatment Guidelines Panel

Rationale for the Panel’s Framework for Assessing the Risk of Progression to
Severe COVID-19
Although mortality associated with COVID-19 in children is low overall, severe disease can occur,
especially in those with risk factors.6 Risk stratification for severe disease in children remains
challenging. Imprecise definitions of comorbid conditions, insufficient granularity for differentiating
the severity of comorbidities (e.g., mild vs. severe lung disease, poorly controlled vs. well-controlled
diabetes), and small sample sizes limit the conclusions that can be drawn from individual studies and
make comparing findings across studies difficult.
Further, asymptomatic SARS-CoV-2 infection detected during admission screening for children who
are hospitalized for reasons other than COVID-19 may affect the estimated risk of severe COVID-19,
particularly for patient groups that may have protocolized admissions (e.g., children with febrile
neutropenia, infants aged <90 days with fever). In addition, published data evaluating these associations
in children are limited largely to case series without control groups and observational studies with
methodologic limitations.
Despite these challenges, a risk-stratification framework needs to be developed that identifies the patient
groups likely to benefit from receiving treatment and prioritizes patients who are most likely to benefit
when supplies are limited. Both the Pediatric Infectious Diseases Society and the American Academy of
Pediatrics advocate for a risk-stratified approach toward identifying the patients who are at the highest
risk of progression to severe COVID-19 among those eligible for therapies under Food and Drug
Administration (FDA) Emergency Use Authorizations (EUAs).5,7
The Panel’s approach to risk stratification and prioritization considers COVID-19 vaccination status,
immune function, clinical risk factors, the strength of evidence demonstrating an association between
each clinical risk factor and severe disease, and expert opinion.6,8-21 See Special Considerations in
Children for more information on clinical risk factors. Table 3b provides the Panel’s framework for this
risk stratification. The Panel suggests that decisions regarding treatment be individualized, particularly
for patients in the intermediate risk category. The number and severity of comorbid conditions and a
child’s vaccination status, including the time since vaccination, should be considered.
Comorbid conditions associated with severe COVID-19 are separated into the following categories in
Table 3b:
• Strong or Consistent Association With Progression to Severe COVID-19: Comorbid conditions for
which the published literature most consistently supports an increased risk of severe COVID-19.
Patients in this category are moderately or severely immunocompromised, at risk of severe
COVID-19, and not expected to develop an adequate immune response to COVID-19 vaccination.
• Moderate or Inconsistent Association With Progression to Severe COVID-19: Comorbid
conditions and ages for which the published literature supports an association with severe
COVID-19, but the data that support that association may be moderate or inconsistent. In addition,
the absolute risk of progression to severe disease or death is likely modest for any of the patients
in this category.
• Weak or Unknown Association With Progression to Severe COVID-19: Comorbid conditions
for which the data suggesting an association with severe COVID-19 are weak or for which an
association is unknown. Patients with no comorbidities are included in this category.
Vaccination Status
Because COVID-19 vaccines are highly effective in preventing severe disease, individuals who are not

immunocompromised and who are vaccinated are likely to have a low absolute risk of severe disease.
Therefore, the potential for benefit from antiviral treatment is less clear. Patients with up-to-date
vaccination status (i.e., those who have received the recommended booster dose(s), if eligible, or have
completed the primary series but are not yet eligible for a booster) are at the lowest risk of progression
to severe COVID-19.22 For patients who have had the primary series of vaccinations (i.e., those who
are fully vaccinated but not up to date), the level of protection against severe disease may be less than
it is for patients who are up to date, but data comparing these groups are limited.22 However, evidence
suggests that vaccine protection against severe COVID-19 wanes over time, so clinicians should
consider the time since a child’s vaccination when making treatment decisions.23,24
Health Disparities
COVID-19-related outcomes are worse among medically underserved populations, although this factor
is not strictly a comorbid condition. Some racial and ethnic groups experience disproportionate rates
of COVID-19 hospitalization and are less likely to receive specific therapies.25-28 These factors may be
relevant when making clinical decisions about treatment.29,30 See Special Considerations in Children for
more information.
Rationale for the Panel’s Recommendations for Drug Therapies

Ritonavir-boosted nirmatrelvir has received an FDA EUA for the treatment of mild to moderate
COVID-19 in nonhospitalized adolescents aged ≥12 years and weighing ≥40 kg who are at high risk of
progression to severe COVID-19.31
The EPIC-HR trial enrolled adults aged ≥18 years who were at high risk of severe COVID-19; they
were randomized to receive ritonavir-boosted nirmatrelvir or placebo. The primary outcome of COVID-
19-related hospitalization or all-cause mortality occurred in 8 of 1,039 patients (0.8%) who received
ritonavir-boosted nirmatrelvir and in 66 of 1,046 patients (6.3%) who received placebo, an 89% relative
risk reduction.32 No pediatric patients were included in the trial, and no pediatric safety data were made
available.
Ritonavir has been used extensively in pediatric patients as a pharmacokinetic booster for the treatment
of HIV and hepatitis C, and it has a known and tolerable side effect profile. In the FDA EUA, the dose
of ritonavir-boosted nirmatrelvir authorized for adolescents aged ≥12 years and weighing ≥40 kg is
expected to result in a drug exposure similar to that observed in adults.31
Given the high efficacy of ritonavir-boosted nirmatrelvir in adults, its overall manageable side effect
profile, the pediatric clinical experience with ritonavir, and the convenience of an oral medication, the
Panel recommends the use of ritonavir-boosted nirmatrelvir for nonhospitalized adolescents ≥12 years
of age and weighing ≥40 kg who have mild to moderate COVID-19 and who are at the highest risk of
progression to severe COVID-19 (BIII).
Because of the potential for significant drug-drug interactions with some concomitant medications,
ritonavir-boosted nirmatrelvir may not be the safest choice for some patients. See Ritonavir-Boosted
Nirmatrelvir (Paxlovid) and Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid)
and Concomitant Medications for more information.
Remdesivir
Remdesivir is approved by the FDA for use in hospitalized and nonhospitalized pediatric patients aged
≥28 days and weighing ≥3.0 kg.33 Remdesivir is expected to be active against the Omicron variant of

concern (VOC), although in vitro and clinical data are currently limited.34
In a study that included nonhospitalized adults with mild to moderate COVID-19 who were at high
risk of progression to severe disease, treatment with 3 consecutive days of intravenous (IV) remdesivir
resulted in an 87% relative reduction in the risk of hospitalization or death, when compared to placebo.35
Although adolescents aged ≥12 years were eligible for inclusion, the trial included only 8 patients aged
<18 years; therefore, no conclusions regarding the efficacy of remdesivir in children can be made from
this trial. In addition, clinical experience data from hospitalized children with COVID-19 who received
remdesivir through a compassionate use program have been reported.2,36 Given the demonstrated
efficacy of remdesivir in the overall study population, its overall favorable side effect profile, and
clinical experience with remdesivir in hospitalized children, remdesivir, as an alternative to ritonavir-
boosted nirmatrelvir, can be considered for children aged ≥12 years who are at the highest risk of
progression to severe COVID-19 (CIII).
For nonhospitalized children aged <12 years who are at the highest risk of progression to severe
disease and for children who are at intermediate risk of severe disease, there is insufficient evidence
to recommend either for or against the routine use of remdesivir for the treatment of COVID-19. An
additional, important consideration is that remdesivir requires an IV infusion for 3 consecutive days, so
logistical constraints may preclude the administration of remdesivir in many settings.

Although 4 anti-SARS-CoV-2 monoclonal antibody (mAb) products have received FDA EUAs for the
treatment of nonhospitalized adolescents aged ≥12 years and weighing ≥40 kg who are at high risk of
severe COVID-19, only bebtelovimab is currently available for use, as it is the only anti-SARS-CoV-2
mAb with in vitro activity against the Omicron VOC and its subvariants (BA.1, BA1.1., BA.2, BA.4,
BA.5).37
Bebtelovimab was studied in different arms of the Phase 2 BLAZE-4 clinical trial in nonhospitalized
patients, which was conducted before the emergence of the Omicron VOC.37 Although in vitro data
showed that bebtelovimab demonstrated activity against all known Omicron subvariants, no clinical data
determine the efficacy of bebtelovimab for the treatment of COVID-19 caused by the Omicron VOC.
Therefore, there is insufficient evidence for the Panel to recommend either for or against the use of
bebtelovimab in pediatric patients aged ≥12 years who have mild to moderate COVID-19 and who are at
the highest risk of progression to severe COVID-19.
Pharmacologic Therapies Not Recommended for Nonhospitalized Children With

COVID-19
Molnupiravir
The FDA EUA for molnupiravir is limited to people aged ≥18 years, and there are no data on the
safety of molnupiravir in children.38 The mechanism of action of molnupiravir has raised concerns
about potential mutagenesis in mammalian cells. See Molnupiravir and Therapeutic Management of
Nonhospitalized Adults With COVID-19 for additional information.
Corticosteroids
Corticosteroids are not indicated for the treatment of COVID-19 in nonhospitalized children. However,
corticosteroids should be used per usual standards of care in children with asthma and croup triggered by
SARS-CoV-2 infection. Children with COVID-19 who are receiving corticosteroids for an underlying
condition should continue this therapy as directed by their health care providers.

References
1. Schuster JE, Halasa NB, Nakamura M, et al. A description of COVID-19-directed therapy in children admitted
to US intensive care units 2020. J Pediatric Infect Dis Soc. 2022;11(5):191-198. Available at:
2. Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe
COVID-19. Pediatrics. 2021;147(5):e202004780. Available at:
3. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children
with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2. J Pediatric Infect Dis Soc.
4. Dulek DE, Fuhlbrigge RC, Tribble AC, et al. Multidisciplinary guidance regarding the use of
immunomodulatory therapies for acute coronavirus disease 2019 in pediatric patients. J Pediatric Infect Dis
Soc. 2020;9(6):716-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32808988.
5. Wolf J, Abzug MJ, Anosike BI, et al. Updated guidance on use and prioritization of monoclonal antibody
therapy for treatment of COVID-19 in adolescents. J Pediatric Infect Dis Soc. 2022;11(5):177-185. Available
6. Havers FP, Whitaker M, Self JL, et al. Hospitalization of adolescents aged 12–17 years with laboratory-
confirmed COVID-19—COVID-NET, 14 states, March 1, 2020–April 24, 2021. MMWR Morb Mortal Wkly
Rep. 2021;70(23):851-857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34111061.
7. Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment
of coronavirus disease 2019 in children and adolescents. J Pediatric Infect Dis Soc. 2021;10(5):629-634.
8. Graff K, Smith C, Silveira L, et al. Risk factors for severe COVID-19 in children. Pediatr Infect Dis J.
9. Fernandes DM, Oliveira CR, Guerguis S, et al. Severe acute respiratory syndrome coronavirus 2 clinical
syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr. 2021;230:23-31.
13. Mukkada S, Bhakta N, Chantada GL, et al. Global characteristics and outcomes of SARS-CoV-2 infection
in children and adolescents with cancer (GRCCC): a cohort study. Lancet Oncol. 2021;22(10):1416-1426.
Washington, DC, metropolitan region. J Pediatr. 2020;223:199-203. Available at: https://www.ncbi.nlm.nih.

18. Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in
Wuhan: a single center’s observational study. World J Pediatr. 2020;16(3):251-259. Available at:
19. Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients
with coronavirus disease 2019 (COVID-19) in a children’s hospital in New York City, New York. JAMA
Pediatr. 2020;174(10):e202430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492092.
20. Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations associated with COVID-19 among children and
adolescents—COVID-NET, 14 states, March 1, 2020–August 14, 2021. MMWR Morb Mortal Wkly Rep.
21. Wanga V, Gerdes ME, Shi DS, et al. Characteristics and clinical outcomes of children and adolescents aged
<18 years hospitalized with COVID-19—six hospitals, United States, July–August 2021. MMWR Morb
22. Centers for Disease Control and Prevention. Stay up to date with your COVID-19 vaccines. 2022. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html. Accessed July 25, 2022.
23. Dorabawila V, Hoefer D, Bauer UE, et al. Risk of infection and hospitalization among vaccinated and
unvaccinated children and adolescents in New York after the emergence of the Omicron variant. JAMA.
24. Klein NP, Stockwell MS, Demarco M, et al. Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2
mRNA vaccination in preventing COVID-19-associated emergency department and urgent care encounters
and hospitalizations among nonimmunocompromised children and adolescents aged 5–17 years—VISION
Network, 10 states, April 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(9):352-358. Available
25. Antoon JW, Grijalva CG, Thurm C, et al. Factors associated with COVID-19 disease severity in US children
and adolescents. J Hosp Med. 2021;16(10):603-610. Available at:
26. Parcha V, Booker KS, Kalra R, et al. A retrospective cohort study of 12,306 pediatric COVID-19 patients in
the United States. Sci Rep. 2021;11(1):10231. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33986390.
27. Holmes L, Jr, Wu C, Hinson R, et al. Black-White risk differentials in pediatric COVID-19 hospitalization and
intensive care unit admissions in the USA. J Racial Ethn Health Disparities. 2022;Published online ahead of
28. Woodruff RC, Campbell AP, Taylor CA, et al. Risk factors for severe COVID-19 in children. Pediatrics.
2021;149(1):e2021053418. Available at: https://pubmed.ncbi.nlm.nih.gov/34935038/.
29. Wiltz JL, Feehan AK, Molinari NM, et al. Racial and ethnic disparities in receipt of medications for treatment
of COVID-19—United States, March 2020–August 2021. MMWR Morb Mortal Wkly Rep. 2022;71(3):96-
30. Gold JAW, Kelleher J, Magid J, et al. Dispensing of oral antiviral drugs for treatment of COVID-19 by ZIP
code-level social vulnerability—United States, December 23, 2021–May 21, 2022. MMWR Morb Mortal Wkly
Rep. 2022;71(25):825-829. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35737571.
32. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults
pubmed/35172054.
33. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2022. Available at: https://www.

accessdata.fda.gov/drugsatfda_docs/label/2022/214787Orig1s015lbl.pdf.
SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252. Available at: https://
www.ncbi.nlm.nih.gov/pubmed/35085683.
36. Mendez-Echevarria A, Perez-Martinez A, Gonzalez Del Valle L, et al. Compassionate use of remdesivir in
children with COVID-19. Eur J Pediatr. 2021;180(4):1317-1322. Available at:

Therapeutic Management of Hospitalized
This section outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the
therapeutic management of children (i.e., pediatric patients aged <18 years) who are hospitalized for
COVID-19. Throughout this section, the term “COVID-19” refers to the acute, primarily respiratory
illness due to infection with SARS-CoV-2. Multisystem inflammatory syndrome in children (MIS-C)
refers to the postinfectious inflammatory condition.
Treatment Considerations for Children With COVID-19

Currently, no pediatric clinical trial results evaluating the treatment of COVID-19 have been published.
Data evaluating pharmacologic therapy in children with COVID-19 are limited largely to descriptive
reports.1,2 Therefore, more high-quality randomized trials, observational studies, and pharmacokinetic
studies are urgently needed. Whenever possible, clinical trials of therapeutics and multicenter
observational cohorts should enroll children with COVID-19.
Published guidance documents on the treatment of COVID-19 in children have been mostly extrapolated
from recommendations for adults with COVID-19, recommendations for children with other viral
infections, and expert opinion.3-5 Applying adult data from COVID-19 trials to children is a unique
challenge because most children experience a mild course of illness with COVID-19. Relative to adults,
children with COVID-19 have substantially lower mortality and less need for hospitalization. Because
of these differences in epidemiology and disease severity, the effect sizes for children are likely to be
smaller than those observed in adults; therefore, to produce a beneficial outcome, the number needed
to treat is higher. Collectively, these factors influence the risk versus benefit balance for pharmacologic
therapies in children.
Other challenges are the uncertainty about which comorbid conditions place children at the highest
risk of severe COVID-19 and the uncertainty about the absolute magnitude of the increased risk from
those comorbid conditions. For children with COVID-19, the number and severity of their comorbid
conditions influence decisions about pharmacologic treatment. For more information on risk factors for
children with COVID-19, see Special Considerations in Children.
Recommendations
In the absence of sufficient clinical trial data on the treatment of children with COVID-19, the Panel’s
recommendations for the therapeutic management of hospitalized children are based largely on
adult safety and efficacy data from clinical trials, the child’s risk of disease progression, and expert
opinion (see Table 3c). For the Panel’s recommendations for adults, see Therapeutic Management of
Hospitalized Adults With COVID-19.
In general, adult data are most applicable to older children with severe COVID-19 and predominantly
lower respiratory tract disease. Extrapolation of adult data to children with SARS-CoV-2 infection who
present with clinical syndromes common to other respiratory viruses (e.g., bronchiolitis, croup, asthma)
is challenging. No evidence indicates that these syndromes should be managed differently when caused
by SARS-CoV-2 infection. Clinical judgment is needed when applying these recommendations to
patients, particularly young children.

Table 3c. Therapeutic Management of Hospitalized Children With COVID-19
Disease Severity Panel’s Recommendations
For children aged ≥12 years admitted for COVID-19, use prophylactic
Hospitalized for COVID-19
anticoagulation unless contraindicated (BIII).
For children admitted for COVID-19 who are at the highest risk of
progression to severe COVID-19,a consider using remdesivirb for
children aged 12–17 years (CIII). There is insufficient evidence for using
Does Not Require Supplemental Oxygen remdesivir in children aged 28 days to <12 years.
For children admitted for reasons other than COVID-19 who have mild to
moderate COVID-19 and are at the highest risk of progression,a refer to
Therapeutic Management of Nonhospitalized Children With COVID-19.
• Remdesivirb (BIII)
Requires Conventional Oxygenc
• Dexamethasone plus remdesivirb for children with increasing oxygen
needs, particularly adolescents (BIII)
• Dexamethasone (BIII)
Requires Oxygen Through High-Flow • Dexamethasone plus remdesivirb (BIII)
Device or NIVd For children who do not have rapid (e.g., within 24 hours) improvement in
oxygenation after initiation of dexamethasone, baricitinibe or tocilizumab
can be considered for children aged 12–17 years (BIII) and for children
Dexamethasonef (AIII)
For children who do not have rapid (e.g., within 24 hours) improvement in
Requires MV or ECMOf oxygenation after initiation of dexamethasone, baricitinibe or tocilizumab
may be considered for children aged 12–17 years (BIII) and for children
a
F or example, for children who are severely immunocompromised regardless of COVID-19 vaccination status and those
who are unvaccinated and have additional risk factors for progression (see Therapeutic Management of Nonhospitalized
Children With COVID-19).
b
The clinical benefit of remdesivir is greatest if it is initiated within 10 days of symptom onset. Remdesivir should be
given for 5 days or until hospital discharge, whichever comes first.
c
Conventional oxygen refers to oxygen supplementation that is not high-flow oxygen, NIV, MV, or ECMO.
d
Patients who are receiving NIV or MV at baseline and require a substantial increase in baseline support should be treated
per the recommendations for patients requiring new NIV or MV.
e
Tofacitinib is an alternative if baricitinib is not available (BIII).
f
For children who started receiving remdesivir before admission to the ICU, the remdesivir should be continued to
complete the treatment course.
Key: ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; MV = mechanical ventilation; NIV =
noninvasive ventilation

Rationale for the Panel’s Recommendations for Drug Therapies
Remdesivir
Remdesivir is approved by the Food and Drug Administration (FDA) for hospitalized and
nonhospitalized pediatric patients aged ≥28 days and weighing ≥3 kg.6 Remdesivir is expected to
be active against the Omicron variant of concern, although in vitro and in vivo data are currently
limited (see Remdesivir).7 For most hospitalized patients, remdesivir should be administered for 5
days or until the patient is ready for discharge, whichever comes first. Treatment may be extended
to 10 days for severely ill patients who have not clinically improved or for patients who are severely
immunocompromised.
In a trial conducted predominantly among hospitalized patients with COVID-19 who did not receive
supplemental oxygen at enrollment, a 5-day course of remdesivir was associated with greater clinical
improvement when compared with the standard of care.8 Remdesivir was also studied in ACTT-1, a
double-blind, placebo-controlled, randomized trial for hospitalized adults with COVID-19 who received
remdesivir for 10 days (or until hospital discharge) or placebo.9 The study reported that the remdesivir
arm had a shorter time to clinical recovery than the placebo arm (10 days vs. 15 days; P < 0.001). A
subgroup analysis demonstrated that patients who received conventional oxygen therapy had the greatest
benefit. No benefit was detected for patients who did not receive supplemental oxygen or for those who
received noninvasive ventilation (NIV) or mechanical ventilation. No statistically significant differences
in mortality or in the need for new mechanical ventilation were detected, and the benefit of remdesivir in
this study was limited to patients with symptoms for <10 days.
Three open-label trials in adults compared remdesivir to a local standard of care.10,11 The World Health
Organization’s Solidarity trial enrolled hospitalized adult patients with COVID-19 in 35 countries. In
the overall cohort, no difference in hospital mortality was demonstrated (14.5% in the remdesivir arm
vs. 15.6% in the usual care arm; rate ratio 0.91; 95% CI, 0.82–1.02; P = 0.12). However, in the subset of
patients receiving supplemental oxygen but not NIV or mechanical ventilation, remdesivir significantly
reduced the risk of in-hospital mortality by 13% (14.6% vs. 16.3%; rate ratio 0.87; 95% CI, 0.76–0.99; P
= 0.03).10
The CATCO study demonstrated similar findings. Treatment with remdesivir, when compared with
standard care, reduced the need for mechanical ventilation in hospitalized adults with COVID-19 (8%
vs. 15%; relative risk 0.53; 95% CI, 0.38–0.75). In this study, 87% of patients in both the remdesivir
arm and standard of care arm received dexamethasone.12 In contrast to these 2 studies, the DisCoVeRy
trial demonstrated no difference for any clinical outcome when the use of remdesivir plus usual care was
compared to usual care alone.11
The efficacy of remdesivir has not been evaluated in clinical trials of hospitalized children with
COVID-19. A Phase 2/3, single-arm, open-label study evaluated the safety, tolerability, and
pharmacokinetics of remdesivir in 53 hospitalized children with COVID-19.13 Children weighing 3 kg to
<40 kg received remdesivir 5 mg/kg on Day 1, followed by remdesivir 2.5 mg/kg daily. Adverse events
included acute kidney injury (11%) and an increase in alanine transaminase levels (8%). However, this
study did not have a placebo group, limiting the ability to draw conclusions regarding the significance of
these adverse events. Published observational data are limited to descriptive case series.1,2
Findings from the adult trials and the pediatric pharmacokinetic study led the Panel to recommend
remdesivir for hospitalized children who have a new or increasing need for conventional oxygen (BIII)
and to recommend remdesivir in combination with dexamethasone for children who require oxygen

through a high-flow device or NIV (BIII). It is not known if remdesivir offers an additional clinical
benefit to standard care in younger children with SARS-CoV-2 infection who are receiving respiratory
support for bronchiolitis, asthma, or croup.
For children hospitalized for COVID-19 who do not require supplemental oxygen, the Panel
recommends remdesivir for children aged 12 to 17 years who are at the highest risk for progression
to severe disease (CIII). This recommendation was extrapolated from the findings of the PINETREE
study, which demonstrated a reduction in hospitalization among high-risk, unvaccinated adults treated
in the outpatient setting.14 However, there is insufficient evidence for or against the use of remdesivir
in children aged 28 days to <12 years and weighing ≥3 kg who do not require supplemental oxygen.
Given the reported clinical experience with the use of remdesivir among younger patients,13 the use of
remdesivir in high-risk, younger children who do not require supplemental oxygen may be considered
on a case-by-case basis.
Dexamethasone
Dexamethasone was evaluated in the RECOVERY trial, which was an open-label, randomized trial
conducted in the United Kingdom.15 The trial compared the use of up to 10 days of dexamethasone 6
mg, administered by intravenous injection or orally, with usual care among hospitalized adults with
COVID-19. The primary outcome was all-cause mortality at 28 days, which occurred in 22.9% of
patients randomized to receive dexamethasone versus 25.7% of patients randomized to receive usual
care (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001). Patients who required mechanical
ventilation or extracorporeal membrane oxygenation (ECMO) had the greatest effect size (29.3%
vs. 41.4%; rate ratio 0.64; 95% CI, 0.51–0.81). No difference in outcomes was observed for patients
who did not require supplemental oxygen (17.8% vs. 14.0%; rate ratio 1.19; 95% CI, 0.92–1.55). For
the 28-day mortality outcome, a difference between arms was observed for patients who required
supplemental oxygen (23.3% vs. 26.2%; rate ratio 0.82; 95% CI, 0.72–0.94). However, it should be
noted that these patients were a heterogeneous group, including those who received either conventional
oxygen or NIV. See Corticosteroids for detailed information.
The safety and efficacy of using dexamethasone or other corticosteroids for the treatment of COVID-19
have not been evaluated in pediatric patients. Given that the mortality for adults in the placebo arm in
the RECOVERY trial was substantially greater than the mortality generally reported for children with
COVID-19, caution is warranted when extrapolating from recommendations for adults and applying
them to patients aged <18 years.
However, because of the effect size observed in the RECOVERY trial, the Panel recommends the use
of dexamethasone for children who require mechanical ventilation or ECMO (AIII). The Panel also
recommends the use of dexamethasone, with or without concurrent remdesivir, for children who
require oxygen through a high-flow device or NIV (BIII). The Panel does not recommend routine
use of corticosteroids for children who require only conventional oxygen, but corticosteroids can be
considered in combination with remdesivir for patients with increasing oxygen needs, particularly
adolescents (BIII).
There is evidence demonstrating that the use of corticosteroids does not benefit infants with viral
bronchiolitis not related to COVID-19, and current American Academy of Pediatrics guidelines
recommend against the use of corticosteroids in this population.16 There are no COVID-19-specific
data to support the use of corticosteroids in children with bronchiolitis due to SARS-CoV-2 infection.
Corticosteroids should be used per the usual standards of care in children with asthma and croup
triggered by SARS-CoV-2.

The use of dexamethasone for the treatment of severe COVID-19 in children who are profoundly
immunocompromised has not been evaluated, and there is a potential risk of harm. Therefore, the
use of corticosteroids should be considered on a case-by-case basis in consultation with relevant
specialists, and the benefits and risks of the therapy should be weighed. If dexamethasone is not
available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be
considered. The dexamethasone dose for pediatric patients is 0.15 mg/kg (with a maximum dose of 6
mg) once daily for ≤10 days.
Baricitinib
The Janus kinase inhibitor baricitinib was recently approved by the FDA for the treatment of COVID-19
in hospitalized adults. An FDA Emergency Use Authorization (EUA) for baricitinib remains active
for the treatment of COVID-19 in hospitalized children aged 2 to 17 years who require supplemental
oxygen, NIV, mechanical ventilation, or ECMO.17
In the COV-BARRIER trial, adults with COVID-19 pneumonia were randomized to receive baricitinib
or standard care. Patients treated with baricitinib showed a reduction in mortality when compared
with those who received standard care; the reduction was greatest in patients who received high-flow
oxygen or NIV. Similarly, the ACTT-2 trial in adults showed that patients who received baricitinib plus
remdesivir had improved time to recovery when compared with patients who received remdesivir alone.
This effect was most pronounced in patients who received high-flow oxygen or NIV.18 In the ACTT-4
trial, 1,010 patients were randomized 1:1 to receive baricitinib plus remdesivir or dexamethasone
plus remdesivir. The study reported no difference between the arms for the outcome of mechanical
ventilation-free survival.19
In the RECOVERY trial, 8,156 patients, including 33 children aged 2 to 17 years, were randomized
to receive baricitinib or usual care (95% received corticosteroids).20 Treatment with baricitinib was
associated with a 13% proportional reduction in mortality, with the greatest effect size occurring in
patients who received NIV. The RECOVERY investigators included these patients in a meta-analysis
and found that treatment with baricitinib was associated with a 20% proportional reduction in mortality
(rate ratio 0.80; 95% CI, 0.72–0.89; P < 0.0001). See Kinase Inhibitors: Janus Kinase Inhibitors
and Bruton’s Tyrosine Kinase Inhibitors and Therapeutic Management of Hospitalized Adults With
COVID-19 for additional information. These data in adults indicate that baricitinib is likely to be most
beneficial for patients receiving noninvasive forms of respiratory support.
Several open-label trials and cohort studies have evaluated baricitinib in children with autoinflammatory
and rheumatic diseases, including many children aged <5 years, and found the treatment was well
tolerated; however, the pharmacokinetics of baricitinib in younger children are not well studied.21-24
Information on the safety and effectiveness of the use of baricitinib in children with COVID-19 is
limited to case reports.
In contrast to the strong recommendation for its use for adults, baricitinib is not considered the standard
of care for all children who require high-flow oxygen or NIV because of the low mortality in children
with COVID-19 (especially in young children) and the limited data on the use of baricitinib in these
children.
Extrapolating from clinical trials among adults with COVID-19, the Panel recommends that:
• For children who require oxygen through a high-flow device or NIV and do not have rapid (e.g.,
within 24 hours) improvement in oxygenation after initiation of dexamethasone, baricitinib can
be considered for children aged 12 to 17 years (BIII) and for children aged 2 to 11 years (CIII).

• For children who require mechanical ventilation or ECMO and do not have rapid (e.g., within
24 hours) improvement in oxygenation after initiation of dexamethasone, baricitinib may be
considered for children aged 12 to 17 years (BIII) and for children aged 2 to 11 years (CIII).
Clinicians should consult with specialists experienced in treating children with immunosuppression (e.g.,
with pediatric infectious disease, pediatric rheumatology) when considering administering baricitinib
to hospitalized children with COVID-19. Data from adults indicate that baricitinib should be initiated
promptly; ideally, it should be initiated at the onset of clinical deterioration or respiratory failure.
Tofacitinib
There are no data on the efficacy of tofacitinib in pediatric patients with COVID-19; the Panel’s
recommendation is extrapolated from data in adults. The STOP-COVID trial compared tofacitinib to
the standard of care in adults hospitalized for COVID-19 pneumonia.25 The standard of care included
glucocorticoids for most patients. The study demonstrated a reduction in mortality and respiratory failure
at Day 28 for the tofacitinib arm when compared with the placebo arm. Tofacitinib has been studied
less extensively than baricitinib for the treatment of COVID-19. Thus, tofacitinib, as an alternative to
baricitinib, is recommended to be used in combination with dexamethasone in adults with COVID-19
who require high-flow oxygen or NIV. See Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s
Tyrosine Kinase Inhibitors and Therapeutic Management of Hospitalized Adults With COVID-19 for
additional information.
No trials have evaluated the safety of using tofacitinib in children with COVID-19. Overall, there has
been more clinical experience with the use of tofacitinib than baricitinib in children, particularly when
used in children with juvenile idiopathic arthritis (JIA) as young as 2 years of age. A Phase 1 study
was conducted to define the pharmacokinetics and safety of using tofacitinib in children,26 and a Phase
3, double-blind, randomized, placebo-controlled trial investigated the efficacy of using tofacitinib in
children with JIA.27 Tofacitinib is available as a liquid formulation for children.
Given the established safety of tofacitinib in the pediatric population, tofacitinib can be considered an
alternative for children hospitalized for COVID-19 if baricitinib is not available (BIII). The dose of
tofacitinib that should be used to treat hospitalized children with COVID-19 has not been established.
As with baricitinib, the dose of tofacitinib for hospitalized children with COVID-19 likely needs to be
higher than the dose typically used to treat pediatric rheumatologic diseases. Therefore, clinicians should
consult with specialists experienced in treating children with immunosuppression (e.g., with pediatric
infectious disease, pediatric rheumatology) when considering administering tofacitinib to hospitalized
children with COVID-19.
Tocilizumab
Tocilizumab is an interleukin (IL)-6 inhibitor that has received an FDA EUA for the treatment
of hospitalized adults and children with COVID-19 who are aged ≥2 years, receiving systemic
corticosteroids, and require supplemental oxygen, NIV, mechanical ventilation, or ECMO.28 Two
large randomized controlled trials (REMAP-CAP and RECOVERY) conducted among hospitalized
adults with COVID-19 have demonstrated reductions in mortality with the use of tocilizumab. See
Interleukin-6 Inhibitors and Therapeutic Management of Hospitalized Adults With COVID-19 for
additional information.
The RECOVERY trial was an open-label study that included hospitalized adults who had an oxygen
saturation of <92% on room air or were receiving supplemental oxygen therapy; patients also had
C-reactive protein levels ≥75 mg/L.29 Patients were randomized to receive tocilizumab plus usual care
or usual care alone. Mortality at 28 days was significantly lower in the tocilizumab arm compared to

the usual care arm. The REMAP-CAP trial included adults with suspected or confirmed COVID-19
who were admitted to an intensive care unit and received either respiratory (i.e., NIV or mechanical
ventilation) or cardiovascular organ (i.e., vasopressor/inotrope) support.30 Patients were randomized
within 24 hours of organ failure to receive either tocilizumab or sarilumab (the majority received
tocilizumab) or to receive standard care. The median number of organ support-free days was higher for
those who received tocilizumab than for those who received standard care, and in-hospital mortality
was lower in the combined tocilizumab or sarilumab arm than in the standard care arm. In both
studies, the majority of patients received dexamethasone (82% in the RECOVERY trial and 93% in the
REMAP-CAP trial).
Studies have evaluated the use of tocilizumab for the treatment of non-COVID-19 conditions in
children, including JIA31-35 and chimeric antigen receptor T cell-related cytokine release syndrome.36
The FDA approved tocilizumab for use in children aged ≥2 years for these indications.31-35 The use of
tocilizumab for children with severe cases of COVID-19 has been described only in case series.37-39
Extrapolating from clinical trials among adults with COVID-19, the Panel recommends that:
• For children who require oxygen through a high-flow device or NIV and who do not have
rapid (e.g., within 24 hours) improvement in oxygenation after initiation of dexamethasone,
tocilizumab can be considered for children aged 12 to 17 years (BIII) and for children aged 2 to
11 years (CIII).
• For children who require mechanical ventilation or ECMO and who do not have rapid (e.g., within
24 hours) improvement in oxygenation after initiation of dexamethasone, if tocilizumab has not
been started, addition of tocilizumab may be considered for children aged 12 to 17 years (BIII)
and for children aged 2 to 11 years (CIII).
Data from REMAP-CAP and RECOVERY are most likely to be applicable to high-risk adolescent
patients. Clinicians should consult with specialists experienced in treating children with
immunosuppression (e.g., with pediatric infectious disease, pediatric rheumatology) when considering
the use of tocilizumab in younger children with COVID-19.
Sarilumab
Sarilumab, a monoclonal antibody that blocks IL-6 receptors, is not authorized by the FDA for the
treatment of COVID-19. Data evaluating the efficacy of sarilumab for the treatment of COVID-19
hyperinflammation are limited, and there is a lack of pediatric dosing information. Therefore, the Panel
recommends against the use of sarilumab in hospitalized children with COVID-19, except in a clinical
trial (AIII).
Anticoagulation for Children With COVID-19

Limited data characterize the risk of thromboembolic disease in children with COVID-19. In a
multicenter, retrospective cohort study that included 814 pediatric patients with COVID-19 or MIS-C,40
thromboembolic events were detected in 2.1% of patients with COVID-19 and in 6.5% of patients
with MIS-C. No trials to define the optimal approach to anticoagulation have been conducted among
children. Therefore, the Panel recommends prophylactic anticoagulation for children aged ≥12 years
who are hospitalized for COVID-19, unless there are contraindications (BIII). There is insufficient
evidence for the Panel to recommend either for or against anticoagulation in younger hospitalized
children with COVID-19, although institutional standards for anticoagulation should be followed. There
is insufficient evidence for the Panel to recommend either for or against high-intensity anticoagulation
for children of any age with COVID-19.

References
1. Schuster JE, Halasa NB, Nakamura M, et al. A description of COVID-19-directed therapy in children admitted
to US intensive care units 2020. J Pediatric Infect Dis Soc. 2022;11(5):191-198. Available at:
2. Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe
COVID-19. Pediatrics. 2021;147(5):e202004780. Available at:
4. Dulek DE, Fuhlbrigge RC, Tribble AC, et al. Multidisciplinary guidance regarding the use of
immunomodulatory therapies for acute coronavirus disease 2019 in pediatric patients. J Pediatric Infect Dis
Soc. 2020;9(6):716-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32808988.
5. Wolf J, Abzug MJ, Anosike BI, et al. Updated guidance on use and prioritization of monoclonal antibody
therapy for treatment of COVID-19 in adolescents. J Pediatric Infect Dis Soc. 2022;11(5):177-185. Available
6. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214787Orig1s015lbl.pdf.
8. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in
patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at:
9. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J
10. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with
COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet.
11. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care
alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a Phase 3, randomised,
controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221. Available at:
12. Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada:
a randomized controlled trial. CMAJ. 2022;194(7):E242-E251. Available at:
13. Ahmed A, Rojo P, Agwu A, et al. Remdesivir treatment for COVID-19 in hospitalized children: CARAVAN
interim results. 2022. Available at: https://www.croiconference.org/abstract/remdesivir-treatment-for-covid-19-
in-hospitalized-children-caravan-interim-results/. Accessed July 7, 2022.
15. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients
pubmed/32678530.
16. Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline: the diagnosis, management, and
prevention of bronchiolitis. Pediatrics. 2014;134(5):e1474-e1502. Available at: https://www.ncbi.nlm.nih.gov/

pubmed/25349312.
baricitinib. 2022. Available at: https://www.fda.gov/media/143823/download.
2022;400(10349):359-368. Available at: https://pubmed.ncbi.nlm.nih.gov/35908569/.
21. Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of
autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041-3052. Available at:
22. Kim H, Dill S, O’Brien M, et al. Janus kinase (JAK) inhibition with baricitinib in refractory juvenile
dermatomyositis. Ann Rheum Dis. 2021;80(3):406-408. Available at:
23. Vanderver A, Adang L, Gavazzi F, et al. Janus kinase inhibition in the Aicardi-Goutieres syndrome. N Engl J
24. Kim H, Brooks KM, Tang CC, et al. Pharmacokinetics, pharmacodynamics, and proposed dosing of the
oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients. Clin
Pharmacol Ther. 2018;104(2):364-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29134648.
26. Ruperto N, Brunner HI, Zuber Z, et al. Pharmacokinetic and safety profile of tofacitinib in children with
polyarticular course juvenile idiopathic arthritis: results of a Phase 1, open-label, multicenter study. Pediatr
Rheumatol Online J. 2017;15(1):86. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29282090.
27. Ruperto N, Brunner HI, Synoverska O, et al. Tofacitinib in juvenile idiopathic arthritis: a double-blind,
placebo-controlled, withdrawal Phase 3 randomised trial. Lancet. 2021;398(10315):1984-1996. Available at:
28. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Actemra
(tocilizumab). 2021. Available at: https://www.fda.gov/media/150321/download.
31. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course
juvenile idiopathic arthritis: results from a Phase 3, randomised, double-blind withdrawal trial. Ann Rheum
Dis. 2015;74(6):1110-1117. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24834925.
32. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab for polyarticular-course
juvenile idiopathic arthritis in the open-label two-year extension of a Phase III trial. Arthritis Rheumatol.
33. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic
arthritis. N Engl J Med. 2012;367(25):2385-2395. Available at:

34. DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile
idiopathic arthritis. Arthritis Care Res (Hoboken). 2012;64(7):1001-1010. Available at: https://www.ncbi.nlm.
nih.gov/pubmed/22290637.
35. Horneff G, Schulz AC, Klotsche J, et al. Experience with etanercept, tocilizumab and interleukin-1
inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther.
2017;19(1):256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29166924.
36. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced
cytokine release syndrome. Expert Rev Clin Immunol. 2019;15(8):813-822. Available at:
37. Derespina KR, Kaushik S, Plichta A, et al. Clinical manifestations and outcomes of critically ill children and
adolescents with coronavirus disease 2019 in New York City. J Pediatr. 2020;226:55-63. Available at:
38. Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and outcomes of children with coronavirus
disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units. JAMA
Pediatr. 2020;174(9):868-873. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392288.
40. Whitworth H, Sartain SE, Kumar R, et al. Rate of thrombosis in children and adolescents hospitalized
with COVID-19 or MIS-C. Blood. 2021;138(2):190-198. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33895804.

Therapeutic Management of Hospitalized
Pediatric Patients With Multisystem Inflammatory
Syndrome in Children (MIS-C) (With Discussion on
Multisystem Inflammatory Syndrome in Adults [MIS-A])
Last Updated: February 24, 2022
This section outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for
the therapeutic management of pediatric patients with multisystem inflammatory syndrome in children
(MIS-C). The Centers for Disease Control and Prevention’s (CDC) case definition for MIS-C includes
“an individual aged <21 years.”1 The recommendations in this section encompass this age group. There
are no randomized controlled trials that compare treatment approaches for MIS-C. However, data from
descriptive and observational comparative effectiveness studies are available to guide treatment for
MIS-C. For information on the clinical manifestations of MIS-C, see Special Considerations in Children.
Multisystem Inflammatory Syndrome in Adults

It should be noted that adults can present with a syndrome similar to MIS-C, termed multisystem
inflammatory syndrome in adults (MIS-A).2 The published literature on MIS-A is restricted to small
case series that provide little data to guide treatment decisions for patients with MIS-A.3 Although Panel
members extrapolate from MIS-C data to aid in the management of individuals with MIS-A, it should be
emphasized that this approach to managing MIS-A has not been studied.

Table 3d. Therapeutic Management of Hospitalized Pediatric Patients With MIS-C
Patient Condition Panel’s Recommendations

Initial treatment for MIS-C includes both immunomodulatory and antithrombotic therapy.
Initial Immunomodulatory Therapy:
• IVIG 2 g/kg IBW/dose (up to a maximum total dose of 100 g)a IV plus low-to-moderate
dose methylprednisolone (1–2 mg/kg/day) IVa or another glucocorticoid at an equivalent
dosea (AIIb).
• The Panel recommends against the routine use of IVIG monotherapy for the treatment of
MIS-C unless glucocorticoid use is contraindicated (AIIb).
Intensification Immunomodulatory Therapy:
• For children with refractory MIS-C who do not improve within 24 hours of initial
immunomodulatory therapy, start one of the following (listed in alphabetical order) (AIII):
• High-dose anakinra 5–10 mg/kg IV or SUBQ daily (BIIb), or
• Higher-dose glucocorticoid (e.g., methylprednisolone 10–30 mg/kg/day IV or
equivalent glucocorticoid) (BIIb),b or
MIS-C
• Infliximabc 5–10 mg/kg IV for 1 dose (BIIb).
Antithrombotic Treatment:
• Low-dose aspirin (3–5 mg/kg/day, up to maximum daily dose of 81 mg) PO for all
patients without risk factors for bleeding (AIII), AND
• Anticoagulation for patients who fall under 1 of the following clinical scenarios:
• Therapeutic anticoagulation for patients with large CAAs according to the American
Heart Association guidelines for Kawasaki disease (AIII).
• Therapeutic anticoagulation for patients with moderate to severe LV dysfunction who
have no risk factors for bleeding (AIII).
• For patients with MIS-C who do not have large CAAs or moderate to severe LV
dysfunction, consider prophylactic or therapeutic anticoagulation on an individual
basis, taking into consideration risk factors for thrombosis. See Table 3e for additional
information.
a
Duration of therapy may vary. See duration in table and text below.
b
In certain patients with severe illness, intensification therapy may include dual therapy with higher-dose glucocorticoids
and infliximab or anakinra. Anakinra and infliximab should not be given in combination.
c
Infliximab should not be used in patients with macrophage activation syndrome.
Key: CAA = coronary artery aneurysm; IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LV
= left ventricular; MIS-C = multisystem inflammatory syndrome in children; PO = oral; SUBQ = subcutaneously

Table 3e. Dosing Regimens for the Drugs Recommended for the Treatment of MIS-C
Dosing Regimens
For infants, children, and adolescents unless
Drug Name otherwise specified. The doses listed are for Adverse Events Monitoring Parameters
FDA-approved indications for other diseases or
from reported experiences or clinical trials.
Intravenous • IVIG 2 g/kg IBW/dose (up to a maximum total • Hypersensitivity • Renal function
Immunoglobulin dose of 100 g) IV for 1 dose • F ever • Urine output
• In the event of cardiac dysfunction or fluid • Chills • CBC with differential
overload, consider administering IVIG in • Flushing • Infusion or injection-
divided doses (1 g/kg IBW/dose IV every 24 related AE
hours for 2 doses). • Hemolytic anemia
• Anaphylaxis
• Signs and symptoms
of hemolysis
Methyl- • Methylprednisolone 1 to 2 mg/kg/dose IV • Adrenal suppression • Blood pressure
prednisolone every 12 hours • Hyperglycemia • CBC with differential
• If the patient with MIS-C does not respond • Sodium retention • BMP
to 1–2 mg/kg/dose IV every 12 hours, • Fluid retention
increase the dose to 10–30 mg/kg/day (up
to maximum of 1,000 mg/day) IV for 1 to 3 • Leukocytosis
days. • Immune suppression
Anakinra Anakinra 5–10 mg/kg/day IV (preferred) or • Headache • CBC with differential
SUBQ in 1 to 4 divided doses • Fever • LFTs
• Hypersensitivity • Scr
• Immune suppression
• Transaminitis
Infliximab Infliximab 5–10 mg/kg/dose IV for 1 dose • Infusion-related • Monitor vital signs
reaction every 2–10 minutes
• Headache during infusion
• Immune suppression • CBC with differential
Aspirin Aspirin 3–5 mg/kg/dose (up to maximum of 81 • Gastrointestinal ulcers • Signs or symptoms of
mg/dose) PO once daily • Hypersensitivity bleeding
• Renal dysfunction • Renal function
Enoxaparin Enoxaparin Prophylaxis • Increased risk of • CBC with differential
Aged >2 Months to <18 Years: bleeding • Renal function
• 0.5 mg/kg/dose (up to maximum of 30 mg/ • Thrombocytopenia
dose) SUBQ every 12 hours
Enoxaparin Treatment
Aged >2 Months to <18 Years:
• 1 mg/kg/dose SUBQ every 12 hours
• Monitor antifactor Xa activity (treatment goal:
0.5 to 1).
Key: AE = adverse effect; BMP = blood mineral panel; CBC = complete blood count; FDA = Food and Drug Administration;
IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LFT = liver function test; MIS-C =
multisystem inflammatory syndrome in children; PO = orally; Scr = serum creatinine; SUBQ = subcutaneously

Treatment Considerations for Children With MIS-C
Initial Immunomodulatory Therapy for MIS-C
The Panel recommends consultation with a multidisciplinary team when managing immunomodulating
therapy for children with MIS-C (AIII). The multidisciplinary team may include experts in cardiology,
hematology, infectious disease, intensive care, and rheumatology. MIS-C is defined by multiorgan
dysfunction, and input from other pediatric subspecialists may be needed depending on the presentation
of the individual patient. Thus, children with MIS-C should be cared for at centers with access to these
pediatric specialists.
Intravenous immunoglobulin (IVIG) and glucocorticoids are the most commonly used
immunomodulatory medications in reported cohorts of children with MIS-C.4-12 The American
College of Rheumatology has outlined initial diagnostic and treatment considerations in MIS-C and
recommends IVIG in combination with glucocorticoids as first-tier therapy for most hospitalized
children with MIS-C.13 Multiple nonrandomized studies suggest that front-line IVIG in combination
with glucocorticoids is associated with less treatment failure, faster recovery of cardiac function, shorter
intensive care unit (ICU) stay, and decreased requirement for treatment escalation compared to IVIG
monotherapy.5,14-17 Based on these data, the Panel recommends using IVIG in combination with low-to-
moderate-dose glucocorticoids for children hospitalized with MIS-C (AIIb). The Panel recommends
against the routine use of IVIG monotherapy for the treatment of MIS-C unless glucocorticoid use is
contraindicated (AIIb).
IVIG should be given at a dose of 2 g/kg of ideal body weight up to a maximum dose of 100 grams. The
patient’s cardiac function and fluid status should be monitored carefully during the IVIG infusion. IVIG
can be given in divided doses of 1 g/kg of ideal body weight over 2 days if there is a concern about the
patient’s fluid status. Methylprednisolone 1 to 2 mg/kg/day, or another glucocorticoid at an equivalent
dose, is considered low-to-moderate glucocorticoid dosing. Once there is clinical improvement (i.e., the
child is afebrile, end organ dysfunction resolves, and inflammatory markers are trending downward),
a steroid taper should be initiated. Typically, the taper lasts for several weeks to avoid rebound
inflammation and is guided by the clinical status of the patient.
There remains uncertainty regarding the use of glucocorticoid monotherapy versus IVIG plus
glucocorticoids as initial therapy for MIS-C because comparative studies evaluating these 2 treatment
approaches have not been conducted. There are limited published data on long-term outcomes in
children with MIS-C who were treated with initial glucocorticoid monotherapy. Due to the risk of
coronary artery aneurysms in patients with MIS-C, and the proven benefit of IVIG in reducing the
frequency of coronary artery aneurysms in patients with Kawasaki disease, many clinicians continue to
incorporate IVIG into the treatment regimen for MIS-C.12,18 Currently, there is insufficient evidence for
the Panel to recommend either for or against the use of glucocorticoid monotherapy for MIS-C.
Summary of Published Data on Initial Immunomodulatory Therapy for MIS-C

Intravenous Immunoglobulin in Combination With Glucocorticoids
No randomized clinical trials evaluating IVIG plus glucocorticoids for the treatment of MIS-C have been
completed. The comparative benefit of adding steroids to IVIG for MIS-C treatment has been estimated
in observational cohorts using statistical techniques to adjust for confounders. The first of these studies
employed observation data from a national surveillance system cohort in France and used propensity
matching to compare short-term outcomes in children with MIS-C who were treated initially with IVIG
(2 gm/kg) alone or IVIG and methylprednisolone (most patients received 1.6–2 mg/kg/day for 5 days).14
The study team observed a lower risk of treatment failure (defined as persistence of fever 2 days after

treatment or recurrent fever within 7 days), lesser requirement for hemodynamic support, less severe left
ventricular dysfunction, and shorter ICU stays among the children initially treated with the combination
therapy.14 This was a small study, and only 32 patients treated with IVIG and methylprednisolone and 64
patients treated with IVIG alone could be matched based on propensity score.
A larger study in the United States analyzed data from the Overcoming COVID-19 surveillance registry
to evaluate immunomodulatory therapy for MIS-C. Initial treatment with IVIG plus glucocorticoids
(n = 103) was associated with a lower risk of cardiovascular dysfunction (measured using a composite
outcome of left ventricular ejection fraction of <55% or vasopressor use) on or after Day 2 compared
to treatment with IVIG alone in an equal number of propensity score-matched patients. The composite
outcome occurred in 17% of the patients in the IVIG plus glucocorticoids group versus 31% of the
patients in the IVIG alone group (risk ratio 0.56; 95% CI, 0.34–0.94).15 In addition, patients treated with
the combination of IVIG and glucocorticoids were less likely to require adjunctive immunomodulatory
therapy than those treated with IVIG alone. Methylprednisolone, the most prescribed glucocorticoid,
was administered to 353 patients (68% of the patients, including nonpropensity matched patients, in the
entire cohort). Among these patients, the dosing of methylprednisolone ranged from 2 mg/kg/day in 284
patients (80%) to 10 to 30 mg/kg/day in 69 patients (20%).
A third study, the international and pragmatic BATS study, compared patients with MIS-C who received
IVIG alone (n = 246) to those who received IVIG and glucocorticoids (n = 208). This study found
similar rates for the composite outcome of inotropic support or mechanical ventilation by Day 2 or later
or death in both treatment arms. The outcome occurred in 44 of 221 participants (21%) in the IVIG
alone arm versus 56 of 180 participants (31%) in the IVIG plus glucocorticoids arm (OR 0.77; 95% CI,
0.33–1.82). However, escalation of immunomodulatory treatment was less common among the patients
who received IVIG plus glucocorticoids than among those who received IVIG alone (OR 0.18; 95%
CI; 0.10–0.33). This study was notable for including patients with suspected MIS-C (i.e., patients who
did not meet CDC or World Health Organization [WHO] criteria for MIS-C) and voluntary reporting of
included cases by pediatricians. This multicenter study included sites from 34 counties with potential for
more variability in supportive care. In addition, the overall percentage of patients with abnormal cardiac
findings (12% of the 538 patients) was lower than in other cohorts.16
Intravenous Immunoglobulin Monotherapy
The use of IVIG is long established for Kawasaki disease, a syndrome that has overlapping
manifestations with MIS-C, and thus the product’s safety profile is well understood. In Kawasaki
disease, IVIG prevents the development of coronary artery aneurysms,18,19 a complication also observed
in some patients with MIS-C. IVIG is the most frequently used therapy for MIS-C. In a national survey
of U.S. institutional protocols for managing MIS-C, IVIG was the first-line therapy in 98% of 40
participating centers.20
Data on the efficacy of IVIG in MIS-C is extrapolated from case series that show mostly favorable
outcomes. In a series of 539 MIS-C cases, 77% of the children received IVIG. A sizeable proportion of
these children had reduced left ventricular ejection fraction at admission (172 of 503 evaluable patients
[34.2%]); the symptom resolved by Day 30 in 156 of the children (90.7%). Although these studies have
not described the occurrence of specific adverse events related to IVIG use, the dosing used (IVIG 2 g/
kg) has a well-established safety profile when used for Kawasaki disease.12
A limitation of all published studies on IVIG use for MIS-C is the frequent and often rapid
sequential addition of other immunomodulatory therapies, such as corticosteroids. In addition, there
is accumulating evidence that glucocorticoids given in combination with IVIG are more effective
as treatment for MIS-C (see discussion above). However, IVIG monotherapy may be a reasonable

treatment option for a small subset of patients with MIS-C who are stable (i.e., not in shock or with
organ-threatening disease) and have contraindications to glucocorticoid therapy. Such contraindications
may include concern about the impact on diagnostic evaluation or on the underlying medical condition.
Glucocorticoid Monotherapy
The BATS study described above also evaluated initial treatment with IVIG (n = 246) compared to
glucocorticoids (n = 99) and found no differences in primary or secondary outcomes between these
2 cohorts.16 However, in a subgroup analysis of patients who met the WHO criteria for MIS-C, the
glucocorticoid alone group (n = 78) had significantly fewer patients who required respiratory support by
Day 2 or later or who died than the IVIG alone group (n = 192).
The BATS study has several limitations. The length of follow-up in this study was not clearly defined,
and most outcome measures were evaluated around Day 2 of treatment. Rates of coronary artery
aneurysms and myocardial dysfunction and scarring as long-term outcomes were not reported. Further,
many patients received additional immunomodulatory agents after Day 1, including 47 patients in the
initial glucocorticoids alone group who also received IVIG. This study did not compare initial therapy
with glucocorticoids alone versus IVIG in combination with glucocorticoids. Further studies are needed
to replicate these findings and to evaluate the long-term outcomes in patients with MIS-C treated with
glucocorticoids alone.
Intensification Immunomodulatory Therapy for MIS-C

Children with MIS-C typically respond briskly to immunomodulatory therapy and show clinical
improvements within the first 24 hours of treatment. Treatment response is characterized by resolution
of fever, improvement of organ function, and reduced levels of inflammatory markers, particularly
C-reactive protein. By contrast, refractory disease is often accompanied by persistent fever, worsening
organ dysfunction, and increasing levels of inflammatory markers. Intensification therapy is
recommended for children with refractory MIS-C who do not improve within 24 hours of initial
immunomodulatory therapy (AIII). Children with uncontrolled MIS-C despite treatment with IVIG and
low-to-moderate-dose glucocorticoids will often continue to deteriorate without further intervention, and
this decline in clinical status can be quite rapid.
There are no comparative studies evaluating intensification therapies for MIS-C. Available data
on this topic are limited to results from cohort studies in patients with MIS-C, expert opinion, and
experience in treating other hyperinflammatory syndromes in children, such as Kawasaki disease and
macrophage activation syndrome. For children with refractory MIS-C, the Panel recommends additional
immunomodulatory therapy (in alphabetical order) with anakinra (BIIb), higher-dose glucocorticoids
(BIIb), or infliximab (BIIb). Currently, there is insufficient evidence to determine which of these agents is
most effective for intensification therapy in patients with refractory MIS-C. In certain patients with severe
illness, intensification therapy may include dual therapy with higher-dose glucocorticoids and anakinra
(BIII) or higher-dose glucocorticoids and infliximab (BIII). Anakinra and infliximab should not be
used in combination. A second dose of IVIG is not commonly reported in the literature as a strategy for
intensification therapy in MIS-C. This may be due to the high rates of IVIG resistance, the rapid pace of
disease escalation, and the risk for fluid overload in MIS-C patients.8 Therefore, the Panel recommends
against a second dose of IVIG for intensification therapy in patients with refractory MIS-C (BIII).
Patients with MIS-C who receive multiple immunomodulatory agents are at risk for infection and need
to be monitored carefully. Most children with MIS-C were previously healthy. In patients who have an
immune disorder or are taking immunosuppression therapy, the risk of infection is greater. The risks and
benefits of treating immunocompromised MIS-C patients with immunomodulatory agents need to be
evaluated on a case-by-case basis.

Summary of Published Data for Intensification Immunomodulatory Therapy for MIS-C
High-Dose Glucocorticoids
High-dose glucocorticoid therapy is defined as methylprednisolone (or an equivalent corticosteroid)
dosed at 10 to 30 mg/kg/day given intravenously (IV). Often, this higher dose of glucocorticoids is
given for 1 to 3 days with a subsequent return to low-to-moderate dosing (1–2 mg/kg/day). Multiple
observational studies have reported the use of high-dose glucocorticoids (methylprednisolone 10–30
mg/kg/day) in children with MIS-C.15,21-23 In addition, single-center treatment protocols for MIS-C that
incorporate high-dose glucocorticoids into the treatment algorithm have been published. Implementation
of the protocols has resulted in positive clinical outcomes in patients with MIS-C.17 There is substantial
experience using high-dose glucocorticoids in pediatric patients with other inflammatory conditions,
such as Kawasaki disease and macrophage activation syndrome.
Anakinra
Anakinra is the most commonly used biologic medication for the treatment of MIS-C in the United
States.20 Multiple, noncomparative, observational cohorts have reported on the use of anakinra in
patients with MIS-C.8,9,11 This medication has been used extensively with a good safety record in
pediatric patients with other hyperinflammatory syndromes (e.g., systemic juvenile idiopathic arthritis,
macrophage activation syndrome).24-26 Anakinra has also been used successfully to treat IVIG-resistant
Kawasaki disease. Anakinra has a short half-life (4–6 hours), and the medication can be stopped quickly,
which many providers regard as a benefit relative to longer-acting immunomodulators. High-dose
anakinra (5–10 mg/kg/day) is recommended for MIS-C based on the improved efficacy of anakinra
used at higher doses for macrophage activation syndrome. The duration of anakinra therapy varies in the
literature and is used by some patients for long periods (e.g., up to 2 weeks) as a steroid sparing agent.
Infliximab
The Panel recommends a single dose of infliximab 5 to 10 mg/kg IV as an option for intensification
therapy. Infliximab has been studied for the treatment of MIS-C in a single-center retrospective study
that compared patients treated with IVIG alone (n = 20) to those treated with IVIG and a single dose
of infliximab 10 mg/kg IV (n = 52).27 Of note, infliximab was used as first-line therapy in this study,
and the patients were not treated with glucocorticoids. The patients who received IVIG and infliximab
were more likely to be admitted to the ICU and had more severe illness than those who received IVIG
alone. Yet, the patients who received the combination therapy were less likely to require additional
therapy after 24 hours (the primary outcome). In addition, patients who received IVIG and infliximab
had shorter admissions to the ICU and less cardiac dysfunction. These results show that infliximab has
a therapeutic effect in MIS-C. Infliximab is approved by the Food and Drug Administration for use
in children with inflammatory bowel disease and is used widely to treat juvenile idiopathic arthritis.
Infliximab has been employed in IVIG-resistant Kawasaki disease.28,29 Although the half-life of
infliximab in MIS-C is unknown, it likely has effects that persist for several weeks. This extended period
of drug activity can allow for a steroid-sparing effect in MIS-C.
Antithrombotic Treatment for MIS-C

There is general agreement that patients with MIS-C who do not have risk factors for bleeding should
receive low-dose aspirin (AIII). This recommendation is largely due to experience in children with
Kawasaki disease and the likelihood of analogous platelet activation and endothelial dysfunction in
children with MIS-C.30 Children treated with aspirin and steroids should also receive gut protection.
Patients with MIS-C who have large coronary artery aneurysms (Z-score ≥10) should receive therapeutic
anticoagulation according to the American Heart Association guidelines for Kawasaki disease (AIII).
Children with left ventricular dysfunction are at risk for intracardiac thrombosis. Patients with MIS-C

and moderate-to-severe left ventricular dysfunction should receive therapeutic anticoagulation, unless
contraindicated due to bleeding risk factors (AIII).
There is less consensus on the use of either prophylactic or therapeutic anticoagulation in patients with
MIS-C who do not have large coronary artery aneurysms and/or moderate-to-severe left ventricular
dysfunction. Children with MIS-C have marked elevations in D-dimer levels and other abnormalities of
coagulation, which suggests that they may be at increased risk for thrombosis.31 In 1 study of children
with acute COVID-19 and MIS-C, indwelling catheters, older age (>12 years), malignancy, admission
to the ICU, and elevated D-dimer levels were all independent risk factors for thrombosis.32 There is
less known about the risk of bleeding in children with MIS-C who are treated with anticoagulation.
Major bleeding events have been reported in MIS-C patients treated with anticoagulation.32 Given
the uncertainty regarding the benefit of anticoagulation for MIS-C, prophylactic or therapeutic
anticoagulation for children with MIS-C who do not have large coronary artery aneurysms or moderate-
to-severe left ventricular dysfunction should be considered on a case-by-case basis, taking into account
the risk factors for thrombosis.
Antiviral Therapy in MIS-C

The role of antiviral therapy in treating MIS-C has not been systematically studied; however, it is not
expected to be beneficial because MIS-C is considered an immune-mediated phenomenon that occurs
weeks after a primary SARS-CoV-2 infection. Therefore, the Panel recommends against the use of
remdesivir for patients with MIS-C (AIII).
Critical Care Management

Shock occurs in approximately 50% of patients with MIS-C, and may include elements of distributive,
cardiogenic, or hypovolemic shock.12,33,34 In general, clinicians should manage shock in patients with
MIS-C per the usual critical care standards as outlined in the Pediatric Surviving Sepsis Campaign
Guidelines.35
References
1. Centers for Disease Control and Prevention. Information for healthcare providers about multisystem
inflammatory syndrome in children (MIS-C). 2021. Available at:
https://www.cdc.gov/mis/mis-c/hcp/index.html. Accessed February 7, 2022.
2. Centers for Disease Control and Prevention. Multisystem inflammatory syndrome in adults (MIS-A) case
definition information for healthcare providers. 2021. Available at:
https://www.cdc.gov/mis/mis-a/hcp.html. Accessed February 7, 2022.
associated with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR
4. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre
of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available
5. Belhadjer Z, Auriau J, Meot M, et al. Addition of corticosteroids to immunoglobulins is associated with
recovery of cardiac function in multi-inflammatory syndrome in children. Circulation. 2020;142(23):2282-
6. Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during
the COVID-19 pandemic in Paris, France: prospective observational study. BMJ. 2020;369:m2094. Available

7. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269. Available at:
8. Pouletty M, Borocco C, Ouldali N, et al. Paediatric multisystem inflammatory syndrome temporally associated
with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort. Ann Rheum Dis.
9. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and
adolescents. N Engl J Med. 2020;383(4):334-346. Available at:
10. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York
State. N Engl J Med. 2020;383(4):347-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32598830.
11. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS-CoV-2-
induced multisystem inflammatory syndrome in children. J Clin Invest. 2020;130(11):5942-5950. Available at:
13. American College of Rheumatology. Clinical guidance for pediatric patients with multisystem inflammatory
syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. 2022.
Available at: https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-
MIS-C-Hyperinflammation.pdf.
14. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone
vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA.
15. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and
outcomes. N Engl J Med. 2021;385(1):23-34. Available at:
16. McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J
17. Jonat B, Gorelik M, Boneparth A, et al. Multisystem inflammatory syndrome in children associated with
coronavirus disease 2019 in a children’s hospital in New York City: patient characteristics and an institutional
protocol for evaluation, management, and follow-up. Pediatr Crit Care Med. 2021;22(3):e178-e191. Available
18. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma
globulin. N Engl J Med. 1986;315(6):341-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2426590.
19. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet.
20. Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: survey of protocols
for early hospital evaluation and management. J Pediatr. 2021;229:33-40. Available at:
21. Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the
coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc. 2020;9(3):393-398. Available at:
22. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for
primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663-675. Available at:
23. Inoue Y, Okada Y, Shinohara M, et al. A multicenter prospective randomized trial of corticosteroids in primary

therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr. 2006;149(3):336-341.
24. Eloseily EM, Weiser P, Crayne CB, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic
lymphohistiocytosis. Arthritis Rheumatol. 2020;72(2):326-334. Available at:
25. Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebo-controlled trial with
the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis
(ANAJIS trial). Ann Rheum Dis. 2011;70(5):747-754. Available at:
26. Ter Haar NM, van Dijkhuizen EHP, Swart JF, et al. Treatment to target using recombinant interleukin-1
receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a
five-year follow-up study. Arthritis Rheumatol. 2019;71(7):1163-1173. Available at:
27. Cole LD, Osborne CM, Silveira LJ, et al. IVIG compared to IVIG plus infliximab in multisystem
inflammatory syndrome in children. Pediatrics. 2021. Available at:
28. Mori M, Hara T, Kikuchi M, et al. Infliximab versus intravenous immunoglobulin for refractory Kawasaki
disease: a Phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial. Sci Rep.
29. Yamaji N, da Silva Lopes K, Shoda T, et al. TNF-alpha blockers for the treatment of Kawasaki disease in
children. Cochrane Database Syst Rev. 2019;8:CD012448. Available at:
30. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of
Kawasaki disease: a scientific statement for health professionals from the American Heart Association.
Circulation. 2017;135(17):e927-e999. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28356445.
31. Ankola AA, Bradford VR, Newburger JW, et al. Coagulation profiles and viscoelastic testing in multisystem
inflammatory syndrome in children. Pediatr Blood Cancer. 2021;68(12):e29355. Available at:
32. Whitworth H, Sartain SE, Kumar R, et al. Rate of thrombosis in children and adolescents hospitalized with
COVID-19 or MIS-C. Blood. 2021;138(2):190-198. Available at:
in children - United States, March–July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1074-1080.
35. Weiss SL, Peters MJ, Agus MSD, et al. Perspective of the Surviving Sepsis Campaign on the management
of pediatric sepsis in the era of coronavirus disease 2019. Pediatr Crit Care Med. 2020;21(11):e1031-e1037.

Care of Critically Ill Adults With COVID-19
Hemodynamics
• For adults with COVID-19 and shock, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using
dynamic parameters, skin temperature, capillary refilling time, and/or lactate levels over static parameters to assess
fluid responsiveness (BIIa).
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using buffered/balanced
crystalloids over unbalanced crystalloids (BIIa).
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against the initial use of
albumin for resuscitation (BI).
• For adults with COVID-19 and shock, the Panel recommends norepinephrine as the first-line vasopressor (AI).
• For adults with COVID-19 and shock, the Panel recommends titrating vasoactive agents to target a mean arterial
pressure (MAP) of 60 to 65 mm Hg over higher MAP targets (BI).
• The Panel recommends against using hydroxyethyl starches for intravascular volume replacement in adult patients
with COVID-19 and sepsis or septic shock (AI).
• When norepinephrine is available, the Panel recommends against using dopamine for adult patients with COVID-19
and shock (AI).
• As a second-line vasopressor, the Panel recommends adding either vasopressin (up to 0.03 units/min) (BIIa) or
epinephrine (BIIb) to norepinephrine to raise MAP to target or adding vasopressin (up to 0.03 units/min) (BIIa) to
decrease norepinephrine dosage.
• The Panel recommends against using low-dose dopamine for renal protection (AI).
• The Panel recommends using dobutamine in adult patients with COVID-19 who show evidence of cardiac dysfunction
and persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BIII).
• The Panel recommends that all adult patients with COVID-19 who require vasopressors have an arterial catheter
placed as soon as practical, if the resources to do so are available (BIII).
• For adult patients with refractory septic shock who have completed a course of corticosteroids to treat COVID-19, the
Panel recommends using low-dose corticosteroid therapy (“shock-reversal”) over no corticosteroid therapy (BIIa).
Oxygenation and Ventilation
• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel
recommends starting therapy with high-flow nasal cannula (HFNC) oxygen; if patients fail to respond, noninvasive
ventilation (NIV) or intubation and mechanical ventilation should be initiated (BIIa).
• For adults with COVID-19 and acute hypoxemic respiratory failure who do not have an indication for endotracheal
intubation and for whom HFNC oxygen is not available, the Panel recommends performing a closely monitored trial of
NIV (BIIa).
• For adults with persistent hypoxemia who require HFNC oxygen and for whom endotracheal intubation is not
indicated, the Panel recommends a trial of awake prone positioning (BIIa).
• The Panel recommends against the use of awake prone positioning as a rescue therapy for refractory hypoxemia to
avoid intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).
• If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled
setting due to the enhanced risk of exposing health care practitioners to SARS-CoV-2 during intubation (AIII).
• For mechanically ventilated adults with COVID-19 and acute respiratory distress syndrome (ARDS):
• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body weight) over
higher VT ventilation (VT >8 mL/kg) (AI).
• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).

Summary Recommendations, continued
• The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).
• For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy
(BIIa).
• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel
recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).
• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBAs) or a
continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep
sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous
NMBA infusion for up to 48 hours, as long as the patient’s anxiety and pain can be adequately monitored and
controlled (BIII).
• For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and
other rescue strategies:
• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).
• If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment
maneuvers (AIIa).
• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in
oxygenation is observed, the treatment should be tapered off (CIII).
Pharmacologic Interventions
• In the absence of a proven or suspected bacterial infection, the Panel recommends against the use of empiric broad-
spectrum antibiotics in adult patients with severe or critical COVID-19 (BIII).
• As with any hospitalized patient, adult patients with COVID-19 who receive antibiotics should be reassessed daily to
minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
Extracorporeal Membrane Oxygenation
• There is insufficient evidence for the Panel to recommend either for or against the use of extracorporeal membrane
oxygenation in adults with COVID-19 and refractory hypoxemia.

Introduction to Critical Care Management of
Adults With COVID-19
COVID-19 can progress to critical illness, including hypoxemic respiratory failure, acute respiratory
distress syndrome (ARDS), septic shock, cardiac dysfunction, thromboembolic disease, hepatic and/
or renal dysfunction, central nervous system disease, and exacerbation of underlying comorbidities in
both adults and children. In addition, multisystem inflammatory syndrome in adults (MIS-A) can occur
several weeks or months after SARS-CoV-2 infection, which can lead to critical illness.
Many of the initial recommendations for the management of critically ill adults with COVID-19 in
these Guidelines were extrapolated from experience with other causes of sepsis and respiratory failure.1
However, there is now a rapidly growing body of evidence regarding the management of critically ill
patients with COVID-19.
Treating patients with COVID-19 in the intensive care unit (ICU) often requires managing underlying
illnesses or COVID-19-related morbidities. As with any patient who is admitted to the ICU, clinicians
also need to focus on preventing ICU-related complications.
Selected Clinical Manifestations of COVID-19 Critical Illness

Inflammatory Response Due to COVID-19 in Adults
Patients with COVID-19 may express increased levels of pro-inflammatory cytokines and anti-
inflammatory cytokines, which has previously been referred to as “cytokine release syndrome” or
“cytokine storm.” However, these terms are both imprecise and misnomers, because the magnitude of
cytokine elevation in many patients with COVID-19 is modest compared to that in patients with many
other critical illnesses, such as sepsis and ARDS.2,3 In addition, some patients with elevated cytokine
levels have no specific pathology that can be attributed to the elevated levels.
Patients with COVID-19 and severe pulmonary involvement often manifest extrapulmonary disease
and exhibit laboratory markers of acute inflammation. Patients with these manifestations of severe
pulmonary disease typically progress to critical illness 10 to 12 days after the onset of COVID-19
symptoms.
Multisystem Inflammatory Syndrome in Adults

There are case reports describing patients who had evidence of acute or recent SARS-CoV-2 infection
(confirmed by a nucleic acid amplification test [NAAT] or an antigen or antibody test) with minimal
respiratory symptoms but with laboratory markers of severe inflammation (e.g., elevated levels of
C-reactive protein [CRP], ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) and
various other symptoms, including fever and shock. These patients also had signs of cardiovascular,
gastrointestinal, dermatologic, and neurologic disease. This constellation of signs and symptoms has
been designated MIS-A.4 To date, most adults with MIS-A have survived. This syndrome is similar to
multisystem inflammatory syndrome in children (MIS-C), which is much more well described.
The current case definition for MIS-A from the Centers for Disease Control and Prevention states that
patients must be aged ≥21 years, be hospitalized for ≥24 hours or have an illness that results in death,
and meet the clinical and laboratory criteria outlined below. The patient should not have a more likely
alternative diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition).

Clinical Criteria
Patients must have a subjective or documented fever (≥38.0°C) for ≥24 hours prior to hospitalization or
within the first 3 days of hospitalization and at least 3 of the following clinical criteria, which must have
occurred prior to hospitalization or within the first 3 days of hospitalization. At least 1 must be a primary
clinical criterion.
• Primary clinical criteria:
• Severe cardiac illness. This includes myocarditis; pericarditis; coronary artery dilatation/
aneurysm; or new-onset right or left ventricular dysfunction (left ventricular ejection fraction
<50%), second- or third-degree atrioventricular block, or ventricular tachycardia. Cardiac arrest
alone does not meet this criterion.
• Rash AND nonpurulent conjunctivitis
• Secondary clinical criteria:
• New-onset neurologic signs and symptoms. These include encephalopathy in a patient without
prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy (including
Guillain-Barré syndrome).
• Shock or hypotension that are not attributable to medical therapy (e.g., sedation, renal
replacement therapy)
• Abdominal pain, vomiting, or diarrhea
• Thrombocytopenia (platelet count <150,000 cells/µL)
Laboratory Criteria
• The presence of laboratory evidence of inflammation AND SARS-CoV-2 infection
• Elevated levels of at least 2 of the following:
• CRP
• Ferritin
• Interleukin (IL)-6
• Erythrocyte sedimentation rate
• Procalcitonin
• A positive SARS-CoV-2 test result for current or recent infection using a reverse transcription
polymerase chain reaction, serology, or antigen test
These criteria must be met by the end of Day 3 of hospitalization, where the date of hospital admission
is Day 0.
Because there is no specific diagnostic test for MIS-A, diagnosis of this inflammatory syndrome is one
of exclusion after other causes (e.g., bacterial sepsis) have been eliminated. Although there are currently
no controlled clinical trial data in patients with MIS-A to guide treatment of the syndrome, case reports
have described the use of intravenous immunoglobulin, corticosteroids, or anti-IL-1 receptor antagonist
therapy.5-7
COVID-19-Induced Cardiac Dysfunction, Including Myocarditis

The published literature describes cardiac injury or dysfunction in up to 24% of adults who are
hospitalized with COVID-19.8 COVID-19 may be associated with an array of cardiovascular

complications, including acute coronary syndrome, myocarditis, stress (Takotsubo) cardiomyopathy,
arrythmias, and thromboembolic disease.9
Thromboembolic Events and COVID-19

Critically ill adults with COVID-19 have been observed to have a prothrombotic state and higher rates
of venous thromboembolic disease. In some studies, thromboemboli have been diagnosed even in
patients who received chemical prophylaxis with heparinoids.10-12 Autopsy studies provide additional
evidence of both thromboembolic disease and microvascular thrombosis in patients with COVID-19.13
Some authors have called for routine surveillance of ICU patients for venous thromboembolism.14 See
Antithrombotic Therapy in Patients With COVID-19 for a more detailed discussion.
Renal and Hepatic Dysfunction Due to COVID-19

Although SARS-CoV-2 is primarily a pulmonary pathogen, renal and hepatic dysfunction are
consistently described in adults with severe COVID-19.15 In a 2020 multicenter cohort study of critically
ill adults in the United States, 20.6% of patients developed acute kidney injury (AKI) that was treated
with renal replacement therapy (RRT).16 In a cohort of critically ill adults in Brazil, the development of
an AKI that required RRT was associated with poor prognosis.17
Other Intensive Care Unit-Related Complications

When treating patients with COVID-19, clinicians also need to minimize the risk of conventional ICU
complications. Patients who are critically ill with COVID-19 are at risk for nosocomial infections,
such as ventilator-associated pneumonia, hospital-acquired pneumonia, catheter-related bloodstream
infections, and other complications of critical illness care.
Critically ill patients with COVID-19 may also experience prolonged delirium and/or encephalopathy.
The risk factors that are associated with delirium include the use of mechanical ventilation, restraints,
benzodiazepines, opioids, vasopressors, and antipsychotics.18,19 Neurological manifestations of COVID-19
have been described in a significant proportion of hospitalized patients and are more frequent in patients
with severe disease.20 Autopsy studies have reported both macrovascular and microvascular thrombosis
with evidence of hypoxic ischemia.21 Adequate management of critically ill patients with COVID-19
includes paying careful attention to best sedation practices and monitoring for stroke.
Important Considerations in the Care of Critically Ill Patients With COVID-19

Interactions Between Drugs Used to Treat COVID-19 and Drugs Used to Treat Comorbidities
All ICU patients should be routinely monitored for drug-drug interactions. The potential for drug-drug
interactions between investigational medications or medications that are used off-label to treat
COVID-19 and concurrent drugs should be considered.
Sedation Management in Adults With COVID-19

International guidelines provide recommendations on the prevention, detection, and treatment of pain,
sedation, and delirium in ICU patients.22,23 Sedation management strategies, such as maintaining a light
level of sedation (when appropriate) and minimizing sedative exposure, have shortened the duration of
mechanical ventilation and the length of stay in the ICU for patients without COVID-19.24,25
The Society of Critical Care Medicine’s (SCCM) ICU Liberation Campaign promotes the ICU
Liberation Bundle (A-F) to improve post-ICU patient outcomes. The A-F Bundle includes the following
elements:

A. Assess, prevent, and manage pain;
B. Both spontaneous awakening and breathing trials;
C. Choice of analgesia and sedation;
D. Delirium: assess, prevent, and manage;
E. Early mobility and exercise; and
F. Family engagement and empowerment.
The A-F Bundle also provides frontline staff with practical application strategies for each element.26
The A-F Bundle should be incorporated using an interprofessional team model. This approach helps
standardize communication among team members, improves survival, and reduces long-term cognitive
dysfunction of patients.27 Despite the known benefits of the A-F Bundle, its impact has not been
directly assessed in patients with COVID-19; however, use of the Bundle should be encouraged, when
appropriate, to improve ICU patient outcomes. Prolonged mechanical ventilation of COVID-19 patients,
coupled with deep sedation and potentially neuromuscular blockade, increases the workload of ICU
staff. Additionally, significant drug shortages may force clinicians to use older sedatives with prolonged
durations of action and active metabolites, impeding routine implementation of SCCM’s PADIS
guidelines. This puts patients at additional risk for ICU and post-ICU complications.
Post-Intensive Care Syndrome

Post-intensive care syndrome (PICS) is a spectrum of cognitive, psychiatric, and/or physical disability
that affects survivors of critical illness and persists after a patient leaves the ICU.28 Patients with PICS
may present with varying levels of impairment, including profound muscle weakness (ICU-acquired
weakness); problems with thinking and judgment (cognitive dysfunction); and mental health problems,
such as problems sleeping, post-traumatic stress disorder (PTSD), depression, and anxiety. ICU-acquired
weakness affects 33% of all patients who receive mechanical ventilation, 50% of patients with sepsis,
and ≤50% of patients who remain in the ICU for ≥1 week.29-31 Cognitive dysfunction affects 30%
to 80% of patients discharged from the ICU.32-34 About 50% of ICU survivors do not return to work
within 1 year after discharge.35 Although no single risk factor has been associated with PICS, there are
opportunities to minimize the risk of PICS through medication management (using the A-F Bundle),
physical rehabilitation, follow-up clinics, family support, and improved education about the syndrome.
PICS also affects family members who participate in the care of their loved ones. In 1 study, a third of
family members who had major decision-making roles experienced mental health problems, such as
depression, anxiety, and PTSD.36
Some patients with COVID-19 who have been treated in the ICU express manifestations of PICS.37
Although specific therapies for COVID-19-induced PICS are not yet available, physicians should
maintain a high index of suspicion for cognitive impairment and other related problems in survivors of
severe or critical COVID-19 illness.
Advance Care Planning and Goals of Care

The advance care plans and the goals of care for all critically ill patients must be assessed at hospital
admission and regularly thereafter. This is an essential element of care for all patients. Information on
palliative care for patients with COVID-19 can be found on the National Coalition for Hospice and
Palliative Care website.
To guide shared decision making in cases of serious illness, advance care planning should include
identifying existing advance directives that outline a patient’s preferences and values. Values and care

preferences should be discussed, documented, and revisited regularly for patients with or without prior
directives. Specialty palliative care teams can facilitate communication between clinicians and surrogate
decision makers, support frontline clinicians, and provide direct patient care services when needed.
Surrogate decision makers should be identified for all critically ill patients with COVID-19 at hospital
admission. Infection-control policies for COVID-19 often create communication barriers for surrogate
decision makers, and most surrogates will not be physically present when discussing treatment options
with clinicians. Many decision-making discussions will occur via telecommunication.
Acknowledgments
The Surviving Sepsis Campaign (SSC), an initiative supported by SCCM and the European Society of
Intensive Care Medicine, issued Guidelines on the Management of Critically Ill Adults with Coronavirus
Disease 2019 (COVID-19) in March 2020, and a revised version was published in March 2021.1 The
COVID-19 Treatment Guidelines Panel (the Panel) has based the recommendations in this section on the
SSC COVID-19 guidelines with permission, and the Panel gratefully acknowledges the work of the SSC
COVID-19 Guidelines Panel. The Panel also acknowledges the contributions and expertise of Andrew
Rhodes, MBBS, MD, of St. George’s University Hospitals in London, England, and Waleed Alhazzani,
MBBS, MSc, of McMaster University in Hamilton, Canada.
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COVID-19. J Am Soc Nephrol. 2021;32(1):161-176. Available at:
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treated with renal replacement therapy in the intensive care unit: a multicenter study in Sao Paulo, Brazil.
PLoS One. 2022;17(1):e0261958. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35030179.
18. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med.
19. Pun BT, Badenes R, Heras La Calle G, et al. Prevalence and risk factors for delirium in critically ill patients
with COVID-19 (COVID-D): a multicentre cohort study. Lancet Respir Med. 2021;9(3):239-250. Available at:
20. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease
2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. Available at:
21. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of COVID-19. N Engl J Med.
22. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and
delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. Available at:
23. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of
pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med.
24. Kress JP, Vinayak AG, Levitt J, et al. Daily sedative interruption in mechanically ventilated patients at risk for
coronary artery disease. Crit Care Med. 2007;35(2):365-371. Available at:
25. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning
protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a
randomised controlled trial. Lancet. 2008;371(9607):126-134. Available at:
26. Society of Critical Care Medicine. ICU liberation bundle (A-F). Available at:

https://www.sccm.org/ICULiberation/ABCDEF-Bundles. Accessed March 28, 2022.
27. Barnes-Daly MA, Phillips G, Ely EW. Improving hospital survival and reducing brain dysfunction at seven
California community Hospitals: implementing PAD guidelines via the ABCDEF bundle in 6,064 patients.
Crit Care Med. 2017;45(2):171-178. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27861180.
28. Society of Critical Care Medicine. Post-intensive care syndrome. 2013. Available at:
https://www.sccm.org/MyICUCare/THRIVE/Post-intensive-Care-Syndrome.
29. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year
longitudinal prospective study. Crit Care Med. 2014;42(4):849-859. Available at:
30. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective
multicenter study. JAMA. 2002;288(22):2859-2867. Available at:
31. Ali NA, O’Brien JM, Jr., Hoffmann SP, et al. Acquired weakness, handgrip strength, and mortality in critically
ill patients. Am J Respir Crit Care Med. 2008;178(3):261-268. Available at:
32. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl
J Med. 2013;369(14):1306-1316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24088092.
33. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability
among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794. Available at:
34. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes
study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med.
35. Kamdar BB, Sepulveda KA, Chong A, et al. Return to work and lost earnings after acute respiratory distress
syndrome: a 5-year prospective, longitudinal study of long-term survivors. Thorax. 2018;73(2):125-133.
36. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of
intensive care unit patients. Am J Respir Crit Care Med. 2005;171(9):987-994. Available at:
37. Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute
COVID-19. JAMA. 2020;324(6):603-605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644129.

Hemodynamics for Adults
Last Updated: July 8, 2021
Most of the hemodynamic recommendations below are similar to those previously published in the
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
Ultimately, adult patients with COVID-19 who require fluid resuscitation or hemodynamic management
of shock should be treated and managed identically to adult patients with septic shock.1
Recommendation
• For adults with COVID-19 and shock, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends using dynamic parameters, skin temperature, capillary refilling time, and/or lactate
levels over static parameters to assess fluid responsiveness (BIIa).
Rationale
In a systematic review and meta-analysis of 13 randomized clinical trials in intensive care unit (ICU)
patients without COVID-19 (n = 1,652),2 dynamic assessment to guide fluid therapy reduced mortality
(risk ratio 0.59; 95% CI, 0.42–0.83), ICU length of stay (weighted mean difference -1.16 days; 95% CI,
-1.97 to -0.36), and duration of mechanical ventilation (weighted mean difference -2.98 hours; 95% CI,
-5.08 to -0.89). Dynamic parameters used in these trials included stroke volume variation (SVV), pulse
pressure variation (PPV), and stroke volume change with passive leg raise or fluid challenge. Passive leg
raising, followed by PPV and SVV, appears to predict fluid responsiveness with the greatest accuracy.3
The static parameters included components of early goal-directed therapy (e.g., central venous pressure,
mean arterial pressure [MAP]).
Resuscitation of patients with shock who do not have COVID-19 based on serum lactate levels has
been summarized in a systematic review and meta-analysis of seven randomized clinical trials (n =
1,301). Compared with central venous oxygen saturation-guided therapy, early lactate clearance-directed
therapy was associated with a reduction in mortality (relative ratio 0.68; 95% CI, 0.56–0.82), shorter
ICU stay (mean difference -1.64 days; 95% CI, -3.23 to -0.05), and shorter duration of mechanical
ventilation (mean difference -10.22 hours; 95% CI, -15.94 to -4.50).4
Recommendation
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using
buffered/balanced crystalloids over unbalanced crystalloids (BIIa).
Rationale
A pragmatic randomized trial compared the use of balanced and unbalanced crystalloids for intravenous
(IV) fluid administration in critically ill adults without COVID-19 (n = 15,802). The rate of the
composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction was
lower in the balanced crystalloids group than in the unbalanced crystalloids group (OR 0.90; 95% CI,
0.82–0.99; P = 0.04).5 A secondary analysis compared outcomes in a subset of patients with sepsis (n
= 1,641). Compared to treatment with unbalanced crystalloids, treatment with balanced crystalloids
resulted in fewer deaths (aOR 0.74; 95% CI, 0.59–0.93; P = 0.01) and more vasopressor-free and renal
replacement-free days.6 A subsequent meta-analysis of 21 non-COVID-19 randomized controlled trials
(n = 20,213) that included the pragmatic trial cited above compared balanced crystalloids to 0.9% saline

for resuscitation of critically ill adults and children. The trial reported nonsignificant differences between
the treatment groups in hospital mortality (OR 0.91; 95% CI, 0.83–1.01) and acute kidney injury (OR
0.92; 95% CI, 0.84–1.00).7
Recommendation
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against
the initial use of albumin for resuscitation (BI).
Rationale
A meta-analysis of 20 non-COVID-19 randomized controlled trials (n = 13,047) that compared the use
of albumin or fresh-frozen plasma to crystalloids in critically ill patients found no difference in all-cause
mortality between the treatment groups.8 In contrast, a meta-analysis of 17 non-COVID-19 randomized
controlled trials (n = 1,977) that compared the use of albumin to crystalloids specifically in patients with
sepsis observed a reduction in mortality among the patients who received albumin (OR 0.82; 95% CI,
0.67–1.0; P = 0.047).9 Given the higher cost of albumin and the lack of a definitive clinical benefit, the
Panel recommends against the routine use of albumin for initial acute resuscitation of patients with
COVID-19 and shock (BI).
Recommendation
• For adults with COVID-19 and shock, the Panel recommends norepinephrine as the first-choice
vasopressor (AI).
Rationale
Norepinephrine increases MAP due to its vasoconstrictive effects, with little change in heart rate
and less increase in stroke volume compared to dopamine. Dopamine increases MAP and cardiac
output, primarily due to an increase in stroke volume and heart rate. Norepinephrine is more potent
than dopamine and may be more effective at reversing hypotension in patients with septic shock.
Dopamine may be particularly useful in patients with compromised systolic function, but it causes more
tachycardia and may be more arrhythmogenic than norepinephrine.10 It may also influence the endocrine
response via the hypothalamic pituitary axis and have immunosuppressive effects.11 A systematic review
and meta-analysis of 11, non-COVID-19 randomized controlled trials that compared vasopressors used
to treat patients with septic shock found that norepinephrine use resulted in lower all-cause mortality
(RR 0.89; 95% CI, 0.81–0.98) and a lower risk of arrhythmias (RR 0.48; 95% CI, 0.40–0.58) than
dopamine use.12 Although the beta-1 activity of dopamine would be useful in patients with myocardial
dysfunction, the greater risk of arrhythmias limits its use.13,14
Recommendation
• For adults with COVID-19 and shock, the Panel recommends titrating vasoactive agents to target a
MAP of 60 to 65 mm Hg, over higher MAP targets (BI).
Rationale
A recent individual patient-data meta-analysis of two, non-COVID-19 randomized controlled trials (n
= 894) comparing higher versus lower blood pressure targets for vasopressor therapy in adult patients
with shock reported no significant difference between the patients in the higher and lower target groups
in 28-day mortality (OR 1.15; 95% CI, 0.87–1.52), 90-day mortality (OR 1.08; 95% CI, 0.84–1.44),
myocardial injury (OR 1.47; 95% CI, 0.64–3.56), or limb ischemia (OR 0.92; 95% CI, 0.36–2.10).15
The risk of arrhythmias was increased in patients allocated to the higher target group (OR 2.50; 95%

CI, 1.35–4.77). Similarly, the recently published “65 Trial,” a randomized clinical trial in patients
without COVID-19 (n = 2,463), reported no significant difference in mortality between patients with
vasopressor therapy guided by a MAP target of 60 to 65 mm Hg and those with treatment guided by a
higher, standard of care MAP target (41% vs. 43.8%; RR 0.93; 95% CI, 0.85–1.03).16 With an indication
of improved outcome with lower MAP targets (and no firm indication of harm), the Panel recommends
titrating vasoactive agents to a MAP target of 60 to 65 mm Hg (BI).
Additional Recommendations for Adults With COVID-19 and Shock Based on

General Principles of Critical Care
• The Panel recommends against using hydroxyethyl starches for intravascular volume
replacement in adult patients with COVID-19 and sepsis or septic shock (AI).
• When norepinephrine is available, the Panel recommends against using dopamine for adult
patients with COVID-19 and shock (AI).
• As a second line vasopressor, the Panel recommends adding either vasopressin (up to 0.03 units/
min) (BIIa) or epinephrine (BIIb) to norepinephrine to raise MAP to target or adding vasopressin
(up to 0.03 units/min) (BIIa) to decrease norepinephrine dosage.
• The Panel recommends against using low-dose dopamine for renal protection (AI).
• The Panel recommends using dobutamine in adult patients with COVID-19 who show evidence
of cardiac dysfunction and persistent hypoperfusion despite adequate fluid loading and the use of
vasopressor agents (BIII).
• The Panel recommends that all adult patients with COVID-19 who require vasopressors have an
arterial catheter placed as soon as practical, if resources are available (BIII).
• For adult patients with refractory septic shock who have completed a course of corticosteroids to
treat COVID-19, the Panel recommends using low-dose corticosteroid therapy (“shock-reversal”)
over no corticosteroid therapy (BIIa).
• A typical corticosteroid regimen in septic shock is hydrocortisone 200 mg IV per day
administered either as an infusion or in intermittent doses. The duration of hydrocortisone
therapy is usually a clinical decision.
• Adult patients who are receiving corticosteroids for COVID-19 are receiving sufficient
replacement therapy such that they do not require additional hydrocortisone.
References
1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for
management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. Available at:
2. Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating dynamic assessment of fluid responsiveness
into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-1545.
3. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable
patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. Available at:
4. Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided
therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453.
5. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J

6. Brown RM, Wang L, Coston TD, et al. Balanced crystalloids versus saline in sepsis. A secondary analysis of
the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-1495. Available at:
7. Antequera Martin AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for
resuscitation in critically ill adults and children. Cochrane Database Syst Rev. 2019;7:CD012247. Available
8. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids versus crystalloids for fluid resuscitation in critically ill
people. Cochrane Database Syst Rev. 2018;8:CD000567. Available at:
9. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with
sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39(2):386-391. Available at:
10. Regnier B, Rapin M, Gory G, Lemaire F, Teisseire B, Harari A. Haemodynamic effects of dopamine in septic
shock. Intensive Care Med. 1977;3(2):47-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/893773.
11. Beck G, Brinkkoetter P, Hanusch C, et al. Clinical review: immunomodulatory effects of dopamine in general
inflammation. Crit Care. 2004;8(6):485-491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15566620.
12. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressors for the treatment of septic shock:
systematic review and meta-analysis. PLoS One. 2015;10(8):e0129305. Available at:
13. Regnier B, Safran D, Carlet J, Teisseire B. Comparative haemodynamic effects of dopamine and dobutamine
in septic shock. Intensive Care Med. 1979;5(3):115-120. Available at:
14. De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the
splanchnic circulation in septic shock: which is best? Crit Care Med. 2003;31(6):1659-1667. Available at:
15. Lamontagne F, Day AG, Meade MO, et al. Pooled analysis of higher versus lower blood pressure targets
for vasopressor therapy septic and vasodilatory shock. Intensive Care Med. 2018;44(1):12-21. Available at:
16. Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day
mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial. JAMA.

Oxygenation and Ventilation for Adults
The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations in this section were
informed by the recommendations in the Surviving Sepsis Campaign Guidelines for managing sepsis
and COVID-19 in adults.
Severe illness in people with COVID-19 typically occurs approximately 1 week after the onset of
symptoms. The most common symptom is dyspnea, which is often accompanied by hypoxemia. Patients
with severe disease typically require supplemental oxygen and should be monitored closely for worsening
respiratory status, because some patients may progress to acute respiratory distress syndrome (ARDS).
Goal of Oxygenation
The optimal oxygen saturation (SpO2) in adults with COVID-19 who are receiving supplemental oxygen
is unknown. However, a target SpO2 of 92% to 96% seems logical, considering that indirect evidence
from patients without COVID-19 suggests that an SpO2 of <92% or >96% may be harmful.
The potential harm of maintaining an SpO2 of <92% was demonstrated during a trial that randomly
assigned patients with ARDS who did not have COVID-19 to either a conservative oxygen strategy
(target SpO2 of 88% to 92%) or a liberal oxygen strategy (target SpO2 of ≥96%). The trial was stopped
early due to futility after enrolling 205 patients, but increased mortality was observed at Day 90 in the
conservative oxygen strategy arm (between-group risk difference of 14%; 95% CI, 0.7% to 27%) and a
trend toward increased mortality was observed at Day 28 (between-group risk difference of 8%; 95% CI,
-5% to 21%).1
The results of a meta-analysis of 25 randomized trials that involved patients without COVID-19
demonstrate the potential harm of maintaining an SpO2 of >96%. This study found that a liberal oxygen
supplementation strategy (median fraction of inspired oxygen [FiO2] of 0.52) was associated with an
increased risk of in-hospital mortality (relative risk 1.21; 95% CI, 1.03–1.43) when compared to a more
conservative SpO2 supplementation strategy (median FiO2 of 0.21).2
Acute Hypoxemic Respiratory Failure

In adults with COVID-19 and acute hypoxemic respiratory failure, conventional oxygen therapy may be
insufficient to meet the oxygen needs of the patient. Options for providing enhanced respiratory support
include using high-flow nasal canula (HFNC) oxygen, noninvasive ventilation (NIV), intubation and
mechanical ventilation, or extracorporeal membrane oxygenation. In this section, mechanical ventilation
refers to the delivery of positive pressure ventilation through an endotracheal or tracheostomy tube. NIV
refers to the delivery of either continuous positive airway pressure (CPAP) or bilevel positive airway
pressure (BiPAP) through a noninvasive interface, such as a face mask or nasal mask.
Nonmechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure

High-Flow Nasal Cannula Oxygen and Noninvasive Ventilation
Recommendations
• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen
therapy, the Panel recommends starting therapy with HFNC oxygen; if patients fail to respond,
NIV or intubation and mechanical ventilation should be initiated (BIIa).

• For adults with COVID-19 and acute hypoxemic respiratory failure who do not have an indication
for endotracheal intubation and for whom HFNC oxygen is not available, the Panel recommends
performing a closely monitored trial of NIV (BIIa).
Rationale
HFNC oxygen is preferred over NIV in patients with acute hypoxemic respiratory failure. As there
are no studies that directly compare the use of HFNC oxygen and NIV delivered by a mask in patients
with COVID-19, this guidance is based on data from an unblinded clinical trial in patients without
COVID-19 who had acute hypoxemic respiratory failure. Study participants were randomized to receive
HFNC oxygen, conventional oxygen therapy, or NIV. The patients in the HFNC oxygen arm had more
ventilator-free days (mean of 24 days) than those in the conventional oxygen therapy arm (mean of 22
days) or the NIV arm (mean of 19 days; P = 0.02). In addition, 90-day mortality was higher in both the
conventional oxygen therapy arm (HR 2.01; 95% CI, 1.01–3.99) and the NIV arm (HR 2.50; 95% CI,
1.31–4.78) than in the HFNC oxygen arm. In the subgroup of severely hypoxemic patients (those with a
ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2] ≤200 mm Hg), the
intubation rate was lower in the HFNC oxygen arm than in the conventional oxygen therapy arm or the
NIV arm (HR 2.07 and 2.57, respectively).3
The trial’s findings were corroborated by a meta-analysis of 8 trials with 1,084 participants that assessed
the effectiveness of oxygenation strategies. Compared to NIV, HFNC oxygen reduced the rate of
intubation (OR 0.48; 95% CI, 0.31–0.73) and intensive care unit (ICU) mortality (OR 0.36; 95% CI,
0.20–0.63).4
One small study compared the use of NIV delivered by a helmet device to HFNC oxygen in patients
with COVID-19. The HENIVOT trial randomized 109 patients with moderate or severe COVID-19
(defined as those who had PaO2/FiO2 <200 mm Hg) to receive either NIV via a helmet device or HFNC
oxygen. The study found no difference between the arms in the primary outcome of respiratory support-
free days. However, only 30% of the patients in the NIV arm required endotracheal intubation compared
to 51% of patients in the HFNC oxygen arm (P = 0.03).5
Two larger studies have compared NIV with conventional oxygen therapy. The RECOVERY-RS trial
was an adaptive randomized controlled trial that was essentially conducted as 2 separate trials that
compared NIV and HFNC oxygen to the same conventional oxygen therapy control group.6 The trial
was stopped early and enrolled fewer than a third of the planned sample size of 4,002 participants.
Between April 2020 and May 2021, 1,273 adults with COVID-19-related acute hypoxemic respiratory
failure were randomized to receive NIV (n = 380), HFNC oxygen (n = 418), or conventional oxygen
therapy (n = 475). The primary endpoint was a composite of endotracheal intubation or death within 30
days. The proportion of patients who met the primary endpoint was significantly lower in the NIV arm
compared to the conventional oxygen therapy arm (36.3% vs. 44.4%; P = 0.03), and this difference was
entirely due to a reduction in the number of patients who required intubation and not due to mortality.
There was no significant difference between the HFNC oxygen arm and the conventional oxygen
therapy arm in the occurrence of the primary endpoint (44.3% vs. 45.1%; P = 0.83).
There was substantial crossover between the groups, but an inverse probability weighting analysis that
corrected for the bias that this may have introduced did not change the results. Adverse events were
more common in the NIV arm. Initially, a comparison between NIV and HFNC oxygen was not planned,
but a post hoc analysis found that the proportion of patients who required endotracheal intubation or
who died was lower in the NIV arm than in the HFNC oxygen arm (34.6% vs. 44.3%; P = 0.02).
In contrast to the RECOVERY-RS trial, the HiFlo-COVID trial randomized 220 patients to receive
HFNC oxygen or conventional oxygen therapy and found that a smaller proportion of patients in the
HFNC oxygen arm required intubation (34.3% vs. 51.0%; P = 0.03). Patients in the HFNC arm also had

a shorter median time to recovery (11 vs. 14 days; P = 0.047).7
The conflicting results of these studies make it difficult to draw inferences from the data. Additionally,
the RECOVERY-RS trial was stopped long before it reached its planned sample size for reasons that
were not related to futility, efficacy, or harm, and inferring benefit in this context is questionable.
Furthermore, the Panel recognizes that in patients who need more oxygen support than a conventional
nasal cannula can provide, most clinicians will administer oxygen via a HFNC and subsequently
progress to NIV if needed. Therefore, the pertinent clinical question is whether HFNC oxygen or NIV
should be used in situations where a patient fails to respond to conventional oxygen therapy. Other than
the post hoc analysis in the RECOVERY-RS trial, no study has specifically investigated this question.
NIV is an aerosol-generating procedure, and it may increase the risk of nosocomial transmission
of SARS-CoV-2.8,9 It remains unclear whether the use of HFNC oxygen results in a lower risk of
nosocomial SARS-CoV-2 transmission than NIV.
Awake Prone Positioning in Nonmechanically Ventilated Adults

Recommendations
• For adults with persistent hypoxemia who require HFNC oxygen and for whom endotracheal
intubation is not indicated, the Panel recommends a trial of awake prone positioning (BIIa).
• The Panel recommends against the use of awake prone positioning as a rescue therapy for
refractory hypoxemia to avoid intubation in patients who otherwise meet the indications for
intubation and mechanical ventilation (AIII).
• Patients who can adjust their position independently and tolerate lying prone can be considered for
awake prone positioning.
• Awake prone positioning is acceptable and feasible for pregnant patients and can be performed in
the left lateral decubitus position or the fully prone position.10
• Some patients do not tolerate awake prone positioning. Failure rates as high as 63% have been
reported in the literature.11
• Awake prone positioning should not be used as a substitute for intubation and mechanical
ventilation in patients with refractory hypoxemia who otherwise meet the indications for these
interventions.
• Awake prone positioning may be infeasible or impractical in patients with:
• Spinal instability
• Facial or pelvic fractures
• An open chest or unstable chest wall
• Awake prone positioning should be used with caution in patients with confusion, delirium, or
hemodynamic instability and in patients who cannot independently change position or who have
had recent abdominal surgery, nausea, or vomiting.
Rationale
Awake prone positioning, or having a nonintubated patient lie on their stomach, may improve
oxygenation and prevent the patient from progressing to requiring intubation and mechanical ventilation.
Although prone positioning has been shown to improve oxygenation and outcomes in patients with
moderate to severe ARDS who are receiving mechanical ventilation,12,13 there is less evidence regarding
the benefit of prone positioning in awake patients who require supplemental oxygen without mechanical

ventilation. Several case series of patients with COVID-19 who required oxygen or NIV have reported
that awake prone positioning improves oxygenation,14-17 and some series have also reported low
intubation rates after awake prone positioning.14,16
The Awake Prone Positioning Meta-Trial Group conducted the largest trial to date on awake prone
positioning. This was a prospective, multinational meta-trial of 6 open-label, randomized, controlled,
superiority trials that compared awake prone positioning to standard care in adults who required HFNC
oxygen for acute hypoxemic respiratory failure due to COVID-19.
The study enrolled 1,126 patients between April 2, 2020, and January 26, 2021, and the intention-to-
treat analysis included 1,121 patients. Of the 564 patients who underwent awake prone positioning, 223
(40%) met the primary composite endpoint of intubation or death within 28 days of enrollment; among
the 557 patients who received standard care, 257 (46%) met the primary endpoint (relative risk 0.86;
95% CI, 0.75−0.98). Regarding the individual components of the composite endpoint, the incidence
of intubation by Day 28 was lower in the awake prone positioning arm than in the standard care arm
(HR for intubation 0.75; 95% CI, 0.62−0.91). There was no difference in 28-day mortality between the
awake prone positioning arm and the standard care arm (HR for mortality 0.87; 95% CI, 0.68−1.11).
During the first 14 days of the study, the median daily duration of awake prone positioning was 5.0
hours (IQR 1.6–8.8 hours). However, the median daily duration varied from 1.6 hours to 8.6 hours
across the individual trials. Longer daily durations for awake prone positioning were associated with
treatment success by Day 28. This study evaluated the incidences of certain adverse events, including
skin breakdown, vomiting, and central or arterial line dislodgement. These events occurred infrequently
during the study, and the incidences for these events were similar between the arms. No cardiac arrests
occurred during awake prone positioning.18
Though the optimal daily duration of awake prone positioning is unclear, only 25 of 151 patients
(17%) who had an average of ≥8 hours of awake prone positioning per day met the primary endpoint
of intubation or death in the Awake Prone Positioning Meta-Trial, compared with 198 of 413 patients
(48%) who remained in awake prone positioning for <8 hours per day. This is consistent with past
clinical trials of prone positioning in mechanically ventilated patients with ARDS, during which clinical
benefits were observed with longer durations of prone positioning.12,13
Intubation for Mechanical Ventilation

Recommendation
• If intubation becomes necessary, the procedure should be performed by an experienced
practitioner in a controlled setting due to the enhanced risk of exposing health care practitioners to
SARS-CoV-2 during intubation (AIII).
Rationale
It is essential to closely monitor hypoxemic patients with COVID-19 for signs of respiratory
decompensation. To ensure the safety of both patients and health care workers, intubation should be
performed in a controlled setting by an experienced practitioner.
Mechanically Ventilated Adults

General Considerations
Recommendations
For mechanically ventilated adults with COVID-19 and ARDS:

• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body
weight) over higher VT ventilation (VT >8 mL/kg) (AI).
• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).
• The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).
Rationale
There is no evidence that ventilator management of patients with hypoxemic respiratory failure due to
COVID-19 should differ from ventilator management of patients with hypoxemic respiratory failure due
to other causes.
Positive End-Expiratory Pressure and Prone Positioning in Mechanically Ventilated Adults

With Moderate to Severe ARDS
Recommendations
For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a
lower PEEP strategy (BIIa).
• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized
ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone
ventilation (BIIa).
Rationale
PEEP is beneficial in patients with ARDS because it prevents alveolar collapse, improves oxygenation,
and minimizes atelectotrauma, a source of ventilator-induced lung injury. A meta-analysis of individual
patient data from the 3 largest trials that compared lower and higher levels of PEEP in patients without
COVID-19 found lower rates of ICU mortality and in-hospital mortality with higher levels of PEEP in
those with moderate (PaO2/FiO2 100–200 mm Hg) and severe ARDS (PaO2/FiO2 <100 mm Hg).19
Although there is no clear standard as to what constitutes a high level of PEEP, a conventional threshold
is >10 cm H2O.20 Recent reports have suggested that, in contrast to patients with non-COVID-19 causes
of ARDS, some patients with moderate or severe ARDS due to COVID-19 have normal static lung
compliance. In these patients, higher PEEP levels may cause harm by compromising hemodynamics
and cardiovascular performance.21,22 Other studies have reported that patients with moderate to severe
ARDS due to COVID-19 had low lung compliance, similar to the lung compliance seen in patients with
conventional ARDS.23-26 These seemingly contradictory observations suggest that COVID-19 patients
with ARDS are a heterogeneous population, and assessments for responsiveness to higher levels of
PEEP should be individualized based on oxygenation and lung compliance. Clinicians should monitor
patients for known side effects of higher levels of PEEP, such as barotrauma and hypotension.
In the prepandemic PROSEVA study of patients with moderate or severe early ARDS (PaO2/FiO2 <150
mm Hg) who required mechanical ventilation, the patients who were randomized to undergo prone
positioning for ≥16 hours per day had improved survival compared to those who remained in the supine
position throughout their course of mechanical ventilation.12 A meta-analysis evaluated the results
of the PROSEVA study and 7 other randomized controlled trials that investigated the use of prone
positioning in people with ARDS. The subgroup analysis revealed that patients who remained prone for
≥12 hours per day had a lower mortality rate than those who remained in the supine position (risk ratio
0.74; 95% CI, 0.56–0.99). Prone positioning improved oxygenation in all of the trials; patients in the
prone positioning arms had higher PaO2/FiO2 on Day 4 than those in the supine positioning arms (mean

difference of 23.5 mm Hg; 95% CI, 12.4–34.5).27
The use of prone positioning may be associated with serious adverse events, including unplanned
extubation or central catheter removal; however, the meta-analysis found no differences in the
frequencies of these events between the prone positioning and supine positioning arms. The use of prone
positioning was associated with an increase in the frequency of pressure sores (risk ratio 1.22; 95% CI,
1.06–1.41) and endotracheal tube obstruction (risk ratio 1.76; 95% CI, 1.24–2.50) in the 3 studies that
evaluated these complications.
Neuromuscular Blockade in Mechanically Ventilated Adults With Moderate to Severe ARDS

Recommendations
For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents
(NMBAs) or a continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires
ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel
recommends using a continuous NMBA infusion for up to 48 hours, as long as the patient’s
anxiety and pain can be adequately monitored and controlled (BIII).
Rationale
The recommendation for intermittent boluses of NMBAs or a continuous infusion of NMBAs to
facilitate lung protection may require a health care provider to enter the patient’s room frequently for
close clinical monitoring. Therefore, in some situations, the risks of SARS-CoV-2 exposure and the need
to use personal protective equipment for each entry into a patient’s room may outweigh the benefit of
NMBA treatment.
Rescue Therapies for Mechanically Ventilated Adults With ARDS

Recommendations
For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized
ventilation and other rescue strategies:
• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers
(CIIa).
• If recruitment maneuvers are used, the Panel recommends against the use of staircase
(incremental PEEP) recruitment maneuvers (AIIa).
• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid
improvement in oxygenation is observed, the treatment should be tapered off (CIII).
Rationale
A recruitment maneuver refers to a temporary increase in airway pressure during mechanical ventilation
to open collapsed alveoli and improve oxygenation. No studies have assessed the effect of recruitment
maneuvers on oxygenation in patients with severe ARDS due to COVID-19. However, a systematic
review and meta-analysis of 6 trials of recruitment maneuvers in patients with ARDS who did not have
COVID-19 found that recruitment maneuvers reduced mortality, improved oxygenation 24 hours after
the maneuver, and decreased the need for rescue therapy.28 Because recruitment maneuvers can cause
barotrauma or hypotension, patients should be closely monitored during recruitment maneuvers. If a
patient decompensates during recruitment maneuvers, the maneuver should be stopped immediately.

The importance of properly performing recruitment maneuvers was illustrated by an analysis of 8
randomized controlled trials in patients without COVID-19 (n = 2,544) that found that recruitment
maneuvers did not reduce hospital mortality (risk ratio 0.90; 95% CI, 0.78–1.04). However, a subgroup
analysis found that traditional recruitment maneuvers significantly reduced hospital mortality (risk ratio
0.85; 95% CI, 0.75–0.97). Mortality was higher among patients who were treated with incremental
PEEP titration recruitment maneuvers than among those who were treated with traditional recruitment
maneuvers, but this difference was not statistically significant (risk ratio 1.06; 95% CI, 0.97–1.17).20
Although there are no published studies on the use of inhaled nitric oxide in patients with COVID-19, a
Cochrane review of 13 trials that evaluated the use of inhaled nitric oxide in patients with ARDS found
no mortality benefit.29 Because the review showed a transient benefit for oxygenation, it is reasonable to
attempt using inhaled nitric oxide as a rescue therapy in patients with COVID-19 and severe ARDS after
other options have failed. However, if the use of nitric oxide does not improve a patient’s oxygenation,
it should be tapered quickly to avoid rebound pulmonary vasoconstriction, which may occur when nitric
oxide is discontinued after prolonged use.
References
1. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress
syndrome. N Engl J Med. 2020;382(11):999-1008. Available at:
2. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus
conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-
3. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory
failure. N Engl J Med. 2015;372(23):2185-2196. Available at:
4. Ni YN, Luo J, Yu H, et al. The effect of high-flow nasal cannula in reducing the mortality and the rate of
endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy
and noninvasive positive pressure ventilation. A systematic review and meta-analysis. Am J Emerg Med.
5. Grieco DL, Menga LS, Cesarano M, et al. Effect of helmet noninvasive ventilation vs high-flow nasal oxygen
on days free of respiratory support in patients With COVID-19 and moderate to severe hypoxemic respiratory
failure: the HENIVOT randomized clinical trial. JAMA. 2021;325(17):1731-1743. Available at:
6. Perkins GD, Ji C, Connolly BA, et al. Effect of noninvasive respiratory strategies on intubation or mortality
among patients with acute hypoxemic respiratory failure and COVID-19: The RECOVERY-RS randomized
7. Ospina-Tascon GA, Calderon-Tapia LE, Garcia AF, et al. Effect of high-flow oxygen therapy vs conventional
oxygen therapy on invasive mechanical ventilation and clinical recovery in patients with severe COVID-19: a
randomized clinical trial. JAMA. 2021;326(21):2161-2171. Available at:
8. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of
transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One.
9. Yu IT, Xie ZH, Tsoi KK, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital
wards but not in others? Clin Infect Dis. 2007;44(8):1017-1025. Available at:

COVID_pos_preg_patients_4-30-20_final.pdf.
11. Hallifax RJ, Porter BM, Elder PJ, et al. Successful awake proning is associated with improved clinical
outcomes in patients with COVID-19: single-centre high-dependency unit experience. BMJ Open Respir Res.
2020;7(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32928787.
12. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N
13. Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic Society/European Society of Intensive
Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-1263.
14. Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention:
experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33. Available at:
15. Elharrar X, Trigui Y, Dols AM, et al. Use of prone positioning in nonintubated patients with COVID-19 and
hypoxemic acute respiratory failure. JAMA. 2020;323(22):2336-2338. Available at:
16. Sartini C, Tresoldi M, Scarpellini P, et al. Respiratory parameters in patients with COVID-19 after using
noninvasive ventilation in the prone position outside the intensive care unit. JAMA. 2020;323(22):2338-2340.
17. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency
department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-
18. Ehrmann S, Li J, Ibarra-Estrada M, et al. Awake prone positioning for COVID-19 acute hypoxaemic
respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med.
19. Briel M, Meade M, Mercat A, et al. Higher vs. lower positive end-expiratory pressure in patients with
acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA.
20. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of
critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887.
21. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330.
22. Tsolaki V, Siempos I, Magira E, et al. PEEP levels in COVID-19 pneumonia. Crit Care. 2020;24(1):303.
23. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in critically ill patients in the seattle region-case
series. N Engl J Med. 2020;382(21):2012-2022. Available at:
24. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill
adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770.
25. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with
COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. Available at:
26. Schenck EJ, Hoffman K, Goyal P, et al. Respiratory mechanics and gas exchange in COVID-19-associated
respiratory failure. Ann Am Thorac Soc. 2020;17(9):1158-1161. Available at:

27. Munshi L, Del Sorbo L, Adhikari NKJ, et al. Prone position for acute respiratory distress syndrome. a
systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Supplement_4):S280-S288. Available at:
28. Goligher EC, Hodgson CL, Adhikari NKJ, et al. Lung recruitment maneuvers for adult patients with
acute respiratory distress syndrome. a systematic review and meta-analysis. Ann Am Thorac Soc.
2017;14(Supplement_4):S304-S311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29043837.
29. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome
(ARDS) in children and adults. Cochrane Database Syst Rev. 2016(6):CD002787. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27347773

Pharmacologic Interventions for Critically Ill
Patients
Empiric Broad-Spectrum Antibiotic Therapy

Recommendations
• In the absence of a proven or suspected bacterial infection, the COVID-19 Treatment Guidelines
Panel (the Panel) recommends against the use of empiric broad-spectrum antibiotics in
patients with severe or critical COVID-19 (BIII).
• As with any hospitalized patient, patients with COVID-19 who receive antibiotics should be
reassessed daily to minimize the adverse consequences of unnecessary antimicrobial therapy
(AIII).
Rationale
Variable rates of community- and hospital-acquired infections have been reported in adult patients
with COVID-19. Bacterial coinfection at the time of hospitalization has been reported in 1% to 3.5%
of patients with COVID-19.1,2 Secondary infections have been reported in 14% to 37% of intensive
care unit patients, but the reported rates have been influenced by differences in the severity of illness,
duration of hospitalization, method of diagnosis, and time period studied.3,4
There are no clinical trials that have evaluated the use of empiric broad-spectrum antibiotics in patients
with severe or critical COVID-19 or other coronavirus infections. Routine, empiric use of antibiotics in
patients with severe or critical COVID-19 is not recommended (BIII); this recommendation is intended
to mitigate the unintended consequences of side effects and resistance. The use of antibiotics may be
considered in specific situations, such as the presence of a lobar infiltrate on a chest X-ray, leukocytosis,
an elevated serum lactate level, microbiologic data, or shock.
The use of antibiotics in patients with severe or critical COVID-19 should follow guidelines established
for other hospitalized patients (i.e., for hospital-acquired pneumonia, ventilator-associated pneumonia,
or central line-associated bloodstream infection). It is unclear whether using the corticosteroids or other
immunomodulatory agents that are recommended in the Guidelines should alter such approaches.
Therapeutic Management of Hospitalized Adults With COVID-19

See Therapeutic Management of Hospitalized Adults With COVID-19 for the Panel’s recommendations
on when to use baricitinib, dexamethasone, remdesivir, and tocilizumab.
Immune-Based Therapy
See the Immunomodulators section for recommendations on the use of immunomodulators.
Adjunctive Therapy
Recommendations regarding the use of adjunctive therapies in critical care settings, including
antithrombotic therapy and vitamin C, can be found in Antithrombotic Therapy in Patients With
COVID-19, Therapeutic Management of Hospitalized Adults With COVID-19, and Vitamin C.

References
1. Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with
COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26(12):1622-1629. Available
2. Garcia-Vidal C, Sanjuan G, Moreno-Garcia E, et al. Incidence of co-infections and superinfections in
hospitalized patients with COVID-19: a retrospective cohort study. Clin Microbiol Infect. 2021;27(1):83-88.
3. Zangrillo A, Beretta L, Scandroglio AM, et al. Characteristics, treatment, outcomes and cause of death of
invasively ventilated patients with COVID-19 ARDS in Milan, Italy. Crit Care Resusc. 2020;22(3):200-211.
4. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia
in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-

Extracorporeal Membrane Oxygenation for
Adults
Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel to recommend either
for or against the use of extracorporeal membrane oxygenation (ECMO) in adults with COVID-19
and refractory hypoxemia.
Rationale
ECMO has been used as a short-term rescue therapy in patients with acute respiratory distress syndrome
(ARDS) caused by COVID-19 and refractory hypoxemia. However, there is no conclusive evidence
that ECMO is responsible for better clinical outcomes regardless of the cause of hypoxemic respiratory
failure.1-4
The clinical outcomes for patients with ARDS who are treated with ECMO are variable and depend
on multiple factors, including the etiology of hypoxemic respiratory failure, the severity of pulmonary
and extrapulmonary illness, the presence of comorbidities, and the ECMO experience of the individual
center.5-7 Several multicenter, observational cohort studies from the first half of 20208-10 reported that
patients who required ECMO for COVID-19 had a similar mortality to patients in a 2018 randomized
study who did not have COVID-19 but who had ARDS and received ECMO.3
However, a recent analysis reported worse outcomes over time among patients who required ECMO for
COVID-19.11 The analysis used data from 4,812 patients in the international Extracorporeal Life Support
Organization (ELSO) Registry who had COVID-19 and who received ECMO in 2020. At centers that
provided ECMO throughout 2020, patients who started ECMO before May 1, 2020, had a 90-day
mortality of 36.9% after ECMO initiation (95% CI, 34.1% to 39.7%). At the same centers, patients
who initiated ECMO between May 2 and December 31, 2020, had a 90-day mortality of 51.9% (95%
CI, 50.0% to 53.8%). Furthermore, at centers that started using ECMO for patients with COVID-19
after May 1, 2020, the 90-day mortality after ECMO initiation was 58.9% (95% CI, 55.4% to 62.3%).
These observational data should be interpreted with caution, as they may reflect a changing case mix of
patients with COVID-19 who were referred for ECMO.
Without data from controlled trials that have evaluated the use of ECMO in patients with COVID-19
and hypoxemic respiratory failure (e.g., ARDS), the benefits of ECMO cannot be clearly defined for this
patient population.
Clinicians who are interested in using ECMO should try to enter their patients into clinical trials
or clinical registries so that more informative data can be obtained. More information on the use of
ECMO in patients with COVID-19 can be found on ELSO’s Extracorporeal Membrane Oxygenation in
COVID-19 website and ClinicalTrials.gov.
References
1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory
support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a
multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. Available at:

2. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-
induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit
Care Med. 2013;187(3):276-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23155145.
3. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory
distress syndrome. N Engl J Med. 2018;378(21):1965-1975. Available at:
4. Munshi L, Walkey A, Goligher E, Pham T, Uleryk E, Fan E. Venovenous extracorporeal membrane
oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir
5. Bullen EC, Teijeiro-Paradis R, Fan E. How I select which patients with ARDS should be treated with
venovenous extracorporeal membrane oxygenation. Chest. 2020;158(3):1036-1045. Available at:
6. Henry BM, Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress
syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J Crit
Care. 2020;58:27-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32279018.
7. Mustafa AK, Alexander PJ, Joshi DJ, et al. Extracorporeal membrane oxygenation for patients with
COVID-19 in severe respiratory failure. JAMA Surg. 2020;155(10):990-992. Available at:
8. Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation support in
COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet.
9. Schmidt M, Hajage D, Lebreton G, et al. Extracorporeal membrane oxygenation for severe acute
respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med.
10. Shaefi S, Brenner SK, Gupta S, et al. Extracorporeal membrane oxygenation in patients with severe
respiratory failure from COVID-19. Intensive Care Med. 2021;47(2):208-221. Available at:
11. Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation for COVID-19:
evolving outcomes from the international Extracorporeal Life Support Organization Registry. Lancet.

Introduction to Critical Care Management of
COVID-19 may lead to critical illness in children, including hypoxemic respiratory failure, acute
respiratory distress syndrome (ARDS), septic shock, cardiac dysfunction, thromboembolic disease,
hepatic or renal dysfunction, central nervous system disease, and exacerbation of underlying
comorbidities. In addition, multisystem inflammatory syndrome in children (MIS-C) is a rare,
postinfectious complication of SARS-CoV-2 and is frequently associated with critical illness.
Data informing the optimal management of children with acute COVID-19 or MIS-C are limited. In
general, management should follow the principles of pediatric critical care usually applied to non-
COVID-19-related illness, such as the Pediatric Acute Lung Injury Consensus Conference (PALICC)
recommendations and the Surviving Sepsis Campaign International Guidelines for the Management
of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. For patients with COVID-19
in the intensive care unit (ICU), treatment often requires managing underlying illnesses other than
COVID-19 that may have contributed to the need for ICU admission, as well as managing COVID-19
complications. Finally, prevention of ICU-related complications is critical to achieving optimal clinical
outcomes for any patient admitted to the ICU.
Selected Clinical Manifestations of COVID-19 Critical Illness

Inflammatory Response
Patients with COVID-19 may develop a hyperinflammatory state, which appears to be distinct from
classic “cytokine storm” syndromes (e.g., macrophage activation syndrome in juvenile idiopathic
arthritis, familial hemophagocytic lymphohistiocytosis). This phenomenon is less well-described in
children than in adults.

MIS-C is a rare, postinfectious complication of SARS-CoV-2 that is characterized by persistent fever,
systemic inflammation, and multisystem organ dysfunction. The majority of children with MIS-C
require ICU-level care, primarily for shock and for vasopressor and inotropic support.1-3 For details on
the definition of MIS-C, clinical features, and recommended treatments, see Special Considerations
in Children and Therapeutic Management of Hospitalized Pediatric Patients With Multisystem
Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory
Syndrome in Adults [MIS-A]).
Cardiac Dysfunction, Including Myocarditis

Although cardiac involvement is common in patients with MIS-C,2,4 cardiac manifestations have rarely
been described in children with acute COVID-19. Myocarditis, cardiac conduction abnormalities, and
coronary artery aneurysms have been reported in patients with MIS-C. Myocarditis may also occur after
SARS-CoV-2 vaccination, particularly in adolescent males, although the clinical course generally is
relatively mild.5
Thromboembolic Events
Limited data characterize the prevalence of thromboembolic disease in children with COVID-19 or
MIS-C. In a multicenter, retrospective cohort study including 814 hospitalized patients with COVID-19

or MIS-C, thromboembolic events were detected in 2.1% of patients with COVID-19 and 6.5% of
patients with MIS-C.6 The same study conducted a multivariable analysis and found that the following
variables were associated with increased risk of thromboembolic events: children aged ≥12 years,
MIS-C, central venous catheters, and underlying malignancies. See Antithrombotic Therapy in Patients
With COVID-19 for additional recommendations.
Acute Kidney Injury

Acute kidney injury is estimated to occur in 12% to 44% of hospitalized children with COVID-19 or
MIS-C, but the need for renal replacement therapy is extremely rare.7-10
Neurologic Involvement
Neurologic involvement is common in children with COVID-19 or MIS-C and is estimated to occur
in approximately 30% to 40% of children hospitalized with these conditions.2,11 Severe neurologic
manifestations, including severe encephalopathy, stroke, demyelinating conditions, cerebral edema, and
Guillain-Barré syndrome, have also been described.11
Important Considerations in the Care of Critically Ill Patients With COVID-19

Considerations for the care of children with COVID-19 or MIS-C should generally follow the usual
principles of pediatric critical care. Sedation management and considerations related to post-intensive
care syndrome–pediatric (PICS-p) are discussed below. See Oxygenation and Ventilation for Children,
Hemodynamic Considerations for Children, and Extracorporeal Membrane Oxygenation for Children
for more information on pediatric critical care.
Sedation Management
Guidelines for the management of pain, agitation, neuromuscular blockade, delirium, and early mobility
(PANDEM) in infants and children admitted to the pediatric ICU have recently been published.12 In
general, children with COVID-19 or MIS-C who require mechanical ventilation should be managed
per the usual critical care for patients with respiratory failure who require mechanical ventilation. The
usual care includes sedation with the minimal effective dose required to tolerate mechanical ventilation,
optimize gas exchange, and minimize the risk of ventilator-induced lung injury. Using validated pain and
sedation scales, the critical care team should set a sedation/pain target based on the phase of ventilation.
Two large randomized controlled trials examined the use of protocols to manage sedation titration
in children receiving mechanical ventilation.13,14 In both studies, participants received usual care or
protocol-driven care implemented by nurses. The studies found that the use of the protocols did not
demonstrate a significant benefit on outcomes, such as the duration of ventilation. However, a patient’s
risk of harm from protocolized sedation is generally low, which led the Society of Critical Care
Medicine to issue a conditional recommendation, based on low-level evidence, in its PANDEM clinical
practice guidelines suggesting the use of protocolized sedation in children who are critically ill and
receiving mechanical ventilation.12
Studies evaluating data on the effect of early mobility protocols on critically ill children are limited.
One trial evaluated the safety and feasibility of early mobilization in 58 patients who were randomized
to receive usual care or early physical therapy, occupational therapy, and speech therapy consultation
within 72 hours of admission to the pediatric ICU.15 Although no differences between the arms
were demonstrated for clinical, functional, or quality of life outcomes, the study found that the early
rehabilitation consultations were safe and feasible.
Ongoing trials are measuring the effect of early mobilization on patient-centered outcomes in children

receiving mechanical ventilation. The PANDEM guideline statement issued by the Society of Critical
Care Medicine conditionally recommends, based on a low quality of evidence, implementing early
mobilization strategies in children when feasible, which likely would apply to children with COVID-19
or MIS-C.12
Post-Intensive Care Syndrome

In recent years, there has been a growing awareness that PICS can occur in pediatric patients. PICS-p
has been demonstrated to have a multifaceted effect on the physical, cognitive, emotional, and social
health of child survivors of critical illness and their families.16 Furthermore, many pediatric survivors
of sepsis or ARDS manifest significant impairments in physical, cognitive, and emotional health.17-19
Although no clear data characterize the prevalence of PICS-p or long-term morbidity in children with
COVID-19 or MIS-C, the prevalence is expected to be similar to that observed in other populations with
similar illness severities.
Acknowledgments
For these pediatric recommendations, the COVID-19 Treatment Guidelines Panel integrated the
recommendations from pediatric-specific guidelines, including the European Society of Paediatric and
Neonatal Intensive Care’s recommendations20 for the care of critically ill children with COVID-19
and the Surviving Sepsis Campaign’s perspective on managing sepsis in children with COVID-19.21
In addition, recommendations from several non-COVID-19-specific treatment guidelines, such as the
Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-
Associated Organ Dysfunction in Children,22 the PALICC recommendations,23 and the Society of Critical
Care Medicine’s PANDEM guidelines,12 were integrated.
References
3. Alsaied T, Tremoulet AH, Burns JC, et al. Review of cardiac involvement in multisystem inflammatory
syndrome in children. Circulation. 2021;143(1):78-88. Available at:
4. Valverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute cardiovascular manifestations in 286 children
with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation.
5. Jain SS, Steele JM, Fonseca B, et al. COVID-19 vaccination-associated myocarditis in adolescents. Pediatrics.
6. Whitworth H, Sartain SE, Kumar R, et al. Rate of thrombosis in children and adolescents hospitalized with
COVID-19 or MIS-C. Blood. 2021;138(2):190-198. Available at:
7. Raina R, Chakraborty R, Mawby I, et al. Critical analysis of acute kidney injury in pediatric COVID-19
patients in the intensive care unit. Pediatr Nephrol. 2021;36(9):2627-2638. Available at:
8. Kari JA, Shalaby MA, Albanna AS, et al. Acute kidney injury in children with COVID-19: a retrospective
study. BMC Nephrol. 2021;22(1):202. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34059010.

9. Basalely A, Gurusinghe S, Schneider J, et al. Acute kidney injury in pediatric patients hospitalized with acute
COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19. Kidney Int.
10. Bjornstad EC, Krallman KA, Askenazi D, et al. Preliminary assessment of acute kidney injury in critically
ill children associated with SARS-CoV-2 infection: a multicenter cross-sectional analysis. Clin J Am Soc
Nephrol. 2021;16(3):446-448. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33144276.
11. LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic involvement in children and adolescents hospitalized
in the United States for COVID-19 or multisystem inflammatory syndrome. JAMA Neurol. 2021;78(5):536-
12. Smith HAB, Besunder JB, Betters KA, et al. 2022 Society of Critical Care Medicine clinical practice
guidelines on prevention and management of pain, agitation, neuromuscular blockade, and delirium in
critically ill pediatric patients with consideration of the ICU environment and early mobility. Pediatr Crit Care
Med. 2022;23(2):e74-e110. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35119438.
13. Curley MA, Wypij D, Watson RS, et al. Protocolized sedation vs usual care in pediatric patients mechanically
ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379-389. Available at:
14. Blackwood B, Tume LN, Morris KP, et al. Effect of a sedation and ventilator liberation protocol vs usual care
on duration of invasive mechanical ventilation in pediatric intensive care units: a randomized clinical trial.
15. Fink EL, Beers SR, Houtrow AJ, et al. Early protocolized versus usual care rehabilitation for pediatric
neurocritical care patients: a randomized controlled trial. Pediatr Crit Care Med. 2019;20(6):540-550.
16. Manning JC, Pinto NP, Rennick JE, Colville G, Curley MAQ. Conceptualizing post intensive care syndrome
in children—the PICS-p framework. Pediatr Crit Care Med. 2018;19(4):298-300. Available at:
17. Herrup EA, Wieczorek B, Kudchadkar SR. Characteristics of postintensive care syndrome in survivors of
pediatric critical illness: a systematic review. World J Crit Care Med. 2017;6(2):124-134. Available at:
18. Keim G, Watson RS, Thomas NJ, Yehya N. New morbidity and discharge disposition of pediatric acute
respiratory distress syndrome survivors. Crit Care Med. 2018;46(11):1731-1738. Available at:
19. Watson RS, Asaro LA, Hutchins L, et al. Risk factors for functional decline and impaired quality of life after
pediatric respiratory failure. Am J Respir Crit Care Med. 2019;200(7):900-909. Available at:
20. Rimensberger PC, Kneyber MCJ, Deep A, et al. Caring for critically ill children with suspected or proven
coronavirus disease 2019 infection: recommendations by the Scientific Sections’ Collaborative of the
European Society of Pediatric and Neonatal Intensive Care. Pediatr Crit Care Med. 2021;22(1):56-67.
22. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign international guidelines for the
management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med.
23. Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome:
consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care

Hemodynamic Considerations for Children
Children with acute COVID-19 infrequently experience shock requiring hemodynamic support.
However, similar to children with sepsis or septic shock from other causes, children with COVID-19 and
shock should be evaluated and managed per the Surviving Sepsis Campaign International Guidelines for
the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children.1,2
Shock occurs in approximately half of the patients with multisystem inflammatory syndrome in children
(MIS-C); reported prevalence ranges from 35% to 80%.3-5 Limited data inform optimal hemodynamic
management for MIS-C. Given that the physiology observed in patients with MIS-C results from
a combination of distributive, cardiogenic, and, occasionally, hypovolemic shock, the COVID-19
Treatment Guidelines Panel (the Panel) suggests that clinicians use the management principles outlined
in the Surviving Sepsis Campaign’s guidelines for children, as well as the principles for clinical
management of heart failure and general critical care, as appropriate. The Panel’s recommendations
apply to the care of children and infants >37 weeks gestational age.
Recommendation
• For children with COVID-19 or MIS-C and shock, the COVID-19 Treatment Guidelines Panel
(the Panel) recommends a target mean arterial pressure (MAP) between the fifth and fiftieth, or
greater than the fiftieth, percentiles for age (AIII).
Rationale
There are no clinical trials that support specific hemodynamic targets for children with septic shock
due to COVID-19, MIS-C, or any other etiology. The panel members for the pediatric Surviving
Sepsis Campaign guidelines were divided on the most appropriate MAP target and made no specific
recommendation for a target MAP. Therefore, for children with COVID-19 or MIS-C, clinicians should
use the same approach used for children without COVID-19 and target a MAP between the fifth and
fiftieth, or greater than the fiftieth, percentiles for age. When MAP cannot be reliably measured, systolic
blood pressure is a reasonable alternative.2
Recommendation
• The Panel recommends that, when available, a combination of serial clinical assessments; cardiac
ultrasound or echocardiography; and/or laboratory markers, including lactate levels, should be
used to monitor the response to resuscitation in children with COVID-19 or MIS-C and shock
(BIII).
Rationale
Observational data from children with non-COVID-19-related sepsis suggest that using clinical
assessment alone limits the ability to classify patients with sepsis as having “warm” (i.e., likely to
require fluid or vasopressors) or “cold” (i.e., likely to require inotropes) shock, when compared with
assessments that include objective measures of cardiac output/index or systemic vascular resistance.6,7
Cardiac ultrasonography can be performed at the bedside and serially, and it may provide additional
clinical data on volume responsiveness and cardiac function.8 Data from studies evaluating use of
cardiac ultrasound in children with COVID-19 and MIS-C are limited to reports from case series.9

However, given the spectrum of hemodynamic perturbations observed and because approximately a
third of children with MIS-C exhibit left ventricular dysfunction, cardiac ultrasonography may have
particular value in MIS-C.4
Elevated lactate level is associated with worse outcomes in children with non-COVID-19-related
sepsis, although the specific threshold is unknown and has varied from 2 mmol/L to 4 mmol/L across
studies.10,11 Data on serial lactate measures are limited to a single observational study demonstrating
an association between normalization in lactate and a decreased risk of persistent organ dysfunction
in children with non-COVID-19-related sepsis (adjusted relative risk 0.47; 95% CI, 0.29–0.78).12
The role of serial lactate measures has not been systematically evaluated for COVID-19 or MIS-C.
An observational study of 1,080 children with MIS-C demonstrated an association between elevated
markers of inflammation (e.g., C-reactive protein, procalcitonin), brain natriuretic peptide (BNP) or
N-terminal proBNP (NT-proBNP), and troponin and the presence of cardiac dysfunction, shock, and the
need for intensive care unit admission. However, the timing of the laboratory values in the study was not
available, so the elevated markers may reflect, rather than predict, severe illness.3
Recommendation
• The Panel recommends administration of balanced crystalloids rather than 0.9% saline for the
initial resuscitation of children with shock due to COVID-19 or MIS-C (CIIb).
Rationale
No published clinical trials directly compare balanced/buffered crystalloids with 0.9% saline
administered to children with sepsis of any etiology, although an international randomized trial is
underway (ClinicalTrials.gov Identifier NCT04102371). Two observational studies using administrative
data compared the use of balanced/buffered crystalloids to 0.9% saline in propensity-matched cohorts
of children with non-COVID-19-related severe sepsis or septic shock. One of the studies compared
patients who received any or only Ringer’s lactate solution in the first 3 days of admission with patients
who received only normal saline. The study demonstrated no differences between the arms for 30-day
mortality or frequency of acute kidney injury.13
The other study compared patients receiving only balanced fluids with those receiving only 0.9%
saline. The study demonstrated that the balanced-fluid arm had lower mortality (12.5% vs. 15.9%; OR
0.76; 95% CI, 0.62–0.93; P = 0.007), reduced acute kidney injury (16.0% vs. 19.2%; OR 0.82; 95%
CI, 0.68–0.98; P = 0.028), and fewer days on vasoactive infusions (3.0 days vs. 3.3 days; P < 0.001)
than the saline arm.14 No published studies focused on patients with COVID-19 or MIS-C, although
hyponatremia is common in patients with MIS-C, and decisions about the type of fluid therapy used
should be individualized for this population.
Recommendations
• The Panel recommends the use of epinephrine or norepinephrine rather than dopamine in
children with COVID-19 or MIS-C and shock (BIIa).
• There is insufficient evidence to differentiate between norepinephrine or epinephrine as a first-line
vasoactive drug in children with COVID-19 or MIS-C. The choice of vasoactive agent should
be individualized and based on clinical examination, laboratory data, and data from cardiac
ultrasound or echocardiography.
Rationale
Use of vasoactive infusions should be considered for children with shock due to COVID-19 if signs of

shock persist after resuscitation with 40 mL/kg to 60 mL/kg of fluid, or sooner if there is evidence of
cardiac dysfunction or signs of fluid overload (e.g., tachypnea, hepatomegaly). Similar principles may
be applied to patients with MIS-C, particularly because their clinical presentation overlaps significantly
with the clinical presentation of children with septic shock due to other causes. However, given the
high prevalence of cardiac dysfunction in patients with MIS-C, clinicians should consider performing
echocardiography or cardiac ultrasound early in the initial resuscitation if MIS-C is suspected and
consider initiating a vasoactive infusion if cardiac dysfunction is identified.
Data from pediatric studies comparing vasopressors are limited, and there are no data specific to patients
with COVID-19 or MIS-C. Two small pediatric trials compared epinephrine with dopamine in patients
with non-COVID-19-related fluid-refractory septic shock.15,16 One study randomized 63 children to
receive dopamine 5 µg/kg/min to 10 µg/kg/min and 57 children to receive epinephrine 0.1 µg/kg/min
to 0.3 µg/kg/min. Mortality by Day 28 was 14.2% in the dopamine arm and 7% in the epinephrine
arm (OR 6.5; 95% CI, 1.1–37.8; P = 0.03). In the other study, 31 children were randomized to receive
incremental doses of dopamine 10 µg/kg/min to 20 µg/kg/min, and 29 children were randomized to
receive incremental doses of epinephrine 0.1 to 0.3 µg/kg/min. The primary outcome of shock resolution
within 1 hour occurred in 4 children (13%) receiving dopamine and 12 children (41%) receiving
epinephrine (OR 4.8; 95% CI, 1.3–17.2; P = 0.019).
No pediatric trials have compared norepinephrine to other vasoactive agents in patients with sepsis, but
based on data from studies of adults, the pharmacologic properties of norepinephrine and dopamine
(see Hemodynamics for Adults), and the 2020 Surviving Sepsis Campaign guidelines for children,
norepinephrine is suggested over dopamine.2
Collectively, this evidence is insufficient to recommend norepinephrine versus epinephrine as a first-line
vasoactive agent in children with COVID-19 or MIS-C. Further, given the varied physiology observed
with MIS-C in particular, decisions about which vasopressor to use should be individualized based on
clinical and laboratory data and findings from bedside cardiac ultrasound or echocardiography.
Recommendation
inodilators (including dobutamine or milrinone) in children with COVID-19 or MIS-C who show
evidence of cardiac dysfunction and persistent hypoperfusion despite adequate fluid loading and
the use of vasopressor agents.
Rationale
Data from studies evaluating use of inodilators in children with COVID-19, MIS-C, and non-COVID-
19-related sepsis are limited to reports from case series. However, the majority of the pediatric Surviving
Sepsis Campaign guidelines panel (77%) would use an inodilator at least some of the time for patients
with non-COVID-19-related sepsis, cardiac dysfunction, and persistent hypoperfusion despite adequate
fluid loading and the use of vasopressor agents.2 Expert consultation from specialists in pediatric
cardiology and critical care medicine is recommended in this scenario.
Additional Recommendations
• For the acute resuscitation of children with COVID-19 or MIS-C and shock, the Panel
recommends the use of crystalloids rather than albumin (AIIb).
• The Panel recommends against using hydroxyethyl starches for intravascular volume
replacement in children with COVID-19 or MIS-C and sepsis or septic shock (AIII).

• For children with refractory shock who have recently completed a course of corticosteroids to treat
COVID-19, the Panel recommends using low-dose corticosteroid therapy (“shock-reversal”) over
no corticosteroid therapy (CIII).
• Children who are currently receiving corticosteroids for COVID-19 or MIS-C are generally
receiving sufficient glucocorticoid replacement therapy and do not require additional
hydrocortisone for refractory shock.
References
6. Egan JR, Festa M, Cole AD, et al. Clinical assessment of cardiac performance in infants and children
following cardiac surgery. Intensive Care Med. 2005;31(4):568-573. Available at:
7. Razavi A, Newth CJL, Khemani RG, Beltramo F, Ross PA. Cardiac output and systemic vascular resistance:
clinical assessment compared with a noninvasive objective measurement in children with shock. J Crit Care.
2017;39:6-10. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28088009.
8. Ranjit S, Aram G, Kissoon N, et al. Multimodal monitoring for hemodynamic categorization and management
of pediatric septic shock: a pilot observational study. Pediatr Crit Care Med. 2014;15(1):e17-26. Available at:
9. Kennedy TM, Dessie A, Kessler DO, et al. Point-of-care ultrasound findings in multisystem inflammatory
syndrome in children: a cross-sectional study. Pediatr Emerg Care. 2021;37(6):334-339. Available at:
10. Scott HF, Brou L, Deakyne SJ, et al. Association between early lactate levels and 30-day mortality in clinically
suspected sepsis in children. JAMA Pediatr. 2017;171(3):249-255. Available at:
11. Bai Z, Zhu X, Li M, et al. Effectiveness of predicting in-hospital mortality in critically ill children by
assessing blood lactate levels at admission. BMC Pediatr. 2014;14:83. Available at:
12. Scott HF, Brou L, Deakyne SJ, et al. Lactate clearance and normalization and prolonged organ dysfunction in
pediatric sepsis. J Pediatr. 2016;170:149-155 e141-144. Available at:
13. Weiss SL, Keele L, Balamuth F, et al. Crystalloid fluid choice and clinical outcomes in pediatric sepsis: a
matched retrospective cohort study. J Pediatr. 2017;182:304-310 e310. Available at:

14. Emrath ET, Fortenberry JD, Travers C, McCracken CE, Hebbar KB. Resuscitation with balanced fluids is
associated with improved survival in pediatric severe sepsis. Crit Care Med. 2017;45(7):1177-1183. Available
15. Ventura AM, Shieh HH, Bousso A, et al. Double-blind prospective randomized controlled trial of dopamine
versus epinephrine as first-line vasoactive drugs in pediatric septic shock. Crit Care Med. 2015;43(11):2292-
16. Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-blind randomized clinical trial
comparing dopamine and epinephrine in pediatric fluid-refractory hypotensive septic shock. Pediatr Crit Care
Med. 2016;17(11):e502-e512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27673385.

Oxygenation and Ventilation for Children
The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations in this section were
informed by recommendations from the Surviving Sepsis Campaign’s guidelines for managing adult
sepsis, pediatric sepsis, and COVID-19, as well as by recommendations from the 2015 Pediatric Acute
Lung Injury Consensus Conference (PALICC).
Goal of Oxygenation
Recommendations
• An oxygen saturation (SpO2) target of 92% to 97% is recommended for most children with
COVID-19 who require supplemental oxygen (AIIb).
• For children with severe pediatric acute respiratory distress syndrome (PARDS; i.e., with an
oxygenation index ≥16 or SpO2 index ≥12.3), an SpO2 of <92% can be considered to minimize
exposure to a high fraction of inspired oxygen (FiO2), but prolonged periods of SpO2 <88% should
be avoided (CIII).
Rationale
The optimal SpO2 in children with COVID-19 is unknown. However, there is no evidence that the target
SpO2 should differ from the 2015 PALICC recommendation.1 An SpO2 of 92% to 97% is recommended
for most children with COVID-19 who require supplemental oxygen. The potential harm of hyperoxia
in children was demonstrated in a recent meta-analysis of 11 observational studies of children without
COVID-19.2 The study demonstrated that critically ill children with hyperoxia had greater odds of
mortality than those without hyperoxia (OR 1.59; 95% CI, 1.00–2.51). However, there was significant
heterogeneity across the included studies for populations, definitions of hyperoxia, and the timing of
assessment for mortality outcomes. For children with severe PARDS (i.e., with an oxygenation index
≥16 or SpO2 index ≥12.3),1 an SpO2 <92% can be considered to minimize exposure to a high FiO2.
Although no evidence clearly identifies a safe minimum SpO2 in children, prolonged exposure to SpO2
<88% should be avoided. When SpO2 is <92%, monitoring oxygen delivery markers, including central
venous SpO2, is suggested.3
High-Flow Nasal Cannula Oxygen and Noninvasive Ventilation for Children With
COVID-19 and Acute Respiratory Failure
Recommendation
• For infants and children with COVID-19 and persistent respiratory failure despite conventional
oxygen therapy who have no indicators for endotracheal intubation, a time-limited trial of
noninvasive ventilation (NIV) or high-flow nasal cannula (HFNC) oxygen is recommended
(AIIa). There is insufficient evidence for the Panel to recommend either for or against the use
of HFNC oxygen over NIV or the use of NIV over HFNC oxygen in infants and children with
COVID-19.

Rationale
No high-quality studies evaluate the use of HFNC oxygen or NIV in children with COVID-19.
Therefore, when choosing a mode of respiratory support for children with COVID-19, the principles
of management used for patients without COVID-19 should be followed. Both the Surviving Sepsis
Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ
Dysfunction in Children and PALICC recommend the use of NIV for children with respiratory failure
who have no indication for intubation.4,5
Furthermore, the response to NIV, particularly for children with more severe hypoxemia or high work
of breathing, should be gauged early (within the first several hours). If the patient does not show
improvement, intubation should be considered. To unload respiratory muscles, bilevel modes of NIV
(with inspiratory pressure augmentation, such as BiPAP), if tolerated, are preferred over the use of
continuous positive airway pressure (CPAP) alone, although CPAP is an alternative for children who
cannot achieve an adequate seal with the NIV interface or who have significant patient-ventilator
asynchrony.4
HFNC oxygen is a relatively new, but increasingly used, mode of respiratory support for infants and
children with acute respiratory failure.6 Data from studies evaluating the effectiveness of HFNC oxygen
relative to NIV or conventional oxygen are limited to studies of children with pneumonia in limited-
resource settings and studies of children with bronchiolitis. Two randomized controlled trials of children
with pneumonia were conducted in limited-resource settings. One study demonstrated a slightly lower
relative risk of mortality with the use of HFNC oxygen when compared with conventional oxygen
therapy (adjusted HR 0.79; 95% CI, 0.54–1.16), although the results were not statistically significant.7
The other trial demonstrated that children treated with bubble CPAP ventilation had a lower proportion
of mortality than children who received low-flow oxygen (relative risk 0.25; 95% CI, 0.07–0.89; P
= 0.02).8 The results also indicated that for the composite outcome of treatment failure, there was no
difference between the use of HFNC oxygen and bubble CPAP (relative risk 0.50; 99.7% CI, 0.11–2.29).
A randomized, noninferiority trial compared HFNC oxygen (2 L/kg/min) and nasal CPAP among
142 infants aged <6 months with bronchiolitis not caused by COVID-19.9 The primary outcome was
treatment failure within 24 hours, defined as an increase of ≥1 point in the modified Wood’s Clinical
Asthma Score (M-WCAS) or Échelle Douleur Inconfort Nouveau-Né (EDIN) score (a neonatal pain and
discomfort scale), a respiratory rate >60 breaths/min and an increase of >10 breaths/min from baseline,
or >2 severe apnea episodes per hour. Treatment failure occurred more often in the HFNC oxygen arm
than in the nasal CPAP arm (51% vs. 31%), a result that failed to meet the prespecified noninferiority
margin. Notably, in the HFNC arm, 72% of the patients who had treatment failure were managed
successfully with nasal CPAP, and there were no differences between the arms for intubation rates or
length of stay.
A systematic review of the noninferiority trial and 2 smaller trials comparing HFNC to nasal CPAP
summarized the results of 213 infants and children aged ≤2 years with bronchiolitis.10 Treatment failure
in the 2 smaller trials was rare, and no differences were detected between the HFNC and nasal CPAP
arms for any of the clinical outcomes.11,12
In a study that assessed whether higher flow rates of HFNC oxygen improved outcomes, 286 infants
aged ≤6 months and with severe bronchiolitis were randomized to receive HFNC oxygen 2 L/kg/min or
HFNC oxygen 3 L/kg/min.13 The primary outcome of treatment failure (i.e., an increase of ≥1 point in
M-WCAS or EDIN score, a respiratory rate >60 breaths/min and an increase of >10 breaths/min from
baseline, or >2 severe apnea episodes per hour) occurred in 38.7% of the infants in the 2 L/kg/min arm
and in 38.9% of the infants in the 3 L/kg/min arm (P = 0.98). Patient discomfort, as measured by EDIN
score, occurred more often in the 3 L/kg/min arm than in the 2 L/kg/min arm (43% vs. 16%, P = 0.002).

HFNC oxygen is increasingly being used in children. These studies highlight the potential role of an
HFNC oxygen trial in the management of children with acute respiratory failure due to COVID-19,
particularly for infants and young children who may have NIV-related challenges, such as poor mask fit,
discomfort, or patient-ventilator asynchrony. For the use of HFNC oxygen in children, consider flow rates
of up to 2 L/kg/min, with a maximum of 60 L/min. If patients do not improve within the first few hours
of receiving HFNC oxygen, their treatment should be escalated to NIV or intubation.
Awake Prone Positioning for Children Not Receiving Mechanical Ventilation

Recommendations
• There is insufficient evidence for the Panel to recommend either for or against a trial of awake
prone positioning for children with persistent hypoxemia who require HFNC oxygen or NIV and do
not require endotracheal intubation.
• For patients with refractory hypoxemia who meet the indications for intubation and mechanical
ventilation, the Panel recommends against the use of awake prone positioning as a rescue therapy
to avoid intubation (AIII).
Rationale
There are no high-quality pediatric data evaluating the effect of awake prone positioning on clinical
outcomes in children with COVID-19 or non-COVID-19-related illness. Awake prone positioning may be
considered for older children and adolescents (see Oxygenation and Ventilation for Adults). In addition,
pediatric clinicians should consider a child’s developmental stage and ability to comply with the protocols
for awake prone positioning.
Intubation for Mechanical Ventilation in Children With Acute COVID-19

Recommendations
• If intubation becomes necessary, the Panel recommends that an experienced practitioner perform
the procedure in a controlled setting due to the enhanced risk of exposing health care practitioners
to SARS-CoV-2 during intubation (AIII).
• The Panel recommends using cuffed endotracheal tubes over uncuffed endotracheal tubes in
children who require endotracheal intubation (AIIb).
Rationale
To optimize the safety of patients and health care workers and maximize first-attempt success, intubation
should be performed in a controlled setting by an experienced practitioner. In addition, cuffed endotracheal
tubes are preferred for children of all ages with COVID-19 to minimize leak around the endotracheal tube,
ensure delivery of ventilator pressure, decrease the risk of aspiration, reduce the need for endotracheal tube
exchange, and reduce aerosolization of respiratory secretions during mechanical ventilation.3,14-16
General Considerations for Children With COVID-19 and PARDS Who Require
Mechanical Ventilation
Recommendations
For children with COVID-19 and PARDS who require mechanical ventilation:
• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body
weight) over higher VT ventilation (VT >8 mL/kg) (AIIb).

• The Panel recommends targeting plateau pressures of ≤28 cm H2O for children with normal chest
wall compliance and ≤32 cm H2O for those with impaired chest wall compliance (AIII).
• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy (i.e.,
>10–15 cm H2O or higher in patients with severe PARDS) over a lower PEEP strategy, titrated
based on observed responses in oxygenation, hemodynamics, and respiratory system compliance
(BIIb).
• The Panel recommends permissive hypercapnia (e.g., pH >7.15 to 7.30), if needed, to remain
within lung-protective strategies and to minimize ventilator-associated lung injury, provided the
patient does not have a coexisting condition that would be worsened by acidosis (e.g., severe
pulmonary hypertension, ventricular dysfunction, intracranial hypertension) (AIII).
• The Panel recommends against the routine use of inhaled nitric oxide (AIII).
Rationale
There is no evidence that ventilator management of children with PARDS due to COVID-19
should differ from ventilator management of patients with PARDS due to other causes. The Panel’s
recommendations are derived from the 2015 PALICC recommendations.1,3 Since the publication of the
PALICC recommendations, no randomized trials have provided significant new evidence, although
some observational data support some of the PALICC recommendations.
A large observational study conducted in 71 international pediatric intensive care units identified that
for patients with mild to moderate acute respiratory distress syndrome (ARDS), less adherence to the
recommended VT of 5 mL/kg to 8 mL/kg (or 3 mL/kg to 6 mL/kg for patients with severe ARDS) was
associated with higher mortality and with more time on ventilation.17 In general, supraphysiologic VT
ventilation (>8 mL/kg) should not be used in patients with PARDS, and VT should be adjusted within
the acceptable range to maintain other lung-protective ventilation targets (e.g., maintaining ≤28 cm H2O
plateau pressure). The use of ultra-low VT ventilation (<4 mL/kg) has not been systematically studied in
children, so it should be used with caution.
The ARDS Network established a ventilator protocol that includes suggested low PEEP/high FiO2
levels.18 The protocol suggests that for patients receiving FiO2 ≥0.6, a PEEP level of ≥10 cm H2O
would be implemented, which aligns with recommendations from PALICC. Two observational studies
have identified better clinical outcomes associated with use of the suggested (or higher) PEEP levels
compared to lower PEEP levels.17,19 The multicenter studies, including nearly 1,500 pediatric patients
with ARDS, each demonstrated that PEEP levels lower than those recommended by the ARDS Network
were associated with higher mortality.
Inhaled nitric oxide can be considered as a rescue therapy for children with severe PARDS and
COVID-19. In a small, randomized trial, the use of inhaled nitric oxide resulted in reduced use of
extracorporeal membrane oxygenation (ECMO).20 However, inhaled nitric oxide has a heterogeneous
treatment effect, and many patients do not show improved gas exchange. Although adverse effects are
rare, use of inhaled nitric oxide can have a substantial effect on health care costs. Therefore, inhaled
nitric oxide should not be considered routine therapy for children with PARDS or COVID-19 who are
receiving mechanical ventilation.
Fluid Management for Children With PARDS

Recommendation
• Following an initial resuscitation in children with PARDS due to COVID-19, clinicians should
monitor and titrate fluid balance to maintain adequate intravascular volume while aiming to

prevent positive fluid balance (BIIb).
Rationale
There is no evidence that fluid management in children with PARDS due to COVID-19 should
differ from fluid management in patients with PARDS due to other causes. Therefore, the Panel’s
recommendation aligns with the PALICC recommendation.1 No pediatric randomized trials have directly
compared a liberal versus conservative fluid strategy in PARDS of any etiology. Several observational
studies have demonstrated an association between greater fluid overload and worse clinical outcomes,
including fewer ventilator-free days and increased mortality.21-23
In a multicenter study of 168 children with acute lung injury, daily and cumulative fluid balance
were measured over the first 7 days after participants met the inclusion criteria. After adjustment for
demographic characteristics, pediatric risk of mortality III (PRISM III) scores, vasopressor use, and
the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2), an increasing
cumulative fluid balance on Day 3 was associated with fewer ventilator-free days, but no association
with mortality was detected.21
A more recent, single-center study including 732 children with acute lung injury demonstrated an
association between higher cumulative fluid balance on Days 5 to 7 and increased mortality (for 100
mL/kg on Day 5; OR 1.34; 95% CI, 1.11–1.61) after adjustment for oxygenation index, the number
of nonpulmonary organ failures, immunocompromised status, and vasopressor scores. Also, greater
cumulative fluid balance on Days 4 to 7 was associated with a lower probability of successful extubation
by Day 28.23 Collectively, the findings from these pediatric observational studies demonstrate the
potential harm of fluid overload in children with PARDS, particularly after 3 to 4 days of illness.
These results are consistent with the findings from FACTT, a trial of conservative versus liberal fluid
management strategies in adults.24 In adults, FACTT found no difference between arms for 60-day
mortality, but the conservative strategy arm demonstrated improved oxygenation and less time on
mechanical ventilation and in the intensive care unit when compared with the liberal strategy arm.
However, no analysis of data from prospective pediatric trials delineates a causal relationship between a
specific, protocolized, fluid management strategy, or the timing of such a strategy, and clinical outcomes.
Therefore, an individualized fluid management approach that is titrated to maintain intravascular volume
while preventing excessive positive fluid balance, as suggested by the 2015 PALICC recommendation,
is appropriate.1
Neuromuscular Blockade for Mechanically Ventilated Children With Severe PARDS

Recommendation
• For mechanically ventilated children with severe PARDS and COVID-19, the Panel recommends
minimal yet effective use of neuromuscular blocking agents in conjunction with sedation, if
sedation alone is inadequate to achieve lung-protective ventilation (BIII).
Rationale
There is no evidence that the use of neuromuscular blockade in children with COVID-19 should differ
from practices used for severe PARDS from other causes. Therefore, the Panel’s recommendation
aligns directly with the PALICC recommendation.1 Since the publication of the 2015 PALICC
recommendation, no new data support significant changes to the recommendation.

Therapies for Mechanically Ventilated Children With Severe PARDS and Refractory
Hypoxemia
Recommendations
For children with severe PARDS and refractory hypoxemia after other oxygenation strategies have been
optimized:
• The Panel recommends inhaled nitric oxide as a rescue therapy; if no rapid improvement in
oxygenation is observed, inhaled nitric oxide should be discontinued (BIIb).
• The Panel recommends prone positioning for 12 to 16 hours per day over no prone positioning
(BIII).
recruitment maneuvers, but if they are used in children, slow, incremental and decremental
adjustments in PEEP are preferred to sustained inflation maneuvers.
• There is insufficient evidence for the Panel to recommend either for or against the use of high-
frequency oscillatory ventilation (HFOV) in children with PARDS.
Rationale
There is no evidence that the use of inhaled nitric oxide, prone positioning, or HFOV in children with
COVID-19 should differ from practices used for severe PARDS from other causes. Therefore, the
Panel’s recommendations are largely based on PALICC recommendations.1 Since the publication of the
2015 PALICC recommendations, many new trials evaluating these practices have been conducted.
One randomized controlled trial and 2 propensity-matched, observational studies have evaluated the
use of inhaled nitric oxide in PARDS since the publication of the PALICC recommendations. The
randomized controlled trial included 55 patients and found that the use of inhaled nitric oxide resulted
in no statistical difference between arms for 28-day mortality (8% mortality in the inhaled nitric oxide
arm vs. 28% in the placebo arm), although the trial was underpowered for this outcome.20 However, the
inhaled nitric oxide arm had approximately 5 more ventilator-free days than the placebo arm, a result
that was primarily mediated by avoiding the use of ECMO. These results have been corroborated by
observational studies, which also reported more ventilator-free days for patients who received inhaled
nitric oxide.25,26 Although the evidence is insufficient to recommend the use of inhaled nitric oxide
for all patients with ARDS, in cases of severe hypoxemia, it can be considered as a rescue therapy to
potentially avoid the use of ECMO.
No new studies have evaluated the role of prone positioning in PARDS, although a large, multicenter
trial is ongoing. Therefore, the Panel’s recommendation to consider prone positioning in cases of
severe PARDS aligns with the PALICC recommendation and is supported by adult data, primarily from
PROSEVA, a trial on prone positioning in patients with ARDS.27
The 2015 PALICC recommendations included the use of careful recruitment maneuvers with
incremental and decremental adjustments in PEEP.1 In children, this approach to recruitment maneuvers
is preferred over sustained inflation maneuvers due to the increased risk of harm from barotrauma and
hemodynamic compromise in patients with sustained inflation. Clinical trials in adults have highlighted
the potential harm from recruitment maneuvers applied to patients who may not have recruitable
lung.28,29 Therefore, although there is insufficient evidence to recommend for or against the use of
recruitment maneuvers in children with refractory hypoxemia, if recruitment maneuvers are used, the
preferred strategy is slow, incremental increases and decreases of PEEP.

Since the publication of the 2015 PALICC recommendations, 2 small randomized controlled trials have
examined the use of HFOV for PARDS.30,31 Neither study found a significant difference for mortality.
Several observational studies using propensity matching have shown either no difference in outcomes
between the HFOV and conventional ventilation arms or a potential for higher mortality or a longer
ventilation time with the use of HFOV, when compared with conventional ventilation.32-36 In some of
these analyses, residual confounding has been a concern. A large, multicenter randomized controlled
trial of HFOV for PARDS is ongoing. Therefore, the Panel has determined that there is insufficient
evidence to recommend for or against the use of HFOV in COVID-19-related PARDS. Some concerns
have been raised about the use of HFOV and aerosolization of COVID-19, although adding a filter to the
expiratory limb of the HFOV circuit may alleviate these concerns.

More than half of the patients with multisystem inflammatory syndrome in children (MIS-C) require
mechanical ventilation or NIV.37-39 For these patients with MIS-C, the indications for mechanical
ventilation vary and include shock or cardiac dysfunction, pulmonary edema, procedural preparation
(e.g., to facilitate sedation for central venous catheter placement), respiratory failure, or neurologic
failure. The management of oxygenation and ventilation in children with MIS-C should follow the usual
principles of shock management outlined in the Surviving Sepsis Campaign guidelines for children, as
well as the principles for clinical management of heart failure and general critical care, as appropriate.5
References
1. Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome:
consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care
2. Lilien TA, Groeneveld NS, van Etten-Jamaludin F, et al. Association of arterial hyperoxia with outcomes
in critically ill children: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(1):e2142105.
3. Rimensberger PC, Cheifetz IM, Pediatric Acute Lung Injury Consensus Conference Group. Ventilatory
support in children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute
Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S51-S60. Available at:
4. Essouri S, Carroll C, Pediatric Acute Lung Injury Consensus Conference Group. Noninvasive support and
ventilation for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury
Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S102-S110. Available at:
6. Willer RJ, Johnson MD, Cipriano FA, et al. Implementation of a weight-based high-flow nasal cannula
protocol for children with bronchiolitis. Hosp Pediatr. 2021;11(8):891-895. Available at:
7. Maitland K, Kiguli S, Olupot-Olupot P, et al. Randomised controlled trial of oxygen therapy and high-flow
nasal therapy in African children with pneumonia. Intensive Care Med. 2021;47(5):566-576. Available at:
8. Chisti MJ, Salam MA, Smith JH, et al. Bubble continuous positive airway pressure for children with
severe pneumonia and hypoxaemia in Bangladesh: an open, randomised controlled trial. Lancet.

9. Milesi C, Essouri S, Pouyau R, et al. High flow nasal cannula (HFNC) versus nasal continuous positive
airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants:
a multicenter randomized controlled trial (TRAMONTANE study). Intensive Care Med. 2017;43(2):209-216.
10. Moreel L, Proesmans M. High flow nasal cannula as respiratory support in treating infant bronchiolitis: a
systematic review. Eur J Pediatr. 2020;179(5):711-718. Available at:
11. Sarkar M, Sinha R, Roychowdhoury S, et al. Comparative study between noninvasive continuous positive
airway pressure and hot humidified high-flow nasal cannulae as a mode of respiratory support in infants
with acute bronchiolitis in pediatric intensive care unit of a tertiary care hospital. Indian J Crit Care Med.
12. Vahlkvist S, Jurgensen L, la Cour A, et al. High flow nasal cannula and continuous positive airway pressure
therapy in treatment of viral bronchiolitis: a randomized clinical trial. Eur J Pediatr. 2020;179(3):513-518.
13. Milesi C, Pierre AF, Deho A, et al. A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/
min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2).
Intensive Care Med. 2018;44(11):1870-1878. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30343318.
14. Weiss M, Dullenkopf A, Fischer JE, et al. Prospective randomized controlled multi-centre trial of cuffed or
uncuffed endotracheal tubes in small children. Br J Anaesth. 2009;103(6):867-873. Available at:
15. Shi F, Xiao Y, Xiong W, Zhou Q, Huang X. Cuffed versus uncuffed endotracheal tubes in children: a meta-
analysis. J Anesth. 2016;30(1):3-11. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26296534.
16. Matava CT, Kovatsis PG, Lee JK, et al. Pediatric airway management in COVID-19 patients: consensus
guidelines from the Society for Pediatric Anesthesia’s Pediatric Difficult Intubation Collaborative and the
Canadian Pediatric Anesthesia Society. Anesth Analg. 2020;131(1):61-73. Available at:
17. Bhalla AK, Klein MJ, Emeriaud G, et al. Adherence to lung-protective ventilation principles in pediatric acute
respiratory distress syndrome: a pediatric acute respiratory distress syndrome incidence and epidemiology
study. Crit Care Med. 2021;49(10):1779-1789. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34259438.
18. Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress
syndrome. N Engl J Med. 2000;342(18):1301-1308. Available at:
19. Khemani RG, Parvathaneni K, Yehya N, et al. Positive end-expiratory pressure lower than the ARDS network
protocol is associated with higher pediatric acute respiratory distress syndrome mortality. Am J Respir Crit
20. Bronicki RA, Fortenberry J, Schreiber M, Checchia PA, Anas NG. Multicenter randomized controlled trial of
inhaled nitric oxide for pediatric acute respiratory distress syndrome. J Pediatr. 2015;166(2):365-369 e361.
21. Valentine SL, Sapru A, Higgerson RA, et al. Fluid balance in critically ill children with acute lung injury. Crit
22. Lima L, Menon S, Goldstein SL, Basu RK. Timing of fluid overload and association with patient outcome.
Pediatr Crit Care Med. 2021;22(1):114-124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32947381.
23. Black CG, Thomas NJ, Yehya N. Timing and clinical significance of fluid overload in pediatric acute
respiratory distress syndrome. Pediatr Crit Care Med. 2021;22(9):795-805. Available at:
24. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network,

Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N
25. Gupta P, Richardson T, Hall M, et al. Effect of inhaled nitric oxide on outcomes in children with acute lung
injury: propensity matched analysis from a linked database. Crit Care Med. 2016;44(10):1901-1909. Available
26. Bhalla AK, Yehya N, Mack WJ, et al. The association between inhaled nitric oxide treatment and ICU
mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome. Crit Care Med.
27. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N
28. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial Investigators,
Cavalcanti AB, Suzumura EA, et al. Effect of lung recruitment and titrated positive end-expiratory pressure
(PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical
trial. JAMA. 2017;318(14):1335-1345. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28973363.
29. Hodgson CL, Cooper DJ, Arabi Y, et al. Maximal recruitment open lung ventilation in acute respiratory
distress syndrome (PHARLAP): a Phase II, multicenter randomized controlled clinical trial. Am J Respir Crit
30. Samransamruajkit R, Rassameehirun C, Pongsanon K, et al. A comparison of clinical efficacy between high
frequency oscillatory ventilation and conventional ventilation with lung volume recruitment in pediatric acute
respiratory distress syndrome: a randomized controlled trial. Indian J Crit Care Med. 2016;20(2):72-77.
31. El-Nawawy A, Moustafa A, Heshmat H, Abouahmed A. High frequency oscillatory ventilation versus
conventional mechanical ventilation in pediatric acute respiratory distress syndrome: a randomized controlled
study. Turk J Pediatr. 2017;59(2):130-143. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29276865.
32. Gupta P, Green JW, Tang X, et al. Comparison of high-frequency oscillatory ventilation and conventional
mechanical ventilation in pediatric respiratory failure. JAMA Pediatr. 2014;168(3):243-249. Available at:
33. Guo YX, Wang ZN, Li YT, et al. High-frequency oscillatory ventilation is an effective treatment for
severe pediatric acute respiratory distress syndrome with refractory hypoxemia. Ther Clin Risk Manag.
34. Bateman ST, Borasino S, Asaro LA, et al. Early high-frequency oscillatory ventilation in pediatric acute
respiratory failure. A propensity score analysis. Am J Respir Crit Care Med. 2016;193(5):495-503. Available
35. Rowan CM, Loomis A, McArthur J, et al. High-frequency oscillatory ventilation use and severe pediatric
ARDS in the pediatric hematopoietic cell transplant recipient. Respir Care. 2018;63(4):404-411. Available at:
36. Wong JJ, Liu S, Dang H, et al. The impact of high frequency oscillatory ventilation on mortality in paediatric
acute respiratory distress syndrome. Crit Care. 2020;24(1):31. Available at:
37. Yasuhara J, Watanabe K, Takagi H, Sumitomo N, Kuno T. COVID-19 and multisystem inflammatory
syndrome in children: a systematic review and meta-analysis. Pediatr Pulmonol. 2021;56(5):837-848.

Extracorporeal Membrane Oxygenation for
Children
Recommendation
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that the use of extracorporeal
membrane oxygenation (ECMO) should be considered for children with acute COVID-19 or
multisystem inflammatory syndrome in children (MIS-C) who have refractory hypoxemia or
shock when hemodynamic parameters cannot be maintained or lung-protective strategies result in
inadequate gas exchange (CIII). Candidacy for ECMO should be determined on a case-by-case
basis by the multidisciplinary team.
Rationale
ECMO is used as a rescue therapy for children with refractory hypoxemia or shock. Similar to outcomes
for adults, outcomes for children managed with venovenous ECMO are variable and are influenced
by the etiology and duration of respiratory failure and by underlying comorbid medical conditions.1,2
In addition, studies have shown that pediatric centers that treat fewer patients with ECMO have
worse outcomes than facilities that treat a high volume of patients with ECMO.3,4 No randomized
trials evaluate the efficacy or benefit of ECMO for hypoxemic respiratory failure in children without
COVID-19 beyond the neonatal period. In an observational study of 122 children with severe pediatric
acute respiratory distress syndrome (PARDS), 90-day mortality for children treated with ECMO and for
those supported without ECMO was similar (25% vs. 30%).5
The Pediatric Acute Lung Injury Consensus Conference recommends considering ECMO for patients
with severe PARDS from reversible causes or for children who are candidates for lung transplantation.6
The Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and
Sepsis-Associated Organ Dysfunction in Children issued a weak recommendation, based on very low
quality of evidence, to use venovenous ECMO for children with PARDS and refractory hypoxemia.7
Venoarterial ECMO has been used successfully for the treatment of refractory shock in children,
although no trials evaluate this approach, and the potential benefits must be weighed against risks of
bleeding or thromboembolic events.8-10 The Surviving Sepsis Campaign guidelines for children issued a
weak recommendation, based on very low quality of evidence, for use of venoarterial ECMO in children
with shock that is refractory to all other treatments; however, a standardized definition of refractory
shock in children is not available.7
Studies evaluating data on the use of ECMO in children with COVID-19 and MIS-C are limited to case
reports and case series.11-13 A publicly available registry for pediatric patients with COVID-19 on ECMO
is maintained by the multinational Extracorporeal Life Support Organization (ELSO). In-hospital
mortality at 90 days was about 30%, which is similar to reports from non-COVID-19 ECMO cohorts.14,15
ELSO has published guidelines for use of ECMO in COVID-19.16 In general, ECMO candidacy for
children with COVID-19 or MIS-C should be assessed using criteria similar to those used for other
causes of severe respiratory failure or shock. Cannulation approaches and management principles should
follow published international guidelines and local protocols for non-COVID-19 patients.
Pediatric clinicians should consider entering patients into clinical trials or registries to inform future

recommendations regarding use of ECMO in children with COVID-19. The following resources provide
more information on an international ECMO registry and on clinical trials evaluating ECMO in children
with COVID-19:
• The ELSO registry for ECMO in COVID-19
• ClinicalTrials.gov
References
1. Zabrocki LA, Brogan TV, Statler KD, et al. Extracorporeal membrane oxygenation for pediatric respiratory
failure: survival and predictors of mortality. Crit Care Med. 2011;39(2):364-370. Available at:
2. Gow KW, Heiss KF, Wulkan ML, et al. Extracorporeal life support for support of children with malignancy
and respiratory or cardiac failure: the extracorporeal life support experience. Crit Care Med. 2009;37(4):1308-
3. Freeman CL, Bennett TD, Casper TC, et al. Pediatric and neonatal extracorporeal membrane oxygenation:
does center volume impact mortality? Crit Care Med. 2014;42(3):512-519. Available at:
4. Gonzalez DO, Sebastiao YV, Cooper JN, Minneci PC, Deans KJ. Pediatric extracorporeal membrane
oxygenation mortality is related to extracorporeal membrane oxygenation volume in US hospitals. J Surg Res.
5. Barbaro RP, Xu Y, Borasino S, et al. Does extracorporeal membrane oxygenation improve survival in pediatric
acute respiratory failure? Am J Respir Crit Care Med. 2018;197(9):1177-1186. Available at:
6. Dalton HJ, Macrae DJ, Pediatric Acute Lung Injury Consensus Conference Group. Extracorporeal support in
children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury
Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S111-S117. Available at:
8. Schlapbach LJ, Chiletti R, Straney L, et al. Defining benefit threshold for extracorporeal membrane
oxygenation in children with sepsis—a binational multicenter cohort study. Crit Care. 2019;23(1):429.
9. Ramanathan K, Yeo N, Alexander P, et al. Role of extracorporeal membrane oxygenation in children with
sepsis: a systematic review and meta-analysis. Crit Care. 2020;24(1):684. Available at:
10. Oberender F, Ganeshalingham A, Fortenberry JD, et al. Venoarterial extracorporeal membrane oxygenation
versus conventional therapy in severe pediatric septic shock. Pediatr Crit Care Med. 2018;19(10):965-972.
11. Di Nardo M, Hoskote A, Thiruchelvam T, et al. Extracorporeal membrane oxygenation in children with
coronavirus disease 2019: preliminary report from the collaborative european chapter of the extracorporeal life
support organization prospective survey. ASAIO J. 2021;67(2):121-124. Available at:
12. Alfoudri H, Shamsah M, Yousuf B, AlQuraini N. Extracorporeal membrane oxygenation and extracorporeal
cardiopulmonary resuscitation for a COVID-19 pediatric patient: a successful outcome. ASAIO J.

14. Extracorporeal Life Support Organization. Registry dashboard of ECMO-supported COVID-19 patient
data. 2022. Available at: https://www.elso.org/Registry/FullCOVID-19RegistryDashboard.aspx?
goHash=1&sO=1&all=true&NA= false&Eur=false&Asia=false&La=false&Africa=false&AA=false&Neo=
true&Ped=true&Adlt=false&AllDts=true&YTD=false#TheFilter. Accessed May 18, 2022.
15. Extracorporeal Life Support Organization. ELSO live registry dashboard of ECMO patient data. 2022.
Available at: https://www.elso.org/Registry/ELSOLiveRegistryDashboard.aspx. Accessed May 20, 2022.
16. Badulak J, Antonini MV, Stead CM, et al. Extracorporeal membrane oxygenation for COVID-19: updated
2021 guidelines from the extracorporeal life support organization. ASAIO J. 2021;67(5):485-495. Available at:

Antiviral Drugs That Are Approved, Authorized, or
Under Evaluation for the Treatment of COVID-19
Remdesivir is the only antiviral drug that is approved by the Food and Drug Administration (FDA) for the treatment
of COVID-19. Ritonavir-boosted nirmatrelvir (Paxlovid), molnupiravir, and certain anti-SARS-CoV-2 monoclonal
antibodies (mAbs) have received Emergency Use Authorizations from the FDA for the treatment of COVID-19.
This section focuses on the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for using
small-molecule antiviral drugs to treat COVID-19. These recommendations are based on the available data. For
recommendations and information regarding the use of anti-SARS-CoV-2 mAbs, see Anti-SARS-CoV-2 Monoclonal
Antibodies.
Recommendations for Treating Nonhospitalized Patients
• The Panel recommends the following anti-SARS-CoV-2 therapies as preferred treatments for COVID-19. These drugs
are listed in order of preference:
• Ritonavir-boosted nirmatrelvir (Paxlovid) (AIIa)
• Remdesivir (BIIa)
• The Panel recommends the following anti-SARS-CoV-2 therapies as alternative treatments for COVID-19. These drugs
should ONLY be used when neither of the preferred treatments are available, feasible to use, or clinically appropriate.
These drugs are listed in alphabetical order:
• Bebtelovimab (CIII)
• Molnupiravir (CIIa)
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for detailed recommendations.
Recommendations for Treating Hospitalized Patients
• See Therapeutic Management of Hospitalized Adults With COVID-19 for the Panel’s recommendations on using
remdesivir with or without immunomodulators in certain hospitalized patients.
Antiviral Drugs That the Panel Recommends Against
• The Panel recommends against the use of the following drugs for the treatment of COVID-19, except in a clinical
trial:
• Interferons for nonhospitalized patients (AIIa)
• Interferon alfa or lambda for hospitalized patients (AIIa)
• Ivermectin (AIIa)
• Nitazoxanide (BIIa)
• The Panel recommends against the use of the following drugs for the treatment of COVID-19:
• Chloroquine or hydroxychloroquine and/or azithromycin for hospitalized (AI) and nonhospitalized patients (AIIa)
• Lopinavir/ritonavir and other HIV protease inhibitors for hospitalized (AI) and nonhospitalized patients (AIII)
• Systemic interferon beta for hospitalized patients (AI)
The sections on Chloroquine or Hydroxychloroquine and/or Azithromycin, Lopinavir/Ritonavir and Other HIV Protease
Inhibitors, and Nitazoxanide have been archived. The Panel will no longer be updating the information on these
therapies.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak 

Antiviral Therapy
Because SARS-CoV-2 replication leads to many of the clinical manifestations of COVID-19, antiviral
therapies are being investigated for the treatment of COVID-19. These drugs prevent viral replication
through various mechanisms, including blocking SARS-CoV-2 entry, inhibiting the activity of
SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp),
and causing lethal viral mutagenesis.1-3 Because viral replication may be particularly active early in the
course of COVID-19, antiviral therapy may have the greatest impact before the illness progresses to the
hyperinflammatory state that can characterize the later stages of disease, including critical illness.4 For
this reason, it is necessary to understand the role of antiviral medications in treating mild, moderate,
severe, and critical illness in order to optimize treatment for people with COVID-19.
The following sections describe the underlying rationale for using different antiviral medications,
provide the COVID-19 Treatment Guidelines Panel’s recommendations for using these medications to
treat COVID-19, and summarize the existing clinical trial data. Additional antiviral therapies will be
added to this section of the Guidelines as new evidence emerges.
References
4. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic
staging proposal. J Heart Lung Transplant. 2020;39(5):405-407. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32362390.

Remdesivir
Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral RNA-dependent RNA
polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir
has demonstrated in vitro activity against SARS-CoV-2.1 In a rhesus macaque model of SARS-CoV-2
infection, remdesivir treatment was initiated soon after inoculation; the remdesivir-treated animals had
lower virus levels in the lungs and less lung damage than the control animals.2 Remdesivir is expected to
be active against the Omicron (B.1.1.529) variant of concern and its BA.2 subvariant.3-5
Intravenous remdesivir is approved by the Food and Drug Administration (FDA) for the treatment
of COVID-19 in adults and pediatric patients aged ≥28 days and weighing ≥3 kg. In high-risk,
nonhospitalized patients with mild to moderate COVID-19, remdesivir should be started within 7 days
of symptom onset and administered for 3 days. Hospitalized patients should receive remdesivir for 5
days or until hospital discharge, whichever comes first.6 See Table 4d for more information.
Remdesivir has been studied in several clinical trials for the treatment of COVID-19. The
recommendations from the COVID-19 Treatment Guidelines Panel (the Panel) are based on the results
of these studies. See Table 4a for more information.
Recommendations
For the Panel’s recommendations and information on the clinical efficacy of remdesivir in high-risk,
nonhospitalized patients with mild to moderate COVID-19, see Therapeutic Management of
Nonhospitalized Adults With COVID-19.
For the Panel’s recommendations and information on the clinical efficacy of remdesivir with or without
immunomodulators in certain hospitalized patients, see Therapeutic Management of Hospitalized Adults
With COVID-19.
There are no data on using combinations of antiviral therapies or combinations of antiviral therapies and
anti-SARS-CoV-2 monoclonal antibodies for the treatment of COVID-19. Clinical trials are needed to
determine the role of combination therapy in certain patients.
Monitoring and Adverse Effects

Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated transaminase levels, an increase
in prothrombin time without a change in the international normalized ratio, and hypersensitivity
reactions.
Before starting patients on remdesivir, the FDA recommends performing estimated glomerular filtration
rate (eGFR), liver function, and prothrombin time tests as clinically appropriate and repeating these
tests during treatment as clinically indicated. However, it should be noted that in the PINETREE study,
in which outpatients with mild to moderate COVID-19 received remdesivir for 3 days, baseline serum
creatinine was not required in patients weighing >48 kg.7 Remdesivir may need to be discontinued if a
patient’s alanine transaminase (ALT) level increases to >10 times the upper limit of normal, and it should
be discontinued if increases in ALT levels and signs or symptoms of liver inflammation are observed.6
Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for at least

1 hour after the infusion as clinically appropriate.
Patients who are severely immunocompromised may have prolonged SARS-CoV-2 replication, which
may lead to rapid viral evolution. There is concern that using a single antiviral agent in these patients
may result in the emergence of resistant virus.8 Additional studies are needed to assess this risk. The role
of combination antiviral therapy in the treatment of COVID-19 is not yet known.
Considerations in Patients With Renal Insufficiency

Each 100-mg vial of remdesivir lyophilized powder contains 3 g of sulfobutylether beta-cyclodextrin
sodium (SBECD), and each 100 mg/20-mL vial of remdesivir solution contains 6 g of SBECD.6 SBECD
is a vehicle that is primarily eliminated through the kidneys. A patient with COVID-19 who receives a
loading dose of remdesivir 200 mg would receive 6 g to 12 g of SBECD, depending on the formulation.
This amount of SBECD is within the safety threshold for patients with normal renal function.9
Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities.
Clinicians may consider preferentially using the lyophilized powder formulation (which contains less
SBECD) in patients with renal impairment.
Because both remdesivir formulations contain SBECD, patients with an eGFR of <50 mL/min were
excluded from some clinical trials of remdesivir; other trials had an eGFR cutoff of <30 mL/min. The
FDA product label does not recommend using remdesivir in patients with an eGFR of <30 mL/min due
to a lack of data.10
In 2 observational studies that evaluated the use of the solution formulation of remdesivir (not the
reconstituted lyophilized powder formulation) in hospitalized patients with COVID-19, no significant
differences were reported in the incidences of adverse effects or acute kidney injury between patients with
an estimated creatinine clearance (CrCl) of <30 mL/min and those with an estimated CrCl of ≥30 mL/
min.11,12 In 1 study, 20 patients had an estimated CrCl of <30 mL/min and 115 had an estimated CrCl of
≥30 mL/min;11 the other study included 40 patients who had an estimated CrCl of <30 mL/min and 307
patients who had an estimated CrCl of ≥30 mL/min.12 These observational data suggest that remdesivir
can be used in patients with an eGFR of <30 mL/min if the potential benefits outweigh the risks.
Drug-Drug Interactions
Currently, no clinical drug-drug interaction studies of remdesivir have been conducted. In vitro,
remdesivir is a minor substrate of cytochrome P450 (CYP) 3A4 and a substrate of the drug transporters
organic anion transporting polypeptide (OATP) 1B1 and P-glycoprotein. It is also an inhibitor of
CYP3A4, OATP1B1, OATP1B3, and multidrug and toxin extrusion protein (MATE) 1.6
Minimal to no reduction in remdesivir exposure is expected when remdesivir is coadministered with
dexamethasone, according to information provided by Gilead Sciences (written communication, July
2020).
See Table 4d for more information.
Remdesivir should be offered to pregnant individuals if it is indicated.
While pregnant patients were excluded from the clinical trials that evaluated the safety and efficacy
of remdesivir for the treatment of COVID-19, subsequent reports on the use of remdesivir in pregnant
patients have been reassuring. Among 86 pregnant and postpartum patients who were hospitalized with
severe COVID-19 and who received remdesivir through a compassionate use program, the therapy was

well tolerated, with a low rate of serious adverse effects.13
Among 95 pregnant patients with moderate, severe, or critical COVID-19 who were included in a
secondary analysis of data from a COVID-19 pregnancy registry in Texas, the composite maternal
and neonatal outcomes were similar between those who received remdesivir (n = 39) and those who
did not.14 Remdesivir was discontinued in 16.7% of patients due to elevated levels of transaminases. It
was not possible to determine whether these elevated levels were secondary to the drug, COVID-19,
or pregnancy-related conditions, although in each case the elevated levels occurred before the patient
received remdesivir.
The results of the secondary analysis should be interpreted with caution, given that clinicians were more
likely to choose to administer remdesivir to pregnant patients with more severe illness. Those who were
treated with remdesivir were more likely to have had COVID-19 for a longer duration by the time they
were admitted to the hospital. They were also more likely to require oxygen support at admission and to
have a longer hospital stay.
A systematic review of 13 observational studies that included 113 pregnant people also reported few
adverse effects of remdesivir in pregnant patients with COVID-19. The most common adverse advent
was a mild elevation in transaminase levels.15
Please see Special Considerations in Children, Therapeutic Management of Nonhospitalized Children
With COVID-19, and Therapeutic Management of Hospitalized Children With COVID-19.
References
1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at:
2. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with
SARS-CoV-2. Nature. 2020;585(7824):273-276. Available at:
4. Gilead Sciences. Gilead statement on Veklury (remdesivir) and the SARS-CoV-2 Omicron variant. 2021.
Available at: https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-veklury-
remdesivir-and-the-sars-cov-2-omicron-variant. Accessed June 7, 2022.
8. Gandhi S, Klein J, Robertson AJ, et al. De novo emergence of a remdesivir resistance mutation during
treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nat Commun.

9. European Medicines Agency Committee for Human Medicinal Products. Background review for cyclodextrins
used as excipients. 2014. Available at: https://www.ema.europa.eu/en/documents/report/background-review-
cyclodextrins-used-excipients-context-revision-guideline-excipients-label-package_en.pdf.
10. Adamsick ML, Gandhi RG, Bidell MR, et al. Remdesivir in patients with acute or chronic kidney disease and
COVID-19. J Am Soc Nephrol. 2020;31(7):1384-1386. Available at:
11. Pettit NN, Pisano J, Nguyen CT, et al. Remdesivir use in the setting of severe renal impairment: a theoretical
concern or real risk? Clin Infect Dis. 2021;73(11):e3990-e3995. Available at:
12. Ackley TW, McManus D, Topal JE, Cicali B, Shah S. A valid warning or clinical lore: an evaluation
of safety outcomes of remdesivir in patients with impaired renal function from a multicenter matched
cohort. Antimicrob Agents Chemother. 2021;65(2):e02290-20. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33229428.
13. Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with
severe coronavirus disease 2019. Clin Infect Dis. 2021;73(11):e3996-e4004. Available at:
14. Gutierrez R, Mendez-Figueroa H, Biebighauser JG, et al. Remdesivir use in pregnancy during the
SARS-CoV-2 pandemic. J Matern Fetal Neonatal Med. 2022;Published online ahead of print. Available at:
15. Budi DS, Pratama NR, Wafa IA, et al. Remdesivir for pregnancy: a systematic review of antiviral therapy for
COVID-19. Heliyon. 2022;8(1):e08835. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35128114.

Table 4a. Remdesivir: Selected Clinical Data
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for
RDV. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations. Studies of hospitalized
patients are listed first, followed by 1 study of nonhospitalized patients.
Methods Results Limitations and Interpretation

ACTT-1: Multinational, Double-Blind, Placebo-Controlled Trial of Remdesivir in Hospitalized Patients With COVID-19 in 10 Countries1
Key Inclusion Criteria: Participant Characteristics: Key Limitations:
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 59 years; 64% men; 53% White, 21% Black, 13% • Wide range of disease severity among
• ≥1 of the following: Asian, 24% Hispanic/Latinx patients; study not powered to detect
• Coexisting conditions: 26% with 1; 55% with ≥2 differences within subgroups
• Pulmonary infiltrates
• 13% not on oxygen; 41% on supplemental oxygen; 18% on • Study not powered to detect differences
• SpO2 ≤94% on room air in mortality between arms
HFNC oxygen or NIV; 27% on MV or ECMO
• Need for supplemental oxygen, HFNC oxygen, • No data on longer-term morbidity
NIV, MV, or ECMO • Median time from symptom onset to randomization: 9 days (IQR
6–12 days) Interpretation:
Key Exclusion Criteria:
• 23% received corticosteroids during study • In patients with severe COVID-19, RDV
• ALT or AST >5 times ULN reduced the time to clinical recovery.
Primary Outcomes:
• eGFR <30 mL/min • The benefit was most apparent in
• Time to clinical recovery: 10 days in RDV arm vs. 15 days in
Interventions: placebo arm (rate ratio for recovery 1.29; 95% CI, 1.12–1.49; P hospitalized patients who were receiving
• RDV 200 mg IV on Day 1, then RDV 100 mg IV < 0.001) supplemental oxygen.
once daily for up to 9 more days (n = 541) • Benefit of RDV greatest in patients randomized during first 10 • There was no observed benefit in those
• Placebo for up to 10 days (n = 521) days after symptom onset and those who required supplemental on HFNC oxygen, NIV, MV, or ECMO,
oxygenation at enrollment but the study was not powered to detect
Primary Endpoint: differences within subgroups.
• No difference in time to recovery for patients on HFNC oxygen,
• Time to clinical recovery
NIV, MV, or ECMO at enrollment
Key Secondary Endpoints:
Secondary Outcomes:
• Clinical status at Day 15, as measured by an OS
• Improvement in clinical status at Day 15 more likely in RDV arm
• Mortality by Day 29 (OR 1.5; 95% CI, 1.2–1.9; P < 0.001)
• Occurrence of SAEs • No difference between arms in mortality by Day 29
• Occurrence of SAEs: 25% in RDV arm vs. 32% in placebo arm

CATCO: Multicenter, Open-Label, Pragmatic RCT of Remdesivir in Hospitalized Patients With COVID-19 in Canada2
Key Inclusion Criterion: Participant Characteristics: Key Limitations:
• Laboratory-confirmed SARS-CoV-2 infection • Median age 66 years; 60% men; 41% White • Open-label study
Key Exclusion Criterion: • Median time from symptom onset to randomization: 8 • Information on comorbidities was
days not available for 26% of patients.
• Already receiving RDV
• At entry:
Interventions: Interpretation:
• 54% on low-flow oxygen
• RDV 200 mg IV on Day 0, then RDV 100 mg IV once daily on • RDV did not decrease in-hospital
Days 1–9 (n = 634) • 24% on HFNC oxygen mortality among patients with
• Local SOC (n = 647) • 9% on MV COVID-19 compared to SOC.
• Rates of comorbidities were similar between arms. • Patients who received RDV were
Primary Endpoint:
• 87% in both arms were receiving corticosteroids at less likely to require MV than
• In-hospital mortality
baseline patients who received SOC.
Primary Outcome:
• New need for MV
• In-hospital mortality: 19% in RDV arm vs. 23% in SOC
• Hospital LOS arm (relative risk 0.83; 95% CI, 0.67–1.03)
• Incidence of hepatic dysfunction, incidence of need for Secondary Outcomes:
dialysis, and change in SCr at Day 5
• New need for MV: 8% in RDV arm vs. 15% in SOC arm
(relative risk 0.53; 95% CI, 0.38–0.75)
• No significant difference between arms in hospital LOS
• No difference between arms in incidence of new hepatic
dysfunction, incidence of need for dialysis, or change in
SCr at Day 5

DisCoVeRy: Open-Label, Adaptive RCT of Remdesivir in Hospitalized Patients With Moderate or Severe COVID-19 in Europe3
• Laboratory-confirmed SARS-CoV-2 infection • Median age 64 years; 70% men; 69% White • Open-label study
• Illness of any duration • 74% with ≥1 coexisting condition • 440 participants in this study also
• SpO2 ≤94% on room air or use of supplemental oxygen, • 40% received corticosteroids enrolled in the WHO Solidarity trial.
HFNC oxygen, NIV, or MV • Median time from symptom onset to randomization: 9 days Interpretation:
Key Exclusion Criteria: in both arms • There was no clinical benefit of RDV
• ALT or AST >5 times ULN • 61% with moderate disease; 39% with severe disease in hospitalized patients who were
symptomatic for >7 days and who
• Severe chronic kidney disease Primary Outcome: required supplemental oxygen.
Interventions: • No difference between arms in clinical status at Day 15
(OR 0.98; 95% CI, 0.77–1.25; P = 0.85)
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily
for up to 9 days (n = 429) • A prespecified subgroup analysis based on duration
of symptoms found no significant difference in clinical
• SOC (n = 428)
status between arms.
Primary Endpoint:
Secondary Outcomes:
• Mortality by Day 29: 8% in RDV arm vs. 9% in SOC arm
Key Secondary Endpoints: • Occurrence of SAEs: 33% in RDV arm vs. 31% in SOC arm
• Mortality by Day 29 (P = 0.48)
• Occurrence of SAEs

WHO Solidarity Trial, Final Report: Multinational, Open-Label, Adaptive RCT in Hospitalized Patients With COVID-19 in 35 Countries4
• Not known to have received any study drug • 46% aged 50–69 years; 22% aged ≥70 years; 63% men • Open-label study
Interventions: • Rates of comorbidities were similar between arms • No data on time from symptom
• At entry: onset to enrollment
on Days 1–9 (n = 4,146) • 71% on supplemental oxygen • Data analysis did not separate
receipt of low-flow and high-flow
• Local SOC (n = 4,129) • 9% on MV oxygen
Primary Endpoint: • 68% received corticosteroids during study; 4.6% received
IL-6 inhibitors Interpretation:
• There was no benefit of RDV
Key Secondary Endpoint: Primary Outcome: in patients who were on MV at
• Initiation of MV • In-hospital mortality: 14.5% in RDV arm vs. 15.6% in SOC baseline.
arm (rate ratio 0.91; 95% CI, 0.82–1.02; P = 0.12) • Compared to SOC, RDV had a
• On MV: 42.1% vs. 38.6% (rate ratio 1.13; 95% CI, modest but statistically significant
0.89–1.42; P = 0.32) effect on reducing the risk of death
• Not on MV but receiving oxygen: 14.6% vs. 16.3% (rate or progression to MV in hospitalized
ratio 0.87; 95% CI, 0.76–0.99; P = 0.03) patients who required oxygen.
• Not on oxygen initially: 2.9% vs. 3.8% (rate ratio 0.76;
95% CI, 0.46–1.28; P = 0.30)
Secondary Outcome:
• Initiation of MV: 14.1% in RDV arm vs. 15.7% in SOC arm
(rate ratio 0.88; 95% CI, 0.77–1.00; P = 0.04)

GS-US-540-5774 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared With Standard of Care in Hospitalized Patients With
Moderate COVID-19 in Asia, Europe, and the United States5
• Laboratory-confirmed SARS-CoV-2 infection • Demographic and baseline disease characteristics were • Open-label design may have
• Pulmonary infiltrates similar across arms. affected decisions on concomitant
• Median age 57 years; 61% men; 58% White medications (e.g., more patients in
• SpO2 >94% on room air SOC arm received AZM, HCQ or CQ,
• 84% required no supplemental oxygen; 15% required low- and LPV/RTV) and time of hospital
flow oxygen; 1% required HFNC oxygen or NIV discharge.
• ALT or AST >5 times ULN
• Concomitant medication use in the 10-day RDV, 5-day • No data on time to return to activity
• CrCl <50 mL/min RDV, and SOC arms: for discharged patients
Interventions: • Steroids: 15%, 17%, 19%
Interpretation:
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily • Tocilizumab: 1%, 1%, 5%
for 9 days (n = 193) • Hospitalized patients with moderate
• HCQ or CQ: 11%, 8%, 45% COVID-19 who received 5 days of
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily • LPV/RTV: 6%, 5%, 22% RDV had better clinical status at Day
for 4 days (n = 191) 11 than those who received SOC.
• AZM: 21%, 18%, 31%
• Local SOC (n = 200) • There was no difference in clinical
• Median duration of therapy: 6 days in 10-day RDV arm vs.
Primary Endpoint: 5 days in 5-day RDV arm status at Day 11 between patients
who received 10 days of RDV and
• Clinical status at Day 11, as measured by an OS Primary Outcome: those who received SOC.
• Clinical status at Day 11:
• Significantly better in 5-day RDV arm than in SOC arm
(OR 1.65; 95% CI, 1.09–2.48; P = 0.02)
• No difference between 10-day RDV arm and SOC arm (P
= 0.18)

GS-US-540-5773 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared With Standard of Care in Hospitalized Patients With
Severe COVID-19 in Asia, Europe, and the United States6
• Laboratory-confirmed SARS-CoV-2 infection • Median age: 61 years in 5-day RDV arm vs. 62 years in • Open-label study
• Aged ≥12 years 10-day RDV arm • Lack of placebo arm
• Pulmonary infiltrates and SpO2 ≤94% on room air or • 60% men in 5-day RDV arm; 68% men in 10-day RDV arm • Baseline imbalances in clinical
receipt of supplemental oxygen • Oxygen requirements at baseline for 5-day RDV arm and status of patients in 5-day RDV and
10-day RDV arm: 10-day RDV arms
• None: 17%, 11% Interpretation:
• Need for MV or ECMO
• Low-flow oxygen: 56%, 54% • In hospitalized patients with severe
• Multiorgan failure
• HFNC oxygen or NIV: 24%, 30% COVID-19 who were not receiving
• ALT or AST >5 times ULN MV or ECMO, using RDV for 5 or 10
• MV or ECMO: 2%, 5%
• Estimated CrCl <50 mL/min days had similar clinical benefits.
• Baseline clinical status worse in 10-day arm than in 5-day
Interventions: arm (P = 0.02)
Primary Outcome:
for 4 days (n = 200)
• After adjusting for baseline clinical status:
for 9 days (n = 197) • Proportion with clinical improvement at Day 14: 65% in
5-day RDV arm vs. 54% in 10-day RDV arm (P = 0.14)
Primary Endpoint:

PINETREE: Double-Blind, Placebo-Controlled Trial of Remdesivir for 3 Days in Nonhospitalized Patients With COVID-19 Who Were at High Risk of Disease
Progression in Denmark, Spain, the United Kingdom, and the United States7
• Laboratory-confirmed SARS-CoV-2 infection ≤4 days from • Mean age 50 years; 30% aged ≥60 years; 52% men; 80% • Study halted early due to
screening White, 8% Black administrative issues.
• Aged ≥12 years • 62% with DM; 55% with obesity; 48% with HTN • Vaccinated individuals were
• ≥1 risk factor for disease progression or aged ≥60 years • Median duration of symptoms before first infusion: 5 days excluded.
• Symptom onset ≤7 days from randomization (IQR 3–6 days) Interpretation:
• ≥1 ongoing COVID-19 symptom • Median time from RT-PCR confirmation: 2 days (IQR 1–4 • 3 consecutive days of IV RDV
days) resulted in an 87% relative
Key Exclusion Criteria: reduction in the risk of
Primary Outcomes:
• COVID-19 vaccination hospitalization or death when
• COVID-19-related hospitalization or death from any cause compared to placebo.
• Receipt of supplemental oxygen by Day 28: 2 (0.7%) in RDV arm vs. 15 (5.3%) in placebo
• Previous hospitalization or treatment for COVID-19 arm (HR 0.13; 95% CI, 0.03–0.59; P = 0.008)
Interventions: • Occurrence of AEs: 42% in RDV arm vs. 46% in placebo
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily arm
on Days 2 and 3 (n = 279) Secondary Outcome:
• Placebo (n = 283) • COVID-19-related, medically attended visit or death from
Primary Endpoints: any cause by Day 28: 4 (1.6%) in RDV arm vs. 21 (8.3%)
in placebo arm (HR 0.19; 95% CI, 0.07–0.56)
• COVID-19-related hospitalization or death from any cause
by Day 28
• Occurrence of AEs
Key Secondary Endpoint:
• COVID-19-related, medically attended visit or death from
any cause by Day 28
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; AZM = azithromycin; CQ = chloroquine; CrCl = creatinine clearance; DM =
diabetes mellitus; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; HCQ = hydroxychloroquine; HFNC = high-flow nasal
cannula; HTN = hypertension; IV = intravenous; IL = interleukin; LOS = length of stay; LPV/RTV = lopinavir/ritonavir; MV = mechanical ventilation; NIV = noninvasive
ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse
transcription polymerase chain reaction; SAE = serious adverse event; SCr = serum creatinine; SOC = standard of care; SpO2 = oxygen saturation; ULN = upper limit of
normal; WHO = World Health Organization

References
1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826.
2. Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ.
2022;194(7):E242-E251. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35045989.
3. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted
to hospital with COVID-19 (DisCoVeRy): a Phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221. Available at:
4. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity
randomised trial and updated meta-analyses. Lancet. 2022;399(10339):1941-1953. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35512728.
5. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a
randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32821939.
6. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020:383(19):1827-1837.
7. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med. 2022;386(4):305-

Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that
plays an essential role in viral replication by cleaving the 2 viral polyproteins.1 It has demonstrated
antiviral activity against all coronaviruses that are known to infect humans.2 Nirmatrelvir is packaged
with ritonavir (as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic
boosting agent that has been used to boost HIV protease inhibitors. Coadministration of ritonavir is
required to increase nirmatrelvir concentrations to the target therapeutic range. The Food and Drug
Administration (FDA) issued an Emergency Use Authorization (EUA) for ritonavir-boosted nirmatrelvir
on December 22, 2021, for the treatment of COVID-19.3
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using nirmatrelvir 300 mg
with ritonavir 100 mg (Paxlovid) orally (PO) twice daily for 5 days in nonhospitalized adults and
pediatric patients aged ≥12 years and weighing ≥40 kg with mild to moderate COVID-19 who are
at high risk of disease progression;4 treatment should be initiated as soon as possible and within 5
days of symptom onset (AIIa).
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily due to the ritonavir
component of the combination. Before prescribing ritonavir-boosted nirmatrelvir, clinicians should
carefully review the patient’s concomitant medications, including over-the-counter medications,
herbal supplements, and recreational drugs, to evaluate potential drug-drug interactions.
The following resources provide information on identifying and managing drug-drug interactions.
• Quick reference lists:
• Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant
Medications. Box 1 lists commonly prescribed outpatient medications that are not expected
to have clinically relevant interactions with ritonavir-boosted nirmatrelvir, and Box 2 lists
medications that have clinically relevant drug-drug interactions with ritonavir-boosted
nirmatrelvir.
• Web-based drug-drug interaction checker:
• The Liverpool COVID-19 Drug Interactions website
• Tables with guidance on managing specific drug-drug interactions:
• The Ontario COVID-19 Science Advisory Table
• The FDA EUA fact sheet and checklist for ritonavir-boosted nirmatrelvir
For the Panel’s recommendations on preferred and alternative antiviral therapies for outpatients with
COVID-19, see Therapeutic Management of Nonhospitalized Adults With COVID-19.
Rationale
The EPIC-HR trial demonstrated that starting ritonavir-boosted nirmatrelvir treatment in nonhospitalized
adults with mild to moderate COVID-19 within 5 days of symptom onset reduced the risk of
hospitalization or death through Day 28 by 89% compared to placebo.3,5 This efficacy is comparable

to remdesivir (87% relative reduction)6 and greater than the efficacy reported for molnupiravir (30%
relative reduction).7
Ritonavir-boosted nirmatrelvir is expected to be active against the Omicron (B.1.1.529) variant and its
BA.2 subvariant,8 although there is currently a lack of data on the clinical efficacy of ritonavir-boosted
nirmatrelvir against this variant and subvariant.9-11 Because of the potential for significant drug-drug
interactions with concomitant medications, this regimen may not be the optimal choice for all patients
(see Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir [Paxlovid] and Concomitant
Medications).
Clinical Data
The EPIC-HR study was a multinational randomized trial that compared ritonavir-boosted nirmatrelvir
PO twice daily for 5 days to placebo in nonhospitalized patients aged ≥18 years with mild to moderate
COVID-19 who were at high risk of clinical progression. Eligible patients were randomized within
5 days of symptom onset, were unvaccinated against COVID-19, and had at least 1 risk factor for
progression to severe disease.5 Patients were excluded if they used medications that were either highly
dependent upon CYP3A4 for clearance or strong inducers of CYP3A4.
A total of 2,246 patients enrolled in the trial. The mean age was 46 years, 51% of the patients were men,
and 72% were White. Forty-seven percent of the patients tested negative for SARS-CoV-2 antibodies,
and 66% started study treatment within 3 days of symptom onset.
Patients who were randomized within 3 days of symptom onset (n = 1,379) were included in the
modified intention-to-treat (mITT) analysis. COVID-19-related hospitalizations or all-cause deaths
occurred by Day 28 in 5 of 697 patients (0.72%) in the ritonavir-boosted nirmatrelvir arm and in 44 of
682 patients (6.5%) in the placebo arm. Among the 2,085 patients who were randomized within 5 days
of symptom onset (mITT1 analysis), COVID-19-related hospitalizations and all-cause deaths occurred
in 8 of 1,039 patients (0.77%) in the ritonavir-boosted nirmatrelvir arm and in 66 of 1,046 patients
(6.3%) in the placebo arm (89% relative risk reduction; -5.6% estimated absolute reduction; 95% CI,
-7.2% to -4.0%; P < 0.001). There were no deaths in the ritonavir-boosted nirmatrelvir arm and 13
deaths in the placebo arm.
A total of 2,224 patients who received at least 1 dose of either ritonavir-boosted nirmatrelvir or placebo
were included in the EPIC-HR safety analysis set. Among these patients, dysgeusia and diarrhea
occurred more frequently in ritonavir-boosted nirmatrelvir recipients than in placebo recipients (6% vs.
0.3% and 3% vs. 2%, respectively). Fewer ritonavir-boosted nirmatrelvir recipients discontinued the
study drug due to an adverse event than placebo recipients (2% vs. 4%).
• Nirmatrelvir must be administered with ritonavir to achieve sufficient therapeutic plasma
concentrations.
• Patients should complete the 5-day treatment course of ritonavir-boosted nirmatrelvir. It
is unknown whether a shorter course is less effective or associated with the emergence of
nirmatrelvir-resistant mutations.
• If a patient requires hospitalization after starting treatment, the full treatment course of ritonavir-
boosted nirmatrelvir can be completed at the clinician’s discretion.
• Ritonavir-boosted nirmatrelvir may be used in patients who are hospitalized for a diagnosis other
than COVID-19, provided they have mild to moderate COVID-19, are at high risk of progressing
to severe disease, and are within 5 days of symptom onset.

• There are no data on using combinations of antiviral therapies or combinations of antiviral agents
and anti-SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with
COVID-19. Clinical trials are needed to determine whether combination therapy has a role in the
• Severely immunocompromised patients can experience prolonged periods of SARS-CoV-2
replication, which may lead to rapid viral evolution. There are theoretical concerns that using a
single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies
are needed to assess this risk. The role of combination antiviral therapy or a longer treatment
duration in treating severely immunocompromised patients is not yet known.
• Case reports have described SARS-CoV-2 viral rebound and the recurrence of COVID-19
symptoms in some patients who have completed treatment with ritonavir-boosted nirmatrelvir.
Case reports and results from the EPIC-HR trial also describe instances of increases in
SARS-CoV-2 RNA levels following completion of the treatment course.12,13 The frequency,
mechanism, and clinical implications of these events are not yet known. There are currently
no data on the efficacy of administering longer courses or a second course of ritonavir-boosted
nirmatrelvir.
Monitoring and Adverse Effects

The most common adverse effects of ritonavir-boosted nirmatrelvir are dysgeusia, diarrhea,
hypertension, and myalgia.
Renal impairment reduces the clearance of nirmatrelvir. In patients with suspected renal impairment,
clinicians may consider checking the patient’s renal function to inform the dosing of ritonavir-boosted
nirmatrelvir. The dose should be reduced to nirmatrelvir 150 mg with ritonavir 100 mg twice daily in
patients with moderate renal impairment (i.e., those with an estimated glomerular filtration rate [eGFR]
of ≥30 to <60 mL/min). Ritonavir-boosted nirmatrelvir is not recommended in patients with an eGFR
of <30 mL/min until more data are available. The appropriate dose for patients with severe renal
impairment has not been determined.
Ritonavir-boosted nirmatrelvir is not recommended for patients with known or suspected severe hepatic
impairment (i.e., Child-Pugh Class C), and it should be used with caution in patients with pre-existing
liver diseases, liver enzyme abnormalities, or hepatitis. No pharmacokinetic or safety data are available
for this patient population.
Pregnancy is a risk factor for severe COVID-19.4 However, like many clinical trials of treatments for
COVID-19, the EPIC-HR trial excluded pregnant and lactating individuals. Ritonavir has been used
extensively during pregnancy in people with HIV and has a documented safety profile during pregnancy.
The mechanisms of action for both nirmatrelvir and ritonavir and the results of animal studies of
ritonavir-boosted nirmatrelvir suggest that this regimen can be used safely in pregnant individuals.
Ritonavir-boosted nirmatrelvir should be offered to pregnant and recently pregnant patients with
COVID-19 who qualify for this therapy based on the results of a risk-benefit assessment. The risk-
benefit assessment for using ritonavir-boosted nirmatrelvir in pregnant patients may include factors such
as medical comorbidities, body mass index, and vaccination status. Obstetricians should be aware of
potential drug-drug interactions when prescribing this agent.
Ritonavir-boosted nirmatrelvir is authorized for use in pediatric patients aged ≥12 years and weighing

≥40 kg. The EPIC-HR trial excluded persons aged <18 years. The safety and efficacy of using ritonavir-
boosted nirmatrelvir in pediatric patients has not been established in clinical trials.
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily due to the ritonavir
component of the combination. Boosting with ritonavir, which is a strong CYP3A inhibitor and a
P-glycoprotein inhibitor, is required to increase the exposure of nirmatrelvir to a concentration that is
effective against SARS-CoV-2. However, it may also increase concentrations of certain concomitant
medications, thereby increasing the potential for serious and sometimes life-threatening drug toxicities.
Additionally, ritonavir is an inhibitor, inducer, and substrate of various other drug-metabolizing enzymes
and/or drug transporters.
Because ritonavir-boosted nirmatrelvir is the only highly effective oral antiviral for the treatment of
COVID-19, drug-drug interactions that can be safely managed should not preclude the use of this
medication.
The treatment course of ritonavir-boosted nirmatrelvir for COVID-19 is 5 days. CYP3A4 inhibition
occurs rapidly after initiating ritonavir, with maximum inhibition occurring within 48 hours.14 After
ritonavir is discontinued, 70% to 90% of CYP3A4 inhibition resolves within 2 to 3 days.15 The time
to resolution of inhibition varies based on factors such as the patient’s age; therefore, resolution may
take longer in some individuals, such as in the elderly. When ritonavir is used for 5 days, its induction
properties are less likely to be clinically relevant than when the drug is used chronically (e.g., in people
who take HIV protease inhibitors).16 Both nirmatrelvir and ritonavir are substrates of CYP3A. Thus,
ritonavir-boosted nirmatrelvir should not be given within 2 weeks of administering a strong CYP3A4
inducer (e.g., St. John’s wort, rifampin). Ritonavir-boosted nirmatrelvir is contraindicated in this
setting, as the delayed offset of enzyme induction can reduce the concentrations of nirmatrelvir and
ritonavir, which may render the treatment ineffective against SARS-CoV-2. An alternative treatment for
COVID-19 should be prescribed instead.
See Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant
Medications for guidance on managing potential drug-drug interactions.
References
1. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory
syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule
chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at:
2. Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for
the treatment of COVID-19. Science. 2021;374(6575):1586-1593. Available at:
conditions.html. Accessed April 13, 2022.
5. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with

10. Greasley SE, Noell S, Plotnikova O, et al. Structural basis for the in vitro efficacy of nirmatrelvir against
SARS-CoV-2 variants. J Biol Chem. 2022:101972. Available at:
11. Rai DK, Yurgelonis I, McMonagle P, et al. Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of
SARS-CoV-2 variants of concern. bioRxiv. 2022;Preprint. Available at:
12. Food and Drug Administration. Emergency use authorization (EUA) for Paxlovid (nirmatrelvir tablets
co-packaged with ritonavir tablets): Center for Drug Evaluation and Research (CDER) review. 2021. Available
at: https://www.fda.gov/media/155194/download. Accessed May 9, 2022.
13. Gupta K, Strymish J, Stack G, Charness M. Rapid relapse of symptomatic SARS-CoV-2 infection following
early suppression with nirmatrelvir/ritonavir. Research Square. 2022. Available at:
14. Katzenmaier S, Markert C, Riedel KD, et al. Determining the time course of CYP3A inhibition by potent
reversible and irreversible CYP3A inhibitors using A limited sampling strategy. Clin Pharmacol Ther.
15. Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug
interacting effect. J Antimicrob Chemother. 2020;75(10):3084-3086. Available at:
16. University of Liverpool. Evaluating the interaction risk of COVID-19 therapies. 2022. Available at:
https://covid19-druginteractions.org/prescribing_resources. Accessed May 10, 2022.

Drug-Drug Interactions Between Ritonavir-
Boosted Nirmatrelvir (Paxlovid) and
Concomitant Medications
Ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor and a P-glycoprotein inhibitor, is coadministered
with nirmatrelvir to increase the blood concentration of nirmatrelvir, thereby making it effective against
SARS-CoV-2. Ritonavir may also increase blood concentrations of certain concomitant medications.
Because ritonavir-boosted nirmatrelvir (Paxlovid) is the only highly effective oral antiviral for the treatment
of COVID-19, drug interactions that can be safely managed should not preclude the use of this medication.
Clinicians should be aware that many commonly used medications can be safely coadministered with
ritonavir-boosted nirmatrelvir despite its drug-drug interaction potential. Box 1 includes commonly
prescribed medications that are not expected to have clinically relevant interactions with ritonavir-boosted
nirmatrelvir.
Box 1. Commonly Prescribed Outpatient Medications Not Expected to Have Clinically Relevant
Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Medications Without Clinically Relevant Interactions
These commonly prescribed medications may be coadministered without dose adjustment and without increased
monitoring.a This list is not inclusive of all noninteracting medications within each drug category.
Acid reducing agents Diabetes medications Pain medications
• Famotidine • Empagliflozin • Acetaminophen
• Omeprazole • Insulin • Aspirin
• Pantoprazole • Metformin • Codeine
Allergy medications • P
ioglitazone • Ibuprofen
• Cetirizine Immunosuppressants • Naproxen
• Diphenhydramine • Methotrexate Respiratory medications
• Loratadine • Mycophenolate • Corticosteroids (inhaled)
Anti-infective agents • P
rednisone • Formoterol
• Azithromycin Lipid-modifying agents • Montelukast
• Hydroxychloroquine • Ezetimibe Miscellaneous
Cardiovascular agents • Pitavastatin • Allopurinol
• Aspirin • P
ravastatin • Contraceptives (oral)b
• Atenolol Neuropsychiatric agents • Donepezil
• Carvedilol • Amitriptyline • Enoxaparin
• Furosemide • Bupropion • Finasteride
• Hydrochlorothiazide • Citalopram • Levothyroxine
• Irbesartan • Duloxetine • Ondansetron
• Isosorbide Dinitrate • Escitalopram
• Lisinopril • Fluoxetine
• Losartan • Gabapentin
• Metoprolol • Lorazepam
• Prasugrel • Nortriptyline
• Olanzapine
• Paroxetine
• Sertraline
• Venlafaxine

Medications Without Clinically Relevant Interactions, continued
a
T his list is primarily based on the most common medication searches by U.S. users on the Liverpool COVID-19 Drug
Interactions website between January 1 and April 13, 2022 (internal communication, April 2022). The Liverpool
website classifies these medications as those that have no interaction or weak interaction with ritonavir-boosted
nirmatrelvir.
b
The Food and Drug Administration Emergency Use Authorization for ritonavir-boosted nirmatrelvir suggests that
individuals who use contraceptive products containing ethinyl estradiol consider using a backup, nonhormonal
contraceptive method because coadministration may result in low ethinyl estradiol levels. However, the low level is
not expected to be clinically significant during 5 days of therapy. The progestin concentration of a combined hormonal
contraceptive is expected to remain similar or increase with coadministration, which would maintain the effectiveness
of the oral contraceptive.
Medications That Have Clinically Relevant Drug-Drug Interactions With Ritonavir-

Boosted Nirmatrelvir
Clinicians should be aware that, in some cases, drug-drug interactions with ritonavir-boosted
nirmatrelvir may lead to serious or life-threatening drug toxicities. The recommended treatment course
of ritonavir-boosted nirmatrelvir for COVID-19 is 5 days. After the last dose is administered, most of the
interaction potential resolves within 2 to 3 days, although resolution may take longer in elderly adults.1
Ritonavir-boosted nirmatrelvir should not be given within 2 weeks of administering a strong CYP3A4
inducer (e.g., St. John’s wort, rifampin). Ritonavir-boosted nirmatrelvir is contraindicated in this
setting, because strong CYP3A4 inducers may reduce the concentrations of nirmatrelvir and ritonavir,
rendering the treatment ineffective against SARS-CoV-2. Alternative treatment for COVID-19 should be
prescribed.
Identifying Drug-Drug Interactions

Before prescribing ritonavir-boosted nirmatrelvir, carefully review the patient’s concomitant
medications, including over-the-counter medicines, herbal supplements, and recreational drugs.
Consult 1 or more of the following resources for information on identifying and managing drug-drug
interactions:
• Quick reference lists:
• Box 1 lists commonly prescribed outpatient medications that are not expected to have clinically
relevant interactions with ritonavir-boosted nirmatrelvir.
• Box 2 lists medications that have clinically relevant drug-drug interactions with ritonavir-
boosted nirmatrelvir.
• Web-based drug-drug interaction checker:
• The Liverpool COVID-19 Drug Interactions website
• Tables with guidance on managing specific drug-drug interactions:
• The Ontario COVID-19 Science Advisory Table
• The Food and Drug Administration Emergency Use Authorization fact sheet and checklist for
ritonavir-boosted nirmatrelvir
Consider expert consultation (e.g., with a pharmacist, an HIV specialist, or the patient’s specialist
providers), especially for patients receiving highly specialized therapies or drugs prone to concentration-
dependent toxicities, such as certain anticonvulsant, anticoagulant, antiarrhythmic, chemotherapeutic,
neuropsychiatric, and immunosuppressant drugs.

Management Strategies for Drug-Drug Interactions
Consider the magnitude and significance of the potential interaction when choosing management
strategies for patients who are to receive ritonavir-boosted nirmatrelvir. Potential strategies include:
• Temporarily withholding the concomitant medication,
• Increasing monitoring for potential adverse reactions to the concomitant medication,
• Adjusting the dose of the concomitant medication,
• Using an alternative to the concomitant medication, or
• Using alternative COVID-19 therapies (see Therapeutic Management of Nonhospitalized Adults
With COVID-19).
Use the chosen strategy for the 5-day duration of ritonavir-boosted nirmatrelvir treatment and for at
least 2 to 3 days after treatment completion. The strategy may need to continue for a longer duration if
ritonavir-boosted nirmatrelvir is initiated in an elderly patient or if the interacting medication has a long
half-life.
Box 2. Outpatient Medications That Have Clinically Relevant Drug-Drug Interactions With
Not all medications that may interact with ritonavir-boosted nirmatrelvir are included in Box 2.
Deviation from the recommended strategies may be appropriate in certain clinical scenarios.
Prescribe Alternative COVID-19 Therapy

For these medications, management strategies are not possible or feasible, or the risks outweigh the potential benefits.
Anticonvulsants Cardiovascular agents Pain medications
• Carbamazepine • Amiodarone • Meperidine (pethidine)
• Phenobarbital • Clopidogrela,b
Pulmonary hypertension medications
• Phenytoin • Disopyramide
• Primidone • Dofetilide • Sildenafil
• Dronedarone • Tadalafil
Anti-infective agents • Vardenafil
• Eplerenone
• Glecaprevir/pibrentasvir • Flecainide Miscellaneous
• Rifampin • Ivabradine
• Rifapentine • Bosentan
• Propafenone
• Certain chemotherapeutic agentsc
Immunosuppressants • Quinidine
• Ergot derivatives
• Voclosporin Neuropsychiatric agents • Lumacaftor/ivacaftor
• Clozapine • St. John’s wort
• Lumateperone • Tolvaptan
• Lurasidone
• Midazolam (oral)
• Pimozide

Temporarily Withhold Concomitant Medication, If Clinically Appropriate
Withhold these medications during ritonavir-boosted nirmatrelvir treatment and for at least 2–3 days after treatment
completion. They may need to be withheld for longer if the patient is elderly or the medication has a long half-life. If
withholding is not clinically appropriate, use an alternative concomitant medication or COVID-19 therapy.
Anticoagulants Lipid-modifying agents Erectile dysfunction medications
• Rivaroxaban d
• Atorvastatine
• Avanafil
Anti-infective agents • L
omitapide Respiratory medications
• Lovastatine
• Erythromycin • Salmeterol
• Rosuvastatine
BPH medications • Simvastatine Miscellaneous
• Alfuzosin Migraine medications • Certain chemotherapeutic agentsc
• Silodosin • Colchicineh
• Eletriptan
Cardiovascular agents • Finerenone
• Rimegepant
• Flibanserin
• Aliskiren • Ubrogepant
• Naloxegol
• Ranolazine Neuropsychiatric agents
• Ticagrelorb
• Clonazepamg
• Vorapaxar
• Clorazepateg
Immunosuppressants f
• Diazepamg
• Everolimus • Estazolamg
• Sirolimus • Flurazepamg
• Tacrolimus • Suvorexant
• Triazolamg
Adjust Concomitant Medication Dose and Monitor for Adverse Effects
Consult the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science Advisory Table for specific
dosing recommendations.i If the dose of the concomitant medication cannot be adjusted, withhold the medication (if
clinically appropriate) or use an alternative concomitant medication or COVID-19 therapy.
Anticoagulants Erectile dysfunction medications Pain medications
• Apixaban • Sildenafil • Fentanyl
• Dabigatran • Tadalafil • Hydrocodone
• Edoxaban • Vardenafil • Oxycodone
Anti-infective agents Immunosuppressantsf Pulmonary hypertension medications
• Clarithromycin • Cyclosporine • Riociguat
• Itraconazole Neuropsychiatric agents Miscellaneous
• Ketoconazole
• Alprazolamg • Certain chemotherapeutic agentsc
• Maraviroc
• Aripiprazole • Darifenacin
• Rifabutin
• Brexpiprazole • Elexacaftor/tezacaftor/ivacaftor
BPH medications • Buspirone • Eluxadoline
• Tamsulosin • Cariprazine • Ivacaftor
Cardiovascular agents • Chlordiazepoxideg • Tezacaftor/ivacaftor
• Clobazamg
• Cilostazol
• Iloperidone
• Digoxin
• Pimavanserin
• Mexiletine
• Quetiapine
Diabetes medications • Trazodone
• Saxagliptin

Continue Concomitant Medication and Monitor for Adverse Effects
Pre-emptive dose adjustment is not required but may be considered. Educate patients on potential adverse effects.
Consult the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science Advisory Table for
monitoring guidance and dose adjustment information if needed.i
Anticoagulants Cardiovascular agents Pain medications
• Warfarin • Amlodipine • Buprenorphine
Anti-infective agents • Diltiazem • Hydromorphone
• Felodipine • Methadone
• Cobicistat or ritonavir-boosted
antiretrovirals • N
ifedipine • Morphine
• Isavuconazole • Sacubitril • Tramadol
• Posaconazole • V
alsartan
• Voriconazole • Verapamil
BPH medications Neuropsychiatric agents

• Doxazosin • Haloperidol
• Terazosin • Hydroxyzine
• Mirtazapine
Diabetes medications • Risperidone
• Glyburide • Ziprasidone
• Zolpidem
a
Reduced effectiveness of clopidogrel is likely. It may be acceptable to continue clopidogrel if the benefit of ritonavir-
boosted nirmatrelvir treatment outweighs the risk of reduced clopidogrel effectiveness.
b
F or patients at very high risk of thrombosis (e.g., received a coronary stent within the past 6 weeks), consider
prescribing an alternative antiplatelet (e.g., prasugrel) or an alternative COVID-19 therapy.
c
itonavir-boosted nirmatrelvir may increase concentrations of some chemotherapeutic agents, leading to an increased
R
potential for drug toxicities. Some chemotherapeutic agents may decrease the effectiveness of ritonavir-boosted
nirmatrelvir. Please refer to the FDA EUA ritonavir-boosted nirmatrelvir fact sheet and the prescribing information
for the chemotherapeutic agent and consult the patient’s specialist provider. The University Health Network/Kingston
Health Sciences Centre is an additional resource for evaluating drug-drug interactions for chemotherapeutic agents.
d
F or patients at high risk of arterial or venous thrombosis (e.g., had a stroke within the past 3 months with a CHA2DS2-
VASc score of 7–9 or a pulmonary embolism within the past month), consult the primary or specialty provider and
consider using an alternative anticoagulant or COVID-19 therapy.
e
F or lovastatin and simvastatin, withhold at least 12 hours before initiation of ritonavir-boosted nirmatrelvir, during
treatment, and for 5 days after treatment completion. For atorvastatin and rosuvastatin, withhold at the beginning
of treatment with ritonavir-boosted nirmatrelvir and resume after completion of the 5-day course. If withholding a
statin is not clinically appropriate (e.g., the patient had a recent myocardial infarction), the doses of atorvastatin and
rosuvastatin can be adjusted and continued, and lovastatin and simvastatin should be switched to an alternative statin.
f
onsult a patient’s specialist providers before coadministering these immunosuppressants and ritonavir-boosted
C
nirmatrelvir. These immunosuppressants have significant drug-drug interaction potential with ritonavir, and close
monitoring may not be feasible. Alternative COVID-19 therapy may need to be considered. See the American Society of
Transplantation statement for more information.
g
brupt discontinuation or rapid dose reduction of benzodiazepines may precipitate an acute withdrawal reaction.2 The
A
risk is greatest for patients who have been using high doses of benzodiazepines over an extended period.
h
F or patients with severe hepatic or renal impairment, coadministration of colchicine and ritonavir-boosted nirmatrelvir
is contraindicated due to the potential for serious or life-threatening reactions.
i
For medications not included on the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science
Advisory Table, refer to the medication’s FDA label for information on coadministration with ritonavir or other strong
CYP3A4 and/or P-gp inhibitors.
Key: BPH = benign prostatic hyperplasia; CHA2DS2-VASc = congestive heart failure, hypertension, age, diabetes, stroke,
vascular disease; CYP = cytochrome P450; EUA = Emergency Use Authorization; FDA = Food and Drug Administration;
P-gp = P-glycoprotein

References
1. Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug
interacting effect. J Antimicrob Chemother. 2020;75(10):3084-3086. Available at:
2. Food and Drug Administration. FDA requiring Boxed Warning updated to improve safe use of benzodiazepine
drug class. 2020. Available at: https://www.fda.gov/media/142368/download.

Molnupiravir
Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad
antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results
in viral mutations and lethal mutagenesis.1,2
On December 23, 2021, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for molnupiravir for the treatment of adults with mild to moderate COVID-19 who
are within 5 days of symptom onset, who are at high risk of progressing to severe disease, and for whom
alternative antiviral therapies are not accessible or clinically appropriate.3,4
Molnupiravir has potent antiviral activity against SARS-CoV-2.1,5 As a mutagenic ribonucleoside
antiviral agent, there is a theoretical risk that molnupiravir will be metabolized by the human host cell
and incorporated into the host DNA, leading to mutations. Molnupiravir has been evaluated in 2 in
vivo rodent mutagenicity assays. One study produced equivocal results; in the other study, there was
no evidence for mutagenicity.4 The FDA concluded that, based on the available genotoxicity data and
the 5-day duration of treatment, molnupiravir has a low risk for genotoxicity.4 In addition, there have
been concerns about the potential effects of molnupiravir on SARS-CoV-2 mutation rates; the FDA is
requiring the manufacturer to establish a process to monitor genomic databases for the emergence of
SARS-CoV-2 variants.
Recommendations
• In nonhospitalized patients aged ≥18 years who have mild to moderate COVID-19 and who
are at high risk of disease progression, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends using molnupiravir 800 mg orally (PO) twice daily for 5 days ONLY when
ritonavir-boosted nirmatrelvir (Paxlovid) or remdesivir cannot be used; treatment should be
initiated as soon as possible and within 5 days of symptom onset (CIIa).
• The FDA EUA states that molnupiravir is not recommended for use in pregnant patients because
fetal toxicity has been reported in animal studies of molnupiravir. However, when other therapies
are not available, pregnant people with COVID-19 who are at high risk of progressing to severe
disease may reasonably choose molnupiravir therapy after being fully informed of the risks,
particularly if they are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The
prescribing clinician should document that a discussion of the risks and benefits occurred and that
the patient chose this therapy.
• People who engage in sexual activity that may result in conception should use effective
contraception during and following treatment with molnupiravir. For more details, see the
Considerations in Sexually Active Individuals section below.
• There are no data on the use of molnupiravir in patients who have received COVID-19 vaccines.
The risk-to-benefit ratio is likely to be less favorable in these patients, because molnupiravir has a
lower efficacy compared to other available treatments.
For the Panel’s recommendations on using antiviral therapies in outpatients and prioritizing
outpatient therapies when there are logistical or supply constraints, see Therapeutic Management of
Nonhospitalized Adults With COVID-19.

Rationale
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to
placebo.4 Even though the different treatment options have not been directly compared in clinical trials,
the Panel recommends using molnupiravir only when ritonavir-boosted nirmatrelvir and remdesivir are
not available or cannot be given, because molnupiravir has lower efficacy than the other options. For
more information, see Therapeutic Management of Nonhospitalized Adults With COVID-19.
Molnupiravir is expected to be active against the B.1.1.529 (Omicron) variant of concern, although in
vitro and in vivo data are currently limited.6
• Patients should complete the 5-day treatment course of molnupiravir. It is unknown whether
a shorter course is less effective or associated with the emergence of molnupiravir-resistant
mutations.
• If a patient requires hospitalization after starting treatment, the full treatment course of
molnupiravir can be completed at the health care provider’s discretion.
• Molnupiravir may be used in patients who are hospitalized for a diagnosis other than COVID-19,
provided they have mild to moderate COVID-19 and are at high risk of progressing to severe
disease.
• There are no data on using combination antiviral therapies or combinations of antiviral agents
and anti-SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with
COVID-19. Clinical trials are needed to determine whether combination therapy has a role in the
treatment of SARS-CoV-2 infection.
• Severely immunocompromised patients can experience prolonged periods of SARS-CoV-2
replication, which may lead to rapid viral evolution. There are theoretical concerns that using a
single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies
are needed to assess this risk. The role of combination antiviral therapy in treating severely
immunocompromised patients is not yet known.
Considerations in Sexually Active Individuals

Clinicians should assess a patient’s pregnancy status before initiating molnupiravir, if clinically
indicated.
Patients of childbearing potential should be counseled about abstaining from sex or using reliable
contraception for the duration of therapy and for up to 4 days after receiving molnupiravir. Reproductive
toxicity has been reported in animal studies of molnupiravir, and molnupiravir may be mutagenic during
pregnancy.
The FDA EUA states that men of reproductive potential who are sexually active with individuals of
childbearing potential should be counseled to abstain from sex or use a reliable method of contraception
for the duration of treatment and for at least 3 months after the last dose of molnupiravir.
The FDA EUA states that molnupiravir is not recommended for use in pregnant patients because fetal
toxicity has been reported in animal studies of molnupiravir. However, when other therapies are not
available, pregnant people with COVID-19 who are at high risk of progressing to severe disease may
reasonably choose molnupiravir therapy after being fully informed of the risks, particularly if they

are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should
document that a discussion of the risks and benefits occurred, and that the patient chose this therapy. The
patient should also be informed about the pregnancy surveillance program and offered the opportunity to
participate.
There is currently a lack of data on the use of molnupiravir in lactating people, and molnupiravir may
cause adverse effects in infants who are exposed to the drug through breastfeeding. Because of this,
the FDA EUA states that lactating people should not breastfeed their infants during treatment with
molnupiravir and for 4 days after the final dose. Pumping and discarding breast milk to maintain supply
during this time is recommended.
The MOVe-OUT trial excluded participants aged <18 years. There are no data available on the use of
molnupiravir in children aged <18 years. Molnupiravir is not authorized for use in children aged <18
years due to potential effects on bone and cartilage growth.
Monitoring, Adverse Effects, and Drug Interactions

The most common adverse effects of molnupiravir are diarrhea, nausea, and dizziness. Based on in vitro
studies, neither molnupiravir nor its active metabolite NHC are inhibitors or inducers of major drug-
metabolizing enzymes or inhibitors of major drug transporters. According to the EUA, no drug-drug
interactions have been identified for molnupiravir.
Clinical Trial Data

MOVe-OUT was a multinational, Phase 3 trial that evaluated the use of molnupiravir in nonhospitalized
adults with mild to moderate COVID-19 who were at high risk of progressing to severe COVID-19. The
participants were not pregnant, had not been vaccinated against COVID-19, and were enrolled within 5
days of symptom onset. They were randomized to receive molnupiravir 800 mg PO every 12 hours for
5 days or placebo.7 The primary composite outcome was all-cause hospitalizations (defined as hospital
stays that lasted >24 hours) and deaths by Day 29.
The final analysis included 1,433 participants; the median age was 43 years (with 17% aged >60 years).
Forty-nine percent of the participants were men, 57% were White, 50% were Hispanic/Latinx, and
5% were Black or African American. Among the participants, 74% had a body mass index ≥30 and
16% had diabetes. The time from COVID-19 symptom onset to randomization was ≤3 days in 48% of
participants.
By Day 29, hospitalizations or deaths had occurred in 48 of 709 participants (6.8%) in the molnupiravir
arm and in 68 of 699 participants (9.7%) in the placebo arm (30% relative risk reduction; -3.0% adjusted
difference; 95% CI, -5.9% to -0.1%; P = 0.0218).4 There was 1 death in the molnupiravir arm and 9
deaths in the placebo arm. There were no significant differences between the arms in the proportion of
participants who experienced adverse events or serious adverse events.
References
1. Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis
but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. Available at:
2. Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol. 2021;28(9):740-746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34381216.

conditions.html. Accessed December 27, 2021.
5. Fischer WA, 2nd, Eron JJ, Jr., Holman W, et al. A Phase 2a clinical trial of molnupiravir in patients with
COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl
Med. 2021:eabl7430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34941423.
6. Vangeel L, De Jonghe S, Piet Maes P, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against
SARS-CoV-2 Omicron and other variants of concern. bioRxiv. 2022;Preprint. Available at:
nonhospitalized patients. N Engl J Med. 2021;Published online ahead of print. Available at:

Interferons
Interferons are a family of cytokines with in vitro and in vivo antiviral properties. Interferon beta-1a
has been approved by the Food and Drug Administration (FDA) to treat relapsing forms of multiple
sclerosis, and it has been evaluated in clinical trials for the treatment of COVID-19. Interferon alfa has
been approved to treat hepatitis B and hepatitis C virus infections, and interferon lambda is not currently
approved by the FDA for any use. Both interferon alfa and lambda have also been evaluated for the
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of systemic
interferon beta for the treatment of hospitalized patients with COVID-19 (AI).
• The Panel recommends against the use of interferon alfa or lambda for the treatment of
hospitalized patients with COVID-19, except in a clinical trial (AIIa).
• The Panel recommends against the use of interferons for the treatment of nonhospitalized
patients with mild or moderate COVID-19, except in a clinical trial (AIIa).
Rationale
Many of the early studies that evaluated the use of systemic interferons for the treatment of COVID-19
were conducted in early 2020, before the widespread use of remdesivir and corticosteroids. In addition,
these early studies administered interferons with other drugs that have since been shown to have no
clinical benefit in people with COVID-19, such as lopinavir/ritonavir and hydroxychloroquine.1-3
More recent studies have not demonstrated efficacy for interferons in the treatment of COVID-19, and
some of the trials suggested potential harm in patients with severe disease, such as those who were
on high-flow oxygen, noninvasive ventilation, or mechanical ventilation.4,5 In a large randomized
controlled trial of hospitalized patients with COVID-19, the combination of interferon beta-1a plus
remdesivir showed no clinical benefit when compared to remdesivir alone.4 Similarly, the World
Health Organization Solidarity trial did not show a benefit for interferon beta-1a when this drug was
administered to hospitalized patients, approximately 50% of whom were on corticosteroids.5
Other interferons, including systemic interferon alfa or lambda and inhaled interferons, have also been
evaluated in patients with COVID-19; however, these interferons (with the exception of subcutaneous
interferon alfa) are not available in the United States. The trials that have evaluated interferon alfa and
interferon lambda have generally been small or moderate in size and have not been adequately powered
to assess whether these agents provide a clinical benefit for patients with COVID-19 (see Table 4b).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of interferons for the
Adverse Effects
The most frequent adverse effects of systemic interferon include flu-like symptoms, nausea, fatigue,
weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (e.g., depression,

suicidal ideation). Interferon beta is better tolerated than interferon alfa, but it can cause similar types of
adverse effects.6,7
Additive toxicities may occur when systemic interferons are used concomitantly with other
immunomodulators and chemotherapeutic agents.6,7
According to analyses of data from several large pregnancy registries, exposure to interferon beta-1b
prior to conception or during pregnancy does not lead to an increased risk of adverse birth outcomes (e.g.,
spontaneous abortion, congenital anomaly).8,9 Exposure to interferon beta-1b did not influence birth weight,
height, or head circumference.10
There are currently not enough data on the use of interferons to treat respiratory viral infections in children
to make any recommendations for treating children with COVID-19.
References
1. Alavi Darazam I, Hatami F, Mahdi Rabiei M, et al. An investigation into the beneficial effects of high-dose
interferon beta 1-a, compared to low-dose interferon beta 1-a in severe COVID-19: The COVIFERON II
randomized controlled trial. Int Immunopharmacol. 2021;99:107916. Available at:
2. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in
the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial. Lancet.
3. Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon beta-1b in treatment of severe COVID-19: a
randomized clinical trial. Int Immunopharmacol. 2020;88:106903. Available at:
4. Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir
alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, Phase 3 trial. Lancet
Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672949.
5. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim
WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511. Available at:
6. Interferon alfa-2b (Intron A) [package insert]. Food and Drug Administration. 2018. Available at:
7. Interferon beta-1a (Rebif) [package insert]. Food and Drug Administration. 2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103780s5204lbl.pdf.
8. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G. Pregnancy outcomes in multiple sclerosis following
subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17(4):423-430. Available at:
9. Hellwig K, Duarte Caron F, Wicklein EM, Bhatti A, Adamo A. Pregnancy outcomes from the global pharma-
covigilance database on interferon beta-1b exposure. Ther Adv Neurol Disord. 2020;13:1756286420910310.
10. Burkill S, Vattulainen P, Geissbuehler Y, et al. The association between exposure to interferon-beta during pregnancy
and birth measurements in offspring of women with multiple sclerosis. PLoS One. 2019;14(12):e0227120. Available

Table 4b. Interferons: Selected Clinical Data
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations
for interferons. The studies summarized below are the randomized controlled trials that have had the greatest impact on the Panel’s
recommendations.
ACTT-3: Multinational, Double-Blind RCT of Interferon Beta-1a and Remdesivir in Hospitalized Adults With COVID-191
Key Inclusion Criteria: Participant Characteristics: Key Limitation:
• Evidence of pneumonia (radiographic infiltrates, SpO2 • Mean age 59 years; 38% were aged ≥65 years • OS6 patients were excluded after 270
≤94% on room air, or supplemental oxygen) • 58% men; 32% Latino, 60% White, 17% Black patients were enrolled because of an
• No MV required increased frequency of AEs in this group
• Mean of 8.6 days of symptoms before enrollment
Key Exclusion Criteria: • 90% had ≥1 comorbidity; 58% with HTN; 58% with Interpretation:
• AST or ALT >5 times ULN obesity; 37% with DM • There was no clinical benefit of IFN
beta-1a plus RDV in hospitalized patients
• Impaired renal function Primary Outcome: compared to RDV alone.
• Anticipated hospital discharge or transfer within 72 • Median time to recovery for both arms was 5 days (rate • The use of IFN beta-1a was associated
hours ratio 0.99; 95% CI, 0.87–1.13; P = 0.88). with worse outcomes among patients
Interventions: • In patients on high-flow oxygen or NIV (OS6) at who were OS6 at baseline.
baseline, median time to recovery was >28 days in
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once
IFN beta-1a arm and 9 days in placebo arm (rate ratio
daily for 9 days plus IFN beta-1a 44 µg SQ every other
0.40; 95% CI, 0.22–0.75; P = 0.0031).
day for up to 4 doses (n = 487)
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once Secondary Outcomes:
daily for 9 days plus placebo (n = 482) • No difference between arms in clinical improvement at
14 days (OR 1.01; 95% CI, 0.79–1.28).
Primary Endpoint:
• No difference between arms in mortality by Day 28 in:
• Time to recovery by Day 28
• All patients: 5% vs. 3% (HR 1.33; 95% CI, 0.69–2.55)
• Patients with OS6 at baseline: 21% vs. 12% (HR 1.74;
• Clinical status at Day 14, as measured by an OS 95% CI, 0.51–5.93)
• Mortality by Day 28

WHO Solidarity Trial: Multinational, Open-Label, Adaptive RCT of IV or SQ Interferon Beta-1a or Other Repurposed Drugs in Hospitalized Adults With
COVID-192
• Diagnosis of COVID-19 • 35% aged <50 years; 19% aged ≥70 years; 63% men • Open-label study
• Not expected to be transferred elsewhere within 72 • 70% on supplemental oxygen; 7% on ventilation • IFN beta-1a given as IV or SQ
hours • Approximately 50% received corticosteroids during the formulations at different doses
Interventions: study Interpretation:
• IFN beta-1a 44 µg SQ on day of randomization, Day 3, Primary Outcomes: • IFN beta-1a does not improve mortality
and Day 6 (n = 1,656) • In-hospital mortality was 11.9% for combined IFN beta- for hospitalized patients.
• IFN beta-1a 10 µg IV daily for 6 days for patients on 1a arms and 10.5% in SOC arm (rate ratio 1.16; 95% CI,
high-flow oxygen, ventilation, or ECMO (n = 394) 0.96–1.39).
• IFN beta-1a (either SQ or IV) and LPV/RTV 400 mg/50 • For IFN beta-1a only (without LPV/RTV) recipients
mg twice daily for 14 days (n = 651) vs. SOC recipients, rate ratio was 1.12 (95% CI,
• Local SOC (n = 2,050) 0.83–1.51).
• Among those on ventilation at entry, age-stratified
Primary Endpoint:
rate ratio for in-hospital mortality was 1.40 (95% CI,
• In-hospital mortality 0.93–2.11).
Key Secondary Endpoint: Secondary Outcome:
• Initiation of ventilation • 10% initiated ventilation in the combined IFN beta-1a
arms and SOC arm.

DisCoVeRy Solidarity Trial Add-On: Open-Label, Adaptive RCT of SQ Interferon Beta-1a Plus Lopinavir/Ritonavir, Lopinavir/Ritonavir, or Hydroxychloroquine
in Hospitalized Adults With COVID-19 in France3
• Positive PCR result for SARS-CoV-2 • Median age 63 years; 72% men • Open-label study
• Patients had pulmonary rales or crackles with SpO2 • 29% were obese; 26% with chronic cardiac disease; • Most patients had moderate disease
≤94% or they required supplemental oxygen 22% with DM • No IFN beta-1a arm without LPV/RTV
Interventions: • 36% had severe disease • Study stopped early for futility
• IFN beta-1a 44 ug SQ on Days 1, 3, and 6 plus LPV/RTV • Median of 9 days from symptom onset to randomization
Interpretation:
400 mg/100 mg PO twice daily for 14 days plus SOC (n • 30% received steroids during the study
= 145) • Compared to SOC alone, the use of IFN-
Primary Outcome: beta-1a plus LPV/RTV did not improve
• LPV/RTV 400 mg/100 mg PO twice daily for 14 days clinical status, rate of viral clearance, or
plus SOC (n = 145) • No difference in clinical status at Day 15 for any
intervention compared to SOC: time to viral clearance in hospitalized
• HCQ 400 mg twice on Day 1, then HCQ 400 mg daily for patients with COVID-19.
9 days plus SOC (n = 145) • IFN beta-1a plus LPV/RTV: aOR 0.69 (95% CI, 0.45–
1.04; P = 0.08)
• SOC alone, which included corticosteroids,
anticoagulants, or immunomodulatory agents but not • LPV/RTV: aOR 0.83 (95% CI, 0.55–1.26; P = 0.39)
antivirals (n = 148) • HCQ: aOR 0.93 (95% CI, 0.62–1.41; P = 0.75)
Primary Endpoint: Secondary Outcomes:
• Clinical status at Day 15, as measured by an OS • No difference in clinical status at Day 29 between the
arms.
• No difference in rate and time to SARS-CoV-2 viral
• Clinical status at Day 29 clearance between the arms.
• Rate of SARS-CoV-2 viral clearance • Time to 2 OS-category improvement and hospital
• Time to SARS-CoV-2 viral clearance discharge by Day 29 was longer in LPV/RTV plus IFN
• Time to improvement of 2 OS categories beta-1a and LPV/RTV arms than in SOC arm.
• Time to hospital discharge

Single-Blind RCT of Peginterferon Lambda-1a for Treatment of Outpatients With Uncomplicated COVID-19 in the United States4
• Aged 18–65 years • Median age 36 years; 42% women; 63% Latinx, 28% • Small sample size
• Asymptomatic or symptomatic White
Interpretation:
• Positive RT-PCR result for SARS-CoV-2 within 72 hours • 7% were asymptomatic
• PEG-IFN lambda-1a provided no
of enrollment • Median of 5 days of symptoms before randomization virologic or clinical benefit compared
Key Exclusion Criteria: Primary Outcome: to placebo among outpatients with
uncomplicated COVID-19.
• Current or imminent hospitalization • Median time to cessation of viral shedding was 7 days in
• Respiratory rate >20 breaths/min both arms (aHR 0.81; 95% CI, 0.56–1.19; P = 0.29).
• SpO2 <94% on room air Secondary Outcomes:
• Decompensated liver disease • No difference between PEG-IFN lambda-1a and placebo
arms in:
Interventions:
• Proportion of patients hospitalized by Day 28: 3.3%
• Single dose of PEG-IFN lambda-1a 180 µg SQ (n = 60) for each arm
• Placebo (n = 60) • Time to resolution of symptoms: 8 days vs. 9 days
Primary Endpoint: (HR 0.94; 95% CI, 0.64–1.39)
• Time to first negative SARS-CoV-2 RT-PCR result Other Outcomes:
Key Secondary Endpoints: • Patients who received PEG-IFN lambda-1a were more
• Hospitalizations by Day 28 likely to have transaminase elevations than patients who
received placebo (25% vs. 8%; P = 0.027).
• Time to complete symptom resolution

Double-Blind RCT of Peginterferon Lambda in Outpatients With Laboratory-Confirmed COVID-19 in Canada5

• Positive SARS-CoV-2 PCR result • Median age 46 years; 58% women; 52% White • Small sample size
• Patients were within 7 days of symptom onset, or, if • 19% were asymptomatic Interpretation:
asymptomatic, were within 7 days of first positive SARS- • Mean of 4.5 days of symptoms before randomization • PEG-IFN lambda may accelerate VL
CoV-2 test result
Primary Outcome: decline and clearance in outpatients
Key Exclusion Criterion: with COVID-19; however, the clinical
• 80% in PEG-IFN lambda arm and 63% in placebo arms significance of this finding is unclear.
• Immunosuppression or condition that could be were negative for SARS-CoV-2 RNA at Day 7 (P = 0.15).
worsened by PEG-IFN lambda
Secondary Outcomes:
Interventions:
• VL decline by Day 7 was greater in PEG-IFN lambda arm
• Single dose of PEG-IFN lambda 180 µg SQ (n = 30) than in placebo arm (P = 0.0041).
• Placebo (n = 30) • 1 participant in each arm was admitted to the hospital by
Primary Endpoint: Day 14.
• Proportion of participants with negative nasal mid- Other Outcomes:
turbinate swab for SARS-CoV-2 at Day 7 • 3 participants in each arm had mild elevation of
Key Secondary Endpoints: aminotransferase concentrations. Increase was greater
in PEG-IFN lambda arm.
• Quantitative change in SARS-CoV-2 RNA over time
• Hospitalizations by Day 14
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation;
HCQ = hydroxychloroquine; HTN = hypertension; IFN = interferon; IV = intravenous; LPV/RTV = lopinavir/ritonavir; MV = mechanical ventilation; NIV = noninvasive
ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PEG-IFN = pegylated interferon; RCT =
randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SOC = standard of care; SpO2 = oxygen saturation; SQ =
subcutaneous; ULN = upper limit of normal; VL = viral load
References
1. Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with
COVID-19: a double-bind, randomised, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(12):1365-1376. Available at:
2. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J
3. Ader F, Peiffer-Smadja N, Poissy J, et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus

IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021;27(12):1826-1837. Available at:
4. Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized
placebo-controlled trial. Nat Commun. 2021;12(1):1967. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33785743.
5. Feld JJ, Kandel C, Biondi MJ, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a Phase 2, placebo-controlled randomised
trial. Lancet Respir Med. 2021;9(5):498-510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33556319.

Ivermectin
Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug used to treat several
neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 For these indications,
ivermectin has been widely used and is generally well-tolerated.1,2 Ivermectin is not approved by the
FDA for the treatment of any viral infection.
Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19
Reports from in vitro studies suggest that ivermectin acts by inhibiting host importin alpha/beta-1
nuclear transport proteins, which are part of a key intracellular transport process.3,4 Viruses hijack the
process and enhance infection by suppressing the host’s antiviral response. In addition, ivermectin
docking may interfere with SARS-CoV-2 spike protein attachment to the human cell membrane.5
Some studies of ivermectin have also reported potential anti-inflammatory properties, which have been
postulated to be beneficial in people with COVID-19.6-8
Ivermectin has been shown to inhibit replication of SARS-CoV-2 in cell cultures.9 However,
pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations
necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold
higher than those approved for use in humans.10,11 Although ivermectin appears to accumulate in lung
tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 µM, the half-
maximal inhibitory concentration (IC50) observed in vitro for ivermectin against SARS-CoV-2.12-15
Subcutaneous administration of ivermectin 400 µg/kg had no effect on SARS-CoV-2 viral loads in
hamsters.16 However, there was a reduction in olfactory deficit (measured using a food-finding test) and
a reduction in the interleukin (IL)-6:IL-10 ratio in lung tissues.
The safety and efficacy of ivermectin for the prevention and treatment of COVID-19 have been
evaluated in clinical trials and observational cohorts. Summaries of the studies that informed The
COVID-19 Treatment Guidelines Panel’s (the Panel) recommendation can be found in Table 4c. The
Panel reviewed additional studies, but these studies are not summarized in Table 4c because they have
study design limitations or results that make them less definitive and informative.
Recommendation
• The Panel recommends against the use of ivermectin for the treatment of COVID-19, except in
clinical trials (AIIa).
Rationale
The results of several randomized trials and retrospective cohort studies of ivermectin use in patients
with COVID-19 have been published in peer-reviewed journals or have been made available as
manuscripts ahead of peer review. Most of these studies, especially studies completed earlier in
the pandemic, had incomplete information and significant methodological limitations, which made
excluding common causes of bias difficult. Many of these studies have not been peer reviewed, and
some have now been retracted.
The Panel’s recommendation is primarily informed by recently published randomized controlled
trials.17-20 The primary outcomes of these trials showed that the use of ivermectin for the treatment of
COVID-19 had no clinical benefit. In TOGETHER, an adaptive platform trial conducted in Brazil, there

was no apparent difference between the ivermectin and placebo arms for the primary outcome of risk
of emergency department visits or hospitalization (14.7% vs. 16.4%). Also, there was no statistically
significant difference between the ivermectin and placebo arms in mortality (3.1% vs. 3.5%).
I-TECH, an open-label trial conducted in Malaysia, found no difference between the ivermectin and
standard of care arms (21.6% vs. 17.3%) for the primary outcome of risk of progression to severe
disease. The ivermectin arm had a lower risk of mortality than the standard of care arm (1.2% vs. 4.0%),
but this difference was not statistically significant.
The study populations of both the TOGETHER and I-TECH trials were patients with mild to moderate
disease, and the number of deaths was low (as expected). In these randomized trials, completely
excluding an effect of ivermectin is difficult, because the trials were not powered to detect differences in
secondary outcomes, such as death. However, data from these trials do not provide evidence that the use
of ivermectin benefited the treatment of COVID-19.
Comparisons of the efficacy of ivermectin for the treatment of COVID-19 are complicated by the large
variability of doses and durations of treatment used in the studies. There have been concerns that doses
in early trials were too low and durations of treatment were too short. However, the higher doses (300
μg/kg–400 μg/kg per day for up to 3–5 days) used in the more recent TOGETHER and I-TECH trials
did not demonstrate clinical benefit.
Although there have been many ivermectin studies, only a few trials have been adequately powered,
well-designed, and well-conducted. More recent clinical trials address the limitations of earlier studies
but fail to show clear evidence that ivermectin reduces time to recovery or prevents COVID-19 disease
progression. For this reason, and because several medications now have demonstrated clinical benefit
for the treatment of COVID-19, the Panel recommends against the use of ivermectin for the treatment
of COVID-19, except in a clinical trial (AIIa). Additional adequately powered, well-designed, and well-
conducted trials are needed to evaluate the effect of ivermectin on COVID-19. The Panel will continue
to review emerging data on ivermectin use, including the results from 2 large, ongoing randomized
controlled trials.
See Table 4c for summaries of the key studies that informed the Panel’s recommendation.
Monitoring, Adverse Effects, and Drug-Drug Interactions

• Adverse effects of ivermectin may include dizziness, pruritis, nausea, or diarrhea.21
• Neurological adverse effects have been reported with the use of ivermectin for the treatment of
onchocerciasis and other parasitic diseases, but it is not clear whether these adverse effects were
caused by ivermectin or the underlying conditions.22
• Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate.
• Ivermectin is generally given with water on an empty stomach; however, administering ivermectin
with food increases its bioavailability.
• The FDA first issued a warning in April 2020 that ivermectin intended for use in animals should
not be used to treat COVID-19 in humans. This warning was updated and reiterated in 2021.
Clinical Trials
Several clinical trials evaluating the use of ivermectin for the treatment of COVID-19 are currently
underway or in development. Please see ClinicalTrials.gov for the latest information.

References
1. Omura S, Crump A. Ivermectin: panacea for resource-poor communities? Trends Parasitol. 2014;30(9):445-
2. Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 years of clinical experience with ivermectin: an
overview of safety for an increasing number of indications. J Drugs Dermatol. 2016;15(3):325-332. Available
3. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear
transport importin alpha/beta1 heterodimer. Antiviral Res. 2020;177:104760. Available at:
4. Arevalo AP, Pagotto R, Porfido JL, et al. Ivermectin reduces in vivo coronavirus infection in a mouse
experimental model. Sci Rep. 2021;11(1):7132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33785846.
5. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to
ACE2. In Vivo. 2020;34(5):3023-3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32871846.
6. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and
improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524-529. Available at:
7. DiNicolantonio JJ, Barroso J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for
late-stage COVID-19. Open Heart. 2020;7(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32895293.
8. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear
transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin
Pharmacol. 2009;23(4):449-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19453757.
9. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the
replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at:
10. Chaccour C, Hammann F, Ramon-Garcia S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in
times of urgency. Am J Trop Med Hyg. 2020;102(6):1156-1157. Available at:
11. Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of
ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122-1133. Available at:
12. Arshad U, Pertinez H, Box H, et al. Prioritization of Anti-SARS-CoV-2 drug repurposing opportunities
based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin
Pharmacol Ther. 2020;108(4):775-790. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32438446.
13. Bray M, Rayner C, Noel F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in Antiviral Research,
widespread interest, an FDA warning, two letters to the editor and the authors’ responses. Antiviral Res.
2020;178:104805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32330482.
14. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of
view: antiviral levels are not likely attainable with known dosing regimens. Biotechnol Biotechnologic Equip.
2020;34:469-474. Available at: https://www.tandfonline.com/doi/full/10.1080/13102818.2020.1775118.
15. Jermain B, Hanafin PO, Cao Y, et al. Development of a minimal physiologically-based pharmacokinetic
model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug
repurposing. J Pharm Sci. 2020;109(12):3574-3578. Available at:
16. de Melo GD, Lazarini F, Larrous F, et al. Attenuation of clinical and immunological outcomes during
SARS-CoV-2 infection by ivermectin. EMBO Mol Med. 2021;13(8):e14122. Available at:

17. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19
(IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis.
18. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among
adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-1435. Available at:
19. Lim SCL, Hor CP, Tay KH, et al. Efficacy of ivermectin treatment on disease progression among adults with
mild to moderate COVID-19 and comorbidities: the I-TECH randomized clinical trial. JAMA Intern Med.
20. Reis G, Silva E, Silva DCM, et al. Effect of early treatment with ivermectin among patients with COVID-19.
N Engl J Med. 2022;Published online ahead of print. Available at:
21. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s024s025lbl.pdf.
22. Chandler RE. Serious neurological adverse events after ivermectin—do they occur beyond the indication of
onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382-388. Available at:

Table 4c. Ivermectin: Selected Clinical Data
The clinical trials described in this table are RCTs that had the greatest impact on the Panel’s recommendation. The Panel reviewed other
clinical studies of IVM for the treatment of COVID-19.1-26 However, those studies have limitations that make them less definitive and
informative than the studies summarized in the table.
TOGETHER: Double-Blind, Adaptive, RCT of Ivermectin in Nonhospitalized Patients With COVID-19 in Brazil27
• Positive SARS-CoV-2 antigen test • Median age 49 years; 46% aged ≥50 years; 58% • Health care facility capacity may have
• Within 7 days of symptom onset women; 95% “mixed race” influenced the number and duration
• Most prevalent risk factor: 50% with obesity of emergency setting visits and
• ≥1 high-risk factor for disease progression (e.g., aged hospitalizations.
>50 years, comorbidities, immunosuppression) • Symptom onset: 44% within 3 days
• No details on safety outcomes (e.g., type
Interventions: Primary Outcome: of treatment-emergent AEs) other than
• IVM 400 μg/kg PO per day for 3 days (n = 679) • Composite of emergency setting observation >6 hours grading were reported.
• Placebo (n = 679; not all participants received IVM or hospitalized within 28 days of randomization (ITT): Interpretation:
placebo) 100 (14.7%) in IVM arm vs. 111 (16.4%) in placebo arm
(relative risk 0.90; 95% CrI, 0.70–1.16) • In outpatients with recent COVID-19
Primary Endpoint: infection, IVM did not reduce the
• 171 (81%) of all events were hospitalizations (ITT) need for emergency setting visits or
• Composite of emergency setting observation >6
hours or hospitalized for COVID-19 within 28 days of Secondary Outcomes: hospitalization when compared with
randomization • No difference between IVM and placebo arms in: placebo.
Key Secondary Endpoints: • Viral clearance at Day 7 (relative risk 1.00; 95% CrI,
0.68–1.46)
• Viral clearance at Day 7
• All-cause mortality: 21 (3.1%) vs. 24 (3.5%) (relative
• All-cause mortality
risk 0.88; CrI, 0.49–1.55)

IVERCOR-COVID19: Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Nonhospitalized Patients With COVID-19 in Argentina28
Key Inclusion Criterion: Participant Characteristics: Key Limitation:
• Positive SARS-CoV-2 RT-PCR result within 48 hours of • Mean age 42 years; 8% aged ≥65 years; 47% women • Enrolled a fairly young population with
screening • 24% with HTN; 10% with DM; 58% with ≥1 comorbidity few of the comorbidities that predict
disease progression.
Key Exclusion Criteria: • Median time from symptom onset: 4 days
• Oxygen supplementation or hospitalization Interpretation:
Primary Outcome:
• Concomitant use of CQ or HCQ • Among patients who had recently
• Hospitalization for any reason: 5.6% in IVM arm vs. acquired SARS-CoV-2 infection, there
Interventions: 8.3% in placebo arm (OR 0.65; 95% CI, 0.32–1.31; P = was no evidence that IVM provided any
0.23) clinical benefit.
• Weight-based dose of IVM PO at enrollment and 24
hours later for a maximum total dose of 48 mg (n = Secondary Outcomes:
250) • Need for MV: 2% in IVM arm vs. 1% in placebo arm (P
• Placebo (n = 251) = 0.7)
Primary Endpoint: • All-cause mortality: 2% in IVM arm vs. 1% in placebo
arm (P = 0.7)
• Hospitalization for any reason
• Occurrence of AEs: 18% in IVM arm vs. 21% in placebo
Key Secondary Endpoints: arm (P = 0.6)
• Need for MV
• All-cause mortality

I-TECH: Open-Label RCT of Ivermectin in Patients With Mild to Moderate COVID-19 in Malaysia29
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 63 years; 55% women • Open-label study
within 7 days of symptom onset • 68% received ≥1 dose COVID-19 vaccine; 52% received Interpretation:
• Aged ≥50 years 2 doses
• In patients with mild to moderate
•≥ 1 comorbidity • Most common comorbidities: 75% with HTN; 54% with COVID-19, there was no evidence
DM; 24% with dyslipidemia that IVM provided any clinical benefit,
• Mean duration of symptoms: 5 days including no evidence that IVM reduced
• Required supplemental oxygen progression to severe disease.
• Severe hepatic impairment (ALT >10 times the ULN) Primary Outcome:
• Progression to severe COVID-19 (mITT): 52 (21.6%)
Interventions:
in IVM plus SOC arm vs. 43 (17.3%) in SOC alone arm
• IVM: 400 μg/kg PO daily for 5 days plus SOC (n = 241) (relative risk 1.25; 95% CI, 0.87–1.80; P = 0.25)
• SOC (n = 249) Secondary Outcomes:
Primary Endpoint: • No difference between IVM plus SOC arm and SOC alone
• Progression to severe COVID-19 (i.e., hypoxia requiring arm in:
supplemental oxygen to maintain SpO2 ≥95%) • In-hospital, all-cause mortality: 3 (1.2%) vs. 10 (4.0%)
Key Secondary Endpoints: (relative risk 0.31; 95% CI, 0.09–1.11; P = 0.09)
• In-hospital, all-cause mortality by Day 28 • MV: 4 (1.7%) vs. 10 (4.0%) (relative risk 0.41; 95% CI,
0.13–1.30; P = 0.17)
• MV or ICU admission
• ICU admission: 6 (2.5%) vs. 8 (3.2%) (relative risk
0.78; 95% CI, 0.27–2.20; P = 0.79)
• Occurrence of AEs: 33 (13.7%) in the IVM plus SOC arm
vs. 11 (4.4%) in the SOC alone arm; most with diarrhea
(14 vs. 4)

Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild COVID-19 in Colombia30
• Positive SARS-CoV-2 RT-PCR or antigen test result • Median age 37 years; 4% aged ≥65 years in IVM arm, • Due to low event rates, the primary
• Symptoms ≤7 days 8% in placebo arm; 39% men in IVM arm, 45% in endpoint changed from the proportion of
placebo arm patients with clinical deterioration to the
• Mild disease time to symptom resolution during the
• 79% with no known comorbidities
Key Exclusion Criteria: trial.
• Median symptom onset to randomization: 5 days
• Asymptomatic disease • The study enrolled younger, healthier
Primary Outcome: patients, a population that does not
• Severe pneumonia
• Median time to symptom resolution: 10 days in IVM arm typically develop severe COVID-19.
• Hepatic dysfunction vs. 12 days in placebo arm (HR 1.07; P = 0.53) Interpretation:
Interventions: • Symptoms resolved by Day 21: 82% in IVM arm vs. • In patients with mild COVID-19, IVM 300
• IVM 300 μg/kg PO per day for 5 days (n = 200) 79% in placebo arm μg/kg per day for 5 days did not improve
• Placebo PO (n = 198) Secondary Outcomes: the time to resolution of symptoms.
Primary Endpoint: • Clinical deterioration: no difference between arms
• Time to resolution of symptoms within 21 days • Escalation of care: no difference between arms
Key Secondary Endpoints: • Occurrence of AEs:
• Clinical deterioration • Discontinued treatment due to AEs: 8% in IVM arm vs.
3% in placebo arm
• Escalation of care
• No SAEs were related to intervention

Open-Label RCT of Ivermectin in Hospitalized Patients With COVID-19 in Egypt31

• RT-PCR-confirmed SARS-CoV-2 infection by pharyngeal • Mean age 42 years for IVM arm, 39 years for SOC arm; • Small, open-label study
swab 50% men
Interpretation:
• Hospitalized with mild to moderate COVID-19 • 49% with ≥1 comorbidity
• Use of IVM, when compared with the
Key Exclusion Criterion: Primary Outcome: SOC, did not result in differences in
• Cardiac problems • All-cause mortality by 28 days: 3 (3.7%) in IVM arm vs. all-cause mortality, hospital LOS, or the
4 (4.9%) in SOC arm (P = 1.00) need for MV.
Interventions:
• IVM 12 mg PO once daily for 3 days (n = 82) Secondary Outcomes:
• SOC (n = 82) • Mean hospital LOS: 9 days in IVM arm vs. 11 days in
SOC arm (P = 0.085)
Primary Endpoint:
• Need for MV: 3 (3.7%) in each arm (P = 1.00)
• All-cause mortality by 28 days
• Hospital LOS
• Need for MV

Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild to Moderate COVID-19 in India32
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 53 years; 28% women • Although the primary endpoint was a
• Hospitalized with mild or moderate COVID-19 • 35% with HTN; 36% with DM negative SARS-CoV-2 RT-PCR result
on Day 6, no RT-PCR result or an
Interventions: • 79% with mild COVID-19 inconclusive RT-PCR result was reported
• IVM 12 mg PO for 2 days (n = 55) • Mean 6.9 days from symptom onset for 42% of patients in the IVM arm and
• Placebo PO (n = 57) • 100% received HCQ, steroids, and antibiotics; 21% 23% in the placebo arm.
received RDV; 6% received tocilizumab • The time to discharge was not reported,
Primary Endpoint:
Primary Outcome: and outcomes after discharge were not
• Negative SARS-CoV-2 RT-PCR result on Day 6 evaluated.
• Negative RT-PCR result on Day 6: 24% in IVM arm vs.
Key Secondary Endpoints: 32% in placebo arm (rate ratio 0.8; P = 0.348) Interpretation:
• Symptom resolution by Day 6 • IVM provided no significant virologic or
Secondary Outcomes:
• Discharge by Day 10 clinical benefit for patients with mild to
• Symptom resolution by Day 6: 84% in IVM arm vs. 90% moderate COVID-19.
• Need for ICU admission or MV in placebo arm (rate ratio 0.9; P = 0.36)
• In-hospital mortality • Discharge by Day 10: 80% in IVM arm vs. 74% in
placebo arm (rate ratio 1.1; P = 0.43)
• Need for ICU admission or MV: no difference between
arms
• In-hospital mortality: 0 in IVM arm (0%) vs. 4 in placebo
arm (7%)

RIVET-COV: Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild to Moderate COVID-19 in India33
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 35 years; 89% men • Small sample size
• Nonsevere COVID-19 • 60% to 68% with mild COVID-19 (including Interpretation:
asymptomatic patients); 33% to 40% with moderate
Key Exclusion Criteria: • For patients who received IVM and those
COVID-19
• CrCl <30 mL/min who received placebo, there was no
• Median duration of symptoms: 4–5 days, similar across difference in the proportion of negative
• Transaminases >5 times ULN arms RT-PCR results at Day 5 or clinical
• MI, heart failure, QTc interval prolongation • 10% received concurrent antivirals (RDV, favipiravir, or outcomes.
• Severe comorbidity HCQ); no difference across arms
Interventions: Primary Outcomes:
• Single dose of IVM 24 mg PO (n = 51) • Negative RT-PCR result at Day 5: 48% in IVM 24 mg arm
• Single dose of IVM 12 mg PO (n = 49) vs. 35% in IVM 12 mg arm vs. 31% in placebo arm (P =
0.30)
• Placebo (n = 52)
• Decline of VL at Day 5: no significant difference between
Primary Endpoints: arms
• Negative RT-PCR result at Day 5 Secondary Outcomes:
• Decline of VL at Day 5 • Time to symptom resolution: no difference between arms
Key Secondary Endpoints: • Clinical worsening at Day 14: 8% in IVM 24 mg arm vs.
• Time to symptom resolution 5% in IVM 12 mg arm vs. 11% in placebo arm (P = 0.65)
• Clinical worsening at Day 14 • Number of hospital-free days at Day 28: no difference
between arms
• Number of hospital-free days at Day 28
• Frequency of AEs: no difference between arms; no SAEs
• Frequency of AEs

COVER: Phase 2, Double-Blind RCT of Ivermectin in Nonhospitalized Patients With COVID-19 in Italy34
• Asymptomatic or oligosymptomatic disease • Median age 47 years; 58% men • Small, Phase 2 study
• SARS-CoV-2 infection confirmed by RT-PCR result • 86% with symptoms • 90% of subjects screened were not
• Not hospitalized or receiving supplemental oxygen enrolled for various reasons.
Primary Outcomes:
• Recruitment stopped early because
Key Exclusion Criteria: • Number of SAEs: 0
of decline in the number of COVID-19
• CNS disease • Mean log10 reduction in VL at Day 7: 2.9 in IVM 1,200 μg/ cases.
• Receiving dialysis kg arm vs. 2.5 in IVM 600 μg/kg arm vs. 2.0 in placebo
arm (IVM 1,200 μg/kg vs. placebo, P = 0.099; IVM 600 Interpretations:
• Severe medical condition with <6 months survival μg/kg vs. placebo, P = 0.122) • A high dose of IVM (1,200 μg/kg)
prognosis appears to be safe but not well-tolerated;
• Use of warfarin, antiviral agents, CQ, or HCQ AE Outcomes:
34% discontinued therapy due to AEs.
• 14 (15.1%) discontinued treatment: 11 (34.4%) in IVM
Interventions: • There was no significant difference
1,200 μg/kg arm vs. 2 (6.9%) in IVM 600 μg/kg arm vs.
• IVM 1,200 μg/kg PO once daily for 5 days (n = 32) in reduction of VL between IVM and
1 (3.1%) in placebo arm
placebo arms.
• IVM 600 μg/kg plus placebo PO once daily for 5 days (n • All discontinuations in IVM 1,200 μg/kg arm due to
= 29) tolerability
• Placebo PO (n = 32)
Primary Endpoints:
• Number of SAEs
• Change in VL at Day 7

Double-Blind RCT of Ivermectin, Chloroquine, or Hydroxychloroquine in Hospitalized Adults With Severe COVID-19 in Brazil35
• Hospitalized with laboratory-confirmed SARS-CoV-2 • Mean age 53 years; 58% men • Small sample size
infection • Most common comorbidities: 43% with HTN; 28% with • No clearly defined primary endpoint
• ≥1 of the following severity criteria: DM; 38% with BMI >30
Interpretation:
• Dyspnea • 76% with respiratory failure on admission
• Compared to CQ or HCQ, IVM did not
• Tachypnea (>30 breaths/min) Outcomes: reduce the proportion of hospitalized
• SpO2 <93% • No difference between IVM, CQ, and HCQ arms in: patients with severe COVID-19 who died
• PaO2/FiO2 <300 mm Hg or who required supplemental oxygen,
• Need for supplemental oxygen: 88% vs. 89% vs. 90% ICU admission, or MV.
• Involvement of >50% of lungs by CXR or CT • ICU admission: 28% vs. 22% vs. 21%
Key Exclusion Criterion: • Need for MV: 24% vs. 21% vs. 21%
• Cardiac arrhythmia • Mortality: 23% vs. 21% vs. 22%
Interventions: • Mean number of days of supplemental oxygen: 8 days
for each arm
• IVM 14 mg once daily for 3 days (n = 53)
• Occurrence of AEs: no difference between arms
• CQ 450 mg twice daily on Day 0, then once daily for 4
days (n = 61) • Baseline characteristics significantly associated with
mortality:
• HCQ 400 mg twice daily on Day 0, then once daily for 4
days (n = 54) • Aged >60 years (HR 2.4)
Endpoints: • DM (HR 1.9)
• Need for supplemental oxygen, MV, or ICU admission • BMI >33 (HR 2.0)
• Occurrence of AEs • SpO2 <90% (HR 5.8)
• Mortality
Key: AE = adverse event; ALT = alanine aminotransferase; BMI = body mass index; CNS = central nervous system; CQ = chloroquine; CrCl = creatinine clearance; CT
= computed tomography; CXR = chest X-ray; DM = diabetes mellitus; HCQ = hydroxychloroquine; HTN = hypertension; ICU = intensive care unit; ITT = intention-to-
treat; IVM = ivermectin; LOS = length of stay; MI = myocardial infarction; mITT = modified intention-to-treat; MV = mechanical ventilation; the Panel = the COVID-19
Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PO = orally; RCT = randomized controlled trial;
RDV = remdesivir; RT-PCR = reverse transcriptase polymerase chain reaction; SAE = severe adverse event; SOC = standard of care; SpO2 = oxygen saturation; ULN =
upper limit of normal; VL = viral load

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Table 4d. Characteristics of Antiviral Agents
• RDV is the only antiviral drug that is approved by the FDA for the treatment of COVID-19.
• RTV-boosted nirmatrelvir, MOV, and certain anti-SARS-CoV-2 mAbs have received EUAs from the FDA for the treatment of
COVID-19.
• Other medications that are currently being evaluated in clinical trials for the treatment of COVID-19 are also included in this table. The
inclusion of these drugs does not imply that the Panel recommends their use.
• This table focuses on small-molecule antiviral drugs. For more information regarding anti-SARS-CoV-2 mAbs, please see Table 5c.
• The sections on Chloroquine or Hydroxychloroquine and/or Azithromycin, Lopinavir/Ritonavir and Other HIV Protease Inhibitors, and
Nitazoxanide have been archived. The Panel will no longer be updating the information on these therapies. The Panel recommends
against using these agents to treat COVID-19.
• For many of these antiviral drugs, there are limited or no data on dose modifications for patients with organ failure or those who require
extracorporeal devices. Please refer to product labels or EUAs, when available.
• For drug interaction information, please refer to product labels, EUA fact sheets, and the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the individual drug sections, Therapeutic
Management of Nonhospitalized Adults With COVID-19, Therapeutic Management of Hospitalized Adults With COVID-19, or Antiviral
Therapy Summary Recommendations.
Drug-Drug Interaction Comments and Links to

Dosing Regimens Adverse Events Monitoring Parameters
Potential Clinical Trials
Authorized under FDA EUA for the treatment of mild to moderate COVID-19 in high-risk individuals aged ≥12 years and weighing ≥40 kg.
FDA EUA Doses for COVID-191 • Dysgeusia • Monitor for potential • RTV-boosted nirmatrelvir • Both nirmatrelvir and
eGFR ≥60 mL/min: • Diarrhea AEs due to drug- has significant drug- RTV tablets can be taken
drug interactions with drug interactions. Before with or without food.
• Nirmatrelvir 300 mg (two 150-mg • HTN concomitant medications. prescribing RTV-boosted
tablets) with RTV 100 mg (one 100-mg • Myalgia • A list of clinical trials
• U
se with caution in patients nirmatrelvir, carefully review is available: Ritonavir-
tablet) twice daily for 5 days concomitant medications,
with pre-existing liver Boosted Nirmatrelvir
eGFR ≥30 to 60 mL/min: diseases, liver enzyme including OTC medicines,
• Nirmatrelvir 150 mg (one 150-mg abnormalities, or hepatitis. herbal supplements, and
tablet) with RTV 100 mg (one 100-mg recreational drugs.
• Consider checking renal
tablet) twice daily for 5 days function in patients • See Drug-Drug Interactions

Drug-Drug Interaction Comments and Links to
Potential Clinical Trials
Ritonavir-Boosted Nirmatrelvir (Paxlovid), continued
eGFR <30 mL/min: with

suspected renal etween Ritonavir-
B
•N
ot recommended impairment. Boosted Nirmatrelvir
(Paxlovid) and
Severe Hepatic Impairment (Child-Pugh Concomitant
Class C): Medications for
• Not recommended additional guidance and
resources to assist with
identifying drug-drug
interactions.
Remdesivir
Approved by the FDA for the treatment of COVID-19 in individuals aged ≥28 days and weighing ≥3 kg.
Dose for Adults and Children Weighing • Nausea • Monitor patients for • Clinical drug-drug • RDV should be administered
≥40 kg: •A LT and AST elevations infusion reactions during interaction studies of in settings in which
• RDV 200 mg IV on Day 1, then RDV the infusion and observe RDV have not been health care providers
• Hypersensitivity them for ≥1 hour after conducted. have immediate access to
100 mg IV once daily from Day 2
• Increases in prothrombin time the infusion as clinically • In vitro, RDV is a minor medications to treat severe
Dose for Children Aged ≥28 Days and • Drug vehicle is SBECD, which appropriate. infusion-related reactions or
substrate of CYP3A4, a
Weighing 3 kg to <40 kg: has been associated with HSRs, such as anaphylaxis,
• Monitor renal function, substrate of OATP1B1
• RDV 5 mg/kg IV on Day 1, then RDV renal and liver toxicity. SBECD hepatic function and and P-gp, and an and the ability to activate the
2.5 mg/kg IV once daily from Day 2 accumulation may occur in prothrombin time as inhibitor of CYP3A4, emergency medical system.
Total Treatment Duration: patients with moderate or clinically indicated. OATP1B1, OATP1B3, • A list of clinical trials is
severe renal impairment. • The FDA does not and MATE1. 2
available: Remdesivir
Nonhospitalized Patients:
• Each 100 mg vial of RDV recommend using RDV
• 3 days lyophilized powder contains when eGFR is <30 mL/
Hospitalized Patients: 3 g of SBECD, and each min. See Remdesivir for
100 mg/20 mL vial of RDV information on using
• 5 days or until hospital discharge
solution contains 6 g of RDV in people with renal
SBECD. insufficiency.
• Clinicians may consider
preferentially using
the lyophilized powder
formulation (which contains
less SBECD) in patients with
renal impairment.

Monitoring Drug-Drug Interaction Comments and Links to
Dosing Regimens Adverse Events
Parameters Potential Clinical Trials
Molnupiravir
Authorized under FDA EUA for the treatment of mild to moderate COVID-19 in high-risk individuals aged ≥18 years.
Dose Recommended in FDA EUA: • Diarrhea • Before initiating • Clinical drug-drug • MOV can be taken with or
• MOV 800 mg (4 200-mg capsules) PO • Nausea MOV, assess interaction studies of without food.
every 12 hours for 5 days pregnancy status MOV have not been • Sexually active individuals of
• Dizziness as clinically conducted. reproductive potential should
• Per the FDA, the 5-day course indicated. • Drug-drug interactions use effective contraception
of MOV has a low risk for • Monitor for related to hepatic during and following treatment
genotoxicity.3 See Molnupiravir for potential AEs. metabolism are not with MOV. See Molnupiravir for
details. expected. details.
• If MOV is prescribed for
a pregnant individual, the
prescribing clinician should
document that the risks and
benefits were discussed and
that the patient chose this
therapy. Pregnant patients
should also be offered the
opportunity to participate in
the pregnancy surveillance
program.
• During MOV treatment and
for 4 days after the final dose,
lactating people should not
breastfeed their infants.
• MOV is not authorized for use
in children aged <18 years due
to potential effects on bone and
cartilage growth.
• A list of clinical trials is
available: Molnupiravir

Interferon Alfa
Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
IFN Alfa-2b • AEs associated with inhaled • Respiratory • Low potential for drug- • The nebulized formulation
Dose for COVID-19 in Clinical Trials: therapy (e.g., throat irritation, symptoms after drug interactions of IFN alfa has been the
cough, bronchospasm) inhalation formulation most used in
• Nebulized IFN alfa-2b 5 million clinical trials for the treatment
international units twice daily • Minimal systemic effects expected
of COVID-19. IFN alfa is
• The optimal duration of treatment is usually included as part of a
unclear. combination regimen.
available: Interferon Alfa
Availability:
• Nebulized IFN alfa-2b is not
approved by the FDA for use in
the United States.
Interferon Beta
IFN Beta-1a • Flu-like symptoms (e.g., fever, • CBC with • Low potential for drug- • A list of clinical trials is
Dose for COVID-19 in Clinical Trials: fatigue, myalgia) differential drug interactions available: Interferon Beta
• IFN beta-1a 44 µg SUBQ or IV every • Leukopenia, neutropenia, • Liver enzymes •U se with caution with Availability
other day for up to 3 or 4 doses thrombocytopenia, lymphopenia • Worsening CHF other hepatotoxic
Brand Names of IFN Beta-1a
• Liver function abnormalities (ALT agents.
IFN Beta-1b • Depression, Products:
> AST) suicidal ideation • Reduce dose if ALT >5
Dose for COVID-19 in Clinical Trials: • Avonex, Plegridy, Rebif
• Injection site reactions times ULN.
• IFN beta-1b 8 million international units Brand Names of IFN Beta-1b
• Headache Products:
SUBQ every other day for up to 7 days
total • Hypertonia • Betaseron, Extavia
• Pain
• Rash
• Worsening depression
• Induction of autoimmunity

Interferon Lambda
PEG-IFN Lambda-1a • Liver function abnormalities • CBC with • Low potential for drug-drug • A list of clinical trials is
Dose for COVID-19 in Clinical Trials: • Injection site reactions differential interactions available: Interferon Lambda
• Single dose of PEG-IFN lambda-1a 180 • Liver enzymes • Use with caution with Availability:
µg SUBQ • Monitor for other hepatotoxic agents.
• PEG-IFN lambda-1a is not
potential AEs. approved by the FDA for use
in the United States.
Ivermectin
Dose for COVID-19 in Clinical Trials: • Dizziness • Monitor for • Minor CYP3A4 substrate • Generally given on an empty
• IVM 200–600 μg/kg PO as a single • Pruritis potential AEs. • P-gp substrate stomach with water; however,
dose or a once-daily dose for up to 5 administering IVM with food
• GI effects (e.g., nausea, diarrhea) increases its bioavailability.4
days
• Neurological AEs have been • A list of clinical trials is
reported when IVM has been used available: Ivermectin
to treat parasitic diseases, but it is
not clear whether these AEs were
caused by IVM or the underlying
conditions.
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; CBC = complete blood count; CHF = congestive heart failure; CYP =
cytochrome P450; eGFR = estimated glomerular filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal;
HSR = hypersensitivity reaction; HTN = hypertension; IFN = interferon; IV = intravenous; IVM = ivermectin; mAb = monoclonal antibody; MATE = multidrug and toxin
extrusion protein; MOV = molnupiravir; OATP = organic anion transporting polypeptide; OTC = over the counter; the Panel = the COVID-19 Treatment Guidelines
Panel; PEG-IFN = pegylated interferon; P-gp = P-glycoprotein; PO = orally; RDV = remdesivir; RTV = ritonavir; SBECD = sulfobutylether-beta-cyclodextrin; SUBQ =
subcutaneous; ULN = upper limit of normal
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. 2022. Available at:
2. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2020/214787Orig1s000lbl.pdf.
3. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. 2022. Available at:

4. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2009/050742s024s025lbl.pdf.

Anti-SARS-CoV-2 Antibody Products
The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of anti-SARS-CoV-2 monoclonal
antibodies (mAbs) are based on current knowledge of the in vitro activities of available products against the circulating
SARS-CoV-2 variants and subvariants. These recommendations remain fluid and depend on the prevalence of resistant
variants.
Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19
• Treatment with anti-SARS-CoV-2 mAbs should be considered for patients with mild to moderate COVID-19 who
are hospitalized for a reason other than COVID-19 if they otherwise meet the Food and Drug Administration (FDA)
Emergency Use Authorization (EUA) criteria for outpatient treatment.
• The risk for progression to severe COVID-19 in high-risk patients is substantially greater for those who are not
vaccinated or those who are vaccinated but not expected to mount an adequate immune response to the vaccine
due to an underlying immunocompromising condition. When the available therapies cannot be offered to all eligible
patients, see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There
Are Logistical or Supply Constraints for the Panel’s recommendations.
• At this time, the Panel’s anti-SARS-CoV-2 mAb recommendations are for the treatment of nonhospitalized patients
with mild to moderate COVID-19 who are at high risk of progressing to severe disease.
Bebtelovimab
• The Panel recommends using bebtelovimab 175 mg intravenous injection in patients aged ≥12 years as an
alternative therapy ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to
use, or clinically appropriate (CIII). Treatment should be initiated as soon as possible and within 7 days of symptom
onset. See Therapeutic Management of Nonhospitalized Adults With COVID-19 for further guidance.
• Bebtelovimab should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can
be managed. Patients should be monitored during the injection and observed for at least 1 hour after injection.
Bamlanivimab Plus Etesevimab, Casirivimab Plus Imdevimab, and Sotrovimab
• Because the Omicron (B.1.1.529) variant of concern (VOC) and its subvariants have become dominant in the United
States, the Panel recommends against using bamlanivimab plus etesevimab, casirivimab plus imdevimab, or
sotrovimab for the treatment of COVID-19 (AIII).
Anti-SARS-CoV-2 Monoclonal Antibodies as Post-Exposure Prophylaxis for SARS-CoV-2 Infection
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab for
SARS-CoV-2 post-exposure prophylaxis (PEP), as the Omicron VOC, which is not susceptible to these agents, is
currently the dominant SARS-CoV-2 variant circulating in the United States (AIII).
Anti-SARS-CoV-2 Monoclonal Antibodies as Pre-Exposure Prophylaxis for SARS-CoV-2 Infection
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg (Evusheld) administered as 2
consecutive 3-mL intramuscular injections (BIII) as SARS-CoV-2 pre-exposure prophylaxis (PrEP) for adults and
adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection, who have not been
recently exposed to an individual with SARS-CoV-2 infection, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune response to COVID-19
vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of severe adverse
reactions to a COVID-19 vaccine or any of its components.
• For individuals who previously received a dose of tixagevimab 150 mg plus cilgavimab 150 mg, the FDA EUA states
that a second dose should be administered as soon as possible:
• If the initial dose was administered ≤3 months ago, the second dose should be tixagevimab 150 mg plus
cilgavimab 150 mg.

• If the initial dose was administered >3 months ago, the second dose should be tixagevimab 300 mg plus cilgavimab
300 mg.
• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not be used in unvaccinated
individuals for whom COVID-19 vaccination is recommended and who are anticipated to have an adequate
response.
• If supplies of tixagevimab plus cilgavimab are limited, priority for use as PrEP should be given to those who are at the
highest risk for severe COVID-19 (see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention
of COVID-19 When There Are Logistical or Supply Constraints).
COVID-19 Convalescent Plasma
• The Panel recommends against the use of COVID-19 convalescent plasma (CCP) that was collected prior to the
emergence of the Omicron VOC for the treatment of COVID-19 (AIII).
• The Panel recommends against the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer CCP that
was collected after the emergence of the Omicron VOC for the treatment of immunocompromised patients and
nonhospitalized, immunocompetent patients with COVID-19.
Anti-SARS-CoV-2-Specific Immunoglobulins
• There is insufficient evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2-specific
immunoglobulins for the treatment of COVID-19.

The SARS-CoV-2 genome encodes 4 major structural proteins: spike (S), envelope (E), membrane
(M), and nucleocapsid (N), as well as nonstructural and accessory proteins. The spike protein is
further divided into 2 subunits, S1 and S2, that mediate host cell attachment and invasion. Through its
receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host
cell; this initiates a conformational change in S2 that results in virus-host cell membrane fusion and
viral entry.1 Anti-SARS-CoV-2 monoclonal antibodies (mAbs) that target the spike protein have been
shown to have clinical benefits in treating SARS-CoV-2 infection. The effectiveness of the different
anti-SARS-CoV-2 mAb therapies varies dramatically depending on the circulating variant, and the role
of each anti-SARS-CoV-2 mAb in the treatment of COVID-19 remains fluid. The recommendations
and discussion below pertain only to the use of the authorized anti-SARS-CoV-2 mAb products for the
treatment of COVID-19. Currently, no product is available for post-exposure prophylaxis (PEP). For
recommendations and discussion regarding the use of tixagevimab plus cilgavimab (Evusheld) as pre-
exposure prophylaxis (PrEP), see Prevention of SARS-CoV-2 Infection.
The Omicron (B.1.1.529) variant of concern (VOC) has become the dominant SARS-CoV-2 variant in
the United States.2 This variant, which includes numerous mutations in the spike protein, has markedly
reduced in vitro susceptibility to several anti-SARS-CoV-2 mAbs, especially bamlanivimab plus
etesevimab and casirivimab plus imdevimab (REGEN-COV). Sotrovimab is active against the Omicron
BA.1 and BA.1.1 subvariants, but it has substantially decreased in vitro activity against the Omicron
BA.2 subvariant. Bebtelovimab retains in vitro activity against circulating Omicron subvariants.
Recommendations
The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of anti-
SARS-CoV-2 mAbs are based on current knowledge of the in vitro activities of the available products
against the circulating SARS-CoV-2 variants and subvariants. These recommendations remain fluid
and depend on the prevalence of resistant variants. At this time, the Panel’s anti-SARS-CoV-2 mAb
recommendations are for the treatment of nonhospitalized patients with mild to moderate COVID-19
who are at high risk of progressing to severe disease.
Bebtelovimab
The Panel recommends using bebtelovimab 175 mg intravenous (IV) injection in patients aged ≥12
years as an alternative therapy ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are
not available, feasible to use, or clinically appropriate (CIII). Treatment should be initiated as soon as
possible and within 7 days of symptom onset. See Therapeutic Management of Nonhospitalized Adults
With COVID-19 for further guidance.
Bamlanivimab Plus Etesevimab, Casirivimab Plus Imdevimab, and Sotrovimab

Because the Omicron VOC has become the dominant variant in the United States, the Panel
recommends against using bamlanivimab plus etesevimab, casirivimab plus imdevimab, or
sotrovimab for the treatment of COVID-19 (AIII).
• Treatment with anti-SARS-CoV-2 mAbs should be started as soon as possible after SARS-CoV-2

infection is confirmed by an antigen test or a nucleic acid amplification test and within 7 days of
symptom onset.
• Anti-SARS-CoV-2 mAbs should be administered in a setting where severe hypersensitivity
reactions, such as anaphylaxis, can be managed. Patients should be monitored during the infusion
and observed for at least 1 hour after infusion.
• Treatment with anti-SARS-CoV-2 mAbs should be considered for patients with mild to moderate
COVID-19 who are hospitalized for a reason other than COVID-19 if they otherwise meet the
Emergency Use Authorization (EUA) criteria for outpatient treatment.
• The risk for progression to severe COVID-19 in high-risk patients is substantially greater
for those who are not vaccinated or those who are vaccinated but not expected to mount
an adequate immune response to the vaccine due to an underlying immunocompromising
condition. When the available therapies cannot be offered to all eligible patients, see
Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19
When There Are Logistical or Supply Constraints for the Panel’s recommendations.
• There are no data on the combined use of antiviral agents and anti-SARS-CoV-2 mAbs for the
treatment of nonhospitalized patients with COVID-19. Clinical trials are needed to determine
whether this combination therapy has a role in the treatment of COVID-19.
• Severely immunocompromised patients may have prolonged SARS-CoV-2 replication, leading to
more rapid viral evolution. There is a concern that using a single anti-SARS-CoV-2 mAb in these
patients may result in emergence of resistant virus. Additional studies are needed to assess this
risk. The role of anti-SARS-CoV-2 mAbs plus antiviral therapy in the treatment of COVID-19 is
not yet known.3,4
Anti-SARS-CoV-2 Monoclonal Antibodies That Have Received Emergency Use

Authorizations
Five anti-SARS-CoV-2 mAb products have received EUAs from the Food and Drug Administration
(FDA). Bamlanivimab plus etesevimab, bebtelovimab, casirivimab plus imdevimab, and sotrovimab
received EUAs for the treatment of mild to moderate COVID-19 in nonhospitalized patients with
laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease or
hospitalization. The FDA issued an EUA for tixagevimab plus cilgavimab, a long-acting anti-SARS-
CoV-2 mAb combination, as SARS-CoV-2 PrEP for individuals who do not have SARS-CoV-2 infection,
who have not been recently exposed to an individual with SARS-CoV-2 infection, AND who are at risk
for inadequate immune response to COVID-19 vaccination OR have a documented history of severe
adverse reactions to a COVID-19 vaccine or any of its components (see Prevention of SARS-CoV-2
Infection for more information). The issuance of an EUA does not constitute FDA approval.
The authorized anti-SARS-CoV-2 mAb products, listed alphabetically, are:
• Bamlanivimab plus etesevimab: These neutralizing mAbs bind to different, but overlapping,
epitopes in the spike protein RBD of SARS-CoV-2.
• The distribution of bamlanivimab plus etesevimab has paused in the United States because the
Omicron VOC has markedly reduced in vitro susceptibility to bamlanivimab and etesevimab;
therefore, this regimen is not expected to provide clinical benefit for patients with Omicron
infection.5
• Bebtelovimab: This recombinant neutralizing human mAb binds to the spike protein of
SARS-CoV-2. Bebtelovimab retains in vitro activity against all circulating Omicron subvariants,
but there are no clinical efficacy data on the treatment of patients at high risk for progression to

severe COVID-19.6
• Casirivimab plus imdevimab: These recombinant human mAbs bind to nonoverlapping epitopes of
the spike protein RBD of SARS-CoV-2.
• The distribution of casirivimab plus imdevimab has paused in the United States because the
Omicron VOC has markedly reduced in vitro susceptibility to casirivimab and imdevimab;
therefore, this regimen is not expected to provide clinical benefit for patients with Omicron
infection.7
• Sotrovimab: This mAb was originally identified in 2003 from a survivor of SARS-CoV infection.
It targets an epitope in the RBD of the spike protein that is conserved between SARS-CoV
and SARS-CoV-2. Sotrovimab retains in vitro activity against the Omicron BA.1 and BA.1.1
subvariants, but it has substantially decreased in vitro activity against Omicron BA.2 and is not
expected to provide clinical benefit for patients with Omicron BA.2 infection.8-10
• Because the Omicron BA.2 subvariant is now the dominant circulating subvariant in all
regions of the United States, distribution of sotrovimab has paused, and the Panel no longer
recommends using sotrovimab for the treatment of COVID-19.
• Tixagevimab plus cilgavimab: These recombinant human anti-SARS-CoV-2 mAbs bind to
nonoverlapping epitopes of the spike protein RBD of SARS-CoV-2. The originally authorized
dose of tixagevimab 150 mg plus cilgavimab 150 mg has reduced in vitro activity against the
Omicron BA.1 and BA.1.1 subvariants. However, the FDA updated the EUA to authorize a dose
of tixagevimab 300 mg plus cilgavimab 300 mg, which is expected to maintain activity against
these subvariants. Tixagevimab plus cilgavimab has retained in vitro activity against the Omicron
BA.2 subvariant.11-13
SARS-CoV-2 Variant Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies

In laboratory studies, some SARS-CoV-2 variants that harbor certain mutations have markedly reduced
susceptibility to several of the authorized anti-SARS-CoV-2 mAbs (see Table A).14 The clinical
relevance of the reduced in vitro susceptibility of select variants to anti-SARS-CoV-2 mAbs is under
investigation.
Some key SARS-CoV-2 variants that have been identified are:
• Alpha (B.1.1.7): This variant retains in vitro susceptibility to all anti-SARS-CoV-2 mAb products
currently available through FDA EUAs.15-17
• Beta (B.1.351): This variant has markedly reduced in vitro susceptibility to bamlanivimab
and etesevimab.15,17 In vitro studies also suggest that the Beta variant has markedly reduced
susceptibility to casirivimab; however, the combination of casirivimab and imdevimab appears to
retain activity against the variant.16 Sotrovimab also appears to retain activity against the variant.8
• Gamma (P.1): This variant has markedly reduced in vitro susceptibility to bamlanivimab and
etesevimab.15,18 The Gamma variant also has reduced susceptibility to casirivimab; however,
the combination of casirivimab plus imdevimab appears to retain activity against the variant.16
Sotrovimab also appears to retain activity against the Gamma variant.8
• Delta (B.1.617.2, non-AY.1/AY.2): This VOC retains in vitro susceptibility to all anti-SARS-CoV-2
mAbs currently available through FDA EUAs.15,16
• Omicron (B.1.1.529): This is currently the predominant VOC circulating in the United States
and includes the BA.1, BA.1.1, and BA.2 subvariants. This variant, which includes numerous
mutations in the spike protein, has markedly reduced in vitro susceptibility to some anti-SARS-
CoV-2 mAb products, as noted below:

• Bamlanivimab plus etesevimab and casirivimab plus imdevimab are not expected to be active
against these subvariants.12
• Sotrovimab retains activity against the Omicron BA.1 and BA.1.1 subvariants but has
decreased in vitro activity against the Omicron BA.2 subvariant.8,12,13
• Bebtelovimab retains in vitro activity against all circulating Omicron subvariants.6,9,19
• The originally authorized dose of tixagevimab 150 mg plus cilgavimab 150 mg has reduced in
vitro activity against the Omicron BA.1 and BA.1.1 subvariants.11 However, the FDA updated
the EUA to authorize a dose of tixagevimab 300 mg plus cilgavimab 300 mg, which is expected
to maintain activity against these subvariants. The duration of protection against the BA.1 and
BA.1.1 subvariants remains unclear. Tixagevimab plus cilgavimab has retained in vitro activity
against the Omicron BA.2 subvariant.11-13,20
To define the utility of specific mAbs in the future, ongoing population-based genomic surveillance of
the types and proportions of circulating SARS-CoV-2 variants, as well as studies on the susceptibility of
different variants to available anti-SARS-CoV-2 mAbs, will be important.

Table A. SARS-CoV-2 Variants and Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies
BAM Plus ETE CAS Plus IMD BEB SOT TIX Plus CIL
CDC Anti- Anti- Anti- Anti- Anti-
WHO Pango Notable In Vitro In Vitro In Vitro In Vitro In Vitro
Variant cipated cipated cipated cipated cipated
Label Lineage Mutations Suscept- Suscept- Suscept- Suscept- Suscept-
Class Clinical Clinical Clinical Clinical Clinical
ibilitya ibilitya ibilitya ibilitya ibilitya
Activity Activity Activity Activity Activity
Alpha B.1.1.7 VBM N501Y No change Active No change Active No change Active No change Active No change Active
Beta B.1.351 VBM K417N, Marked Unlikely No changeb Active No change Active No change Active No change Active
E484K, reduction to be
N501Y active
Gamma P.1 VBM K417T, Marked Unlikely No changeb Active No change Active No change Active No change Active
E484K, reduction to be
N501Y active
Delta B.1.617.2, VOC L452R, No change Active No change Active No change Active No change Active No change Active
non-AY.1/ T478K
AY.2
Omicron B.1.1.529/ VOC K417N, Marked Unlikely Marked Unlikely to No change Active No change Active Moderate Actived
BA.1 N440K, reduction to be reduction be active reductionc
G446S, active
E484A,
Q493R,
N501Y
Omicron B.1.1.529/ VOC R346K, Marked Unlikely Marked Unlikely to No change Active No change Active Moderate Actived
BA.1.1 K417N, reduction to be reduction be active reductionc
N440K, active
G446S,
E484A,
Q493R,
N501Y
Omicron B.1.1.529/ VOC T376A, Marked Unlikely Marked Unlikely to No change Active Marked Unlikely No change Active
BA.2 K417N, reduction to be reduction be active reduction to be
N440K, active active
E484A,
Q493R,
N501Y
a
Based on the fold reduction in susceptibility reported in the FDA EUAs.8,11,15,16
b
Marked change for CAS and no change for IMD. The combination of CAS plus IMD appears to retain activity against the variant.
c
Despite the moderately reduced in vitro susceptibility of TIX plus CIL, in vitro PK/PD modeling data suggest that the TIX 300 mg plus CIL 300 mg dose will retain

activity against the Omicron VOC.11
d
The duration of protection against SARS-CoV-2 infection remains unclear.
Key: BAM = bamlanivimab; BEB = bebtelovimab; CAS = casirivimab; CIL = cilgavimab; CDC = Centers for Disease Control
and Prevention; ETE = etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; IMD =
imdevimab; PK/PD = pharmacokinetic/pharmacodynamic; SOT = sotrovimab; TIX = tixagevimab; VBM = variant being
monitored; VOC = variant of concern; WHO = World Health Organization
Clinical Trials
In placebo-controlled, randomized trials in nonhospitalized patients with mild to moderate COVID-19
symptoms and certain risk factors for disease progression, the use of anti-SARS-CoV-2 mAb products
reduced the risk of hospitalization and death (see Table 5a).6,8,15,16 These studies were conducted
before the widespread circulation of the Omicron VOC. The potential impact of this variant and its
susceptibility to different FDA-authorized anti-SARS-CoV-2 mAbs are discussed below.
Bebtelovimab
Based on in vitro data, bebtelovimab is expected to have activity against a broad range of SARS-CoV-2
variants, including the Omicron VOC and its BA.1 and BA.2 subvariants.6,9,19 The Panel’s
recommendation on bebtelovimab is primarily based on laboratory data showing its potent activity
against the Omicron VOC (including the BA.1 and BA.2 subvariants) and other VOCs, as well as on
limited clinical trial data from the Phase 2 BLAZE-4 study.6
The multi-armed, Phase 2 BLAZE-4 study included 1 small, placebo-controlled, randomized trial in
patients at low risk of disease progression. It also included 1 small randomized controlled trial that
compared bebtelovimab alone to an anti-SARS-CoV-2 mAb combination of bamlanivimab, etesevimab,
and bebtelovimab in patients at high risk of disease progression (see Table 5a).6 Among low-risk
individuals, the mean decline in viral load at Day 5 was greater in the 2 bebtelovimab arms than in the
placebo arm. The median time to sustained symptom resolution was 6 days in the bebtelovimab alone
arm and 8 days in the placebo arm (P = 0.003).
Large randomized controlled trials are needed to fully evaluate the efficacy of bebtelovimab in a
high-risk population. Nevertheless, when other therapeutic options are not available, feasible to use, or
clinically appropriate, in vitro susceptibility data and the antiviral activity and clinical benefits observed
in Phase 2 trials support the use of bebtelovimab for nonhospitalized patients with mild to moderate
COVID-19 at high risk of progressing to severe COVID-19. In addition, bebtelovimab has mechanisms
of action similar to those of other authorized anti-SARS-CoV-2 mAbs that have shown definitive clinical
benefits in this population.
Bamlanivimab Plus Etesevimab

The distribution of bamlanivimab plus etesevimab has paused in the United States because
the Omicron VOC and subvariants have markedly reduced in vitro susceptibility to this mAb
regimen.5 Prior to the spread of the Omicron variant, the Phase 3 BLAZE-1 trial had demonstrated a
clinical benefit of bamlanivimab plus etesevimab in people with mild to moderate COVID-19 who are at
high risk for progression to severe disease or hospitalization.21
Casirivimab Plus Imdevimab

The distribution of casirivimab plus imdevimab has paused in the United States because the
Omicron VOC and subvariants have markedly reduced in vitro susceptibility to this mAb
regimen.7 Prior to the spread of the Omicron variant, the FDA had authorized the use of casirivimab
600 mg plus imdevimab 600 mg administered as a single IV infusion for the treatment of people with

mild to moderate COVID-19 who are at high risk for progression to severe disease or hospitalization.8
The recommendation for using the dose of casirivimab 600 mg plus imdevimab 600 mg IV is based on
data from a Phase 3, double-blind, placebo-controlled, randomized trial demonstrating clinical benefit in
outpatients with mild to moderate COVID-19. The FDA also authorized subcutaneous (SUBQ) injection
of the regimen if an IV infusion is not feasible or would delay treatment. SUBQ administration of
casirivimab plus imdevimab requires 4 injections (2.5 mL per injection) at 4 different sites (see the FDA
EUA for details).
Sotrovimab
Sotrovimab retains in vitro activity against the Omicron BA.1 and BA.1.1 subvariants of the Omicron
VOC, but it has substantially decreased in vitro activity against the Omicron BA.2 subvariant and
is not expected to provide clinical benefit for patients with Omicron BA.2 infection.8 Because the
Omicron BA.2 subvariant is now the dominant circulating subvariant in all regions of the United States,
distribution of sotrovimab has paused, and the Panel no longer recommends using sotrovimab to treat
COVID-19.
Data that support the sotrovimab EUA are from the Phase 3 COMET-ICE trial, which included
outpatients with mild to moderate COVID-19 who were at high risk for progression to severe disease
or hospitalization. A total of 1,057 participants were randomized within 5 days of symptom onset to
receive sotrovimab 500 mg IV (n = 528) or placebo (n = 529). The primary endpoint was the proportion
of participants who were hospitalized for ≥24 hours or who died from any cause by Day 29. Endpoint
events occurred in 6 of 528 participants (1%) in the sotrovimab arm and 30 of 529 participants (6%) in
the placebo arm, resulting in a 4.53% absolute difference in the risk of hospitalization or death among
those who received sotrovimab. The adjusted relative risk of hospitalization or death for those who
received sotrovimab was 0.21.8,22
See Table 5a for more information on the clinical trials evaluating the safety and efficacy of anti-SARS-
CoV-2 mAbs in patients with COVID-19.
Criteria for Use of Anti-SARS-CoV-2 Monoclonal Antibodies Under Emergency Use

Authorizations
The FDA EUAs for anti-SARS-CoV-2 mAbs include a list of specific conditions that place patients
at high risk for clinical progression. On May 14, 2021, the FDA revised the EUAs to broaden these
criteria.15,16 Notable changes included lowering the body mass index (BMI) cutoff from ≥35 to >25 and
adding other conditions and factors (e.g., pregnancy, race or ethnicity). Other than being aged ≥12 years,
there are no longer any age criteria restricting the use of these products in patients with the following
conditions: sickle cell disease, neurodevelopmental disorders, medical-related technological dependence,
asthma, cardiovascular disease, hypertension, and chronic lung disease.
For guidance when available therapies cannot be offered to all eligible patients, see Prioritization
of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There Are
Logistical or Supply Constraints.
Recommendations
The strength of the evidence for using anti-SARS-CoV-2 mAbs varies depending on the medical
conditions and other factors that place patients at high risk for progression to severe COVID-19 or
hospitalization. The ratings for the Panel’s recommendations are based on FDA EUA criteria for
identifying high-risk individuals.

• For patients with high-risk conditions that have been represented in clinical trials evaluating
anti-SARS-CoV-2 mAbs, the Panel recommends the use of anti-SARS-CoV-2 mAbs, with the
following ratings:
• Aged ≥65 years (AIIa)
• Obesity (BMI >30) (AIIa)
• Diabetes (AIIa)
• Cardiovascular disease (including congenital heart disease) or hypertension (AIIa)
• Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma,
interstitial lung disease, cystic fibrosis, pulmonary hypertension) (AIIa)
• For patients with conditions that have had limited representation in clinical trials but are
considered a high risk for progression to severe COVID-19 by the Centers for Disease Control and
Prevention (CDC), the Panel recommends the use of anti-SARS-CoV-2 mAbs, with the following
ratings:
• Immunocompromised or receiving immunosuppressive treatment (AIII); many experts
strongly recommend therapy for patients with these conditions, despite limited representation
in clinical trials
• Overweight (i.e., BMI 25–30) as a sole risk factor (BIII)
• Chronic kidney disease (BIII)
• Pregnancy (BIII)
• Sickle cell disease (BIII)
• Neurodevelopmental disorder (e.g., cerebral palsy) or another condition that confers medical
complexity (e.g., genetic or metabolic syndromes, severe congenital anomalies) (BIII)
• Medical-related technological dependence (e.g., tracheostomy, gastrostomy, positive pressure
ventilation not related to COVID-19) (BIII)
• Infants aged <1 year. Although bamlanivimab plus etesevimab is authorized for use in this
high-risk group, the Panel recommends against using this mAb regimen (AIII) because it has
markedly reduced activity against Omicron, the dominant VOC in the United States.
It is important to note that the likelihood of developing severe COVID-19 increases when a person has
multiple high-risk conditions or comorbidities.23-26 Medical conditions or other factors (e.g., race or
ethnicity) that are not listed in the mAb EUAs may also be associated with high risk for progression to
severe COVID-19. The current EUAs state that the use of anti-SARS-CoV-2 mAbs may be considered
for patients with high-risk conditions and factors that are not listed in the EUAs. For additional
information on medical conditions and other factors that are associated with an increased risk for
progression to severe COVID-19, see the CDC webpage People With Certain Medical Conditions. The
decision to use anti-SARS-CoV-2 mAbs for a patient should be based on an individualized assessment
of risks and benefits.8
Using Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for

COVID-19
The anti-SARS-CoV-2 mAbs available through FDA EUAs are not authorized for use in the following
patients:
• Those hospitalized for COVID-19; or

• Those who require oxygen therapy or respiratory support due to COVID-19; or
• Those who are on chronic oxygen therapy due to an underlying non-COVID-19-related
comorbidity and who require an increase in oxygen flow rate from baseline or respiratory support
because of COVID-19.
The FDA EUAs do permit the use of anti-SARS-CoV-2 mAb products in patients who are hospitalized
for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19 and are at high
risk for progressing to severe disease.6,16,27,28
Anti-SARS-CoV-2 mAbs have been evaluated in hospitalized patients with severe COVID-19. A
substudy of the ACTIV-3/TICO trial randomized patients who were hospitalized for COVID-19 to
receive bamlanivimab 7,000 mg or placebo, each in addition to remdesivir. On October 26, 2020, study
enrollment was halted after a prespecified interim futility analysis indicated a lack of clinical benefit for
bamlanivimab.29,30
Prior to the spread of the Omicron VOC, data supported the use of anti-SARS-CoV-2 mAbs in
hospitalized patients with COVID-19 who are seronegative for the anti-spike protein antibody and/
or have evidence of ongoing viral replication. In a subset analysis of the ACTIV-3 trial, 153 of 314
participants (49%) were negative for the anti-spike endogenous neutralizing antibody. The subhazard
ratio (sHR) comparing bamlanivimab to placebo for sustained recovery (defined as discharge home
and remaining at home for ≥14 days through Day 90) was 1.24 among the participants who were
seronegative (CI, 0.90–1.70) versus 0.74 among those who were seropositive (CI, 0.54–1.00).
Furthermore, the difference for sustained recovery between bamlanivimab and placebo was even greater
among the seronegative participants who had high viral loads (sHR 1.89; CI, 1.23–2.91). However, these
results are limited due to the trial’s early termination for futility and small sample size.31
The ACTIV-3/TICO trial also randomized hospitalized patients with COVID-19 to receive sotrovimab
500 mg IV, an anti-SARS-CoV-2 mAb combination of BRII-196 1,000 mg IV plus BRII-198 1,000
mg IV, or placebo, each in addition to remdesivir. On March 1, 2021, study enrollment was halted after
a prespecified interim futility analysis indicated a lack of clinical benefit for sotrovimab or BRII-196
plus BRII-198.32 A subset analysis did not suggest efficacy for sotrovimab in those with or without
endogenous antibodies.
In the RECOVERY study, hospitalized patients with COVID-19 were randomized to receive usual care
with casirivimab 4,000 mg plus imdevimab 4,000 mg IV or usual care alone. There was no difference
in 28-day all-cause mortality between the casirivimab plus imdevimab arm and the usual care arm; 943
of 4,839 patients (19%) in the casirivimab plus imdevimab arm died versus 1,029 of 4,946 patients
(21%) in the usual care arm (rate ratio 0.94; 95% CI, 0.86–1.02; P = 0.14). However, in the subgroup
of patients who were seronegative for the anti-spike protein antibody, there was a significant reduction
in 28-day all-cause mortality in the casirivimab plus imdevimab arm (396 of 1,633 casirivimab plus
imdevimab recipients [24%] died vs. 452 of 1,520 usual care recipients [30%]; rate ratio 0.79; 95% CI,
0.69–0.91; P = 0.0009).33 Under the current EUA, this higher dose of casirivimab plus imdevimab is not
available, and the lower dose is only authorized for use in nonhospitalized patients with COVID-19. In
addition, rapid serology testing that can identify seronegative individuals in real time is currently not
widely available.
Anti-SARS-CoV-2 mAbs may be available through expanded access programs for the treatment
of immunocompromised patients who are hospitalized because of COVID-19. It is not yet known
whether these mAb products provide clinical benefits in people with B-cell immunodeficiency or other
immunodeficiencies.

Monitoring
Bebtelovimab should be administered by IV injection and should only be administered in health care
settings by qualified health care providers who have immediate access to emergency medical services
and medications that treat severe infusion-related reactions. Patients should be monitored during the IV
injection and for at least 1 hour after the injection is completed.
Adverse Effects
Hypersensitivity, including anaphylaxis and infusion-related reactions, has been reported in patients who
received anti-SARS-CoV-2 mAbs. Rash, diarrhea, nausea, vomiting, dizziness, and pruritis have also
been reported.6,8,16,28
Drug-drug interactions are unlikely between the authorized anti-SARS-CoV-2 mAbs and medications
that are renally excreted or that are cytochrome P450 substrates, inhibitors, or inducers (see Table 5c).
The use of anti-SARS-CoV-2 mAbs can be considered for pregnant people with COVID-19, especially
those who have additional risk factors for severe disease (see the EUA criteria for the use of these
products above).
As immunoglobulin (Ig) G mAbs, the authorized anti-SARS-CoV-2 mAbs would be expected to cross
the placenta. There are no pregnancy-specific data on the use of these mAbs; however, other IgG
products have been safely used in pregnant people when their use is indicated. Therefore, authorized
anti-SARS-CoV-2 mAbs should not be withheld during pregnancy. When possible, pregnant and
lactating people should be included in clinical trials that are evaluating the use of anti-SARS-CoV-2
mAbs for the treatment or prevention of COVID-19.
Please see Special Considerations in Children for therapeutic recommendations for children with
COVID-19.
Drug Availability
Bebtelovimab is currently being distributed to all regions without restriction. The broad distribution of
bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab has paused in the United
States because the Omicron VOC has reduced susceptibility to these anti-SARS-CoV-2 mAbs.5,7
References
1. Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends
Immunol. 2020;41(5):355-359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32249063.
2. Centers for Disease Control and Prevention. COVID data tracker: variant proportions. 2022. Available at:
https://covid.cdc.gov/covid-data-tracker/#variant-proportions. Accessed April 19, 2022.
3. Rockett R, Basile K, Maddocks S, et al. Resistance mutations in SARS-CoV-2 Delta variant after sotrovimab
use. N Engl J Med. 2022;386(15):1477-1479. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35263515.
4. Huygens S, Munnink BO, Gharbharan A, Koopmans M, Rijnders B. High incidence of sotrovimab resistance
and viral persistence after treatment of immunocompromised patients infected with the SARS-CoV-2 Omicron
variant. medRxiv. 2022;Preprint. Available at:

5. Public Health Emergency. Bamlanivimab/etesevimab. 2022. Available at: https://www.phe.gov/emergency/
events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/default.aspx. Accessed April 21,
2022.
7. Public Health Emergency. REGEN-COV. 2022. Available at: https://www.phe.gov/emergency/events/
COVID19/investigation-MCM/cas_imd/Pages/default.aspx. Accessed April 21, 2022.
sotrovimab. 2022. Available at: https://www.fda.gov/media/149534/download.
11. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld
(tixagevimab co-packaged with cilgavimab). 2022. Available at:
12. Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
Nature. 2021;602(7898):671-675. Available at: https://pubmed.ncbi.nlm.nih.gov/35016199/.
14. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Accessed April
13, 2022.
15. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of
bamlanivimab and etesevimab. 2022. Available at: https://www.fda.gov/media/145802/download.
REGEN-COV (casirivimab and imdevimab). 2021. Available at:
17. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature.
18. Wang P, Casner RG, Nair MS, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody
neutralization. Cell Host Microbe. 2021;29(5):747-751. Available at:
19. Westendorf K, Zentelis S, Wang L, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2
variants. Cell Rep. 2022;Published online ahead of print. Available at:
20. VanBlargan L, Errico J, Halfmann P, et al. An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes
neutralization by therapeutic monoclonal antibodies. Res Sq. 2021;Preprint. Available at:
21. Dougan M, Azizad M, Mocherla B, et al. A randomized, placebo-controlled clinical trial of bamlanivimab and
etesevimab together in high-risk ambulatory patients with COVID-19 and validation of the prognostic value of
persistently high viral load. Clin Infect Dis. 2021;Published online ahead of print. Available at:

22. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of sotrovimab on hospitalization or death among high-risk
patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1236-1246.
23. Kim L, Garg S, O’Halloran A, et al. Risk factors for intensive care unit admission and in-hospital mortality
among hospitalized adults identified through the US coronavirus disease 2019 (COVID-19)-associated
hospitalization surveillance network (COVID-NET). Clin Infect Dis. 2021;72(9):e206-e214. Available at:
24. Guan WJ, Liang WH, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a
nationwide analysis. Eur Respir J. 2020;55(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32217650.
25. Zhang Y, Luo W, Li Q, et al. Risk factors for death among the first 80,543 COVID-19 cases in China:
relationships between age, underlying disease, case severity, and region. Clin Infect Dis. 2022;74(4):630-638.
26. Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk factors associated with in-hospital mortality in a U.S.
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
27. Food and Drug Administration. Frequently asked questions on the emergency use authorization of
28. Food and Drug Administration. Frequently asked questions on the emergency use authorization of sotrovimab.
29. National Institute of Allergy and Infectious Diseases. Statement—NIH-sponsored ACTIV-3 trial closes
LY-CoV555 sub-study. 2020. Available at: https://www.niaid.nih.gov/news-events/statement-nih-sponsored-
activ-3-trial-closes-ly-cov555-sub-study. Accessed April 20, 2022.
30. ACTIV-TICO LY-CoV555 Study Group, Lundgren JD, Grund B, et al. A neutralizing monoclonal antibody for
hospitalized patients with COVID-19. N Engl J Med. 2021;384(10):905-914. Available at:
31. ACTIV-3/TICO Bamlanivimab Study Group. Responses to a neutralizing monoclonal antibody for
hospitalized patients with COVID-19 according to baseline antibody and antigen levels: a randomized
controlled trial. Ann Intern Med. 2021;175(2):234-243. Available at:
32. ACTIV-3/Therapeutics for Inpatients with COVID-19 Study Group. Efficacy and safety of two neutralising
monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with
COVID-19 (TICO): a randomised controlled trial. Lancet Infect Dis. 2022;22(5):622-635. Available at:
33. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital
with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet.

Table 5a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected
Clinical Data
This table describes only the clinical trials that have evaluated anti-SARS-CoV-2 mAbs for the treatment of COVID-19. Please see
Prevention of SARS-CoV-2 Infection for a discussion of the clinical trials that have evaluated anti-SARS-CoV-2 mAbs for PEP of
SARS-CoV-2 infection.
BLAZE-1: Double-Blind RCT of Bamlanivimab 700 mg Plus Etesevimab 1,400 mg in Nonhospitalized Patients With Mild to Moderate COVID-19 in the United
States and Puerto Rico1
• Aged ≥12 years • Median age 56 years; 30% aged ≥65 years; 53% women • Conducted before widespread
• At high risk for severe COVID-19 or hospitalization • 87% White, 27% Hispanic/Latinx, 8% Black/African American circulation of the Omicron VOC
Interventions: • Mean duration of symptoms was 4 days Interpretation:
• Within 3 days of a positive SARS-CoV-2 test result, • 7
6% with mild COVID-19, 24% with moderate COVID-19 • Compared to placebo, BAM plus ETE
single infusion of: Primary Outcomes: significantly reduced the number of
• BAM 700 mg plus ETE 1,400 mg (n = 511) COVID-19-related hospitalizations
• COVID-19-related hospitalizations or all-cause deaths by Day
and all-cause deaths in high-risk
• Placebo (n = 258) 29: 4 (0.8%) in BAM plus ETE arm vs. 15 (5.8%) in placebo
patients.
Primary Endpoint: arm (change of -5.0%; 95% CI, -8.0% to -2.1%; P < 0.001)
• COVID-19-related hospitalization (defined as ≥24 hours • All-cause deaths by Day 29: 0 in BAM plus ETE arm vs. 4
of acute care) or death from any cause by Day 29 (1.6%) in placebo arm
BLAZE-4, Treatment Arms 9–11: Double-Blind RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab Versus Bebtelovimab Alone Versus Placebo in Low-
Risk, Nonhospitalized Patients With Mild to Moderate COVID-192
• Aged 18–64 years • Median age 35 years; 56% women • Only low-risk patients included
• No risk factors for progression to severe COVID-19 • 36% Hispanic/Latinx, 19% Black/African American • Not powered to assess
• M
ean duration of symptoms prior to enrollment was 3.6 days hospitalizations and deaths
• Conducted before widespread
• ≥1 of the following: Primary Outcomes:
circulation of the Omicron VOC
• SpO2 ≤93% on room air • Proportion with PHVL:
• Respiratory rate ≥30 breaths/min • 13% in BAM plus ETE plus BEB arm vs. 21% in placebo Interpretations:
• Heart rate ≥125 bpm arm (P = 0.098), with a relative reduction of 38% (95% CI, • There were no differences in the
-9% to 65%) proportion of patients with PHVL
across the arms.

BLAZE-4, Treatment Arms 9–11: Double-Blind RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab Versus Bebtelovimab Alone Versus Placebo in Low-
Risk, Nonhospitalized Patients With Mild to Moderate COVID-192, continued
Interventions: • 14% in BEB arm vs. 21% in placebo arm (P = 0.147), • Few COVID-19-related hospitalizations or
• Within 3 days of a positive SARS-CoV-2 test result, with a relative reduction of 34% (95% CI, -15% to 62%) deaths from any cause occurred by Day
single infusion of: Secondary Outcomes: 29 across the arms, as is expected for a
population of individuals who were at low
• BAM 700 mg plus ETE 1,400 mg plus BEB 175 • Mean decline in VL greater in mAb arms vs. placebo arm risk of severe COVID-19.
mg (n = 127) at Day 5 but not at Days 3, 7, or 11
• Compared to placebo, the median time to
• BEB 175 mg (n = 125) • COVID-19-related hospitalizations or all-cause deaths by sustained symptom resolution was shorter
• Placebo (n = 128) Day 29: in the BEB arm.
• 3 (2.4%) in BAM plus ETE plus BEB arm, including 1
Primary Endpoint:
death
• Proportion of patients with PHVL (defined as
• 2 (1.6%) in BEB arm
SARS-CoV-2 VL >5.82 log10 by Day 7)
• 2 (1.6%) in placebo arm
• Median time to sustained symptom resolution:
• Mean change in VL from baseline to Days 3, 5, 7,
and 11 • 7 days in BAM plus ETE plus BEB arm vs. 8 days in
placebo arm (P = 0.289)
• COVID-19-related hospitalization or death from any
cause by Day 29 • 6 days in BEB arm vs. 8 days in placebo arm (P = 0.003)
• Time to sustained symptom resolution
BLAZE-4, Treatment Arms 12 and 13: Open-Label RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab and Bebtelovimab Alone in High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-192
• Aged ≥12 years • Median age 50 years; 52% women • Open-label study
• Weight ≥40 kg • 18% Hispanic/Latinx, 18% Black/African American • No placebo arm
• ≥1 risk factor for progression to severe COVID-19 • Mean duration of symptoms prior to enrollment was 4.7 • Not powered to assess hospitalizations and
days deaths
• 21% had at least 1 dose of COVID-19 vaccine • Conducted before widespread circulation of
• ≥1 of the following:
the Omicron VOC
• SpO2 ≤93% on room air Efficacy Outcomes:
• COVID-19-related hospitalization or death from any cause Interpretation:
• Respiratory rate ≥30 breaths/min
by Day 29: 2 (4%) in BAM plus ETE plus BEB arm vs. 3 • There was no difference in the proportion of
• Heart rate ≥125 bpm (3%) in BEB arm patients who were hospitalized or who died
Interventions: • Mean decline in VL greater in BAM plus ETE plus BEB arm between the arms.
• Within 3 days of a positive SARS-CoV-2 test result, vs. BEB arm at Day 5 but not at Days 3, 7, or 11
single infusion of:

BLAZE-4, Treatment Arms 12 and 13: Open-Label RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab and Bebtelovimab Alone in High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-192, continued
• BAM 700 mg plus ETE 1,400 mg plus BEB 175
mg (n = 50)
• BEB 175 mg (n = 100)
Efficacy Endpoints:
• COVID-19-related hospitalization or death from any
cause by Day 29
• Mean change in VL from baseline to Days 3, 5, 7,
and 11
Double-Blind RCT of Casirivimab Plus Imdevimab in Nonhospitalized Patients With Mild to Moderate COVID-193
• Aged ≥18 years • Median age 50 years • Conducted before widespread circulation of
• Laboratory-confirmed SARS-CoV-2 infection • 35% Hispanic/Latinx, 5% Black/African American the Omicron VOC
• Symptom onset within 7 days of randomization • Median duration of symptoms prior to enrollment was 3 Interpretation:
• For patients included in the modified full analysis days • Compared to placebo, CAS 600 mg plus
only: Primary Outcomes: IMD 600 mg and CAS 1,200 mg plus IMD
• ≥1 risk factor for severe COVID-19 1,200 mg reduced the risk of COVID-19-
• COVID-19-related hospitalizations or all-cause deaths related hospitalizations or all-cause deaths
• Positive SARS-CoV-2 RT-PCR result at baseline through Day 29: in patients with mild to moderate COVID-19.
Interventions: • 7 (1.0%) in CAS 600 mg plus IMD 600 mg arm vs. 24
(3.2%) in placebo arm (P = 0.002)
• Single IV infusion of:
• 18 (1.3%) in CAS 1,200 mg plus IMD 1,200 mg arm vs.
• CAS 600 mg plus IMD 600 mg (n = 736) or 62 (4.6%) in placebo arm (P < 0.001)
placebo (n = 748)
• All-cause deaths:
• CAS 1,200 mg plus IMD 1,200 mg (n = 1,355) or
placebo (n = 1,341) • 1 (0.1%) in CAS 600 mg plus IMD 600 mg arm vs. 1
(0.1%) in placebo arm
Primary Endpoint:
• 1 (< 0.1%) in CAS 1,200 mg plus IMD 1,200 mg arm vs.
• ≥1 COVID-19-related hospitalization or death from 3 (0.2%) in placebo arm
any cause by Day 29

COMET-ICE: Double-Blind RCT of Sotrovimab in Nonhospitalized Patients With Mild to Moderate COVID-19 in Brazil, Canada, Peru, Spain, and the United
States4
• Aged ≥18 years • Median age 53 years; 20% aged ≥65 years; 54% women • Conducted before widespread circulation of
• ≥1 comorbidity or aged ≥55 years • 65% Hispanic/Latinx, 8% Black/African American the Omicron VOC
• Positive SARS-CoV-2 RT-PCR or antigen test result • 63% with obesity; 22% with DM; 17% with moderate to Interpretation:
• Symptom onset ≤5 days before enrollment severe asthma • Compared to placebo, SOT reduced the
Primary Outcome: incidence of all-cause hospitalizations
Key Exclusion Criteria: and deaths among patients with mild to
• Hospitalized or required supplemental oxygen • Hospitalizations or all-cause deaths by Day 29: 6 (1%) in moderate COVID-19.
SOT arm vs. 30 (6%) in placebo arm, including 2 deaths
• Severely immunocompromised (adjusted relative risk 0.21; 95% CI, 0.09–0.50; absolute
Interventions: difference -4.53%; 95% CI, -6.70% to -2.37%; P < 0.001)
• SOT 500 mg IV (n = 528)
Primary Endpoint:
• Hospitalization or death from any cause by Day 29
Key: BAM = bamlanivimab; bpm = beats per minute; BEB = bebtelovimab; CAS = casirivimab; DM = diabetes mellitus; ETE = etesevimab; IMD = imdevimab; IV =
intravenous; mAb = monoclonal antibody; PEP = post-exposure prophylaxis; PHVL = persistently high viral load; RCT = randomized controlled trial; RT-PCR = reverse
transcription polymerase chain reaction; SOT = sotrovimab; SpO2 = oxygen saturation; VL = viral load; VOC = variant of concern
References
1. Dougan M, Azizad M, Mocherla B, et al. A randomized, placebo-controlled clinical trial of bamlanivimab and etesevimab together in high-risk
ambulatory patients with COVID-19 and validation of the prognostic value of persistently high viral load. Clin Infect Dis. 2021;Published online ahead
of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34718468.
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for bebtelovimab. 2022. Available at:
3. Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV antibody combination and outcomes in outpatients with COVID-19. N Engl J Med.
4. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate
COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1236-1246. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35285853.

Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2 that
could help suppress viral replication.1 In August 2020, the Food and Drug Administration (FDA) issued
an Emergency Use Authorization (EUA) for COVID-19 convalescent plasma (CCP) for the treatment of
hospitalized patients with COVID-19. The EUA was revised in February 2021 to limit the authorization
to the use of high-titer CCP for the treatment of hospitalized patients with COVID-19 who are early
in their disease course or who have impaired humoral immunity.2 In December 2021, the EUA was
revised again to authorize the use of CCP only in outpatients or inpatients with COVID-19 who have
immunosuppressive disease or who are receiving immunosuppressive treatment. The testing criteria
used to identify CCP products that contain high levels of anti-SARS-CoV-2 antibodies (i.e., high-titer
products) was also revised.2
The use of CCP should be limited to high-titer products. Products that are not labeled “high titer” should
not be used.
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of CCP
that was collected prior to the emergence of the Omicron (B.1.1.529) variant for the treatment of
COVID-19 (AIII).
• The Panel recommends against the use of CCP for the treatment of COVID-19 in hospitalized,
immunocompetent patients (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer
CCP that was collected after the emergence of Omicron for the treatment of immunocompromised
patients and nonhospitalized, immunocompetent patients with COVID-19.
Rationale
Regarding the Use of COVID-19 Convalescent Plasma Collected Prior to the Emergence of
the Omicron Variant
The Omicron variant is the dominant SARS-CoV-2 variant currently circulating in the United States.
Although in vitro data suggest that the CCP collected from vaccinated and unvaccinated individuals who
have recovered from Omicron infection exhibits neutralizing activity against the Omicron variant,3-6 it
is not possible to extrapolate the potential clinical efficacy of CCP in the current clinical context. This is
due in part to the following factors:
• The current supply of CCP products in the United States was not generated from donors who had
recovered from Omicron infection.7
• Many CCP clinical trials were completed before the Omicron surge, and their results may not
inform the current clinical context.
• The current approaches to testing CCP titers do not account for potential differences in the
neutralizing activity of CCP products against currently circulating variants.
Furthermore, it is difficult to interpret the available data on the in vitro antiviral activity of CCP, since
the published studies use a variety of assays to characterize the neutralizing activity of CCP, and the

level of immunity to COVID-19 can vary across different donor populations.
For Hospitalized, Immunocompetent Patients

Under the revised EUA, the use of CCP is no longer authorized for hospitalized patients who do not
have immunosuppressive disease or who are not receiving immunosuppressive treatments.
Clinical data on the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients, including data from several randomized trials and the U.S. Expanded Access Program (EAP)
for CCP, are summarized in Table 5b.
The initial EUA for CCP for the treatment of hospitalized patients with COVID-19 was issued on the
basis of retrospective, indirect evaluations of efficacy generated from the CCP EAP, which allowed CCP
to be used regardless of titer. Several retrospective analyses of the EAP data have indicated that patients
who received high-titer CCP had a lower relative risk of death than patients who received low-titer
CCP.8,9 The Panel reviewed the EAP analyses and determined that the data were not sufficient to
establish the efficacy or safety of CCP due to potential confounding factors, the lack of randomization,
and the lack of an untreated control group.
Data from the initial randomized clinical trials that evaluated CCP, which were all underpowered, did
not demonstrate the product’s efficacy for the treatment of hospitalized patients with COVID-19.10-17
Subsequently, results from the 3 largest randomized clinical trials that evaluated CCP in hospitalized
patients—RECOVERY,18 CONCOR-1,19 and REMAP-CAP20—found no evidence of benefit for
high-titer CCP in hospitalized patients with COVID-19. All 3 were open-label trials that were stopped
early due to futility.
Although these trials and the EAP did not exclude patients with impaired humoral immunity, most
of the patients enrolled did not report a history of an immunocompromising condition or receipt of
chronic immunosuppressive therapy. After reviewing the collective results from these studies, the Panel
recommends against the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients (AI).
For Nonhospitalized, Immunocompetent Patients

CCP is not authorized for the treatment of nonhospitalized patients with COVID-19 who do not have
immunosuppressive disease or who are not receiving immunosuppressive treatment. Clinical data on
the use of CCP for the treatment of nonhospitalized, immunocompetent patients are summarized in
Table 5b. The data from well-designed clinical trials that evaluated the use of CCP for the treatment of
nonhospitalized patients with COVID-19 are conflicting. All of the following trials were conducted prior
to the emergence of Omicron.
Trials That Demonstrated Efficacy for COVID-19 Convalescent Plasma
• A moderately-sized, double-blind, placebo-controlled, randomized trial evaluated the use of
high-titer CCP in older, nonhospitalized adults with <72 hours of mild COVID-19 symptoms (n
= 160). The patients were aged ≥75 years or aged 65 to 74 years with ≥1 comorbidity. The trial
reported a reduction in the proportion of patients who developed severe respiratory disease within
14 days in the CCP arm (16% in the CCP arm vs. 31% in the placebo arm; relative risk 0.52; 95%
CI, 0.29–0.94; P = 0.03).9
• CSSC-004, a large (n = 1,181), double-blind, placebo-controlled trial that evaluated the use of
high-titer CCP for the treatment of adults with ≤8 days of COVID-19 symptoms, demonstrated a
reduction in the proportion of patients who experienced COVID-19-related hospitalization within

28 days in the CCP arm (2.9% in the CCP arm vs. 6.3% in the placebo arm; absolute risk reduction
of 3.4 percentage points; 95% CI, 1.0–5.8; P = 0.005). Eighty-two percent of the patients were
not vaccinated against COVID-19, and 53 of the 54 hospitalizations that were reported during the
study occurred in unvaccinated patients. No hospitalizations occurred in either arm among fully
vaccinated patients.21
Trials That Demonstrated No Benefit of COVID-19 Convalescent Plasma
• The SIREN-C3PO trial (n = 511) was a single-blind randomized trial that evaluated the use of
high-titer CCP for the treatment of nonhospitalized patients with ≤7 days of mild or moderate
COVID-19 symptoms and ≥1 risk factor for severe COVID-19. This study did not report a
reduction in the proportion of patients who experienced disease progression in the CCP arm (30%
in the CCP arm vs. 32% in the placebo arm; risk difference of 1.9 percentage points; 95% CrI, -6.0
to 9.8).22
• The CONV-ERT study (n = 376) was a double-blind, placebo-controlled randomized trial that
evaluated the use of high-titer, methylene blue-treated CCP for the treatment of nonhospitalized
patients aged ≥50 years with ≤7 days of mild or moderate COVID-19 symptoms. This study did
not report a reduction in the proportion of patients who were hospitalized or died in the CCP arm
(12% in the CCP arm vs. 11% in the placebo arm; relative risk 1.05; 95% CI, 0.78–1.41).23
Differences in patient populations, the placebo used (e.g., some studies used saline and some used non-
SARS-CoV-2 plasma), and CCP manufacturing and testing methods may have contributed to the disparate
outcomes of these clinical trials. Additional well-designed trials are necessary to establish evidence for a
consistent benefit of using CCP in nonhospitalized patients during the current phase of the pandemic.
The emergence of SARS-CoV-2 variants further complicates the assessment of any potential benefit of
CCP for this patient population. Most CCP products that are available in the United States are expected
to have no or very little neutralizing activity against the currently circulating SARS-CoV-2 variants
because they were collected from donors who had COVID-19 prior to the emergence of the Omicron
variant. The Panel recommends against using CCP that was collected prior to the emergence of the
Omicron variant for the treatment of COVID-19 (AIII).
Currently, nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing
to severe disease are eligible to receive several antiviral therapies with proven efficacy. See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for the Panel’s recommendations for this
patient population.
Hospitalized or Nonhospitalized Patients Who Are Immunocompromised

This section pertains to people who are moderately or severely immunocompromised.24 According to the
Centers for Disease Control and Prevention, individuals who qualify as having moderately or severely
immunocompromising conditions are those who:
• Are receiving active treatment for solid tumor and hematologic malignancies.
• Received a solid-organ transplant and are taking immunosuppressive therapy.
• Received chimeric antigen receptor T cell therapy or a hematopoietic stem cell transplant (within 2
years of transplantation or taking immunosuppression therapy).
• Have a moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich
syndrome).
• Have advanced or untreated HIV infection (defined as people with HIV and CD4 T lymphocyte
counts <200 cells/mm3, a history of an AIDS-defining illness without immune reconstitution, or

clinical manifestations of symptomatic HIV).
equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-
related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely
immunosuppressive, tumor-necrosis blockers, and other immunosuppressive or immunomodulatory
biologic agents (e.g., B cell-depleting agents).
Under the EUA issued on December 27, 2021, CCP is authorized for the treatment of COVID-19 in
outpatients or inpatients who have immunosuppressive disease or who are receiving immunosuppressive
treatment.
Although there are no definitive data to support using CCP in patients who are immunocompromised, there
is a physiologic rationale for the use of CCP in this patient population. People who are immunocompromised
are more likely to require hospitalization for breakthrough SARS-CoV-2 infection despite COVID-19
vaccination, become severely ill from COVID-19, and experience prolonged SARS-CoV-2 infection and
shedding.25-27 Although some of this vulnerability may be attributed to impaired cellular immune responses,
numerous studies indicate that people who are immunosuppressed are at risk of having reduced antibody
responses to SARS-CoV-2 infection and/or vaccination.28-30 Furthermore, the subgroup analyses from
several clinical trials suggest that anti-SARS-CoV-2 antibody products are more likely to be effective in
patients who are SARS-CoV-2 seronegative than in patients who are seropositive.31,32 Therefore, patients
who are immunocompromised could potentially benefit from receiving antibody-based therapies in
circumstances where patients without an immunocompromising condition might not.
There are limited clinical data to inform the use of CCP to treat COVID-19 in patients who are
immunocompromised. No randomized, adequately controlled trials evaluating CCP in immunocompromised
patients have been published to date. A prespecified subgroup analysis of 126 critically ill REMAP-CAP
participants with immunodeficiencies suggested that CCP might offer a potential benefit of improved
survival and/or more organ support-free days in this subgroup (OR 1.51; 95% CI, 0.80–2.92); however,
this finding was not statistically significant.20 Data from case reports, case series, and a retrospective case-
control study also suggest a potential benefit of CCP in patients with primary and secondary humoral
immunodeficiencies, including patients with hematologic malignancy, common variable immune deficiency,
or agammaglobulinemia, and those who have received a solid organ transplant.33-46
As noted above, the emergence of SARS-CoV-2 variants further complicates the assessment of any
potential benefit of CCP for patients who are immunocompromised. Studies have shown that prior
infection with the Beta (B.1.351) or Delta (B.1.617.2) variants affords little protection and has reduced
neutralizing antibody responses against the Omicron variant, raising doubts that CCP collected prior to
the emergence of Omicron will be effective.47-50 Thus, the Panel recommends against the use of CCP
collected prior to the emergence of the Omicron variant for the treatment of COVID-19 (AIII).
There is insufficient evidence for the Panel to recommend either for or against the use of high-titer
CCP that was collected after the emergence of Omicron for the treatment of COVID-19 in
immunocompromised patients and nonhospitalized, immunocompetent patients. Adequately
powered, well-designed, and well-conducted randomized clinical trials are needed to provide more
specific, evidence-based guidance on the role of CCP in the treatment COVID-19 in patients who are
immunocompromised.
The safety and efficacy of using CCP during pregnancy have not been evaluated in clinical trials, and
published data on its use in pregnant individuals with COVID-19 are limited to case reports.51 Pathogen-

specific immunoglobulins (Ig) are used clinically during pregnancy to prevent infection from varicella
zoster virus and rabies virus and have been used in clinical trials of congenital cytomegalovirus
infection.52,53 Pregnancy is not a reason to withhold CCP from a patient if it is otherwise indicated.
The safety and efficacy of CCP have not been systematically evaluated in pediatric patients. Published
literature on its use in children is limited to case reports and case series. A few clinical trials that are
evaluating the use of CCP in children are ongoing. The use of CCP may be considered on a case-by-case
basis for hospitalized children who are immunocompromised and meet the EUA criteria for its use. CCP
is not authorized by the FDA for use in immunocompetent patients.
As an alternative to CCP, several antiviral therapies are available for the treatment of children with
COVID-19 who are at high risk of progressing to severe disease. The use of these products in children
may be considered on a case-by-case basis. See Special Considerations in Children for more information.
Adverse Effects
The available data suggest that serious adverse reactions following the administration of CCP are
infrequent and consistent with the risks associated with plasma infusions for other indications. These
risks include transfusion-transmitted infections (e.g., HIV, hepatitis B, hepatitis C), allergic reactions,
anaphylactic reactions, febrile nonhemolytic reactions, transfusion-related acute lung injury, transfusion-
associated circulatory overload, and hemolytic reactions. Hypothermia, metabolic complications, and
post-transfusion purpura have also been described.2,18,54
Additional risks of CCP transfusion include a theoretical risk of antibody-dependent enhancement of
SARS-CoV-2 infection and a theoretical risk of long-term immunosuppression. In the CONCOR-1 trial,
higher levels of full transmembrane spike IgG were associated with worse outcomes, suggesting that the
use of CCP with nonfunctional anti-SARS-CoV-2 antibodies may be harmful.19 A subgroup analysis in
the REMAP-CAP trial showed potential harm in patients who received CCP transfusions more than 7
days after being hospitalized.20
When considering the use of CCP in patients with a history of severe allergic or anaphylactic transfusion
reactions, consultation with a transfusion medicine specialist is advised.
Clinical Trials
Several randomized clinical trials that are evaluating the use of CCP for the treatment of COVID-19 are
underway. Please see ClinicalTrials.gov for the latest information.
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34. Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted
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Table 5b. COVID-19 Convalescent Plasma: Selected Clinical Data
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for CCP.
The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

REMAP-CAP: Multinational, Open-Label RCT of High-Titer CCP in Hospitalized Patients With Critical COVID-191
• Admitted to ICU while receiving respiratory support • Mean age 61 years; 68% men • Open-label study
(HFNC oxygen, NIV, MV, ECMO) and/or vasopressor • 32% on MV • Not all patients in CCP arm received
or inotrope support CCP (86% received CCP as per
• 29% were SARS-CoV-2 antibody negative at baseline
Key Exclusion Criteria: protocol and 95% received some
• 94% received corticosteroids, 45% received RDV, 39% CCP).
• CCP contraindicated received IL-6 inhibitors
• Death imminent Interpretation:
Primary Outcome:
• There was no benefit of CCP in
Interventions: • No difference between arms in median number of organ hospitalized patients with critical
• High-titer CCP (550 mL +/- 150 mL) within 48 hours support-free days by Day 21: 0 days in CCP arm vs. 3 days in COVID-19.
of randomization (n = 1,084) usual care arm (OR 0.97; 95% CrI, 0.82–1.14)
• Usual care (n = 916) Secondary Outcomes:
Primary Endpoint: • No difference between arms in:
• Organ support-free days by Day 21 • In-hospital mortality: 37% in CCP arm vs. 38% in usual care
arm
• Mortality by Day 28 or Day 90
• Median number of respiratory support-free days: 0 days in
• Mortality by Day 28 and Day 90 CCP arm vs. 2 days in usual care arm
• Respiratory support-free days • Median ICU LOS: 21 days in CCP arm vs. 17 days in usual
• ICU LOS care arm

CONCOR-1: Multinational, Open-Label RCT of CCP for Hospitalized Patients With COVID-19 in Canada, the United States, and Brazil2
• Receipt of supplemental oxygen • Mean age 68 years; 59% men • Open-label study
• Within 12 days of respiratory symptom onset • 84% receiving systemic corticosteroids at enrollment • Trial stopped at 78% of planned
enrollment after meeting prespecified
Key Exclusion Criterion: Primary Outcome:
futility criteria for early termination.
• Imminent or current intubation • Intubation or death by Day 30: 32% in CCP arm vs. 28%
in SOC arm (relative risk 1.16; 95% CI, 0.94–1.43, P = Interpretation:
Interventions:
0.18) • There was no benefit of CCP in oxygen-
• 1–2 units CCP (approximately 500 mL) from 1–2 dependent, hospitalized COVID-19
donors (n = 625) Secondary Outcomes:
patients within 12 days of symptom
• SOC (n = 313) • By Day 30, no difference between arms in: onset.
• Time to intubation or death
Primary Endpoint:
• Mortality: 23% in CCP arm vs. 21% in SOC arm
• Intubation or death by Day 30
• Mean ICU LOS: 4.3 days in CCP arm vs. 3.7 days in SOC
Key Secondary Endpoints: arm
• Time to intubation or death by Day 30 • Need for renal dialysis: 1.6% in CCP arm vs. 2.0% in
• Mortality by Day 30 SOC arm
• ICU LOS by Day 30 • Frequency of SAEs by Day 30: 33% in CCP arm vs. 26%
• Need for renal dialysis by Day 30 in SOC arm
• Frequency of SAEs by Day 30
RECOVERY: Open-Label RCT of High-Titer CCP in Hospitalized Patients in the United Kingdom3
• Clinically suspected or laboratory-confirmed SARS- • Mean age 64 years; 64% men • Open-label study
CoV-2 infection • 5% on MV Interpretation:
Key Exclusion Criterion: • 92% received corticosteroids • There was no benefit of CCP in
• CCP contraindicated Primary Outcomes: hospitalized patients with COVID-19.
Interventions: • No difference between arms in:
• Approximately 275 mL per unit of CCP with IgG against • Mortality: 24% in each arm
SARS-CoV-2 spike protein, with sample to cutoff ratio • Mortality in patients without detectable SARS-CoV-2
≥6.0. Administered as 2 units of high-titer CCP (first antibodies: 32% in CCP arm vs. 34% in usual care arm
unit ASAP after randomization, second unit ≥12 hours
later the next day) (n = 5,795) Secondary Outcomes:
• Usual care (n = 5,763) • No difference between arms in:

RECOVERY: Open-Label RCT of High-Titer CCP in Hospitalized Patients in the United Kingdom3, continued
Primary Endpoint: • Proportion discharged by Day 28: 66% in both arms
• All-cause mortality by Day 28 • Proportion who progressed to MV or death by Day 28:
29% in CCP arm vs. 29% in usual care arm
• Time to hospital discharge by Day 28
• Among patients not receiving MV, progression to MV or
death by Day 28
CSSC-004: RCT of Early Treatment With High-Titer CCP in Outpatients With COVID-19 in the United States4
• COVID-19 symptoms for <8 days • Median age 44 years; 7% aged ≥65 years; 57% women; • Patients were at relatively low risk for
79% White disease progression.
• 8% with type 2 DM; 2% with CVD; 38% with BMI ≥30 Interpretation:
• Prior or planned COVID-19–related hospitalization
• 82% were unvaccinated • This trial demonstrated a benefit of CCP
• Receipt of anti-SARS-CoV-2 mAbs
• Median time from symptom onset to transfusion was 6 in unvaccinated outpatients with <8 days
Interventions: days of COVID-19 symptoms.
• Approximately 250 mL of CCP with SARS-CoV-2 spike-
Primary Outcomes:
RBD IgG titer ≥1:320 (n = 592)
• COVID-19–related hospitalization within 28 days: 2.9% in
• Non-SARS-CoV-2 plasma (n = 589)
CCP arm vs. 6.3% in control arm (absolute risk reduction
Primary Endpoint: of 3.4 percentage points; 95% CI, 1.0–5.8; P = 0.005)
• COVID-19–related hospitalization or all-cause death • 53 of 54 hospitalizations occurred in unvaccinated
within 28 days individuals. None occurred in fully vaccinated individuals.
• All-cause deaths within 28 days: 0 in CCP arm vs. 3 in
control arm

CONV-ERT: RCT of High-Titer, Methylene Blue-Treated CCP as an Early Treatment for Outpatients With COVID-19 in Spain5
• Aged ≥50 years • Mean age 56 years; 54% men • Trial was underpowered because it
• Mild or moderate COVID-19 symptoms for ≤7 days • 75% with ≥1 risk factor for COVID-19 progression was terminated early due to rising
vaccination rates among the eligible
Key Exclusion Criteria: • 97% with mild COVID-19 patient population.
• Severe COVID-19 symptoms or requirement for • Median 4.4 days of symptoms prior to enrollment • Methylene blue, which was used for
hospitalization for any reason • Among the 369 patients for whom baseline serologic pathogen inactivation in donor plasma,
• Previous SARS-CoV-2 infection testing was available, 88% were negative for both IgG could have potentially impaired Fc-
anti-SARS-CoV-2 spike and IgM anti-SARS-CoV-2 S1- region functionality of immunoglobulins
• Receipt of >1 COVID-19 vaccination
RBD and negatively impacted product efficacy
Interventions: and blinding.
Primary Outcomes:
• 250–300 mL of high-titer, methylene blue-treated CCP
• Hospitalization within 28 days: 12% in CCP arm vs. 11% Interpretation:
(n = 188)
in placebo arm (relative risk 1.05; 95% CrI, 0.78–1.41) • This trial did not demonstrate a benefit
• 0.9% saline (n = 188)
• Mean change in SARS-CoV-2 VL: -2.41 log10 copies/mL in of CCP in unvaccinated outpatients with
Primary Endpoints: CCP arm vs. -2.32 log10 copies/mL in placebo arm <7 days of COVID-19 symptoms.
• Hospitalization within 28 days Key Secondary Outcomes:
• Mean change in SARS-CoV-2 VL from baseline to Day 7 • Death: 0 in CCP arm vs. 2 in placebo arm (relative risk
Key Secondary Endpoints: 0.20; 95% CI 0.01–4.14)
• Death by Day 60 • No difference between arms in median time to symptom
resolution: 12.0 days for both arms (HR 1.05; 95% CI,
• Time to complete symptom resolution
0.85–1.30)
Double-Blind RCT of Early High-Titer CCP Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina6
• Aged ≥75 years or aged 65–74 years with ≥1 coexisting • Mean age 77 years; 38% men • Small sample size
condition • Most with comorbidities • Early termination because number of
• Mild COVID-19 symptoms for <72 hours COVID-19 cases decreased
Primary Outcome:
Key Exclusion Criterion: • Severe respiratory disease by Day 15: 16% in CCP arm Interpretation:
• Severe respiratory disease vs. 31% in placebo arm (relative risk 0.52; 95% CI, • This trial demonstrated a benefit of CCP
0.29–0.94; P = 0.03) in older adult outpatients with <72 hours
Interventions:
of mild COVID-19 symptoms.
• 250 mL of CCP with IgG against SARS-CoV-2 spike
protein >1:1,000 (n = 80)
• Saline (n = 80)

Double-Blind RCT of Early High-Titer CCP Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina6
Primary Endpoint:
• Severe respiratory disease, defined as respiratory rate
≥30 breaths/min and/or SpO2 <93% on room air by Day
15
SIREN-C3PO: Multicenter, Single-Blind RCT of High-Titer CCP in the United States7
• ED patient with ≤7 days of symptoms • Median age 54 years; 46% men • Imbalance of patients who required
• PCR-confirmed SARS-CoV-2 infection • More patients with immunosuppression in CCP arm than hospital admission during the index visit
in placebo arm (13% vs. 7%) included in the primary analysis
• Aged ≥50 years or aged ≥18 years with ≥1 risk factor
for disease progression • More patients with ≥3 risk factors in CCP arm than in • Slightly more patients with multiple risk
placebo arm (55% vs. 48%) factors, including immunosuppression,
Key Exclusion Criterion: in CCP arm
• Need for supplemental oxygen Primary Outcomes:
Interpretation:
• No difference between arms in proportion with disease
Interventions: • The use of high-titer CCP within 1 week
progression: 30% in CCP arm vs. 32% in placebo arm
• 250 mL high-titer CCP (median titer 1:641) (n = 257) (risk difference 1.9%; 95% CrI, -6.0% to 9.8%) of symptom onset did not prevent
• Saline (n = 254) disease progression in outpatients with
• 25 patients (19 in CCP arm and 6 in placebo arm) COVID-19 who were at high risk of
Primary Endpoint: required hospitalization during the index visit. In a severe disease.
post hoc analysis that excluded these patients, disease
• Disease progression, defined as hospital admission,
progression occurred in 24% in CCP arm vs. 30% in
death, or seeking emergency or urgent care within 15
placebo arm (risk difference 5.8%; 95% CrI, -1.9% to
days of randomization
13.6%).
Secondary Outcomes:
• Severity of illness, as measured by an OS
• All-cause mortality within 30 days: 5 (1.9%) in CCP arm
• All-cause mortality within 30 days vs. 1 (0.4%) in placebo arm
• Hospital-free days over 30 days • No difference between arms in illness severity or mean
number of hospital-free days

Retrospective Evaluation of CCP Antibody Levels and the Risk of Death From COVID-19 in the United States8
• Severe or life-threatening COVID-19 • 31% aged ≥70 years; 61% men; 48% White, 37% • Lack of untreated control arm
• Patients for whom samples of transfused CCP were Hispanic/Latinx
Interpretation:
available for retrospective analysis of antibody titer • 61% in ICU; 33% on MV
• The study data are not sufficient to
Interventions: • 51% received corticosteroids, 31% received RDV establish the efficacy or safety of
• High-titer CCP (n = 515), medium-titer CCP (n = 2,006), Primary Outcomes: COVID-19 CCP.
or low-titer CCP (n = 561), characterized retrospectively • Mortality at 30 days after transfusion: 22% in high-titer
Primary Endpoint: CCP arm vs. 27% in medium-titer CCP arm vs. 30% in
low-titer CCP arm
• Mortality at 30 days after CCP transfusion
• High-titer CCP arm had a lower risk of death than low-
titer CCP arm (relative risk 0.75; 95% CI, 0.61–0.93)
• Mortality was lower among patients who were not
receiving MV before CCP transfusion (relative risk 0.66;
95% CI, 0.48–0.91)
• Among patients who were on MV before CCP transfusion,
there was no difference in mortality between high-titer
and low-titer arms (relative risk 1.02; 95% CI, 0.78–1.32)
Key: ASAP = as soon as possible; BMI = body mass index; CCP = COVID-19 convalescent plasma; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO =
extracorporeal membrane oxygenation; ED = emergency department; Fc = fragment crystallizable; HFNC = high-flow nasal cannula; ICU = intensive care unit; Ig =
immunoglobulin; IL = interleukin; LOS = length of stay; mAb = monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale;
the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; RBD = receptor binding domain; RCT = randomized controlled trial; RDV =
remdesivir; SAE = serious adverse event; SOC = standard of care; SpO2 = oxygen saturation; VL = viral load
References
1. Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, et al. Effect of convalescent plasma on organ support-free days in
critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2021;326(17):1690-1702. Available at:
2. Begin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med.
3. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled,
open-label, platform trial. Lancet. 2021;397(10289):2049-2059. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34000257.
4. Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for COVID-19 with convalescent plasma. N Engl J Med. 2022;Published online

ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35353960.
5. Alemany A, Millat-Martinez P, Corbacho-Monne M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients
with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med. 2022;10(3):278-288. Available at:
6. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med.
7. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with COVID-19. N Engl J Med.
8. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med.

Immunoglobulins: SARS-CoV-2 Specific
Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel to recommend
either for or against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
immunoglobulins for the treatment of COVID-19.
Rationale
Currently, there are no clinical data on the use of SARS-CoV-2 immunoglobulins. Trials evaluating
SARS-CoV-2 immunoglobulins are in development but not yet active and enrolling participants.
Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19
Concentrated antibody preparations derived from pooled plasma collected from individuals who
have recovered from COVID-19 can be manufactured as SARS-CoV-2 immunoglobulin, which
could potentially suppress the virus and modify the inflammatory response. The use of virus-specific
immunoglobulins for other viral infections (e.g., cytomegalovirus [CMV] immunoglobulin for the
prevention of post-transplant CMV infection and varicella zoster immunoglobulin for postexposure
prophylaxis of varicella in individuals at high-risk) has proven to be safe and effective; however, there
are currently no clinical data on the use of such products for COVID-19. Potential risks may include
transfusion reactions. Theoretical risks may include antibody-dependent enhancement of infection.
Clinical Data
There are no clinical data on the use of SARS-CoV-2 immunoglobulins for the treatment of COVID-19.
Similarly, there are no clinical data on use of specific immunoglobulin or hyperimmunoglobulin
products in patients with severe acute respiratory syndrome (SARS) or Middle East respiratory
syndrome (MERS).
Pathogen-specific immunoglobulins are used clinically during pregnancy to prevent varicella zoster
virus (VZV) and rabies and have also been used in clinical trials of therapies for congenital CMV
infection.
Hyperimmunoglobulin has been used to treat several viral infections in children, including VZV,
respiratory syncytial virus, and CMV; efficacy data on their use for other respiratory viruses is limited.

Table 5c. Characteristics of SARS-CoV-2 Antibody-Based Products
• The information in this table is based on data from investigational trials evaluating these products for the treatment or prevention of
COVID-19. The table includes dose recommendations from the FDA EUAs for patients who meet specified criteria.
• There are limited or no data on dose modifications for patients with organ failure or those who require extracorporeal devices. Please refer
to product labels, when available.
• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the
treatment or prevention of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional
safety monitoring.
• The potential additive, antagonistic, or synergistic effects and the safety of using combination therapies for the treatment or prevention of
COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.
• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the Anti-SARS-CoV-2 Monoclonal Antibodies,
Therapeutic Management of Nonhospitalized Adults With COVID-19, and Prevention of SARS-CoV-2 Infection sections of the Guidelines.
Drug-Drug Interaction Comments and Links to Clinical

Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment and PEP of COVID-19 under FDA EUA, but distribution has paused because the Omicron VOC has markedly reduced in vitro
susceptibility to BAM plus ETE.
Dose Recommended in FDA • Nausea • Only for administration • Drug-drug interactions Availability:
EUA for Treatment and PEP of • Dizziness in health care settings are unlikely between •D
istribution of BAM plus ETE has
COVID-19 in Adults and Pediatric by qualified health care BAM plus ETE and paused because the Omicron VOC
Patients Weighing ≥40 kg: • Pruritis providers who have medications that are has markedly reduced in vitro
• BAM 700 mg plus ETE 1,400 mg • Hypersensitivity, including immediate access to renally excreted or that susceptibility to BAM plus ETE,
as a single IV infusion anaphylaxis and infusion- emergency medical are CYP substrates, and this regimen is not expected to
related reactions services and medications inhibitors, or inducers. provide clinical benefit.
Doses Recommended in FDA EUA • These AEs were observed to treat severe infusion
for Treatment and PEP of COVID-19 in multiple trials in which reactions. •H
HS Public Health Emergency
in Neonates, Infants, Children, and participants received either updates on the distribution of BAM
• Monitor during IV infusion plus ETE are available.
Adolescents Weighing <40 kg: the authorized doses of BAM and for ≥1 hour after
• 1 –12 kg: BAM 12 mg/kg plus ETE

Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies), continued
24 mg/kg as a single IV infusion and ETE or higher doses of infusion is completed. • A list of clinical trials is available:
• > 12 kg to 20 kg: BAM 175 mg plus each drug. Bamlanivimab Plus Etesevimab
ETE 350 mg as a single IV infusion
• > 20 kg to <40 kg: BAM 350 mg
plus ETE 700 mg as a single IV
infusion
Bebtelovimab (Anti-SARS-CoV-2 Monoclonal Antibody)
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in FDA EUA • Nausea • Only for administration • Drug-drug Availability:
for Treatment of COVID-19 in Adults • Vomiting in health care settings interactions are • Under the FDA EUA, BEB is
and Pediatric Patients Aged ≥12 by qualified health care unlikely between BEB available for the treatment of
Years and Weighing ≥40 kg: • Pruritis providers who have and medications that high-risk outpatients with mild
• BEB 175 mg as an IV injection over • Rash immediate access to are renally excreted to moderate COVID-19.1 See
at least 30 seconds • Hypersensitivity, including emergency medical services or that are CYP Anti-SARS-CoV-2 Monoclonal
anaphylaxis and infusion- and medications to treat substrates, inhibitors, Antibodies for a list of high-risk
related reactions severe infusion reactions. or inducers. conditions.
• Monitor during IV injection • A list of clinical trials is available:
and for ≥1 hour after Bebtelovimab
injection is completed.
Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment and PEP of COVID-19 under FDA EUA, but distribution has paused because the Omicron VOC has markedly reduced in vitro
susceptibility to CAS plus IMD.
Dose Recommended in FDA EUA for • Hypersensitivity, including • Only for administration • Drug-drug Availability:
Treatment and PEP of COVID-19 in anaphylaxis and infusion- in health care settings interactions are • Distribution of CAS plus IMD
Adults and Pediatric Patients Aged related reactions by qualified health care unlikely between has paused because the Omicron
≥12 Years and Weighing ≥40 kg: • These AEs were observed providers who have CAS plus IMD and VOC has markedly reduced in
in multiple trials in which immediate access to medications that vitro susceptibility to CAS plus
• CAS 600 mg plus IMD 600 mg as a
participants received CAS emergency medical services are renally excreted IMD, and this regimen is not
single IV infusion over 1 hour
600 mg plus IMD 600 mg or and medications to treat or that are CYP expected to provide clinical
• IV infusion is the preferred route higher doses of each drug. severe infusion reactions. substrates, inhibitors, benefit.
of administration. However, when • Monitor during IV infusion or inducers.
IV infusion is not feasible or would • Injection site reactions, or SUBQ injections and for
• HHS Public Health Emergency
delay treatment, CAS 600 mg plus including ecchymosis and updates on the distribution of
erythema, in clinical trial ≥1 hour after infusion or CAS plus IMD are available.
IMD 600 mg can be administered injections are completed.
as 4 SUBQ injections (2.5 mL per participants who received CAS • A list of clinical trials is available:
injection) at 4 different sites. See plus IMD as SUBQ injections Casirivimab Plus Imdevimab

Potential Trials
Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies), continued
the FDA EUA for detailed
information.
Dose Recommended in FDA
EUA for PEP for Individuals With
Ongoing Exposure to SARS-CoV-2:
• After initial dose, repeat dosing
of CAS 300 mg plus IMD 300 mg
by SUBQ injections or IV infusion
every 4 weeks for duration of
ongoing exposure.
Sotrovimab (Anti-SARS-CoV-2 Monoclonal Antibody)
Authorized for the treatment of COVID-19 under FDA EUA, but distribution has paused in the United States because the Omicron BA.2 subvariant has markedly
reduced in vitro susceptibility to SOT.
Dose Recommended in FDA EUA • Rash • Only for administration • Drug-drug interactions Availability:
for Treatment of COVID-19 in • Diarrhea in health care settings are unlikely between •D istribution of SOT has paused
Adults and Pediatric Patients Aged by qualified health care SOT and medications because the Omicron BA.2
≥12 Years and Weighing ≥40 kg: • Hypersensitivity, providers who have that are renally excreted subvariant has markedly reduced
including anaphylaxis immediate access to or that are CYP
• SOT 500 mg as an IV infusion and infusion-related susceptibility to SOT, and SOT is not
over 15 minutes for 50 mL bag or emergency medical services substrates, inhibitors, expected to provide clinical benefit.
reactions and medications to treat or inducers.
over 30 minutes for 100 mL bag •H HS Public Health Emergency
severe infusion reactions.
updates on the distribution of SOT
• Monitor during IV infusion are available.
and for ≥1 hour after
infusion is completed. • A list of clinical trials is available:
Sotrovimab
Tixagevimab Plus Cilgavimab (Evusheld) (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for PrEP of COVID-19 under FDA EUA.
Doses Recommended in FDA EUA • Hypersensitivity, • Use with caution • If a person has received • Under the FDA EUA, TIX plus CIL
for PrEP of COVID-19 in Adults and including anaphylaxis in individuals with a COVID-19 vaccine, for PrEP of COVID-19 is available
Pediatric Patients Aged ≥12 Years and injection-related thrombocytopenia or any TIX plus CIL should be for certain patients at high risk
and Weighing ≥40 kg: reactions coagulation disorder. administered ≥2 weeks of infection. See Prevention of
• TIX 300 mg plus CIL 300 mg as 2 • In 1 clinical trial, cardiac • Monitor for ≥1 hour after after vaccination. SARS-CoV-2 Infection for more
consecutive 3 mL IM injections events were reported in injection. • Drug-drug interactions information.2
participants with cardiac are unlikely between

Potential Trials
Tixagevimab Plus Cilgavimab (Evusheld) (Anti-SARS-CoV-2 Monoclonal Antibody), continued
For patients who previously risk factors (0.6% in TIX T IX plus CIL and • A list of clinical trials is available:
received a dose of TIX 150 mg plus plus CIL arm vs. 0.2% in medications that are Tixagevimab Plus Cilgavimab
CIL 150 mg, administer a second placebo arm). renally excreted or that
dose per the following criteria as are CYP substrates,
soon as possible: inhibitors, or inducers.
• If the initial dose was ≤3 months
ago, the second dose should be
TIX 150 mg plus CIL 150 mg.
• If the initial dose was >3 months
ago, the second dose should be
TIX 300 mg plus CIL 300 mg.
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in FDA EUA • TRALI • Before administering • Drug products should • The decision to use COVID-19 CP
for Treatment of COVID-19: • TACO CP to patients with not be added to the for the treatment of COVID-19 in
• Per the EUA, consider starting a history of severe IV infusion line for the patients aged <18 years should
• Allergic reactions allergic or anaphylactic blood product. be based on an individualized
clinical dosing with 1 high-titer
COVID-19 CP unit (about 200 • A
naphylactic reactions transfusion reactions, assessment of risk and benefit.4
mL), with administration of • Febrile nonhemolytic the Panel recommends • In patients with impaired cardiac
additional CP units based on the reactions consulting a transfusion function and heart failure, it may be
prescribing provider’s medical medicine specialist who necessary to reduce the CP volume
• Hemolytic reactions
judgment and the patient’s clinical is associated with the or decrease the transfusion rate.
• Hypothermia hospital blood bank.
response.
• Metabolic complications Availability:
• Monitor for transfusion-
• Transfusion-transmitted related reactions. • Under the FDA EUA, high-
infections 3 titer COVID-19 CP is available
• Monitor vital signs at
for hospitalized patients with
• Thrombotic events baseline and during and
COVID-19.4 See Convalescent
• Theoretical risk of antibody- after transfusion.
Plasma.
mediated enhancement of • A list of clinical trials is available:
infection and suppressed COVID-19 Convalescent Plasma
long-term immunity

Potential Trials
SARS-CoV-2-Specific Immunoglobulin
Dose in Clinical Trials for • TRALI • Monitor for transfusion- • Drug products should • A list of clinical trials is available:
Treatment of COVID-19: • TACO related reactions. not be added to the SARS-CoV-2 Immunoglobulin
• Dose varies by clinical trial. • Monitor vital signs at IV infusion line for the
• Allergic reactions blood product.
baseline and during and
• Antibody-mediated after transfusion.
enhancement of infection
• RBC alloimmunization
• Transfusion-transmitted
infections3
Key: AE = adverse event; BAM = bamlanivimab; BEB = bebetelovimab; CAS = casirivimab; CIL = cilgavimab; CP = convalescent plasma; CYP = cytochrome P450; ETE
= etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; HHS = U.S. Department of Health and Human Services; IM = intramuscular;
IMD = imdevimab; IV = intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PEP = post-exposure prophylaxis; PrEP = pre-exposure prophylaxis; RBC
= red blood cell; SOT = sotrovimab; SUBQ = subcutaneous; TACO = transfusion-associated circulatory overload; TIX = tixagevimab; TRALI = transfusion-related acute
lung injury; VOC = variant of concern
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for bebtelovimab. 2022. Available at:
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld (tixagevimab co-packaged with
cilgavimab). 2022. Available at: https://www.fda.gov/media/154701/download.
3. Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus. 2016;14(2):152-157. Available
4. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of COVID-19 convalescent plasma for
treatment of coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/141478/download.

Cell-Based Therapy Under Evaluation for the
Treatment of COVID-19
Mesenchymal Stem Cells

Mesenchymal stem cells are investigational products that have been studied extensively for broad
clinical applications in regenerative medicine1 and for their immunomodulatory properties.2 It is
hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell-
mediated inflammatory response induced by SARS-CoV-2.
Recommendation
• The COVID-19 Treatment Guidelines Panel recommends against the use of mesenchymal stem
cells for the treatment of COVID-19, except in a clinical trial (AIIb).
Rationale for Recommendation

No mesenchymal stem cells products are approved by the Food and Drug Administration (FDA) for the
treatment of COVID-19. There are limited data to date to assess the role of mesenchymal stem cells for
the treatment of COVID-19.
The FDA has recently issued several warnings about patients being vulnerable to stem cell treatments
that are illegal and potentially harmful.3 Several umbilical cord blood-derived products are currently
licensed by the FDA for indications such as the treatment of cancer (e.g., stem cell transplant) or rare
genetic diseases, and as scaffolding for cartilage defects and wound beds. None of these products are
approved for the treatment of COVID-19 or any other viral disease.4 In the United States, mesenchymal
stem cells should not be used for the treatment of COVID-19 outside of an FDA-approved clinical trial,
expanded access program, or an Emergency Investigational New Drug application (AIIb).
Rationale for Use in COVID-19

Mesenchymal stem cells are multipotent adult stem cells that are present in most human tissues, including
the umbilical cord. Mesenchymal stem cells can self-renew by dividing and can differentiate into multiple
types of tissues (including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others), which has led
to a robust clinical research agenda in regenerative medicine. It is hypothesized that mesenchymal stem
cells could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by
SARS-CoV-2. Furthermore, because they lack the angiotensin-converting enzyme 2 (ACE2) receptor that
SARS-CoV-2 uses for viral entry into cells, mesenchymal stem cells are resistant to infection.5,6
Clinical Data
Data supporting the use of mesenchymal stem cells in patients who have viral infections, including
SARS-CoV-2 infection, are limited to case reports and small, open-label studies.
Clinical Data for COVID-19

A pilot study of intravenous mesenchymal stem cell transplantation in China enrolled 10 patients with
confirmed COVID-19 categorized according to the National Health Commission of China criteria as
critical, severe, or common type. Seven patients (one with critical illness, four with severe illness, and
two with common-type illness) received mesenchymal stem cells; three patients with severe illness

received placebo. All seven patients who received mesenchymal stem cells recovered. Among the
three severely ill placebo-treated patients, one died, one developed acute respiratory distress syndrome
(ARDS), and one remained stable with severe disease.7
A small clinical trial evaluated human umbilical cord mesenchymal stem cell (hUC-MSC) infusion in
patients with severe COVID-19 who had not responded to standard of care therapies after 7 to 10 days
of treatment. The standard of care therapies included supplemental oxygen, umifenovir/oseltamivir,
antibiotics if indicated, and glucocorticoids. The study was intended as a randomized controlled trial;
however, due to the lack of sufficient hUC-MSCs, it was not possible to randomize the participants as
originally planned. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC
infusion and 29 received standard of care therapies only. The study arms were well balanced with regard
to demographic characteristics, laboratory test results, and disease severity. All 12 participants who
received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to
home. Four patients who received only standard of care therapies progressed to critical illness requiring
mechanical ventilation; three of these patients died. These results are not statistically significant, and
interpretation of the findings is limited by the study’s lack of randomization and small sample size.8
A double-blind randomized controlled trial investigated the safety and efficacy of hUC-MSC infusions
in patients with COVID-19 ARDS. Twenty-four patients were randomized to receive either two
infusions of hUC-MSC (prepared at a single site) or placebo on Day 0 and Day 3. The primary endpoints
were occurrence of prespecified infusion-associated adverse events within 6 hours of each hUC-MSC
infusion; cardiac arrest or death within 24 hours after an infusion; and the incidence of adverse events.
Secondary endpoints included survival at 31 days after hUC-MSC infusion and time to recovery.9
There were no differences between the arms in the primary safety analysis; however, more deaths
occurred in the placebo arm (7 deaths) than in the hUC-MSC arm (2 deaths) by Day 31. Data for
one participant in the hUC-MSC arm who died due to a failed intubation was censored from the
analysis. Time to recovery was shorter in the hUC-MSC arm than in the placebo arm (HR 0.29; 95%
CI, 0.09–0.95). Interpretation of these results is limited by the small sample size and a change in an
eligibility criterion from enrolling only individuals on invasive mechanical ventilation to including those
receiving high-flow oxygen or on noninvasive ventilation.
Clinical Data for Other Viral Infections

In an open-label study of mesenchymal stem cells for the treatment of H7N9 influenza in China, 17
patients received mesenchymal stem cell treatment plus standard of care, and 44 patients received
standard of care only. Three patients (17.6%) in the mesenchymal stem cell arm died versus 24
patients (54.5%) in the standard of care arm. The 5-year follow-up was limited to five patients in the
mesenchymal stem cell arm. No safety concerns were identified.10
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials evaluating mesenchymal stem cells for the treatment of
COVID-19, COVID-19-related ARDS, and COVID-19-associated multisystem inflammatory syndrome
in children (MIS-C).
Adverse Effects
Risks associated with mesenchymal stem cell transfusion appear to be uncommon. The potential risks
include the potential for mesenchymal stem cells to multiply or change into inappropriate cell types,
product contamination, growth of tumors, infections, thrombus formation, and administration site
reactions.11

There are insufficient data to assess the risk of using mesenchymal stem cell therapy during pregnancy.
There are insufficient data to assess the efficacy and safety of using mesenchymal stem cell therapy in
children.
References
1. Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted
characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med.
2. Li N,Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci.
3. Food and Drug Administration. FDA warns about stem cell therapies. 2019. Available at: https://www.fda.gov/
consumers/consumer-updates/fda-warns-about-stem-cell-therapies. Accessed January 26, 2021.
4. Food and Drug Administration. Approved cellular and gene therapy products. 2019. Available at: https://
www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-
products. Accessed January 26, 2021.
5. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S,Drela K. Challenges and controversies in
human mesenchymal stem cell therapy. Stem Cells Int. 2019;2019:9628536. Available at:
6. Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19)-induced
pneumonia. Aging Dis. 2020;11(2):462-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32257554.
7. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of
patients with COVID-19 pneumonia. Aging Dis. 2020;11(2):216-228. Available at:
8. Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells.
Stem Cell Res Ther. 2020;11(1):361. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32811531.
9. Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute
respiratory distress syndrome: A double-blind, Phase 1/2a, randomized controlled trial. Stem Cells Transl Med.
10. Chen J, Hu C, Chen L, et al. Clinical study of mesenchymal stem cell treating acute respiratory distress
syndrome induced by epidemic Influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering
(Beijing). 2020;6(10):1153-1161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32292627.
11. Centers for Disease Control and Prevention. Stem cell and exosome products. 2019. Available at:
https://www.cdc.gov/hai/outbreaks/stem-cell-products.html. Accessed January 26, 2021.

Immunomodulators Under Evaluation for the
Treatment of COVID-19
The hyperactive inflammatory response to SARS-CoV-2 infection plays a central role in the pathogenesis of COVID-19.
See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the
Panel) recommendations on the use of the following immunomodulators for hospitalized patients according to their
disease severity:
• Corticosteroids: dexamethasone
• Interleukin-6 inhibitors: tocilizumab (or sarilumab)
• Janus kinase (JAK) inhibitors: baricitinib (or tofacitinib)
There is insufficient evidence for the Panel to recommend either for or against the use of the following
immunomodulators for the treatment of COVID-19:
• Anakinra
• Fluvoxamine
• Granulocyte-macrophage colony-stimulating factor inhibitors for hospitalized patients
• Inhaled corticosteroids
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a
clinical trial:
• Baricitinib plus tocilizumab (AIII)
• Canakinumab (BIIa)
• Colchicine for nonhospitalized patients (BIIa)
• Intravenous immunoglobulin (IVIG) (non-SARS-CoV-2-specific) for the treatment of patients with acute COVID-19
(AIII). This recommendation should not preclude the use of IVIG for multisystem inflammatory syndrome in children
(MIS-C) or when it is otherwise indicated.
• Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
• JAK inhibitors other than baricitinib and tofacitinib (e.g., ruxolitinib) (AIII)
• Siltuximab (BIII)
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19:
• Colchicine for hospitalized patients (AI)


Corticosteroids
Multiple randomized trials indicate that systemic corticosteroid therapy improves clinical outcomes
and reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen,1,2
presumably by mitigating the COVID-19-induced systemic inflammatory response that can lead to lung
injury and multisystem organ dysfunction. In contrast, in hospitalized patients with COVID-19 who do
not require supplemental oxygen, the use of systemic corticosteroids has not shown any benefits and
may cause harm.3,4 The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the
use of corticosteroids in hospitalized patients with COVID-19 are based on results from these clinical
trials (see Tables 4a and 4b for more information). There are no data to support the use of systemic
corticosteroids in nonhospitalized patients with COVID-19.
Recommendations
For Nonhospitalized Adults With COVID-19
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for the Panel’s
recommendations on the use of dexamethasone or other systemic corticosteroids in certain
nonhospitalized patients.
• There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
corticosteroids for the treatment of COVID-19 in these patients.
• Patients with COVID-19 who are receiving dexamethasone or another corticosteroid for an
underlying condition should continue this therapy as directed by their health care provider (AIII).
For Hospitalized Adults With COVID-19

• See Therapeutic Management of Hospitalized Adults With COVID-19 for the Panel’s
recommendations on the use of dexamethasone or other systemic corticosteroids in certain
hospitalized patients.
corticosteroids for the treatment of COVID-19 in these patients.
Systemic Corticosteroids in Patients With COVID-19

Nonhospitalized Adults
There are no data to support the use of systemic corticosteroids in nonhospitalized patients with
COVID-19. Therefore, the safety and efficacy of using systemic corticosteroids in this population have
not been established. Generally, the use of systemic corticosteroids is associated with adverse events
(e.g., hyperglycemia, neuropsychiatric symptoms, secondary infections), which may be difficult to detect
and monitor in an outpatient setting. For more information, see General Management of Nonhospitalized
Patients With Acute COVID-19.
Hospitalized Adults
The RECOVERY trial was a multicenter, open-label trial in the United Kingdom that randomly
assigned 6,425 hospitalized patients to receive up to 10 days of dexamethasone 6 mg once daily plus
standard care or standard care alone. Mortality at 28 days was lower among the patients who received

dexamethasone than among those who received standard care alone.3 This benefit of dexamethasone
was observed in patients who were mechanically ventilated or who required supplemental oxygen at
enrollment; in contrast, no benefit was seen in patients who did not require supplemental oxygen at
enrollment.3
The CoDEX trial was a multicenter, open-label trial in Brazil that evaluated dexamethasone in patients
who were mechanically ventilated due to acute respiratory distress syndrome (ARDS) induced by
COVID-19. Although the trial was terminated early, the study results support the RECOVERY trial
finding that systemic corticosteroids are beneficial in hospitalized patients with COVID-19. The trial
randomly assigned 299 patients to receive either standard care plus intravenous (IV) dexamethasone 20
mg once daily for 5 days and then dexamethasone 10 mg IV once daily for 5 days or standard care alone.
The mean number of days alive and free from mechanical ventilation over 28 days was greater in the
dexamethasone arm than in the standard care alone arm. However, there were no differences between
the arms in 28-day mortality, the mean number of intensive care unit-free days at 28 days, or the mean
duration of mechanical ventilation at 28 days.5
An observational study evaluated the use of corticosteroids in 15,404 hospitalized patients with
positive SARS-CoV-2 polymerase chain reaction results or antigen test results from the Department
of Veteran Affairs’ database.4 Corticosteroids were administered to 60% of the patients within 48
hours of admission, and 95% of the patients who received corticosteroids received dexamethasone. A
total of 9,450 patients did not receive supplemental oxygen during the study. Of these patients, 3,514
(37%) received dexamethasone, administered for a median duration of 5 days (IQR 3–8 days). Using
average treatment effect estimates, patients who received dexamethasone without supplemental oxygen
had an increased risk of death within 90 days (HR 1.76; 95% CI, 1.47–2.12). Patients who received
dexamethasone either without supplemental oxygen or with low-flow nasal cannula oxygen had a 60%
higher risk of death. Although this study was observational, the investigators employed several statistical
techniques to minimize potential bias, including propensity scoring and weighted analyses. Additionally,
several subgroup and sensitivity analyses in this study confirmed the overall results.
Dose of Dexamethasone
The COVID STEROID 2 trial is the largest study to date that has investigated the use of different doses
of corticosteroids in people with COVID-19.6 This multicenter trial randomized hospitalized patients to
receive up to 10 days of once-daily dexamethasone 6 mg (n = 485) or dexamethasone 12 mg (n = 497).
The median number of days alive without life support at 28 days after randomization was 20.5 days
in the dexamethasone 6 mg arm (IQR 4.0–28.0 days) and 22.0 days in the dexamethasone 12 mg arm
(IQR 6.0–28.0 days), yielding an adjusted mean difference of 1.3 days (95% CI, 0–2.6; P = 0.07). No
differences were found in 28- or 90-day mortality between the arms. Approximately 12% of the patients
in each arm received either an interleukin-6 inhibitor or a kinase inhibitor during the study. While these
conventional analyses did not reach statistical significance, a preplanned Bayesian analysis found a
higher probability of benefit and a lower probability of harm for the 12-mg dose than for the 6-mg dose.7
A smaller randomized controlled trial reported a shorter time to clinical improvement and a lower
frequency of adverse events in patients with COVID-19 who received a lower dose of dexamethasone
(8 mg IV once daily) compared to those who received higher doses (8 mg IV 2 or 3 times daily). A
lower proportion of patients in the low-dose group died within 60 days compared to the intermediate-
and high-dose groups (17% vs. 30% and 41%, respectively; P = 0.06). It is worth noting that this study
included <200 participants.8
A third small, open-label, randomized trial (with <100 participants) found no difference in the median
number of ventilator-free days at 28 days after randomization between patients who received higher

doses of dexamethasone (16 mg IV daily for 5 days, followed by 8 mg daily for 5 days) and those who
received lower doses (6 mg IV daily for 10 days).9
The mixed results from these studies have led the Panel to continue to recommend 6 mg once daily as
the preferred dose for dexamethasone. However, the Panel notes that both the traditional and Bayesian
analyses conducted during the COVID STEROID 2 trial suggest that the 12-mg dose might confer a
benefit in patients who require high levels of respiratory support. As a result, some clinicians might
choose to use the higher dose of dexamethasone in these patients. It should be noted that there are
currently no data evaluating the safety and efficacy of using lower or higher doses of corticosteroids in
combination with other immunomodulators to treat COVID-19.
Combination Immunomodulator Therapy

Using systemic corticosteroids in combination with other agents, including tocilizumab (see
Interleukin-6 Inhibitors)10,11 or baricitinib (see Kinase Inhibitors),12 has been shown to have a clinical
benefit in subsets of hospitalized patients with COVID-19, especially those with early critical illness
and/or those with signs of systemic inflammation. For the Panel’s recommendations on when to use
dexamethasone with another immunomodulator, see Therapeutic Management of Hospitalized Adults
With COVID-19.
Please see Tables 4a and 4b for data from clinical trials that have evaluated the use of corticosteroids in
Systemic Corticosteroids Other Than Dexamethasone

Systemic corticosteroids other than dexamethasone, including hydrocortisone13,14 and
methylprednisolone,15,16 have been studied for the treatment of COVID-19 in several randomized
trials. Some of these trials were stopped early due to under-enrollment following the release of the
RECOVERY trial results. Consequently, the sample size of many these trials was insufficient to assess
efficacy (i.e., there were too few events to definitively confirm or exclude an effect, although many point
estimates suggested a beneficial effect). Therefore, the evidence supporting the use of hydrocortisone or
methylprednisolone for the treatment of COVID-19 is not as strong as the evidence supporting the use of
dexamethasone. Based on the available evidence, the Panel has concluded the following:
• If dexamethasone is not available, alternative glucocorticoids (e.g., prednisone,
methylprednisolone, hydrocortisone) can be used.
• For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (orally or IV)17 are:
• Prednisone 40 mg
• Methylprednisolone 32 mg
• Hydrocortisone 160 mg
• Half-life, duration of action, and frequency of administration vary among corticosteroids.
• Long-acting corticosteroid: Dexamethasone; half-life 36 to 72 hours, administer once daily.
• Intermediate-acting corticosteroids: Prednisone and methylprednisolone; half-life 12 to 36
hours, administer once daily or in 2 divided doses daily.
• Short-acting corticosteroid: Hydrocortisone; half-life 8 to 12 hours, administer in 2 to 4
divided doses daily.
• Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; see
Hemodynamics for more information. Unlike other corticosteroids that have previously been

studied in patients with ARDS, dexamethasone lacks mineralocorticoid activity and thus its effects
on sodium balance and fluid volume are minimal.18
Inhaled Corticosteroids in Patients With COVID-19

Inhaled corticosteroids have been identified as potential COVID-19 therapeutic agents because of their
targeted anti-inflammatory effects on the lungs. In addition, certain inhaled corticosteroids have been
shown to impair viral replication of SARS-CoV-219 and downregulate the expression of the receptors used
for cell entry.20,21 Two open-label randomized controlled trials and 2 double-blind, placebo-controlled trials
provide additional insights regarding the role of inhaled corticosteroids in outpatients with COVID-19, as
described below and in Table 4b.
Recommendation
corticosteroids for the treatment of COVID-19.
Rationale
Inhaled budesonide was studied in 2 open-label randomized controlled trials in outpatients with mild
symptoms of COVID-19.22,23 The small STOIC trial suggested that initiating inhaled budesonide in adult
outpatients with mild COVID-19 may reduce the need for urgent care or emergency department assessment
or hospitalization.22 PRINCIPLE, a larger, open-label trial in nonhospitalized patients with COVID-19
who were at high risk of disease progression, found that using inhaled budesonide did not affect the rate of
hospitalization or death but did reduce the time to self-reported recovery.23 The findings from these trials
should be interpreted with caution given the open-label design of the studies and other limitations.
Inhaled ciclesonide was studied in 2 double-blind, randomized, placebo-controlled trials in outpatients
with mild COVID-19. The primary endpoint in 1 study was time to alleviation of COVID-19-related
symptoms. In this study, the use of inhaled ciclesonide did not reduce the time to self-reported recovery,
but the therapy did reduce the number of subsequent COVID-related emergency department visits or
hospitalizations. The robustness of this conclusion is uncertain given the small number of events, which
is likely due to the relatively small number of participants with comorbidities.24 In the smaller CONTAIN
study, the combined use of inhaled and intranasal ciclesonide did not improve the resolution of fever and/or
respiratory symptoms by Day 7.25
The studies described above that evaluated the use of inhaled corticosteroid therapy in outpatients with
mild COVID-19 have identified inconsistent effects of this therapy on subsequent hospitalization, and
similar placebo-controlled trials have not demonstrated that this therapy improves the time to symptom
resolution. The placebo-controlled studies did not enroll enough patients who were at high risk of disease
progression; therefore, further studies in this population are needed. For additional information on these
trials, see Table 4b.

• Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for
certain adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, avascular
necrosis).
• Patients who are receiving inhaled corticosteroids may develop oral candidiasis.
• The use of systemic corticosteroids may increase the risk of opportunistic fungal infections (e.g.,
mucormycosis, aspergillosis) and reactivation of latent infections (e.g., hepatitis B virus infection,
herpesvirus infections, strongyloidiasis, tuberculosis).26-30

• Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19
during treatment with tocilizumab and corticosteroids.31,32 Many clinicians would initiate
empiric antiparasitic treatment (e.g., with the antiparasitic drug ivermectin) with or without
serologic testing in patients who currently reside or who have previously resided in areas where
Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).33
• Using systemic corticosteroids with other immunosuppressants, such as tocilizumab or baricitinib,
could theoretically increase the risk of secondary infections. However, clinical trials have reported
no difference in the rates of secondary infections between patients who received corticosteroids in
combination with another immunomodulatory agent and those who received corticosteroids alone.
• Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer. Therefore, it could reduce
the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
Clinicians should carefully review a patient’s concomitant medications to assess the potential for
drug-drug interactions.
• Using a CYP3A4 inhibitor with inhaled budesonide may lead to increased systemic absorption of
budesonide, which may result in systemic adverse effects from the corticosteroid.
A short course of betamethasone or dexamethasone, which are both known to cross the placenta, is
routinely used to decrease neonatal complications of prematurity in women with threatened preterm
delivery.34,35
A short course of dexamethasone for the treatment of COVID-19 during pregnancy offers the potential
benefit of decreased maternal mortality and a low risk of fetal adverse effects. Therefore, the Panel
recommends using dexamethasone in hospitalized pregnant patients with COVID-19 who are
mechanically ventilated (AIII) or who require supplemental oxygen but are not mechanically ventilated
(BIII).
The safety and effectiveness of using dexamethasone or other corticosteroids for COVID-19 treatment
have not been sufficiently evaluated in pediatric patients. Caution is warranted when using data from
clinical trials that enrolled adults to inform treatment recommendations for children, particularly younger
children and those who are less severely ill. The Panel recommends using dexamethasone for children
with COVID-19 who require high-flow oxygen, noninvasive ventilation, mechanical ventilation, or
extracorporeal membrane oxygenation (BIII). Corticosteroids are not routinely recommended for
pediatric patients who require only low levels of oxygen support (i.e., administered via a nasal cannula
only) but could be considered on a case-by-case basis. The use of dexamethasone for the treatment of
severe COVID-19 in children who are profoundly immunocompromised has not been evaluated and may
be harmful; therefore, such use should be considered only if the benefit is expected to outweigh the risks.
The dexamethasone dosing regimen for pediatric patients is dexamethasone 0.15 mg/kg per dose (with a
maximum dose of 6 mg) once daily for up to 10 days. There is insufficient evidence to recommend either
for or against the use of inhaled corticosteroids in pediatric patients with COVID-19.
Methylprednisolone or another corticosteroid should be used in combination with IV immunoglobulin
for the initial treatment of multisystem inflammatory syndrome in children (MIS-C) (AIIb). The dosing
regimen for initial therapy is methylprednisolone 1 to 2 mg/kg IV once daily or another glucocorticoid
at an equivalent dose. See Therapeutic Management of Hospitalized Pediatric Patients With Multisystem
Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory

Syndrome in Adults [MIS-A]) for more information on the management of MIS-C.
Clinical Trials
Several clinical trials that are evaluating the use of corticosteroids for the treatment of COVID-19 are
underway or in development. Please see ClinicalTrials.gov for the latest information.
References
1. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, Sterne JAC, Murthy S, et al.
Association between administration of systemic corticosteroids and mortality among critically ill patients with
COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. Available at:
2. Li H, Yan B, Gao R, Ren J, Yang J. Effectiveness of corticosteroids to treat severe COVID-19: a systematic
review and meta-analysis of prospective studies. Int Immunopharmacol. 2021;100:108121. Available at:
4. Crothers K, DeFaccio R, Tate J, et al. Dexamethasone in hospitalised coronavirus-19 patients not on intensive
respiratory support. Eur Respir J. 2021;Published online ahead of print. Available at:
5. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in
patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized
6. COVID STEROID 2 Trial Group, Munch MW, Myatra SN, et al. Effect of 12 mg vs 6 mg of dexamethasone
on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID
STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817. Available at:
7. Granholm A, Munch MW, Myatra SN, et al. Dexamethasone 12 mg versus 6 mg for patients with COVID-19
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in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2022;74(1):229-240.
9. Maskin LP, Bonelli I, Olarte GL, et al. High- versus low-dose dexamethasone for the treatment of COVID-
19-related acute respiratory distress syndrome: a multicenter, randomized open-label clinical trial. J Intensive
13. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support

among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306.
14. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients
with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA.
15. Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. Methylprednisolone in adults hospitalized
with COVID-19 pneumonia: an open-label randomized trial (GLUCOCOVID). Wien Klin Wochenschr.
2021;133(7-8):303-311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33534047.
16. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-
intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial.
Respiration. 2021;100(2):116-126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33486496.
17. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically
administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98. Available at:
18. Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a
multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. Available at:
19. Matsuyama S, Kawase M, Nao N, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication
by targeting the viral replication-transcription complex in cultured Cells. J Virol. 2020;95(1). Available at:
20. Finney LJ, Glanville N, Farne H, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2
in COPD through suppression of type I interferon. J Allergy Clin Immunol. 2021;147(2):510-519 e515.
21. Peters MC, Sajuthi S, Deford P, et al. COVID-19-related genes in sputum cells in asthma. Relationship to
Demographic Features and Corticosteroids. Am J Respir Crit Care Med. 2020;202(1):83-90. Available at:
22. Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19
(STOIC): a Phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available
23. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of
complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive
platform trial. Lancet. 2021;398(10303):843-855. Available at:
24. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment
of adolescents and adults with symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med.
25. Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult
outpatients: CONTAIN Phase II randomised controlled trial. BMJ. 2021;375:e068060. Available at:
26. Garg D, Muthu V, Sehgal IS, et al. Coronavirus disease (COVID-19) associated mucormycosis (CAM): case
report and systematic review of literature. Mycopathologia. 2021;186(2):289-298. Available at:
27. Moorthy A, Gaikwad R, Krishna S, et al. SARS-CoV-2, Uncontrolled diabetes and corticosteroids—an unholy
trinity in invasive fungal infections of the maxillofacial region? A retrospective, multi-centric analysis. J
Maxillofac Oral Surg. 2021;20(3):418-425. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33716414.
28. Machado M, Valerio M, Alvarez-Uria A, et al. Invasive pulmonary aspergillosis in the COVID-19 era: an
expected new entity. Mycoses. 2021;64(2):132-143. Available at:

29. Chauvet P, Mallat J, Arumadura C, et al. Risk factors for invasive pulmonary aspergillosis in critically ill
patients with coronavirus disease 2019-induced acute respiratory distress syndrome. Crit Care Explor.
30. Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19
patients with pre-existing chronic hepatitis B virus infection. Hepatol Res. 2020;50(11):1211-1221. Available
related strongyloides hyperinfection. JAMA. 2020;324(7):623-624. Available at:
34. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the
respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515-525. Available at:
35. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for late
preterm delivery. N Engl J Med. 2016;374(14):1311-1320. Available at:

Table 6a. Systemic Corticosteroids: Selected Clinical Data
systemic corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations. Unless
stated otherwise, the clinical trials listed below only included participants aged ≥18 years.
RECOVERY: Open-Label RCT of Dexamethasone in Hospitalized Patients With COVID-19 in the United Kingdom1
• Hospitalized with suspected or • Mean age 66 years; 64% men; 73% White • Open-label study
laboratory-confirmed SARS-CoV-2 • 56% had ≥1 comorbidity; 24% with DM • Published data did not include results for key
infection secondary endpoints (e.g., cause-specific
• 89% had laboratory-confirmed SARS-CoV-2 infection
Key Exclusion Criteria: mortality, need for renal replacement), AEs, and
• Median duration of DEX therapy: 7 days key subgroups (e.g., patients with comorbidities).
• Physician determination that risks of • At randomization:
participation were too great based on • Patients who required supplemental oxygen (but
patient’s medical history • 16% received MV or ECMO not MV) had variable severity of illness. It is
• 60% required supplemental oxygen but not MV unclear whether all patients in this group benefited
• An indication for corticosteroid therapy
from DEX or whether benefit is restricted to those
outside of the study • 24% required no supplemental oxygen
requiring higher levels of supplemental oxygen.
Interventions: • Received RDV: <1% in both arms
• Patients aged >80 years were preferentially
• DEX 6 mg IV or PO once daily plus SOC • Received tocilizumab or sarilumab: 2% in DEX arm vs. 3% in assigned to receive supplemental oxygen therapy
for up to 10 days or until discharge (n = SOC arm (and not MV).
2,104) Primary Outcome: • High mortality in this study may limit the
• SOC alone (n = 4,321) • All-cause mortality at 28 days: generalizability of results to populations with a
lower baseline mortality.
Primary Endpoint: • All patients: 23% in DEX arm vs. 26% in SOC arm (age-
• All-cause mortality at 28 days adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001) Interpretation:
• Patients who required MV or ECMO at randomization: 29% • In hospitalized patients with severe COVID-19
in DEX arm vs. 41% in SOC arm (rate ratio 0.64; 95% CI, who required supplemental oxygen, DEX reduced
0.51–0.81) mortality at 28 days. The greatest benefit was seen
• Patients who required supplemental oxygen but not MV at in those receiving MV at randomization.
randomization: 23% in DEX arm vs. 26% in SOC arm (rate • There was no survival benefit for DEX in patients
ratio 0.82; 95% CI, 0.72–0.94) who did not require supplemental oxygen at
• Patients who did not require supplemental oxygen at randomization.

CoDEX: Open-Label RCT of Dexamethasone in Patients With Moderate or Severe ARDS and COVID-19 in Brazil2
Key Inclusion Criteria: r andomization: 18% in DEX arm vs. 14% in SOC arm (rate Key Limitations:
• Confirmed or suspected SARS-CoV-2 ratio 1.19, 95% CI, 0.92–1.55) • Open-label study
infection Participant Characteristics: • Underpowered; enrollment stopped after release
• Received MV within 48 hours of meeting • Mean age 61 years; 63% men of data from the RECOVERY trial.
criteria for moderate to severe ARDS • Patients discharged before 28 days were not
• Comorbidities:
(PaO2/FiO2 ≤200 mm Hg) followed for rehospitalization or mortality.
• Obesity: 31% in DEX arm vs. 24% in SOC arm
Key Exclusion Criteria: • High mortality in this study may limit the
• DM: 38% in DEX arm vs. 47% in SOC arm
• Received immunosuppressive drugs in generalizability of results to populations with a
past 21 days • Vasopressor use: 66% in DEX arm vs. 68% in SOC arm lower baseline mortality.
• Death expected within 24 hours • Mean PaO2/FiO2: 131 mm Hg in DEX arm vs. 133 mm Hg in • More than one-third of those randomized to
SOC arm receive SOC also received corticosteroids.
Interventions: • Median duration of DEX therapy: 10 days Interpretation:
• DEX 20 mg IV once daily for 5 days, then • No patients received RDV or tocilizumab
DEX 10 mg IV once daily for 5 days or • Compared with SOC alone, DEX increased the
until ICU discharge (n = 151) • 35% in SOC arm received corticosteroids for indications such number of days alive and free of MV over 28 days
as bronchospasm or septic shock in patients with COVID-19 and moderate to severe
• SOC alone (n = 148)
Primary Outcome: ARDS.
Primary Endpoint:
• Mean number of days alive and free from MV by Day 28: 7 in
• Number of days alive and free from MV DEX arm vs. 4 in SOC arm (P = 0.04)
by Day 28
Secondary Outcomes:
• No differences between arms in all-cause mortality (56% vs.
• All-cause mortality by Day 28 62%), number of ICU-free days, duration of MV, or score on
• Number of ICU-free days by Day 28 6-point OS
• Duration of MV by Day 28 • Mean SOFA score at Day 7: 6.1 in DEX arm vs. 7.5 in SOC arm
• Score on 6-point OS at Day 15 (P = 0.004)
• SOFA score at Day 7 Other Outcome:
• Post hoc analysis of probability of death or MV by Day 15:
68% in DEX arm vs. 80% in SOC arm (OR 0.46)

Observational Cohort Study of Dexamethasone in Hospitalized Patients With COVID-19 Who Were Not on Intensive Respiratory Support in the United States3
• Within 14 days of a positive test result• Mean age 71 years; 95% men; 27% Black, 55% White • Retrospective observational study
for SARS-CoV-2 infection • 77% did not receive IRS within 48 hours • Because nearly all patients on MV or HFNC oxygen
Key Exclusion Criteria: • 83% admitted within 1 day after positive SARS-CoV-2 test received DEX, analysis was restricted to patients
result who did not receive IRS (i.e., those who received
• Recent receipt of corticosteroids
no supplemental oxygen or only low-flow nasal
• Receipt of IRS (defined as HFNC oxygen, • Median duration of DEX for patients who did not receive IRS: cannula oxygen).
NIV, or MV) within 48 hours 5 days for patients who were not on supplemental oxygen
at baseline vs. 6 days for patients on low-flow nasal cannula • Differences between the arms in other therapies
• Hospital LOS of <48 hours received
oxygen
Interventions: • Received RDV: 43% of those who received DEX vs. 13% of Interpretation:
• Corticosteroids (95% of patients those who did not • In hospitalized patients with COVID-19, the use of
received DEX) administered within 48 • Received anticoagulants: 46% of those who received DEX vs. DEX was not associated with a mortality benefit
hours of admission (n = 7,507) 10% of those who did not among those who received low-flow nasal cannula
• No corticosteroids administered (n = oxygen during the first 48 hours after admission,
Primary Outcome: but it was associated with increased mortality
7,433)
• Risk of all-cause mortality at 90 days was higher in those who among those who received no supplemental
Primary Endpoint: received DEX: oxygen during the first 48 hours after admission.
• All-cause mortality at 90 days • For combination of those not on supplemental oxygen and
those on low-flow nasal cannula oxygen: HR 1.59; 95% CI,
1.39–1.81
• For those not on supplemental oxygen: HR 1.76; 95% CI,
1.47–2.12
• For those on low-flow nasal cannula oxygen: HR 1.08; 95%
CI, 0.86–1.36

COVID STEROID 2: Blinded RCT of Dexamethasone 12 mg Versus 6 mg in Hospitalized Adults With COVID-19 and Severe Hypoxemia in Denmark, India,
Sweden, and Switzerland4,5
• Confirmed SARS-CoV-2 infection • Median age 65 years; 31% women • The randomized intervention period was <10 days
• Requiring oxygen ≥10 L/min, NIV, CPAP, • DM: 27% in 12 mg arm vs. 34% in 6 mg arm in some patients because the trial allowed up to 4
or MV days of DEX before enrollment.
• Median time from symptom onset to hospitalization: 7 days in
Key Exclusion Criteria: both arms Interpretation:
• Treated with DEX >6 mg (or equivalent) • Received ICU care: 78% in 12 mg arm vs. 81% in 6 mg arm • Among patients with COVID-19 and severe
hypoxemia, the use of DEX 12 mg once daily did
• Treated with a corticosteroid within past • Oxygen requirements: not result in more days alive without life support
5 days • 54% on oxygen via nasal cannula or face mask (median at 28 days than DEX 6 mg once daily.
• Invasive fungal infection or active TB flow rate 23 L/min)
Interventions: • 25% on NIV
• DEX 12 mg IV once daily for up to 10 • 21% on MV
days (n = 497) • 63% received RDV; 12% received IL-6 inhibitors or JAK
• DEX 6 mg IV once daily for up to 10 days inhibitors
(n = 485) • Median duration of DEX treatment: 7 days in both arms
Primary Endpoint: Primary Outcome:
• Number of days alive without life support • Median number of days alive without life support: 22.0 in 12
(MV, circulatory support, or kidney mg arm vs. 20.5 in 6 mg arm (adjusted mean difference 1.3
replacement therapy) at 28 days days; 95% CI, 0.0–2.6; P = 0.07)
Key Secondary Endpoints: • 63.9% Bayesian probability of clinically important benefit
and 0.3% Bayesian probability of clinically important harm
• Number of days alive without life support
for DEX 12 mg
at 90 days
Secondary Outcomes:
• Number of days alive and out of hospital
at 90 days • At 90 days:
• Mortality at 90 days • Median number of days alive without life support: 84 in 12
mg arm vs. 80 in 6 mg arm (P = 0.15)
• Mortality at 28 days
• Median number of days alive and out of hospital: 62 in 12
• SAEs at 28 days
mg arm vs. 48 in 6 mg arm (P = 0.09)
• Mortality: 32% in 12 mg arm vs. 38% in 6 mg arm
(adjusted relative risk 0.87; 99% CI, 0.70–1.07; P = 0.09)

COVID STEROID 2: Blinded RCT of Dexamethasone 12 mg Versus 6 mg in Hospitalized Adults With COVID-19 and Severe Hypoxemia in Denmark, India,
Sweden, and Switzerland4,5, continued
• At 28 days:
• Mortality: 27% in 12 mg arm vs. 32% in 6 mg arm
(adjusted relative risk 0.86; 99% CI, 0.68–1.08; P = 0.10)
• SAEs, including septic shock and invasive fungal infections:
11% in 12 mg arm vs. 13% in 6 mg arm (adjusted relative
risk 0.83; 99% CI, 0.54–1.29; P = 0.27)
CAPE COVID: Double-Blind RCT of Hydrocortisone Among Critically Ill Patients With COVID-19 in France6
• Laboratory-confirmed SARS-CoV-2 • Mean age 62 years; 70% men; median BMI 28 • Underpowered; enrollment stopped after release
infection or radiographically suspected • 96% had laboratory-confirmed SARS-CoV-2 infection of data from the RECOVERY trial, resulting in
COVID-19 with ≥1 of the following: limited power to detect differences between arms.
• Median symptom duration: 9–10 days
• MV with PEEP ≥5 cm H2O • Limited information about comorbidities
• Required MV at baseline: 81%
• PaO2/FiO2 <300 mm Hg and FiO2 Interpretation:
≥50% on HFNC • Received vasopressors: 24% in hydrocortisone arm vs. 18% in
placebo arm • The use of hydrocortisone did not reduce the
• PaO2/FiO2 <300 mm Hg on reservoir proportion of patients with COVID-19 and acute
mask oxygen • Received RDV or tocilizumab: <5%
respiratory failure who experienced treatment
• Pulmonary severity index >130 • Median duration of treatment with study drug: 11 days in failure by Day 21.
hydrocortisone arm vs. 13 days in placebo arm (P = 0.25)
Primary Outcome:
• Septic shock
• Treatment failure by Day 21: 42% in hydrocortisone arm vs.
• Do-not-intubate orders 51% in placebo arm (P = 0.29)
Interventions: Secondary Outcomes:
• Continuous IV infusion of hydrocortisone • No difference between arms in need for intubation or prone
200 mg per day for 7 days, then 100 mg positioning (too few patients received ECMO or inhaled nitric
per day for 4 days, then 50 mg per day oxide for comparisons)
for 3 days. If patient improved by Day 4,
then IV infusion of hydrocortisone 200 • Among patients who did not require MV at baseline, 50%
mg per day for 4 days, then 100 mg per in hydrocortisone arm vs. 75% in placebo arm required
day for 2 days, then 50 mg per day for 2 subsequent MV
days (n = 76) • No difference between arms in proportion of patients with
• Placebo (n = 73) nosocomial infection by Day 28

CAPE COVID: Double-Blind RCT of Hydrocortisone Among Critically Ill Patients With COVID-19 in France6, continued
Primary Endpoint: • No difference between arms in clinical status on Day 21, but
• Treatment failure (death or dependency 15% died in hydrocortisone arm vs. 27% in placebo arm (P =
on MV or high-flow oxygen) by Day 21 0.06)
• Discharged from ICU by Day 21: 57% in hydrocortisone arm
vs. 44% in placebo arm; 23% in both arms still required MV
• Need for MV, prone positioning, ECMO,
or inhaled nitric oxide
• Nosocomial infection by Day 28
• Clinical status on Day 21, as measured
by a 5-item scale:
• Death
• In ICU and on MV
• Required high-flow oxygen therapy
• Required low-flow oxygen therapy
• Discharged from ICU
REMAP-CAP: Randomized, Open-Label, Adaptive Trial of Hydrocortisone in Patients With Severe COVID-197
• Presumed or laboratory-confirmed • Mean age 60 years; 71% men; 53% White • Open-label study
SARS-CoV-2 infection • Mean BMI 29.7–30.9 • Enrollment stopped after release of data from the
• ICU admission for respiratory or • 50% to 64% required MV RECOVERY trial.
cardiovascular support
Primary Outcome: Interpretation:
Key Exclusion Criteria: • The use of hydrocortisone did not increase the
• No difference between arms in median number of organ
• Presumed imminent death support-free days at Day 21 (0 in each arm) median number of support-free days in either the
• Systemic corticosteroid use fixed-dose or the shock-dependent hydrocortisone
• Median adjusted ORs for primary outcome for hydrocortisone arms, although early termination limited the
• >36 hours since ICU admission arms compared to no hydrocortisone arm: study’s power to detect differences between the
Interventions: • OR 1.43 (95% CrI, 0.91–2.27) with 93% Bayesian study arms.
probability of superiority for fixed-dose hydrocortisone arm
• Hydrocortisone 50 mg IV every 6 hours
for 7 days (n = 137) • OR 1.22 (95% CrI, 0.76–1.94) with 80% Bayesian
probability of superiority for shock-dependent
• Shock-dependent hydrocortisone 50 mg
hydrocortisone arm
IV every 6 hours for duration of shock
for up to 28 days (n = 146) Key Secondary Outcome:
• No hydrocortisone (n = 101) • No difference between arms in in-hospital mortality (30% in

REMAP-CAP: Randomized, Open-Label, Adaptive Trial of Hydrocortisone in Patients With Severe COVID-197, continued
Primary Endpoint: fi xed-dose hydrocortisone arm vs. 26% in shock-dependent
• Number of days free from respiratory hydrocortisone arm vs. 33% in no hydrocortisone arm)
and cardiovascular support by Day 21
Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China8
• Laboratory-confirmed SARS-CoV-2 • Mean age 56 years; 48% men • Small sample size
infection • Median time from symptom onset to randomization: 8 days • Terminated early because of decreasing incidence
• Pneumonia confirmed by chest CT scan • At randomization, 71% were receiving oxygen via nasal of COVID-19 pneumonia at study sites
• Hospitalized on general ward for <72 cannula Interpretation:
hours
Primary Outcome: • The incidence of clinical deterioration did not differ
Key Exclusion Criteria: • Clinical deterioration at 14 days: 4.8% in both arms (OR 1.0; between the methylprednisolone and placebo
• Severe immunosuppression 95% CI, 0.134–7.442; P = 1.00) arms.
• Corticosteroid use for other diseases Secondary Outcomes:
Interventions: • No differences (all P > 0.05) between methylprednisolone arm
• Methylprednisolone 1 mg/kg per day IV and placebo arm for:
for 7 days (n = 43) • Clinical cure at 14 days: 51% vs. 58%
• Saline (n = 43) • Median number of days to clinical cure: 14 vs. 12
Primary Endpoint: • ICU admission: 4.8% in both arms
• Clinical deterioration at 14 days • In-hospital mortality: 0% vs. 2.3%
Key Secondary Endpoints: • Median number of days hospitalized: 17 vs. 13
• Clinical cure at 14 days
• Time to clinical cure
• ICU admission
• Number of days hospitalized

Single-Blind RCT of 3 Doses of Dexamethasone in Hospitalized Patients With Moderate to Severe COVID-19 in Iran9
• PCR-confirmed SARS-CoV-2 infection or • Mean age: 59 years in low-dose arm vs. 59 years in • Small sample size
CT scan showing lung involvement intermediate-dose arm vs. 56 years in high-dose arm
Interpretation:
• Moderate or severe COVID-19 • 50% men
• The time to clinical response was significantly
• Requirement for supplemental oxygen • 23% with DM shorter in the low-dose DEX arm than in the
Key Exclusion Criteria: • 75% received RDV intermediate- or high-dose arms. Patients in the
low-dose arm had a higher probability of survival
• Uncontrolled DM Primary Outcome: than those in the high-dose arm.
• Active fungal or parasitic infection • Mean number of days to clinical response: 4.3 in low-dose
• On MV or receiving vasopressor therapy arm vs. 5.3 in intermediate-dose arm vs. 6.1 in high-dose arm
(P = 0.025)
Interventions:
Secondary Outcomes:
• Low dose: DEX 8 mg IV once daily for up
to 10 days (n = 47) • Mortality at 60 days: 17% in low-dose arm vs. 30% in
intermediate-dose arm vs. 41% in high-dose arm (P = 0.06)
• Intermediate dose: DEX 8 mg IV twice
daily for up to 10 days (n = 40) • AEs (leukocytosis, hyperglycemia, and secondary infections)
occurred more frequently in intermediate-dose and high-dose
• High dose: DEX 8 mg IV 3 times a day arms than in low-dose arm; however, this result was not
for up to 10 days (n = 46) statistically significant.
Primary Endpoint:
• Time to clinical response, as measured
by OS
• Mortality at 60 days

Open-Label Randomized Trial of High-Dose Versus Low-Dose Dexamethasone in Patients With COVID-19-Related ARDS in Argentina10
• Laboratory-confirmed SAR-CoV-2 • Mean age: 60 years in high-dose arm vs. 63 years in low-dose • Small, open-label study
infection arm • Trial was prematurely terminated due to low
• ARDS • 30% women enrollment rate.
• On MV for <72 hours Primary Outcomes: Interpretation:
Key Exclusion Criteria: • Median number of ventilator-free days by Day 28: 0 for both • The use of a higher dose of DEX did not
• Presumed imminent death arms (P = 0.23) increase the median number of ventilator-free
• No difference between arms in mean duration of MV by days in patients with ARDS due to COVID-19.
• Immunosuppression However, the higher dose shortened the time to
Day 28 (19 ± 18 days in high-dose arm vs. 25 ± 22 days in
• Treatment with glucocorticoids low-dose arm; P = 0.078). Cumulative hazard of successful discontinuation of MV.
Interventions: discontinuation from MV was greater in high-dose arm than
• High dose: DEX 16 mg IV once daily for low-dose arm (adjusted subdistribution HR 1.84; 95% CI,
5 days, followed by DEX 8 mg IV once 1.31–2.5; P < 0.001).
daily for 5 days (n = 49) Secondary Outcome:
• Low dose: DEX 6 mg once daily IV for 10 • All-cause mortality:
days (n = 49) • By Day 28: 41% in high-dose arm vs. 39% in low-dose arm
Primary Endpoints: (P > 0.999)
• Number of ventilator-free days by Day 28 • By Day 90: 47% in both arms (P > 0.999)
• Time to discontinuation of MV
• All-cause mortality by Day 28 and Day 90
Key: AE = adverse event; ARDS = acute respiratory distress syndrome; BMI = body mass index; CPAP = continuous positive airway pressure; CT = computed
tomography; DEX = dexamethasone; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation; HFNC = high-flow nasal cannula; ICU = intensive care
unit; IL = interleukin; IRS = intensive respiratory support; IV = intravenous; JAK = Janus kinase; LOS = length of stay; MV = mechanical ventilation; NIV = noninvasive
ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired
oxygen; PCR = polymerase chain reaction; PEEP = positive end-expiratory pressure; PO = orally; RCT = randomized controlled trial; RDV = remdesivir; SAE = serious
adverse event; SOC = standard of care; SOFA = sequential organ failure assessment; TB = tuberculosis

References
1. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-
2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute
respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-1316. Available at:
3. Crothers K, DeFaccio R, Tate J, et al. Dexamethasone in hospitalised coronavirus-19 patients not on intensive respiratory support. Eur Respir J.
4. COVID STEROID 2 Trial Group, Munch MW, Myatra SN, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life
support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817. Available at:
5. Granholm A, Munch MW, Myatra SN, et al. Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned,
secondary Bayesian analysis of the COVID STEROID 2 trial. Intensive Care Med. 2022;48(1):45-55. Available at:
6. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with
COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.
7. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP
COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-1329. Available at:
8. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19
pneumonia: a multicenter, single-blind, randomized control trial. Respiration. 2021;100(2):116-126. Available at:
9. Toroghi N, Abbasian L, Nourian A, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a
three-arm randomized clinical trial. Pharmacol Rep. 2022;74(1):229-240. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34837648.
10. Maskin LP, Bonelli I, Olarte GL, et al. High- versus low-dose dexamethasone for the treatment of COVID-19-related acute respiratory distress
syndrome: a multicenter, randomized open-label clinical trial. J Intensive Care Med. 2022;37(4):491-499. Available at:

Table 6b. Inhaled Corticosteroids: Selected Clinical Data
inhaled corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
PRINCIPLE: Open-Label RCT of Inhaled Budesonide in Nonhospitalized Patients With COVID-191

• Aged ≥65 years or aged ≥50 years with comorbidities • Mean age 64.2 years; 52% women; • Open-label trial
• PCR-confirmed or suspected COVID-19 92% White • Primary endpoint of time to
• ≤14 days of symptoms • 81% with comorbidities reported recovery based on
• Median time from symptom onset to participant self-report
randomization: 6 days Interpretation:
• Already taking inhaled or systemic corticosteroids
Primary Outcomes: • Inhaled budesonide reduced
• Unable to use an inhaler time to reported recovery but not
• Percentage of patients who were
• Contraindication to inhaled budesonide hospitalized or died due to COVID-19 COVID-19-related hospitalization
Interventions: within 28 days: 6.8% in budesonide arm or death.
• Usual care plus budesonide 800 mcg inhaled twice daily for 14 days (n = 1,069) vs. 8.8% in usual care arm (OR 0.75; • The clinical significance of self-
95% CrI, 0.55–1.03). reported time to recovery in an
• Usual care (n = 787) open-label study is unclear.
• Median time to reported recovery: 11.8
Primary Endpoints: days in budesonide arm vs. 14.7 days
• COVID-19-related hospitalization or death up to 28 days from randomization in usual care arm (HR 1.21; 95% CrI,
1.08–1.36).
• Time to reported recovery up to 28 days from randomization
STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults With Early COVID-192
• Aged ≥18 years • Mean age 45 years; 58% women • Small, open-label trial
• ≤7 days of symptoms • 9% with CVD, 5% with DM • Early termination after statistical
Key Exclusion Criteria: • 95% with positive SARS-CoV-2 RT-PCR analysis determined that additional
result participants would not alter study
• Use of inhaled or systemic glucocorticoids in past 7 days outcome
• Median time from symptom onset to
• Known allergy or contraindication to budesonide
randomization: 3 days

STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults with Early COVID-192, continued
Interventions: Primary Outcomes: Interpretation:
• Usual care plus budesonide 800 mcg inhaled twice daily until • Median duration of budesonide use: 7 days. • In adult outpatients with mild COVID-19,
symptom resolution (n = 73) • Percentage of patients with COVID-19-related inhaled budesonide may reduce the need
• Usual care (n = 73) urgent care visit or hospitalization: 1% in for urgent care or ED assessment and/or
budesonide arm vs.14% in usual care arm (relative hospitalization.
Primary Endpoint:
risk reduction 91%).
• COVID-19-related urgent care visit, including ED visit or
hospitalization
Phase 3, Double-Blind RCT of Inhaled Ciclesonide in Nonhospitalized Patients With COVID-193
• Aged ≥12 years • Mean age 43.3 years; 55.3% women; 86.3% White • ED or hospitalization outcome based on
• Positive SARS-CoV-2 molecular or antigen diagnostic test • Mean BMI 29.4 small number of events
result in previous 72 hours • 22.3% with HTN, 7.5% with type 2 DM • Primary endpoint of time to alleviation of
• ≥1 symptom of fever, cough, or dyspnea all symptoms based on participant self-
• Higher rates of DM and asthma in ciclesonide arm report
Key Exclusion Criteria: Primary Outcome: Interpretation:
• Taken inhaled or intranasal corticosteroid within 14 days • Median time to alleviation of all COVID-19-related • Inhaled ciclesonide did not reduce time to
of enrollment or systemic corticosteroid within 90 days of symptoms: 19.0 days in ciclesonide arm vs. 19.0
enrollment reported recovery.
days in placebo arm (HR 1.08; 95% CI, 0.84–
• Unable to use an inhaler 1.38). • The robustness of the conclusion that
inhaled ciclesonide reduced COVID-19-
Interventions: Secondary Outcomes: related ED visits or hospitalization is
• Ciclesonide MDI 160 µg/actuation, 2 actuations twice a day • By Day 30, percentage of patients in whom the uncertain; there were only a small number
for 30 days (n = 197) following outcomes occurred: of events, which is most likely due to the
• Placebo MDI twice a day for 30 days (n = 203) • Alleviation of COVID-19-related symptoms: relatively low rate of comorbidities in the
70.6% in ciclesonide arm vs. 63.5% in placebo study population.
Primary Endpoint:
arm.
• Time to alleviation of all COVID-19-related symptoms by Day
• Subsequent ED visit or hospital admission for
30
COVID-19: 1.0% in ciclesonide arm vs. 5.4% in
Key Secondary Endpoints: placebo arm (OR 0.18; 95% CI, 0.04–0.85).
• Alleviation of COVID-19-related symptoms by Day 30 • Hospital admission or death: 1.5% in ciclesonide
• ED visit or hospital admission for COVID-19 by Day 30 arm vs. 3.4% in placebo arm (OR 0.45; 95% CI,
0.11–1.84).
• Hospital admission or death by Day 30
• No deaths by Day 30 in either arm.

CONTAIN: Double-Blind RCT of Inhaled and Intranasal Ciclesonide in Nonhospitalized Patients With COVID-194
• Aged ≥18 years • Median age 35 years; 54% women; 61% White • Small study with a relatively young,
• Positive SARS-CoV-2 molecular diagnostic test result • 20% with comorbid condition healthy population
• ≥1 symptom of fever, cough, or shortness of breath Primary Outcome: Interpretation:
• Symptom duration ≤6 days • Percentage of patients with resolution of fever • The use of inhaled ciclesonide plus
and all respiratory symptoms at Day 7: 40% in intranasal ciclesonide did not improve
Key Exclusion Criteria: resolution of fever and respiratory
ciclesonide arm vs. 35% in placebo arm (adjusted
• Already taking an inhaled corticosteroid or taken PO or IM risk difference 5.5%; 95% CI, -7.8% to 18.8%). symptoms in nonhospitalized patients
corticosteroids within 7 days of enrollment with COVID-19.
• Unable to use an inhaler Secondary Outcomes:
• No respiratory symptoms • Percentage of patients with resolution of fever
and all respiratory symptoms at Day 14: 66% in
• Use of oxygen at home ciclesonide arm vs. 58% in placebo arm (adjusted
• COVID-19 vaccinated risk difference 7.5%; 95% CI, -5.9% to 20.8%).
Interventions: • Percentage of patients who were admitted to the
hospital by Day 14: 6% in ciclesonide arm vs. 3%
• Ciclesonide MDI 600 µg/actuation and intranasal ciclesonide
in placebo arm (adjusted risk difference 2.3%;
100 µg, both twice a day for 14 days (n = 105)
95% CI, -3.0% to 7.6%).
• Saline placebo MDI and intranasal saline, both twice a day for
14 days (n = 98)
Primary Endpoint:
• Resolution of fever and all respiratory symptoms at Day 7
• Resolution of fever and all respiratory symptoms at Day 14
• Hospital admission by Day 14
Key: BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; ED = emergency department; HTN = hypertension; IM = intramuscular; MDI =
metered dose inhaler; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PO = oral; RCT = randomized controlled trial; RT-PCR
= reverse transcription polymerase chain reaction
References
1. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK
(PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855. Available at:

2. Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label, randomised
controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
3. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic
COVID-19: a randomized clinical trial. JAMA Intern Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34807241.
4. Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN Phase II randomised
controlled trial. BMJ. 2021;375:e068060. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34728476.

Interleukin-6 Inhibitors
Interleukin (IL)-6 is a pleiotropic, proinflammatory cytokine produced by a variety of cell types,

including lymphocytes, monocytes, and fibroblasts. Infection by SARS-CoV induces a dose-dependent
production of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and
hypoxemic respiratory failure can be associated with heightened cytokine release, as indicated by
elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4 It is hypothesized that
modulating IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19.
There are 2 classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor
monoclonal antibodies (mAbs) (e.g., sarilumab, tocilizumab) and anti-IL-6 mAbs (i.e., siltuximab).
These drugs have been evaluated in patients with COVID-19 who have systemic inflammation.
Recommendations
• See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19
Treatment Guidelines Panel’s (the Panel) recommendations on the use of IL-6 inhibitors (e.g.,
sarilumab, tocilizumab) in hospitalized patients who require supplemental oxygen, high-flow
oxygen, noninvasive ventilation (NIV), or mechanical ventilation.
• The Panel recommends against the use of anti-IL-6 mAb therapy (i.e., siltuximab) for the
treatment of COVID-19, except in a clinical trial (BIII).
• Tocilizumab and sarilumab should be used with caution in patients with COVID-19
who have not been adequately represented in clinical trials. This includes patients who are
significantly immunosuppressed, particularly those who have recently received other biologic
immunomodulating drugs, and patients with any of the following:
• Alanine transaminase levels >5 times the upper limit of normal
• A high risk for gastrointestinal perforation
• An uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection
• Absolute neutrophil counts <500 cells/µL
• Platelet counts <50,000 cells/µL
• Known hypersensitivity to tocilizumab or sarilumab
• Tocilizumab and sarilumab should only be given in combination with a course of dexamethasone
(or an alternative corticosteroid at a dose that is equivalent to dexamethasone 6 mg). See the
Corticosteroids section for more information.
• Some clinicians may assess the patient’s clinical response to dexamethasone before deciding
whether tocilizumab or sarilumab is needed.
• In both the REMAP-CAP and the RECOVERY trials, 29% of patients received a second dose of
tocilizumab at the discretion of their treating physician. However, there is currently insufficient
evidence to recommend either for or against a second dose of tocilizumab.5,6
• Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19
during treatment with tocilizumab and corticosteroids.7,8 Many clinicians would initiate empiric

treatment (e.g., with the antiparasitic drug ivermectin) with or without serologic testing in patients
who are from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate
areas).9
Rationale
The results of the RECOVERY and REMAP-CAP trials provide consistent evidence that tocilizumab,
when coadministered with corticosteroids, offers a modest mortality benefit in certain patients with
COVID-19 who are severely ill, who are rapidly deteriorating and have increasing oxygen needs, and
who have a significant inflammatory response.5,6 However, the Panel found it challenging to define the
specific patient populations that would benefit from this intervention. If tocilizumab is not available,
sarilumab may be used as an alternative because it has demonstrated a similar clinical benefit in
improving survival and reducing the duration of organ support in the REMAP-CAP trial.10 However, the
Panel recommends sarilumab only when tocilizumab is not available or is not feasible to use (BIIa)
because the evidence of efficacy for tocilizumab is more extensive than for sarilumab; in addition,
sarilumab is currently only approved for use as a subcutaneous (SQ) injection in the United States.
The data on the efficacy of siltuximab in patients with COVID-19 are currently limited.11
Anti-Interleukin-6 Receptor Monoclonal Antibodies

Tocilizumab
Tocilizumab is a recombinant humanized anti-IL-6 receptor mAb that is approved by the FDA for use
in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen
receptor T cell (CAR T-cell) therapy. Tocilizumab can be dosed as an intravenous (IV) infusion or an SQ
injection. The IV formulation should be used to treat cytokine release syndrome.11
Clinical data on the use of tocilizumab (and other IL-6 inhibitors) for the treatment of COVID-19,
including data from several randomized trials and large observational studies, are summarized in Table
6c.
The initial studies that evaluated the use of tocilizumab for the treatment of COVID-19 produced
conflicting results. Many of these trials were limited by low power, heterogenous populations, and/or a
low frequency of concomitant use of corticosteroids (now the standard of care for patients with severe
COVID-19).12-16
Subsequently, in the setting of background corticosteroid therapy, the 2 largest randomized controlled
trials evaluating tocilizumab, REMAP-CAP and RECOVERY, both reported a mortality benefit of
tocilizumab in certain patients, including patients exhibiting rapid respiratory decompensation associated
with an inflammatory response. REMAP-CAP enrolled critically ill patients who were within 24 hours
of receiving respiratory support in an intensive care unit. The participants were randomized to receive
open-label tocilizumab or usual care. In-hospital mortality was 28% in the tocilizumab arm and 36% in
the usual care arm.5 The RECOVERY trial enrolled hospitalized patients with COVID-19 into an open-
label platform trial that included several treatment options.6 A subset of all trial participants
who had hypoxemia and CRP levels ≥75 mg/L were offered enrollment into a second randomization that
evaluated tocilizumab versus usual care. In this subgroup, the 28-day mortality was 31% in the
tocilizumab arm and 35% in the usual care arm. For additional findings from the REMAP-CAP and
RECOVERY trials and the rationale for using tocilizumab in certain hospitalized patients who are
exhibiting rapid respiratory decompensations due to COVID-19, see Therapeutic Management of
Hospitalized Adults With COVID-19 .

In contrast to the REMAP-CAP and RECOVERY trials, the REMDACTA trial did not find a mortality
benefit of tocilizumab. The trial randomized hospitalized COVID-19 patients, most of whom required
NIV or high-flow oxygen support, to receive tocilizumab or placebo. All the participants received
remdesivir and most received corticosteroids. Tocilizumab use did not reduce 28-day mortality (18% in
the tocilizumab arm and 20% in the placebo arm).17
Despite this conflicting evidence, the Panel’s recommendations for using tocilizumab are based on the
collective evidence from the clinical trials reported to date (see Table 6c).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of tocilizumab for the
Adverse Effects
The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme
levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. In randomized
trials, no excess secondary infections were seen among patients who received combination therapy
compared to control patients. Additional adverse effects of tocilizumab, such as serious infections (e.g.,
tuberculosis [TB], bacterial or fungal infections) and bowel perforation, have been reported.18
There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth
defects or miscarriage. mAbs are actively transported across the placenta as pregnancy progresses (with
the greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus. Given the paucity of data, current recommendations advise against the use of tocilizumab
during pregnancy.19 Whether to use tocilizumab during pregnancy should be a joint decision between
the pregnant individual and their health care provider, and the decision-making process should include a
discussion of the potential risks and benefits.
There are no systematic observational or randomized controlled trial data on the effectiveness of
tocilizumab for the treatment of acute COVID-19 in pediatric patients or multisystem inflammatory
syndrome in children (MIS-C). Tocilizumab has been used for children with cytokine release syndrome
associated with CAR T-cell therapy and systemic and polyarticular juvenile idiopathic arthritis.20 There
is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab in
hospitalized children with COVID-19 or MIS-C.
Drug Availability
On June 24, 2021, the FDA issued an Emergency Use Authorization (EUA) for the use of tocilizumab in
combination with corticosteroids in hospitalized adults and children aged ≥2 years with COVID-19 who
require supplemental oxygen, NIV, mechanical ventilation, or extracorporeal membrane oxygenation.20
Per this EUA, if a patient’s clinical signs or symptoms worsen or do not improve after the first dose of
tocilizumab, 1 additional infusion of tocilizumab may be administered at least 8 hours after the initial IV
infusion. If there is a local or regional shortage of tocilizumab, sarilumab can be used as an alternative
(see Therapeutic Management of Hospitalized Adults With COVID-19).10
Sarilumab
Sarilumab is a recombinant humanized anti-IL-6 receptor mAb that is approved by the FDA for use
in patients with rheumatoid arthritis. It is available as an SQ formulation and is not approved for the
treatment of cytokine release syndrome.

The clinical data on the use of sarilumab as a treatment for COVID-19 are summarized in Table 6c.
An adaptive Phase 2 and 3 double-blind randomized (2:2:1) placebo-controlled trial compared the
efficacy and safety of sarilumab 400 mg IV and sarilumab 200 mg IV to placebo in hospitalized patients
with COVID-19 (ClinicalTrials.gov Identifier NCT04315298). Results from this trial did not support a
clinical benefit of sarilumab in hospitalized patients receiving supplemental oxygen.21
A similar adaptive design study in the United States in patients with severe and critical COVID-19
also failed to show a benefit of sarilumab. In this placebo-controlled trial, there was a reduction in
mortality among the sarilumab recipients with critical COVID-19 pneumonia who required mechanical
ventilation and received corticosteroids at baseline. However, due to the small sample size, this result
was not statistically significant.22 In the REMAP-CAP trial, the efficacy results for sarilumab were
similar to those for tocilizumab. Compared to the patients in the standard of care arm (n = 418), those
in the sarilumab arm (n = 485) had more organ support-free days (OR 1.50; 95% CrI, 1.13–2.00) and a
greater likelihood of survival while hospitalized (OR 1.51; 95% CrI, 1.06–2.20). A notable limitation to
the sarilumab findings in the REMAP-CAP trial is that patients in the standard of care arm were enrolled
earlier in the pandemic than those in the sarilumab arm: randomization closed on November 2020 for the
standard of care arm and continued through April 2021 for the sarilumab arm.10
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of sarilumab for the treatment
of COVID-19.
Adverse Effects
The primary laboratory abnormalities that have been reported with sarilumab treatment are transient
and/or reversible elevations in liver enzyme levels that appear to be dose dependent and rare occurrences
of neutropenia and thrombocytopenia. Additional adverse effects, such as serious infections (e.g., TB,
bacterial or fungal infections) and bowel perforation, have been reported, but only with long-term use of
sarilumab.
There are insufficient data to determine whether there is a sarilumab-associated risk for major birth
defects or miscarriage. mAbs are actively transported across the placenta as pregnancy progresses (with
the greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus.
The only data on sarilumab use in children are from ongoing trials evaluating the drug’s safety in
children with juvenile idiopathic arthritis. There are no systematic observational or randomized
controlled trial data on the efficacy of sarilumab for the treatment of pediatric COVID-19 or MIS-C.
Drug Availability
The IV formulation of sarilumab is not approved by the FDA, but in a clinical trial, a single SQ dose
(using the prefilled syringe, not the prefilled pen) of sarilumab 400 mg was reconstituted in 100 cc 0.9%
NaCl and given as an IV infusion over a 1-hour period.

Anti-Interleukin-6 Monoclonal Antibody
Siltuximab
Siltuximab is a recombinant human-mouse chimeric mAb that binds IL-6 and is approved by the FDA
for use in patients with multicentric Castleman disease. Siltuximab prevents the binding of IL-6 to both
soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling. Siltuximab is dosed as an IV
infusion.
There are limited data on the efficacy of siltuximab in patients with COVID-19.23 There are no data
describing clinical experiences using siltuximab for patients with other novel coronavirus infections (i.e.,
severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of siltuximab for the
Adverse Effects
The primary adverse effects reported for siltuximab have been related to rash. Additional adverse effects
(e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once
every 3 weeks.
There are insufficient data to determine whether there is a siltuximab-associated risk for major birth
defects or miscarriage. mAbs are transported across the placenta as pregnancy progresses (with the
greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus.
The safety and efficacy of siltuximab have not been established in pediatric patients.
References
1. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-
induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of
monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at:
2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at:
3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan,
China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
4. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan,
China. Clin Infect Dis. 2020;71(15):769-777. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.

related strongyloides hyperinfection. JAMA. 2020;324(7):623-624. Available at:
10. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for
critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain
randomized clinical trial. medRxiv. 2021;Preprint. Available at:
11. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T
cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available
12. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19.
13. Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among
critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51. Available at:
14. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized
with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med.
15. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J
16. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N
17. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe
COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at:
18. Charan J, Dutta S, Kaur R, et al. Tocilizumab in COVID-19: a study of adverse drug events reported in the
WHO database. Expert Opin Drug Saf. 2021;20(9):1125-1136. Available at:
19. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline
for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol.
20. Food and Drug Administration. Letter of authorization: EUA for tocilizumab (Actemra) for the treatment of
coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/150319/download.
21. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical
COVID-19: a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(5):522-
22. Sivapalasingam S, Lederer DJ, Bhore R, et al. Efficacy and safety of sarilumab in hospitalized patients with
COVID-19: a randomized clinical trial. Clin Infect Dis. 2022;Published online ahead of print. Available at:
23. Gritti G, Raimondi F, Ripamonti D, et al. IL-6 signalling pathway inactivation with siltuximab in patients with
COVID-19 respiratory failure: an observational cohort study. medRxiv. 2020;Preprint. Available at:

Table 6c. Interleukin-6 Inhibitors: Selected Clinical Data
Last Updated May 31, 2022
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for IL-6
inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
This table may include data from preprints or articles that have not been peer reviewed. This table will be updated as new information
becomes available.
RECOVERY: Open-Label RCT of Tocilizumab and Usual Care in Hospitalized Adults With COVID-19 in the United Kingdom1
• Evidence of COVID-19 progression ≤21 days • Mean age 64 years; 67% men; 76% White • Arbitrary CRP ≥75 mg/L cutoff for
after initial randomization to an intervention • 95% with PCR-confirmed SARS-CoV-2 infection enrollment
within the RECOVERY protocol, defined as: • Difficult to define exact subset of
• At baseline:
• SpO2 <92% on room air or receipt of patients in RECOVERY cohort who were
• 45% on conventional oxygen
supplemental oxygen; and subsequently selected for secondary
• 41% on HFNC oxygen or NIV randomization/tocilizumab trial
• CRP ≥75 mg/L
• 14% on MV
Key Exclusion Criterion: Interpretation:
• 82% on corticosteroids
• Non-SARS-CoV-2 infection • Among hospitalized COVID-19 patients
Primary Outcomes: with hypoxemia and elevated CRP,
Interventions: • 28-day all-cause mortality: 31% in tocilizumab arm vs. 35% in usual tocilizumab was associated with reduced
• Single weight-based dose of tocilizumab care arm (rate ratio 0.85; 95% CI, 0.76–0.94; P = 0.003) all-cause mortality and shorter time to
(maximum 800 mg) and possible second • 28-day all-cause mortality among those who required MV at baseline: discharge alive.
dose (n = 2,022) 49% in tocilizumab arm vs. 51% in usual care arm (risk ratio 0.93;
• Usual care (n = 2,094) 95% CI, 0.74–1.18)
Primary Endpoint: Secondary Outcomes:
• 28-day all-cause mortality • Proportion discharged alive from hospital within 28 days: 57% in
tocilizumab arm vs. 50% in usual care arm (rate ratio 1.22; 95% CI,
Key Secondary Endpoints: 1.12–1.33; P < 0.0001)
• Time to discharge from hospital, alive, • Median time to discharge: 19 days in tocilizumab arm vs. 28 days in
within 28 days usual care arm
• Among those not on MV at enrollment, • Proportion not on MV at baseline who died or required MV within 28
death or receipt of MV within 28 days days: 35% in tocilizumab arm vs. 42% in usual care arm (rate ratio
0.84; 95% CI, 0.77–0.92; P < 0.0001)

REMAP-CAP: Open-Label, Adaptive-Platform RCT of Tocilizumab and Sarilumab in Adults With COVID-19 in 21 Countries in Europe and North America2,3
• ICU admission • Mean age 60 years; 69% men; 75% White • The SOC arm closed in November 2020,
• Suspected or laboratory-confirmed • 86% PCR-confirmed SARS-CoV-2 infection after which patients were randomized
COVID-19 to active arms only; enrollment in the
• Median 14 hours from ICU admission to enrollment tocilizumab and sarilumab arms was
• Receipt of MV, NIV, or cardiovascular • At baseline: partially nonconcurrent with the SOC
support arm, and although comparisons to the
• 68% on HFNC oxygen or NIV
Key Exclusion Criteria: • 32% on MV SOC arm were adjusted for time period,
• >24 hours after ICU admission there is a possibility of bias.
• On corticosteroids: 67% in SOC arm, 82% in tocilizumab arm,
• Presumption of imminent death 89% in sarilumab arm Interpretation:
• Immunosuppression Primary Outcomes • Among patients with respiratory
failure who were within 24 hours of
• ALT >5 times ULN Tocilizumab vs. SOC:
ICU admission, the tocilizumab and
Interventions: • Median organ support-free days: 7 in tocilizumab arm vs. 0 in SOC arm sarilumab arms had higher rates of in-
• SOC plus 1 of the following (drug selection • Improved composite outcome, by ordinal scale: median aOR 1.46 hospital survival and shorter durations
based on provider preference, availability, or (95% CrI, 1.13–1.87) of organ support than the SOC arm.
adaptive probability): • Highest CRP tercile: aOR 1.87 (95% CrI, 1.35–2.59) • These results were reported in a preprint
• Single dose tocilizumab 8 mg/kg IV and • Outcomes consistent across subgroups according to oxygen and are consistent with those for a
possible second dose in 12–24 hours (n requirement at baseline smaller cohort previously published in a
= 952) peer-reviewed article.
• Single dose sarilumab 400 mg IV (n = Sarilumab vs. SOC: • The treatment effect appeared to be
485) • Median organ support-free days: 9 in sarilumab arm vs. 0 in SOC arm strongest in the highest CRP tercile.
• SOC alone (n = 406) • Improved composite outcome, by ordinal scale: median aOR 1.50 • Tocilizumab and sarilumab were
(95% CrI, 1.13–2.00) similarly effective, with a 99%
Primary Endpoint:
• Highest CRP tercile: aOR 1.85 (95% CrI, 1.24–2.69) probability of noninferiority of sarilumab.
• Composite of in-hospital mortality and
organ support-free days to Day 21 (ordinal • Outcomes consistent across subgroups according to oxygen
scale) requirements at study entry
Key Secondary Endpoint: Secondary Outcomes

• In-hospital survival Tocilizumab vs. SOC:
• In-hospital survival: 66% in tocilizumab arm vs. 63% in SOC arm
(aOR 1.42; 95% CrI, 1.05–1.93)
Sarilumab vs. SOC:
• In-hospital survival: 67% in sarilumab arm vs. 63% in SOC arm (aOR
1.51; 95% CrI, 1.06–2.20)

COVACTA: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in 9 Countries in Europe and North America4
• PCR-confirmed SARS-CoV-2 infection • Mean age 61 years; 70% men; 58% White • Modest power to detect differences in
• Hypoxemia • 30% on HFNC oxygen or NIV Day 28 clinical status
• Bilateral chest infiltrates • 38% on MV • More patients in placebo arm
than tocilizumab arm received
Key Exclusion Criteria: • 25% with multiorgan failure corticosteroids.
• Presumption of imminent death • Received corticosteroids at entry or during follow-up: 36% in
tocilizumab arm, 55% in placebo arm Interpretation:
• Presence of active non-SARS-CoV-2 • There was no difference in Day 28
infection Primary Outcome: clinical status or survival between the
Interventions: • Day 28 clinical status: no significant difference between arms (P = tocilizumab and placebo recipients.
0.31) • The median time to discharge was
• Single dose of tocilizumab 8 mg/kg and
possible second dose, plus SOC (n = 294) Secondary Outcomes: significantly shorter in the tocilizumab
• Placebo plus SOC (n = 144) • Median time to discharge: 20 days in tocilizumab arm vs. 28 days in arm than in the placebo arm.
placebo arm (HR 1.35; 95% CI, 1.02–1.79) • Although the result was not statistically
Primary Endpoint:
• Median ICU LOS: 9.8 days in tocilizumab arm vs. 15.5 days in significant, the tocilizumab arm had a
• Day 28 clinical status (ordinal score) shorter ICU LOS than the placebo arm.
placebo arm (difference 5.8 days, 95% CI, –15.0 to 2.9)
Key Secondary Endpoints: • Day 28 mortality: 20% in tocilizumab arm vs. 19% in placebo arm (P
• Time to discharge = 0.94)
• ICU LOS
• Day 28 mortality

EMPACTA: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in 6 Countries in North America, South America, and Africa5
• PCR-confirmed SARS-CoV-2 infection • Mean age 56 years; 59% men; 56% Hispanic/Latinx, 15% Black/ • Moderate sample size
• COVID-19 pneumonia African American, 13% American Indian/Alaska Native
Interpretation:
• 84% with elevated CRP
Key Exclusion Criteria: • In patients with COVID-19 pneumonia,
• Concomitant medications: tocilizumab reduced the likelihood of
• Presumption of imminent death
• Corticosteroids: 80% in tocilizumab arm, 88% in placebo arm progression to MV, ECMO, or death by
• Receiving NIV or MV Day 28 but did not reduce 28-day all-
• RDV: 53% in tocilizumab arm, 59% in placebo arm
Interventions: cause mortality.
Primary Outcome:
• Single dose of tocilizumab 8 mg/kg plus
SOC, possible second dose (n = 249) • Proportion who progressed to MV, ECMO, or death by Day 28:
12% in tocilizumab arm vs. 19% in placebo arm (HR 0.56; 95% CI,
• Placebo plus SOC (n = 128)
0.33–0.97; P = 0.04)
Primary Endpoint:
Secondary Outcomes:
• Progression to MV, ECMO, or death by Day
• Median time to hospital discharge or readiness for discharge: 6.0
28
days in tocilizumab arm vs. 7.5 days in placebo arm (HR 1.16; 95%
Key Secondary Endpoints: CI, 0.91–1.48)
• Time to hospital discharge or readiness for • All-cause mortality by Day 28: 10.4% in tocilizumab arm vs. 8.6% in
discharge (ordinal score) placebo arm (95% CI, –5.2 to 7.8)
• All-cause mortality by Day 28

BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in the United States6
• Laboratory-confirmed SARS-CoV-2 • Median age 60 years; 58% men; 45% Hispanic/Latinx, 43% White • Wide confidence intervals due to small
infection • 50% with BMI ≥30; 49% with HTN; 31% with DM sample size and low event rates
• ≥2 of the following conditions: • 80% receiving oxygen ≤6 L/min; 4% receiving HFNC oxygen; 16% • Few patients received RDV or
• Fever >38°C receiving no supplemental oxygen corticosteroids
• Pulmonary infiltrates • Concomitant medications: Interpretation:
• Need for supplemental oxygen • Corticosteroids: 11% in tocilizumab arm, 6% in placebo arm • There was no benefit of tocilizumab in
• RDV: 33% in tocilizumab arm, 29% in placebo arm preventing MV or death, reducing the
• ≥1 of the following laboratory criteria: risk of clinical worsening, or reducing
• CRP ≥50 mg/L Primary Outcome: the time to discontinuation of oxygen.
• D-dimer >1,000 ng/mL • Day 28 MV or death: 11% in tocilizumab arm vs. 12% in placebo arm This could be due to the low rate of
(HR 0.83; 95% CI, 0.38–1.81; P = 0.64) concomitant corticosteroid use among
• LDH ≥250 U/L
the study participants.
• Ferritin >500 ng/mL Secondary Outcomes:
Key Exclusion Criteria: • Proportion with clinical worsening of disease by Day 28: 19% in
tocilizumab arm vs. 17% in placebo arm (HR 1.11; 95% CI, 0.59–
• Receipt of supplemental oxygen at rate >10 2.10; P = 0.73)
L/min
• Median days to discontinuation of oxygen: 5.0 in tocilizumab arm vs.
• Recent use of biologic agents or small- 4.9 in placebo arm (P = 0.69)
molecule immunosuppressive therapy
• Receipt of immunosuppressive therapy that
increased risk for infection
Interventions:
• Tocilizumab 8 mg/kg plus usual care (n =
161)
• Placebo plus usual care (n = 81)
Primary Endpoint:
• Receipt of MV or death, according to a time
to event analysis; data censored at Day 28
• Clinical worsening by Day 28 (ordinal score)
• Discontinuation of supplemental oxygen
among patients receiving it at baseline

Double-Blind, RCT of Sarilumab in Hospitalized Adults With Severe or Critical COVID-19 in 11 Countries in Europe, North America, South America, and Asia7
• COVID-19 pneumonia • Median age 59 years; 63% men; 77% White, 36% Hispanic/Latinx • Moderate sample size
• Requirement for supplemental oxygen or • 39% on HFNC oxygen, MV, or NIV Interpretation:
intensive care • 42% with BMI ≥30; 43% with HTN; 26% with type 2 DM • Sarilumab showed no mortality
Key Exclusion Criteria: • 20% received systemic corticosteroids before receiving intervention; benefit or reduction in time to clinical
• Low probability of surviving or remaining at 63% received ≥1 dose of corticosteroids during the study improvement in hospitalized adults with
study site COVID-19.
Primary Outcomes:
• Dysfunction of ≥2 organ systems and need • Median time to clinical improvement: 10 days in each sarilumab arm,
for ECMO or renal replacement therapy 12 days in placebo arm
Interventions: • Sarilumab 200 mg arm vs. placebo arm: HR 1.03; 95% CI,
• Sarilumab 400 mg IV (n = 173) 0.75–1.40; P = 0.96
• Sarilumab 200 mg IV (n = 159) • Sarilumab 400 mg arm vs. placebo arm: HR 1.14; 95% CI,
0.84–1.54; P = 0.34
Secondary Outcome:
Primary Endpoint:
• Survival at Day 29: 92% in placebo arm; 90% in sarilumab 200 mg
• Time to clinical improvement of ≥2 points
arm (P = 0.63 vs. placebo); 92% in sarilumab 400 mg arm (P = 0.85
on a 7-point scale
vs. placebo)
• Survival at Day 29

REMDACTA: Double-Blind RCT of Tocilizumab and Remdesivir in Hospitalized Patients With Severe COVID‑19 Pneumonia in Brazil, Russia, Spain, and the
United States8
• Aged ≥12 years • Mean age 59 years; 40% in tocilizumab arm and 34% in placebo arm • During the trial, primary outcome
• PCR-confirmed SARS-CoV-2 infection aged ≥65 years; 63% men; 67% White changed from clinical status on Day
• Respiratory support: 28 to time to discharge or ready for
• Hospitalized with pneumonia confirmed discharge through Day 28
by CXR or CT and requiring supplemental • NIV or HFNC oxygen: 78% in tocilizumab arm, 83% in placebo
oxygen >6 L/min arm • Imbalances in patient characteristics at
baseline between arms
Key Exclusion Criteria: • MV or ECMO: 15% in tocilizumab arm, 11% in placebo arm
• Possible underrepresentation of patients
• eGFR <30 mL/min • Corticosteroid use: with rapidly progressive disease
• ALT or AST >5 times ULN • At baseline: 83% in tocilizumab arm, 86% in placebo arm Interpretation:
• Presence of non-SARS-CoV-2 infection • During trial: 88% in each arm • Compared with placebo plus RDV,
• Treatment with antivirals, CP, CQ, HCQ, JAK Primary Outcome: tocilizumab plus RDV did not shorten
inhibitors the time to discharge or ready for
• Time to discharge or ready for discharge through Day 28: 14 days in
Interventions: each arm (HR 0.97; 95% CI, 0.78–1.19; P = 0.74) discharge in patients with severe
COVID-19 pneumonia.
• Up to 10 days RDV plus: Secondary Outcomes:
• There was no difference in mortality
• Tocilizumab 8 mg/kg IV, with second • No difference between arms: between the arms.
dose within 8–24 hours if indicated (n =
• Proportion who required MV or died by Day 28: 29% in each arm;
434)
time to death not evaluable (HR 0.98; 95% CI, 0.72–1.34; P =
• Placebo (n = 215) 0.90)
Primary Endpoint: • Mean ordinal score for Day 14 clinical status: 2.8 in tocilizumab
• Time to discharge or ready for discharge arm vs. 2.9 in placebo arm (P = 0.72)
through Day 28 • Death by Day 28: 18% in tocilizumab arm vs. 20% in placebo arm;
time to death not evaluable (HR 0.95; 95% CI, 0.65–1.39; P =
0.79)
• Time to MV or death through Day 28
• Day 14 clinical status (ordinal score)
• Time to death through Day 28
Key: ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CP = convalescent plasma; CQ = chloroquine; CRP = C-reactive protein; CT
= computed tomography; CXR = chest X-ray; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate;
HCQ = hydroxychloroquine; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase;
LDH = lactate dehydrogenase; LOS = length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment Guidelines
Panel; PCR = polymerase chain reaction; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; SpO2 = oxygen saturation; ULN = upper limit
of normal

References
1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label,
platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33933206.
2. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med.
3. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the
REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at:
4. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021;384(16):1503-1516.
5. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at:
6. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-
7. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind,
placebo-controlled, phase 3 trial. Lancet Respir Med. 2021;9(5):522-532. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.
8. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical
trial. Intensive Care Med. 2021;47(11):1258-1270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34609549.

Kinase Inhibitors: Janus Kinase Inhibitors and
Bruton’s Tyrosine Kinase Inhibitors
Janus Kinase Inhibitors

Janus kinase (JAK) inhibitors such as baricitinib and tofacitinib have been shown to improve clinical
outcomes among hospitalized patients with COVID-19. The primary mechanism of JAK inhibitors
is interference with phosphorylation of the signal transducer and activator of transcription (STAT)
proteins1,2 involved in vital cellular functions, including signaling, growth, and survival. These kinase
inhibitors are used as treatments for COVID-19 because they can prevent phosphorylation of key
proteins involved in the signal transduction that leads to immune activation and inflammation (e.g.,
the cellular response to proinflammatory cytokines such as interleukin [IL]-6).3 Additionally, JAK
inhibitors, particularly baricitinib, have theoretical direct antiviral activity through interference with viral
endocytosis, potentially preventing SARS-CoV-2 from entering and infecting susceptible cells.4
In May 2022, the Food and Drug Administration (FDA) approved the use of baricitinib for the treatment
of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive ventilation (NIV),
mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).5
Recommendations
• Baricitinib or tofacitinib is recommended in combination with dexamethasone in hospitalized
patients with evidence of inflammation and increasing oxygen needs. See Therapeutic Management
of Hospitalized Adults With COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the
Panel) detailed recommendations and ratings on the use of baricitinib and tofacitinib.
• The Panel recommends against the use of JAK inhibitors other than baricitinib or tofacitinib
for the treatment of COVID-19, except in a clinical trial (AIII).
Rationale
Several large randomized controlled trials have demonstrated that some patients who require
supplemental oxygen and most patients who require a high-flow device, NIV, or mechanical ventilation
benefit from the use of dexamethasone in combination with baricitinib or tofacitinib.
In the RECOVERY trial, baricitinib was associated with a survival benefit among hospitalized
patients, with a treatment effect that was most pronounced among patients receiving NIV or oxygen
supplementation through a high-flow device.6 The COV-BARRIER trial also demonstrated a survival
benefit from baricitinib that was most pronounced among patients receiving high-flow oxygen or NIV.7
In the addendum to the COV-BARRIER trial, the benefit extended to patients receiving mechanical
ventilation.8 Data from the ACTT-29 and ACCT-410 trials support the overall safety of baricitinib and the
potential for benefit, but neither trial studied the drug in combination with dexamethasone as standard care.
The STOP-COVID study examined the use of tofacitinib in people with COVID-19 pneumonia who
were not receiving mechanical ventilation at the time of enrollment.11 The study demonstrated a survival
benefit in patients who received tofacitinib, nearly all of whom also received corticosteroids. Tofacitinib
has less clinical data support than baricitinib, but tofacitinib can be used as an alternative if baricitinib is
not available.
Clinical trial data on the use of JAK inhibitors, including baricitinib and tofacitinib, in patients with

COVID-19 are summarized below and in Table 6d. All related treatment recommendations are reviewed
in Therapeutic Management of Hospitalized Adults With COVID-19.

Adverse effects of JAK inhibitors include infections (typically respiratory and urinary tract infections),
reactivation of herpes virus infections, myelosuppression, transaminase elevations, and, rarely,
gastrointestinal perforation. An FDA review of a large, randomized safety clinical trial in people with
rheumatoid arthritis compared tofacitinib to tumor necrosis factor inhibitors over 4 years and found
that tofacitinib was associated with additional serious adverse events, including heart attack or stroke,
cancer, blood clots, and death.12 Therefore, the FDA now requires new and updated warnings for drugs
in the JAK inhibitor class, including tofacitinib and baricitinib. Data from randomized trials evaluating
the safety of short-term use of JAK inhibitors in patients with COVID-19 have not revealed significant
safety signals, including thrombosis.6,7,9-11
A complete blood count with differential, liver enzyme, and kidney function tests should be obtained
from all patients before administering baricitinib or tofacitinib and during treatment as clinically
indicated. Because of the immunosuppressive effects of baricitinib, all patients receiving the drug should
also be monitored for new infections.
Tofacitinib is a cytochrome P450 (CYP) 3A4 substrate. Dose modifications are required when the drug
is administered with strong CYP3A4 inhibitors or when used with a moderate CYP3A4 inhibitor that is
coadministered with a strong CYP2C19 inhibitor. Coadministration with a strong CYP3A4 inducer is
not recommended. See Table 6g for kinase inhibitor drug characteristics and dosing information.
Baricitinib
In May 2022, the FDA approved the use of baricitinib for the treatment of COVID-19 in hospitalized
adults requiring supplemental oxygen, NIV, mechanical ventilation, or ECMO.5 It is also FDA approved
for the treatment of rheumatoid arthritis.
Baricitinib is an oral JAK inhibitor that is selective for JAK1 and JAK2. It can modulate downstream
inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-
induced STAT3 phosphorylation.13 Baricitinib has postulated antiviral effects by blocking SARS-CoV-2
from entering and infecting lung cells.14 In macaques infected with SARS-CoV-2, baricitinib reduced
inflammation and lung pathology, but an antiviral effect was not confirmed.15
For additional details on clinical trial data for baricitinib, see Table 6d. For information on the Panel’s
recommendations for the use of baricitinib in hospitalized patients with COVID-19, see Therapeutic
Management of Hospitalized Adults With COVID-19.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of baricitinib for the treatment of
COVID-19.
Tofacitinib
Tofacitinib is the prototypical JAK inhibitor, predominantly selective for JAK1 and JAK3, with modest
activity against JAK2, and, as such, can block signaling from gamma-chain cytokines (e.g., IL-2, IL-4)
and glycoprotein 130 proteins (e.g., IL-6, IL-11, interferons). It is an oral agent first approved by the
FDA for the treatment of rheumatoid arthritis and has been shown to decrease levels of IL-6 in patients
with this disease.16 Tofacitinib is also FDA approved for the treatment of psoriatic arthritis, juvenile

idiopathic arthritis, and ulcerative colitis.17
For additional details on clinical trial data for tofacitinib, see Table 6d.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of tofacitinib for the treatment of
COVID-19.
Ruxolitinib
Ruxolitinib is an oral JAK inhibitor selective for JAK1 and JAK2 that is currently approved for
myelofibrosis, polycythemia vera, and acute graft-versus-host disease.18 Like baricitinib, it can modulate
downstream inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent
inhibition of IL-6-induced STAT3 phosphorylation.13 Ruxolitinib also has postulated antiviral effects by
blocking SARS-CoV-2 from entering and infecting lung cells.14
A small, single-blind, Phase 2 randomized controlled trial in patients with COVID-19 in China
compared ruxolitinib 5 mg orally twice daily (n = 20) with placebo (administered as vitamin C 100 mg;
n = 21), both given in combination with standard of care. Treatment with ruxolitinib was associated with
a nonsignificant reduction in the median time to clinical improvement (12 days for ruxolitinib recipients
vs. 15 days for placebo recipients; P = 0.15), defined as a 2-point improvement on a 7-category ordinal
scale or hospital discharge. There was no difference between the arms in the median time to discharge
(17 days for ruxolitinib arm vs. 16 days for placebo arm; P = 0.94). Limitations of this study include
the small sample size.19 A Phase 3 trial of ruxolitinib in patients with COVID-19-associated acute
respiratory distress syndrome is currently in progress (ClinicalTrials.gov Identifier NCT04377620).
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of ruxolitinib for the treatment of
COVID-19.
There is a paucity of data on the use of JAK inhibitors in pregnancy. As small-molecule drugs, JAK
inhibitors are likely to pass through the placenta; therefore, fetal risk cannot be ruled out.20 Decisions
regarding the administration of JAK inhibitors must include shared decision-making between pregnant
individuals and their health care providers, and potential maternal benefit and fetal risks should be
considered. In the decision-making process, factors to be considered include maternal COVID-19
severity, comorbidities, and gestational age. Pregnancy registries provide some outcome data on
tofacitinib use during pregnancy for other conditions (e.g., ulcerative colitis, rheumatoid arthritis,
psoriasis). Among the 33 cases reported, pregnancy outcomes were similar to those among the general
population.21-23
Please see Therapeutic Management of Hospitalized Children With COVID-19 for the Panel’s
recommendations regarding the use of baricitinib or tofacitinib in children.
Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor and cytokine
receptor pathways. The potential benefit of BTK inhibition as a treatment for COVID-19 would be a

reduction in the immunopathology associated with severe disease.
Recommendation
• The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19, except
in a clinical trial (AIII).
Acalabrutinib
Acalabrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat B-cell
malignancies (i.e., chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma).
It has a better toxicity profile than first-generation BTK inhibitors (e.g., ibrutinib) because it has less
off-target activity for other kinases.24 Acalabrutinib is proposed for use in patients with COVID-19
because it can modulate signaling that promotes inflammation.
Data regarding acalabrutinib are limited to the results from a prospective case series of 19 patients with
severe COVID-19.25 The small sample size and lack of a control group limit evaluation of the data to
discern any clinical benefit.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of acalabrutinib for the treatment of
COVID-19.
Ibrutinib
Ibrutinib is a first-generation BTK inhibitor that is FDA approved to treat various B-cell malignancies26
and to prevent chronic graft-versus-host disease in stem cell transplant recipients.27 Based on results
from a small case series, ibrutinib has been theorized to reduce inflammation and protect against ensuing
lung injury in patients with COVID-19.28
Data regarding ibrutinib are limited to those from an uncontrolled, retrospective case series of 6 patients
with COVID-19 who received the drug for a condition other than COVID-19.28 The small sample size
and lack of a control group limit evaluation of the data to discern any clinical benefit.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of ibrutinib for the treatment of
COVID-19.
Zanubrutinib
Zanubrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat mantle cell
lymphoma.29 It has been shown to have fewer toxicities than first-generation BTK inhibitors (e.g.,
ibrutinib) because it has less off-target activity for other kinases.30 Zanubrutinib is proposed to benefit
patients with COVID-19 by modulating signaling that promotes inflammation.
There are no clinical data on the use of zanubrutinib to treat COVID-19.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of zanubrutinib for the treatment of
COVID-19.

Adverse Effects and Monitoring
Hemorrhage and cardiac arrhythmia have occurred in patients who received BTK inhibitors.
There is a paucity of data on human pregnancy and BTK inhibitor use. In animal studies, acalabrutinib
and ibrutinib in doses exceeding the therapeutic human dose were associated with interference
with embryofetal development.26,31 Based on these data, use of BTK inhibitors that occurs during
organogenesis may be associated with fetal malformations. The impact of use later in pregnancy is
unknown. Risks of use should be balanced against potential benefits.
The safety and efficacy of BTK inhibitors have not been evaluated in pediatric patients with COVID-19,
and data on the use of the drugs in children with other conditions are extremely limited. The Panel
recommends against the use of BTK inhibitors for the treatment of COVID-19 in pediatric patients,
except in a clinical trial (AIII).
References
1. Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK)
activation. Biochem J. 2014;462(1):1-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25057888.
2. Bousoik E, Montazeri Aliabadi H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling
pathway. Front Oncol. 2018;8:287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30109213.
3. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe
coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol.
4. Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments.
Lancet Infect Dis. 2020;20(4):400-402. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32113509.
5. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2022. Available at:
8. Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for
the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or
extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir

12. Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events,
cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2021.
Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-
risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed June 27, 2022.
13. McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated
regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183.
14. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory
disease. Lancet. 2020;395(10223):e30-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32032529.
15. Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage
inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell. 2021;184(2):460-
475 e421. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278358.
16. Migita K, Izumi Y, Jiuchi Y, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid
A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208-214.
17. Tofacitinib (Xeljanz) [package insert]. Food and Drug Administration. 2019. Available at: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2019/203214s024,208246s010lbl.pdf.
18. Ruxolitinib (Jakafi) [package insert]. Food and Drug Administration. 2019. Available at: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2019/202192s017lbl.pdf.
19. Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a
multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020;146(1):137-146 e133.
21. Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for
rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755-762. Available at:
22. Mahadevan U, Dubinsky MC, Su C, et al. Outcomes of pregnancies with maternal/paternal exposure in the
tofacitinib safety databases for ulcerative colitis. Inflamm Bowel Dis. 2018;24(12):2494-2500. Available at:
23. Wieringa JW, van der Woude CJ. Effect of biologicals and JAK inhibitors during pregnancy on health-
related outcomes in children of women with inflammatory bowel disease. Best Pract Res Clin Gastroenterol.
2020;44-45:101665. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32359679.
24. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the
treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240. Available at:
25. Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe
COVID-19. Sci Immunol. 2020;5(48). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32503877.
26. Ibrutinib (Imbruvica) [package insert]. Food and Drug Administration. 2015. Available at: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf.
27. Food and Drug Administration. FDA expands ibrutinib indications to chronic GVHD. 2017. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ibrutinib-indications-chronic-
gvhd. Accessed June 27, 2022.
28. Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in
COVID-19-infected patients. Blood. 2020;135(21):1912-1915. Available at:

29. Zanubrutinib (Brukinsa) [package insert]. Food and Drug Administration. 2019. Available at:
30. Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in
patients with relapsed/refractory B-cell malignancies: initial report of a Phase 1 first-in-human trial. Blood.
2015;126(23):832. Available at: https://ashpublications.org/blood/article/126/23/832/136525/The-BTK-
Inhibitor-Bgb-3111-Is-Safe-Tolerable-and.
31. Acalabrutinib (Calquence) [package insert]. Food and Drug Administration. 2017. Available at:

Table 6d. Kinase Inhibitors: Selected Clinical Data
kinase inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as new
information becomes available. Please see ClinicalTrials.gov for more information on clinical trials evaluating kinase inhibitors.

RECOVERY: Open-Label RCT of Baricitinib Versus Usual Care in the United Kingdom1
• Hospitalized with suspected or laboratory- • Mean age 58 years; 66% men; 80% White • Open-label study
confirmed SARS-CoV-2 infection • Median duration of symptoms at enrollment: 9 days Interpretation:
Key Exclusion Criteria: • 91% with laboratory-confirmed SARS-CoV-2 infection • In patients hospitalized for COVID-19,
• eGFR <15 mL/min/1.73m2 • At baseline: BAR reduced the risk of death.
• ANC <500 cells/mm3 • 95% received corticosteroids
• Evidence of active TB • 23% received tocilizumab
• 20% received remdesivir
Interventions:
• 42% received ≥1 COVID-19 vaccine
• BAR 4 mg PO daily for 10 days or until • 6% no supplemental oxygen required
discharge, whichever comes first (n =
• 68% simple oxygen
4,148)
• 24% NIV
• SOC (n = 4,008) • 3% MV
Primary Endpoint: Primary Outcome:
• 28-day mortality • 28-day mortality: 12% in BAR arm vs. 14% in SOC arm (age-adjusted
Key Secondary Endpoints: rate ratio 0.87; 95% CI, 0.77–0.98; P = 0.028)
• Time to discharge from hospital Secondary Outcomes:
• Composite of MV, ECMO, or death • Discharge within 28 days: 80% in BAR arm vs. 78% in SOC arm (age-
adjusted rate ratio 1.10; 95% CI, 1.04–1.15; P = 0.002)
• Median time to discharge: 8 days in both arms
• Composite of MV, ECMO, or death: 16% in BAR arm vs. 17% in SOC
arm (age-adjusted risk ratio 0.89; 95% CI, 0.81–0.98; P = 0.016)

COV-BARRIER: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib in Hospitalized Adults in 12 Countries in Asia, Europe, North America, and
South America2
• Laboratory-confirmed SARS-CoV-2 • Mean age 58 years; 63% men • Results from the ACTT-2 trial prompted
infection • 79% received corticosteroids; 19% received RDV; 13% received a protocol amendment limiting
• Evidence of pneumonia or active, oxygen but no steroids enrollment to participants who required
symptomatic COVID-19 baseline oxygen.
Primary Outcome:
• ≥1 elevated inflammatory marker (CRP, Interpretation:
• Clinical progression or death by Day 28: 28% in BAR arm vs. 31% in
D-dimer, LDH, or ferritin) • Although the primary outcome of
placebo arm (OR 0.85; 95% CI, 0.67–1.08; P = 0.18)
Key Exclusion Criteria: clinical progression or death was not
Secondary Outcomes: significantly different between arms,
• MV or ECMO treatment with BAR plus SOC was
• Mortality by Day 28: 8% in BAR arm vs. 13% in placebo arm (HR
• Receipt of immunosuppressants (including 0.57; 95% CI, 0.41–0.78; P = 0.0018) associated with reduced mortality in
high-dose steroids) hospitalized adults with COVID-19 who
• Mortality by Day 28 for those receiving corticosteroids at baseline:
• Prior receipt of CCP or IVIG 9% in BAR arm vs. 14% in placebo arm (HR 0.63; 95% CI, 0.45– were not receiving MV (see addendum
0.89) below for results for patients who
• ANC <1,000 cells/µL
required MV or ECMO).
• ALC <200 cells/µL
• For patients receiving oxygen but not
• ALT or AST >5 times ULN steroids at baseline, the primary and
• eGFR <30 mL/min secondary outcomes were similar to
the outcomes for the overall study
Interventions: population.
• BAR 4 mg PO once daily for up to 14 days
(n = 764)
Primary Endpoint:
• Clinical progression or death by Day 28
• Mortality by Day 28

COV-BARRIER Addendum: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib in Hospitalized Adults on Mechanical Ventilation or
Extracorporeal Membrane Oxygenation in Argentina, Brazil, Mexico, and the United States3
• Laboratory-confirmed SARS-CoV-2 • Mean age 59 years; 55% men • Very small sample size, exploratory
infection • 86% received corticosteroids; 2% received RDV analysis
• Evidence of pneumonia or active, • High mortality in placebo arm
Outcomes:
symptomatic COVID-19
• Mortality at Day 28: 39% in BAR arm vs. 58% in placebo arm (HR Interpretation:
• ≥1 elevated inflammatory marker (CRP,
0.54; 95% CI, 0.31–0.96; P = 0.030) • In critically ill patients with COVID-19
D-dimer, LDH, or ferritin)
• Number of ventilator-free days and duration of hospitalization: no receiving MV or ECMO, treatment with
• MV or ECMO at baseline BAR and SOC (including corticosteroids)
significant difference between arms
Key Exclusion Criteria: may decrease mortality.
• Receipt of immunosuppressants (including
high-dose steroids)
• Prior receipt of CCP or IVIG
• ANC <1,000 cells/µL
• ALC <200 cells/µL
• ALT or AST >5 times ULN
• eGFR <30 mL/min
Interventions:
• BAR 4 mg PO once daily for up to 14 days
(n = 51)
Key Endpoints:
• Mortality at Day 28
• Number of ventilator-free days
• Duration of hospitalization

ACTT-2: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib Plus Remdesivir in Hospitalized Adults With COVID-19 in 8 Countries in Europe,
North America, and Asia4
• Positive SARS-CoV-2 PCR result • Mean age 55 years; 63% men; 48% White, 15% Black, 10% Asian • Not powered to detect difference in
• Radiographic infiltrates, SpO2 ≤94% on • At baseline: mortality between arms
room air, or requiring supplemental oxygen, • 13% no supplemental oxygen required • Steroids not part of SOC
MV, or ECMO
• 55% conventional oxygen Interpretation:
Key Exclusion Criteria: • 21% HFNC oxygen or NIV • Compared with RDV alone, BAR
• Use of glucocorticoids for COVID-19 • 11% MV or ECMO plus RDV reduced recovery time and
indications improved clinical status, particularly for
• ALT or AST >5 times ULN Primary Outcomes: patients who received HFNC oxygen or
• Median time to recovery: 7 days in BAR arm vs. 8 days in placebo NIV at baseline.
• Impaired renal function
arm (rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03)
Interventions: • Median time to recovery for those receiving HFNC oxygen or NIV: 10
• BAR 4 mg PO once daily for 14 days or until days in BAR arm vs. 18 days in placebo arm (rate ratio for recovery
discharge, plus RDV for 10 days or until 1.51; 95% CI, 1.10–2.08)
discharge (n = 515)
Secondary Outcomes:
• Placebo plus RDV (n = 518)
• Improvement in clinical status at Day 15: greater in BAR arm vs.
Primary Endpoint: placebo arm (OR 1.3; 95% CI, 1.0–1.6)
• Time to recovery by Day 28 • Mortality at Day 28: 5% in BAR arm vs. 8% in placebo arm (HR 0.65;
Key Secondary Endpoints: 95% CI, 0.39–1.09)
• Clinical status at Day 15 as measured by OS

ACTT-4: Double-Blind, Placebo-Controlled, Randomized Trial of Remdesivir With Baricitinib Versus Dexamethasone for Hospitalized Patients Requiring
Supplemental Oxygen in Japan, Mexico, Singapore, South Korea, and the United States5
• Hospitalized and requiring conventional • Median age 58 years; 58% men; 58% White, 34% Hispanic/Latinx • Study closed before completing
oxygen, HFNC oxygen, or NIV • At baseline: enrollment of 1,500 as it was unlikely to
• Laboratory-confirmed SARS-CoV-2 • 85% low-flow oxygen show a difference between arms.
infection • Not powered to analyze differences
• 15% HFNC oxygen or NIV
Key Exclusion Criterion: between ordinal score subgroups HFNC
• Mean duration of symptoms at enrollment: 8 days oxygen or NIV at baseline.
• Receipt of CCP or >1 dose DEX 6 mg (or
equivalent) or BAR before enrollment Primary Outcome: • Few patients died or required MV, which
Interventions: • MV-free survival by Day 29: 87% in BAR arm vs. 88% in DEX arm may have decreased the power to detect
(risk difference 0.6%; 95% CI, -3.6% to 4.8%; P = 0.91) a difference between arms for MV-free
• RDV IV for ≤10 days plus BAR 4 mg PO
survival.
daily for ≤14 days plus DEX placebo IV (n = Secondary Outcomes:
516) • Improved clinical status at Day 15: similar between arms (OR 1.01; • Treatment-related differences in AEs
• RDV IV for ≤10 days plus BAR placebo PO 95% CI, 0.80–1.27) for BAR vs. DEX were mainly related to
plus DEX 6 mg IV daily ≤10 days (n = 494) laboratory abnormalities, not clinical
• For low-flow oxygen at baseline: OR 0.91; 95% CI, 0.70–1.17 events. The clinical relevance of these
Primary Endpoint: • For HFNC oxygen or NIV at baseline: OR 1.64; 95% CI, 0.92–2.90 differences in laboratory abnormalities
• MV-free survival by Day 29 • Median time to recovery: 6 days in BAR arm vs. 5 days in DEX arm is unclear.
Key Secondary Endpoints: (rate ratio 1.04; 95% CI, 0.91–1.19) Interpretation:
• Clinical status at Day 15 as measured by OS Safety Outcomes: • In hospitalized patients requiring
• Time to recovery • Occurrence of treatment-related AEs: 4% in BAR arm vs. 10% in DEX conventional oxygen, HFNC oxygen, or
arm (risk difference 6.0%; 95% CI, 2.8%–9.3%; P = 0.0004) NIV, the use of BAR or DEX resulted in
Key Safety Endpoints: similar MV-free survival by Day 29.
• Occurrence of SAEs: 28% in BAR arm vs. 36% in DEX arm (risk
• Occurrence of treatment-related AEs
difference 7.7%; 95% CI, 1.8%–13.4%; P = 0.012)
• Occurrence of SAEs
• Most SAEs and treatment-related AEs were laboratory abnormalities.

STOP-COVID: Double-Blind, Placebo-Controlled, Randomized Trial of Tofacitinib in Hospitalized Patients With COVID-19 Pneumonia in Brazil6
• Laboratory-confirmed SARS-CoV-2 • Mean age 56 years; 35% women • Small sample size
infection • Median 10 days symptom onset to randomization • RDV not available during trial
• COVID-19 pneumonia on CXR or CT • At baseline: Interpretation:
• Hospitalized for <72 hours • 75% supplemental oxygen • Tofacitinib, when compared with
Key Exclusion Criteria: • 13% HFNC oxygen placebo, led to a lower risk of mortality
• Receiving NIV, MV, or ECMO at baseline or respiratory failure among hospitalized
• Use of glucocorticoids: 79% at baseline, 89% during hospitalization adults with COVID-19 pneumonia, most
• History of or current thrombosis of whom received glucocorticoids.
Primary Outcome:
• Immunosuppression or active cancer
• Mortality or respiratory failure through Day 28: 18% in tofacitinib arm
treatment
vs. 29% in placebo arm (risk ratio 0.63; 95% CI, 0.41–0.97; P = 0.04)
Interventions:
Secondary Outcome:
• Tofacitinib 10 mg PO twice daily for up to
• Mortality through Day 28: 2.8% in tofacitinib arm vs. 5.5% in placebo
14 days or until discharge (n = 144)
arm (HR 0.49; 95% CI, 0.15–1.63)
Primary Endpoint:
• Mortality or respiratory failure through Day
28
• Mortality through Day 28
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate transaminase; BAR
= baricitinib; CCP = COVID-19 convalescent plasma; CRP = C-reactive protein; CT = computed tomography; CXR = chest X-ray; DEX = dexamethasone; ECMO =
extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; HFNC = high-flow nasal cannula; IVIG = intravenous immunoglobulin; LDH =
lactate dehydrogenase; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PCR =
polymerase chain reaction; PO = orally; RCT = randomized controlled trial; RDV = remdesivir; SAE = serious adverse event; SOC = standard of care; SpO2 = oxygen
saturation; TB = tuberculosis; ULN = upper limit of normal
References
1. RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label,
platform trial and updated meta-analysis. Lancet. 2022;400(10349):359-368. Available at: https://pubmed.ncbi.nlm.nih.gov/35908569.
2. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-
BARRIER): a randomised, double-blind, parallel-group, placebo-controlled Phase 3 trial. Lancet Respir Med. 2021;9(12):1407-1418. Available at:

3. Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults
with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.
Lancet Respir Med. 2022;10(4):327-336. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35123660.
4. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021;384(9):795-807.
5. Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised,
double-blind, double placebo-controlled trial. Lancet Respir Med. 2022;Published online ahead of print. Available at:
6. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415.

Colchicine
Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout,
recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to
potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine
has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting
inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3
When colchicine is administered early in the course of COVID-19, these mechanisms could potentially
mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory
properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and
widespread availability have prompted investigation of colchicine for the treatment of COVID-19.
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine
for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
• The Panel recommends against the use of colchicine for the treatment of hospitalized patients
with COVID-19 (AI).
Rationale: Nonhospitalized Patients

COLCORONA, a large, placebo-controlled, randomized trial that evaluated colchicine in outpatients
with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4
However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2
polymerase chain reaction (PCR) result from a nasopharyngeal swab, a slight reduction in
hospitalizations was observed among those who received colchicine.
PRINCIPLE, an open-label, adaptive-platform, randomized trial that evaluated colchicine versus usual
care, was stopped for futility when no significant difference was found between the colchicine and usual
care recipients for the outcome of time to first self-reported recovery from COVID-19.5
The PRINCIPLE trial showed no benefit for colchicine, and the larger COLCORONA trial failed to
reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients
with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events for those
receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment
of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).
Rationale: Hospitalized Patients

In the RECOVERY trial, a large, randomized trial in hospitalized patients with COVID-19, colchicine
demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the
results from this large trial, the Panel recommends against the use of colchicine for the treatment of
COVID-19 in hospitalized patients (AI).

COLCORONA Trial: Nonhospitalized Patients
The COLCORONA trial was a double-blind, placebo-controlled, randomized trial in outpatients who

received a diagnosis of COVID-19 within 24 hours of enrollment.4 Participants were aged ≥70 years
or aged ≥40 years with at least 1 of the following criteria: body mass index ≥30, diabetes mellitus,
uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C
within the past 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of
high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive placebo
or colchicine 0.5 mg twice daily for 3 days, then once daily for 27 days. The primary endpoint was
a composite of death or hospitalization by Day 30; secondary endpoints included components of the
primary endpoint, as well as the need for mechanical ventilation by Day 30. Participants reported by
telephone the occurrence of any study endpoints at 15 and 30 days after randomization; in some cases,
clinical data were confirmed or obtained by medical chart reviews.
Results
• The study enrolled 4,488 participants.
• The primary endpoint occurred in 104 (4.7%) of 2,235 participants in the colchicine arm and 131
(5.8%) of 2,253 participants in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
• There were no statistically significant differences between the arms for the secondary outcomes.
• In a prespecified analysis of 4,159 participants (93% of those enrolled) with SARS-CoV-2
infection confirmed by PCR testing of an nasopharyngeal specimen:
• Participants in the colchicine arm were less likely than those in the placebo arm to reach the
primary endpoint (4.6% vs. 6.0%; OR 0.75; 95% CI, 0.57–0.99; P = 0.04).
• Participants in the colchicine arm had fewer hospitalizations than those in the placebo arm
(4.5% vs. 5.9%; OR 0.75; 95% CI, 0.57–0.99).
• More participants in the colchicine arm than the placebo arm experienced gastrointestinal adverse
events, including diarrhea (13.7% vs. 7.3%; P < 0.0001).
• More pulmonary emboli were reported in the colchicine arm than the placebo arm (11 events
[0.5% of participants] vs. 2 events [0.1% of participants]).
Limitations
• The trial stopped at approximately 75% of the target enrollment, which may have limited the
study’s power to detect differences for the primary outcome.
• Some patient-reported clinical outcomes potentially were misclassified.
PRINCIPLE Trial: Nonhospitalized Patients

PRINCIPLE was a randomized, open-label, platform trial that evaluated colchicine in symptomatic,
nonhospitalized patients with COVID-19.5 Included participants had symptoms for ≤14 days and were
aged ≥65 years or aged ≥18 years with comorbidities or shortness of breath. Participants were randomized
to receive colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included
time to first self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were
analyzed using a Bayesian model. Participants were followed through symptom diaries. Futility was
defined as not reaching a clinically meaningful benefit (i.e., a hazard ratio ≥1.2, corresponding to about
1.5 days of faster recovery in the colchicine arm) for the endpoint of time to first self-reported recovery.
Results
• The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine;
2,081 to receive usual care alone; and 2,704 to receive other treatments.
• The prespecified primary analysis included participants with a positive test for SARS-CoV-2 (156
participants in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments

arm).
• The trial stopped early because of futility; the median time to self-reported recovery was similar in
the colchicine arm and the usual care arm (HR 0.92; 95% CrI, 0.72–1.16).
• Analyses showed no significant differences between the colchicine and usual care arms for self-
reported time to recovery and for hospitalizations or death due to COVID-19.
• There were no statistically significant differences between the colchicine and usual care arms for
the secondary outcomes in both the primary analysis population and in the subgroups, including
the subgroups based on symptom duration, baseline disease severity, age, and comorbidities.
• The occurrence of adverse events was similar in the colchicine and usual care arms.
Limitations
• The study had an open-label design.
• The sample size of the colchicine arm was small.
RECOVERY Trial: Hospitalized Patients

In the RECOVERY trial, hospitalized patients with COVID-19 were randomized 1:1 to receive
colchicine (1 mg followed by 0.5 mg 12 hours later, then 0.5 mg twice daily for 10 days or until
discharge) or usual care.6
Results
• At randomization, 94% of participants were receiving corticosteroids.
• In both arms, the primary endpoint of all-cause mortality at Day 28 occurred in 21% of
participants (rate ratio 1.01; 95% CI, 0.93–1.10; P = 0.77).
• There were no statistically significant differences between the arms for the endpoints of median
time to discharge alive, discharge from the hospital within 28 days, and receipt of mechanical
ventilation or death.
• The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in
the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney
injury and 1 case of rhabdomyolysis.
Limitation
COLCOVID Trial: Hospitalized Patients

COLCOVID was a multicenter, open-label, randomized trial in hospitalized adults with confirmed or
suspected SARS-CoV-2.7 Patients were assigned 1:1 to receive either colchicine (1.5 mg followed by
0.5 mg orally within 2 hours of initial dose, then twice daily for 14 days or until hospital discharge) plus
usual care or usual care alone.
Results
• There were no statistically significant differences between the colchicine and usual care arms for
either of the coprimary outcomes, which were mortality by Day 28 (HR 0.88; 95% CI, 0.70–1.12)
and mechanical ventilation or mortality by Day 28 (HR 0.83; 95% CI, 0.67–1.02).
• More individuals in the colchicine arm than in the usual care arm experienced diarrhea (11.3% vs.

4.5%).
Limitation
GRECCO-19 Trial: Hospitalized Patients

GRECCO-19 was a prospective, open-label, randomized clinical trial that included patients with
COVID-19 from 16 hospitals in Greece.8 Participants were assigned 1:1 to receive colchicine (1.5
mg followed by 0.5 mg after 60 minutes, then 0.5 mg twice daily for up to 3 weeks or until hospital
discharge, whichever comes first) plus the standard of care or the standard of care alone.
Results
• The study enrolled 105 participants.
• Fewer participants in the colchicine arm (1 of 55 participants) than in the standard of care arm
(7 of 50 participants) reached the primary clinical endpoint of clinical status deterioration from
baseline by 2 points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
• Participants in the colchicine arm were significantly more likely to experience diarrhea than those
in the standard of care arm (45.5% vs. 18.0%; P = 0.003).
Limitations
• The sample size and number of clinical events were small.
The results of several small, randomized trials and retrospective cohort studies that evaluated various
doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-
reviewed journals or been made available as preliminary, non-peer-reviewed reports.9-12 Some of those
studies showed benefits of colchicine use, including less need for supplemental oxygen, improvements
in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition,
some studies reported higher discharge rates or fewer deaths among patients who received colchicine
than among those who received comparator drugs or placebos. However, the findings from these studies
are difficult to interpret due to significant design or methodological limitations, including small sample
sizes, open-label designs, differences in the clinical and demographic characteristics of participants, and
differences in the cotreatments (e.g., remdesivir, corticosteroids) permitted in the treatment arms.
Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and pain,
bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as
neuromyotoxicity and blood dyscrasias. Colchicine clearance is decreased in patients with impaired renal
function and may require dose reduction along with increased monitoring for adverse effects. Significant
increases in colchicine plasma levels may occur when colchicine is coadministered with drugs that inhibit
cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp), increasing the risk of colchicine-induced adverse
effects. The risk of myopathy may be increased with concomitant use of certain HMG-CoA reductase
inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated
by CYP3A4 and P-gp pathways.13,14 Fatal colchicine toxicity has been reported in individuals with renal
or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4
inhibitors.

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on
data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has
antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-
analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage
or major fetal malformations. There are no data for colchicine use in pregnant women with acute
COVID-19. Risks of use should be balanced against potential benefits.13,15
Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory
conditions. Although colchicine is generally considered safe and well-tolerated in children, there are no
data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in
children (MIS-C).
References
1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane
Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary
artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for
colchicine. Ann Rheum Dis. 2020;80(5):550-557. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.
4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19
(COLCORONA): a Phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
5. Dorward J, Yu L, Hayward G, et al. Colchicine for COVID-19 in the community (PRINCIPLE): a randomised,
controlled, adaptive platform trial. Br J Gen Pract. 2022;Published online ahead of print. Available at:
6. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;9(12):1419-
7. Diaz R, Orlandini A, Castellana N, et al. Effect of colchicine vs usual care alone on intubation and
28-day mortality in patients hospitalized with COVID-19: a randomized clinical trial. JAMA Netw Open.
8. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and
inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the
GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at:
9. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with
COVID-19. J Clin Med. 2020;9(9):2961. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
10. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients: a clinical trial study.
Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
11. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine
on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med
Microbiol. 2020;2020:8865954. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
12. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe
COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1):e001455.

13. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at:
14. Wiggins BS, Saseen JJ, Page RL, 2nd, et al. Recommendations for management of clinically significant
drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific
statement from the American Heart Association. Circulation. 2016;134(21):e468-e495. Available at:
15. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-
analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at:

Fluvoxamine
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the Food and
Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and is used for other
conditions, including depression. Fluvoxamine is not FDA-approved for the treatment of any infection.
Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells,
resulting in reduced production of inflammatory cytokines.1 In an in vitro study of human endothelial
cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.2 Ongoing studies
are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies
also occur in humans and are clinically relevant in the setting of COVID-19.
Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to
recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
Rationale
Three randomized trials have studied the use of fluvoxamine for the treatment of nonhospitalized
patients with COVID-19. In STOP COVID, a contactless, double-blind randomized placebo-controlled
trial conducted in the United States among nonhospitalized adults with mild COVID-19 diagnosed
within 7 days of symptom onset, fluvoxamine (100 mg up to 3 times daily for 15 days) reduced clinical
deterioration at Day 15.3 Clinical deterioration was defined as shortness of breath plus oxygen saturation
(SpO2) <92% or hospitalization plus SpO2 <92%. This was a small study (≤80 participants per arm)
with limited cases of clinical deterioration and a short follow-up period. In addition, 24% of participants
stopped responding to surveys prior to Day 15.
The subsequent STOP COVID 2, a Phase 3 randomized controlled trial (ClinicalTrials.gov Identifier
NCT04668950) that enrolled >700 participants in the United States and Canada, was stopped for
futility by a data safety monitoring board after lower than expected case rates and treatment effect were
observed.4
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted
in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe
disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10
days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention
in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants
[11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk
0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There
was no statistically significant difference between study arms for the secondary outcomes of need for
hospitalization or time to symptom resolution. There was no significant difference in mortality between
study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine
arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary,
per-protocol analysis of participants who received >80% of possible doses, death was the outcome for
1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo

arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present
to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified.
Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to
therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER
trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the
difference in hospitalizations between arms was not significant.5 Defining the clinical relevance of
the >6 hour emergency department observation time endpoint is difficult, especially its applicability
to practice settings in different countries. Moreover, the endpoint has not been used in other studies
of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-
protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible
doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80%
threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this
level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias
when adherence is associated with factors that influence the outcome; this bias cannot be excluded in
this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence
than in those with >80% adherence, suggesting that factors other than adherence differed in the per-
protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect
the actual effectiveness of the drug, since intolerance and adherence appeared to be related.
Additional studies are needed to provide more specific, evidence-based guidance on the role of
fluvoxamine for the treatment of COVID-19. Further details of the studies discussed are provided in
Table 4c.
Adverse Effects, Monitoring, and Drug-Drug Interactions

When fluvoxamine is used to treat psychiatric conditions, the most common adverse effect is nausea, but
adverse effects can include other gastrointestinal effects (e.g., diarrhea, indigestion), neurologic effects
(e.g., asthenia, insomnia, somnolence, anxiety, headache), and rarely suicidal ideation.
Fluvoxamine is a cytochrome P450 (CYP) 2D6 substrate and a potent inhibitor of CYP1A2 and
CYP2C19 and a moderate inhibitor of CYP2C9, CYP2D6, and CYP3A4.6 Fluvoxamine can enhance the
serotonergic effects of other SSRIs or monoamine oxidase inhibitors (MAOIs), resulting in serotonin
syndrome; therefore, it should not be used within 2 weeks of receipt of other SSRIs or MAOIs.
Fluvoxamine may enhance the anticoagulant effects of antiplatelets and anticoagulants; therefore,
patients receiving these drugs should be closely monitored.
Fluvoxamine is not thought to increase the risk of congenital abnormalities; however, the data on its use
in pregnancy are limited.7,8 The association of SSRI use in the late third trimester with a small, increased
risk of primary persistent pulmonary hypertension in newborns has not been excluded, although the
absolute risk is likely low.9 The risk of fluvoxamine use in pregnancy for the treatment of COVID-19
should be balanced with the potential benefit.
Fluvoxamine is approved by the FDA for the treatment of obsessive-compulsive disorder in children
aged ≥8 years.10 Adverse effects due to SSRI use seen in children are similar to those seen in adults,
although children and adolescents appear to have higher rates of behavioral activation and vomiting than
adults.11 There are no data on the use of fluvoxamine for the prevention or treatment of COVID-19 in

children.
Clinical Trials
See ClinicalTrials.gov for the latest information on studies of fluvoxamine and COVID-19.
References
1. Rosen DA, Seki SM, Fernandez-Castaneda A, et al. Modulation of the sigma-1 receptor-IRE1 pathway is
beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478). Available at:
2. Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/
stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J
Basic Med Sci. 2016;19(9):977-984. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27803785.
3. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with
symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292-2300. Available at:
4. Lenze E. Fluvoxamine for early treatment of COVID-19: the STOP COVID clinical trials. 2021. Available
at: https://rethinkingclinicaltrials.org/news/august-20-2021-fluvoxamine-for-early-treatment-of-covid-19-the-
stop-covid-clinical-trials-eric-lenze-md/. Accessed December 8, 2021.
5. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of
emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform
clinical trial. Lancet Glob Health. 2021;Published online ahead of print. Available at:
6. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug
interactions: an update. Curr Drug Metab. 2002;3(1):13-37. Available at:
7. Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following
antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry.
8. Furu K, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy
and risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798. Available
9. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent
pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151. Available at:
10. Fluvoxamine maleate tablets [package insert]. Food and Drug Administration. 2019. Available at:
11. Safer DJ, Zito JM. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age
group: children versus adolescents. J Child Adolesc Psychopharmacol. 2006;16(1-2):159-169. Available at:

Table 6e. Fluvoxamine: Selected Clinical Data
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations
for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s
recommendations.
TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil1
• Aged ≥50 years or aged ≥18 years with comorbidities • Median age 50 years; 58% women; 95% self- • The >6-hour emergency setting observation
• Laboratory-confirmed SARS-CoV-2 infection identified as mixed race endpoint has not been used in other studies
• 13% with uncontrolled HTN; 13% with type 2 DM; of interventions for nonhospitalized patients
• ≤7 days of symptoms who are at high risk for hospitalization and
50% with BMI ≥30 kg/m2
Key Exclusion Criteria: death
• Mean of 3.8 days from symptom onset to
• Use of an SSRI randomization • As this was an adaptive platform trial
• Severe mental illness where multiple investigational treatments
Primary Outcome: or placebos were being evaluated
• Cirrhosis, recent seizures, severe ventricular cardia • Proportion of patients who met the primary simultaneously, not all patients in the placebo
arrythmia composite endpoint: 11% in fluvoxamine arm vs. arm received a placebo that was matched
Interventions: 16% in placebo arm (relative risk 0.68; 95% CrI, to fluvoxamine by route of administration,
0.52–0.88) dosing frequency, or duration of therapy
• Fluvoxamine 100 mg PO twice daily for 10 days (n = 741)
Secondary Outcomes: • PP analyses are not randomized
• Placebo (route, dosing frequency, and duration for some
comparisons, and they introduce bias when
patients may have differed from fluvoxamine) (n = 756) • 87% of clinical events were hospitalizations.
adherence is associated with factors that
Primary Endpoint: • No difference between arms in COVID-19-related influence the outcome
• Composite endpoint of emergency setting observation hospitalizations: 10% in fluvoxamine arm vs. 13%
• Adherence was self-reported and not verified
for >6 hours or hospitalization due to progression of in placebo arm (OR 0.77; 95% CI, 0.55–1.05)
• No difference between arms in time to symptom Interpretation:
COVID-19 within 28 days after randomization
resolution. • Fluvoxamine reduced the proportion of
Key Secondary Endpoints: patients who met the composite endpoint of
• Adherence: 74% in fluvoxamine arm vs. 82% in
• Occurrence of COVID-19-related hospitalizations COVID-19-related hospitalization or retention
placebo arm (OR 0.62; 95% CI, 0.48–0.81). 11%
• Time to symptom resolution in fluvoxamine arm vs. 8% in placebo arm stopped in an emergency setting for >6 hours.
drug due to issues of tolerability.

TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil1, continued
• Proportion of patients who were adherent to study drugs, • Mortality (ITT): 2% in fluvoxamine arm • The use of fluvoxamine did not impact the incidence of
defined as receiving >80% of possible doses vs. 3% in placebo arm (OR 0.68; 95% COVID-19-related hospitalizations.
• Mortality in both the primary ITT population and a PP CI, 0.36–1.27) • It is difficult to define the clinical relevance of the >6-hour
population that included patients who took >80% of the • Mortality (PP): <1% in fluvoxamine emergency setting observation endpoint and apply it to
study medication doses arm vs. 2% in placebo arm (OR 0.09; practice settings in different countries.
95% CI, 0.01–0.47) • Fluvoxamine did not have a consistent impact on
mortality.
• Fluvoxamine did not impact time to symptom resolution.
STOP COVID: Double-Blind RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in the United States2
• Aged ≥18 years • Mean age 46 years; 72% women; 25% • Small sample size
• Positive SARS-CoV-2 PCR result Black • Short follow-up period
• ≤7 days of symptoms • 56% with obesity; 20% with HTN; • Ascertaining clinical deterioration was challenging
17% with asthma because all assessments were done remotely
• Median of 4 days from symptom onset • 24% of patients stopped responding to follow-up prior to
• Immunocompromised to randomization Day 15 but were included in the final analysis
• Unstable medical comorbidities Primary Outcome: Interpretation:
Interventions: • Clinical deterioration: 0% in • Fluvoxamine reduced the proportion of patients who
• Fluvoxamine 50 mg PO for 1 dose, then fluvoxamine 100 fluvoxamine arm vs. 8.3% in placebo experienced clinical deterioration.
mg twice daily, then fluvoxamine 100 mg 3 times daily arm (absolute difference 8.7%; 95%
CI, 1.8% to 16.4%) • Due to significant limitations, it is difficult to draw
through Day 15 (n = 80)
definitive conclusions about the efficacy of using
• Placebo (n = 72) Secondary Outcome: fluvoxamine to treat COVID-19.
Primary Endpoint: • No patients in fluvoxamine arm
• Clinical deterioration within 15 days of randomization. and 4 patients in placebo arm were
Clinical deterioration was defined as: hospitalized.
• Having dyspnea or being hospitalized for dyspnea or
pneumonia; and
• Having SpO2 <92% on room air or requiring
supplemental oxygen to attain SpO2 ≥92%
• Hospitalization

Key: BMI = body mass index; DM = diabetes; HTN = hypertension; ITT = intention-to-treat; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase
chain reaction; PO = oral; PP = per protocol; RCT = randomized controlled trial; SpO2 = oxygen saturation; SSRI = selective serotonin reuptake inhibitor
References
1. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation
among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2021;Published online ahead of print.
2. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized

Granulocyte-Macrophage Colony-Stimulating
Factor Inhibitors
Last Updated: March 24, 2022
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a myelopoietic growth factor and pro-

inflammatory cytokine that plays a central role in a broad range of immune-mediated diseases. GM-CSF,
which is secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and
fibroblasts, regulates macrophage number and function. It acts as a pro-inflammatory signal, prompting
macrophages to launch an immune cascade that ultimately results in tissue damage.1,2 GM-CSF is
believed to be a key driver of lung inflammation in severe and critical COVID-19 pneumonia, operating
upstream of other pro-inflammatory cytokines and chemokines.1-6 Anti-GM-CSF monoclonal antibodies
(mAbs) may mitigate inflammation by inhibiting this signaling axis upstream and thus minimizing
downstream production of numerous pro-inflammatory mediators involved in the pathogenesis of
COVID-19.7 Gimsilumab, lenzilumab, namilumab, and otilimab target GM-CSF directly, neutralizing
the biological function of GM-CSF by blocking the interaction of GM-CSF with its cell surface
receptor.1,8,9 Mavrilimumab targets the alpha subunit of the GM-CSF receptor, blocking intracellular
signaling of GM-CSF.8,10 None of these agents are currently FDA approved for any indication.
Recommendation
recommend either for or against the use of GM-CSF inhibitors for the treatment of hospitalized
Rationale
Clinical data are lacking to definitively establish the potential benefits and risks associated with the use
of GM-CSF inhibitors in patients with COVID-19. Data from a double-blind randomized controlled trial
of lenzilumab did show a significant improvement in the primary endpoint of ventilator-free survival
through Day 28 among those who received the GM-CSF inhibitor.11 However, preliminary data from a
large, double-blind randomized trial of otilimab (primary endpoint: alive and free of respiratory failure
at Day 28) and published results of a small, double-blind, randomized trial of mavrilimumab (primary
endpoint: proportion alive and off supplemental oxygen at Day 14) did not show a survival benefit for
the GM-CSF inhibitors compared to placebo.12-14 The study populations differed; the lenzilumab and
mavrilimumab studies primarily included patients on room air or low-flow oxygen and excluded patients
receiving mechanical ventilation, whereas the otilimab study included only patients receiving high-flow
oxygen, noninvasive ventilation, or mechanical ventilation. Lenzilumab and mavrilimumab continue to
be investigated, whereas clinical development of otilimab for the treatment of COVID-19 has ceased.

Lenzilumab, mavrilimumab, namilumab, and otilimab have been evaluated in clinical trials in
hospitalized adults with SARS-CoV-2 pneumonia.12-15 Clinical data are not yet published for
gimsilumab. The Panel’s recommendations are based on the results of the available clinical studies.
Selected clinical data on the use of anti-GM-CSF mAbs for the treatment of COVID-19 are summarized
in Table 6f.
Clinical Trials
See ClinicalTrials.gov for a list of ongoing clinical trials that are evaluating the use of GM-CSF

inhibitors for the treatment of COVID-19.
Adverse Effects
The primary risks associated with GM-CSF inhibitors being reported and evaluated are related to
bacterial infection. Other adverse events that have been reported with these agents include acute
kidney injury and elevated liver transaminases.10 Autoimmune pulmonary alveolar proteinosis has been
associated with a high-titer of anti-GM-CSF auto-antibodies.16
Pregnant patients have been excluded from clinical trials evaluating GM-CSF inhibitors for the
treatment of COVID-19. There is insufficient evidence to recommend for or against their use in pregnant
individuals with COVID-19.
There are no data on the use of GM-CSF inhibitors in children.
References
1. Mehta P, Porter JC, Manson JJ, et al. Therapeutic blockade of granulocyte macrophage colony-stimulating
factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med.
2. Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, et al. Inflammatory profiles across the spectrum of
disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021;6(57). Available at:
3. Hamilton JA. GM-CSF in inflammation and autoimmunity. Trends Immunol. 2002;23(8):403-408. Available
4. Lotfi N, Thome R, Rezaei N, et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: an update.
Front Immunol. 2019;10:1265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31275302.
5. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan,
China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
6. Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in
severe COVID-19 patients. Natl Sci Rev. 2020;7(6):998-1002. Available at:
7. De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19
pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol.
8. Lang FM, Lee KM, Teijaro JR, Becher B, Hamilton JA. GM-CSF-based treatments in COVID-19: reconciling
opposing therapeutic approaches. Nat Rev Immunol. 2020;20(8):507-514. Available at:
9. Temesgen Z, Assi M, Shweta FNU, et al. GM-CSF neutralization with lenzilumab in severe COVID-19
pneumonia: a case-cohort study. Mayo Clin Proc. 2020;95(11):2382-2394. Available at:
10. Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF
receptor-alpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I,
first-in-human study. Ann Rheum Dis. 2011;70(9):1542-1549. Available at:
11. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab in hospitalised patients with COVID-19 pneumonia

(LIVE-AIR): a Phase 3, randomised, placebo-controlled trial. Lancet Respir Med. 2021. Available at:
12. Patel J, Beishuizen A, Ruiz XB, et al. A randomized trial of otilimab in severe COVID-19 pneumonia
(OSCAR). medRxiv. 2021. Available at: https://www.medrxiv.org/content/10.1101/2021.04.14.21255475v1.
13. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab efficacy and safety in newly hospitalized COVID-19
subjects: results from the live-air Phase 3 randomized double-blind placebo-controlled trial. medRxiv. 2021.
14. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia
and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind,
randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(6):e410-e418. Available at:
15. Fisher BA, Veenith T, Slade D, et al. Namilumab or infliximab compared with standard of care in hospitalised
patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label,
adaptive, Phase 2, proof-of-concept trial. Lancet Respir Med. 2021. Available at:
16. Chaulagain CP, Pilichowska M, Brinckerhoff L, Tabba M, Erban JK. Secondary pulmonary alveolar
proteinosis in hematologic malignancies. Hematol Oncol Stem Cell Ther. 2014;7(4):127-135. Available at:

Table 6f. Granulocyte-Macrophage Colony-Stimulating Factor
Inhibitors: Selected Clinical Data
Last Updated: March 24, 2022
GM-CSF inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as new
information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating GM-CSF inhibitors.
LIVE-AIR: Double-Blind RCT of Lenzilumab in Hospitalized Patients With Severe COVID-19 Pneumonia in the United States and Brazil1,2
• Hospitalized with SARS-CoV-2 pneumonia • Mean age 61 years; 65% men; 72% White • Not powered to detect a survival
• SpO2 ≤94% on room air or required low-flow • 55% BMI ≥30 benefit
supplemental oxygen, HFNC oxygen, or NIV • At baseline: 41% received HFNC oxygen or NIV • Access to supportive care differed
across study sites
Key Exclusion Criteria: • 94% received corticosteroids; 72% received RDV; 69%
• MV or ECMO received corticosteroids and RDV Interpretation:
• Bacterial pneumonia, fungal or viral infection • Median CRP 79 mg/L • Lenzilumab improved ventilator-free
survival in participants with hypoxemia
• 48-hour survival not expected Primary Outcome: who were not receiving MV, with the
• Use of IL-1 inhibitors, IL-6 inhibitors, kinase inhibitors, • Survival without MV through Day 28: 84% in lenzilumab greatest benefit among those with
or mAbs within prior 8 weeks arm vs. 78% in placebo arm (HR 1.54; 95% CI, 1.02– lower CRP levels.
2.32; P = 0.040)
Interventions:
• 3 doses of lenzilumab 600 mg IV 8 hours apart (n = 236) Key Secondary Outcomes:
• Placebo (n = 243) • Mortality: 10% in lenzilumab arm vs. 14% in placebo arm
(HR 0.72; 95% CI, 0.42–1.23; P = 0.24)
Primary Endpoint:
• Incidence of death or requiring MV or ECMO: 15% in
• Survival without MV through Day 28 lenzilumab arm vs. 21% in placebo arm (HR 0.67; 95%
Key Secondary Endpoints: CI, 0.41–1.10; P = 0.11)
• Mortality Exploratory Outcome:
• Incidence of death or requiring MV or ECMO • Survival without MV for baseline CRP <150 mg/L: 90% in
lenzilumab arm vs. 79% in placebo arm (HR 2.54; 95%
Exploratory Endpoint:
CI, 1.46–4.41; P = 0.0009)
• Survival without MV, stratified by baseline CRP

MASH-COVID: Double-Blind RCT of Mavrilimumab in Hospitalized Patients With Severe COVID-19 Pneumonia and Systemic Hyperinflammation in the United
States3
• Hospitalization with SARS-CoV-2 pneumonia • Median age 57 years; 65% men; 40% African American • Very small sample size
• SpO2 <92% on room air or required supplemental oxygen • At baseline: • Ended early due to slow enrollment
• CRP >5 mg/dL • 50% required HFNC oxygen or NIV Interpretation:
Key Exclusion Criteria: • 65% received corticosteroids • Among participants with systemic
• MV • 75% received RDV hyperinflammation and severe
COVID-19 pneumonia, there was no
• ANC <1,500/mm3 Primary Outcome: evidence that use of mavrilimumab
• Uncontrolled bacterial infection • Alive and off supplemental oxygen at Day 14: 57% in improved supplemental oxygen–free
mavrilimumab arm vs. 47% in placebo arm (OR 1.48; survival by Day 14.
Interventions:
95% CI, 0.43–5.16; P = 0.76)
• Mavrilimumab 6 mg/kg as single IV infusion (n = 21)
Key Secondary Outcomes:
• Mortality at Day 28: 1 (5%) in mavrilimumab arm vs. 3
Primary Endpoint: (16%) in placebo arm (HR 3.72; 95% CI, 0.39–35.79; P =
• Alive and off supplemental oxygen at Day 14 0.22)
Key Secondary Endpoints: • Alive without respiratory failure at Day 28: 95% in
mavrilimumab arm vs. 79% in placebo arm (OR 5.33;
95% CI, 0.54–52.7; P = 0.43)
• Alive without respiratory failure at Day 28

OSCAR: Double-Blind RCT of Otilimab in Patients With Severe COVID-19 Pneumonia in 17 Countries4
• Hospitalized with SARS-CoV-2 pneumonia • Mean age 59 years; 72% men; 66% White • Changes in SOC during study may
• Required HFNC oxygen, NIV, or MV ≤48 hours before • At baseline: have affected outcomes.
dosing • 77% received HFNC oxygen or NIV; 22% received MV Interpretation:
• CRP or ferritin >ULN • 83% received corticosteroids; 34% received RDV • For participants with severe COVID-19
Key Exclusion Criteria: pneumonia, use of otilimab did not
Primary Outcome: significantly reduce the probability of
• Death likely <48 hours • Alive and free of respiratory failure at Day 28: 71% in respiratory failure or death.
• Multiple organ failure otilimab arm vs. 67% in placebo arm (model-adjusted
• SOFA score >10 if in ICU difference 5.3%; 95% CI, -0.8 to 11.4; P = 0.09)
• ECMO Key Secondary Outcome:
• Dialysis • All-cause mortality at Day 60: 23% in otilimab arm vs.
• High-dose noradrenaline (>0.15 ug/kg/min) or equivalent 24% in placebo arm (model-adjusted difference -2.4%;
95% CI, -8.0 to 3.3; P = 0.41)
• >1 vasopressor
Interventions:
• Otilimab 90 mg IV as single infusion (n = 395)
Primary Endpoint:
• Alive and free of respiratory failure at Day 28
• All-cause mortality at Day 60
Key: ANC = absolute neutrophil count; BMI = body mass index; CRP = C-reactive protein; ECMO = extracorporeal membrane oxygenation; GM-CSF = granulocyte-
macrophage colony-stimulating factor; HFNC = high-flow nasal cannula; ICU = intensive care unit; IL = interleukin; IV = intravenous; mAb = monoclonal antibody; MV
= mechanical ventilation; NIV = noninvasive ventilation; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; SOFA = sequential organ failure
assessment; SpO2 = oxygen saturation; ULN = upper limit of normal
References
1. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a Phase 3, randomised, placebo-
controlled trial. Lancet Respir Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34863332.
2. Temesgen Z, Kelley CF, Cerasoli F, et al. Early lenzilumab treatment of COVID-19 patients using c-reactive protein as a biomarker improves efficacy:
results from the Phase 3 ‘LIVE-AIR’ trial. medRxiv. 2022;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.12.30.21267140v1.

3. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-
COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(6):e410-e418. Available
4. Patel J, Beishuizen A, Ruiz X, et al. A randomized trial of otilimab in severe COVID-19 pneumonia (OSCAR). medRxiv. 2021;Preprint. Available at:

Immunoglobulins: Non-SARS-CoV-2 Specific
Recommendation
• The COVID-19 Treatment Guidelines Panel recommends against the use of non-severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific intravenous immunoglobulin
(IVIG) for the treatment of acute COVID-19, except in a clinical trial (AIII). This
recommendation should not preclude the use of IVIG when otherwise indicated for the treatment
of complications that arise during the course of COVID-19.
Rationale for Recommendation

It is unknown whether products derived from the plasma of donors without confirmed SARS-CoV-2
infection contain high titer of SARS-CoV-2 neutralizing antibodies. Furthermore, although other blood
components in IVIG may have general immunomodulatory effects, it is unclear whether these theoretical
effects will benefit patients with COVID-19.

This study has not been peer reviewed.
A retrospective, non-randomized cohort study of IVIG for the treatment of COVID-19 was conducted
across eight treatment centers in China between December 2019 and March 2020. The study showed no
difference in 28-day or 60-day mortality between 174 patients who received IVIG and 151 patients who
did not receive IVIG.1 More patients in the IVIG group had severe disease at study entry (71 patients
[41%] with critical status in the IVIG group vs. 32 patients [21%] in the non-IVIG group). The median
hospital stay was longer in the IVIG group (24 days) than in the non-IVIG group (16 days), and the
median duration of disease was also longer (31 days in the IVIG group vs. 23 days in the non-IVIG
group). A subgroup analysis that was limited to the critically ill patients suggested a mortality benefit at
28 days, which was no longer significant at 60 days.
The results of this study are difficult to interpret because of important limitations in the study design.
In particular, patients were not randomized to receive either IVIG or no IVIG, and the patients in the
IVIG group were older and more likely to have coronary heart disease than those in the non-IVG group.
In addition, the IVIG group had a higher proportion of patients with severe COVID-19 disease at study
entry. Patients in both groups also received many concomitant therapies for COVID-19.
IVIG is commonly used in pregnancy for other indications such as immune thrombocytopenia with an
acceptable safety profile.2,3
IVIG has been widely used in children for the treatment of a number of conditions. including Kawasaki
disease, and is generally safe.4 IVIG has been used in pediatric patients with COVID-19 and multiorgan
inflammatory syndrome in children (MIS-C), especially those with a Kawasaki disease-like presentation,
but the efficacy of IVIG in the management of MIS-C is still under investigation.

References
1. Shao Z, Feng Y, Zhong L, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical patients
with COVID-19: A multicenter retrospective cohort study. medRxiv. 2020;Preprint. Available at:
2. Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 207: thrombocytopenia in
pregnancy. Obstet Gynecol. 2019;133(3):e181-e193. Available at:
3. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice
guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. Available at:
4. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin
Immunol. 2017;13(3):247-258. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27590181.

Last Updated: October 19, 2021
Endogenous interleukin (IL)-1 is elevated in patients with COVID-19.1,2 In addition, SARS-CoV-2

infection causes epithelial damage that leads to the release of IL-1 beta, which recruits inflammatory
cells and induces the release of IL-1 beta in monocytes. This in turn leads to the release of more IL-1 to
recruit and activate additional innate immune cells. Drugs that block the IL-1 receptor (e.g., anakinra) or
drugs that block IL-1 signaling (e.g., canakinumab) can potentially interrupt this autoinflammatory loop.
These drugs are being investigated as potential treatments for COVID-19.
Anakinra is a recombinant human IL-1 receptor antagonist. It is approved by the Food and Drug
Administration (FDA) to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes,
specifically neonatal-onset multisystem inflammatory disease.3 It is used off-label to treat severe
chimeric antigen receptor T cell-mediated cytokine release syndrome and macrophage activation
syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.
Canakinumab is a human monoclonal antibody that targets the beta subunit of IL-1 and is approved by
the FDA for the treatment of systemic juvenile idiopathic arthritis and Still’s disease.
Recommendations
recommend either for or against the use of anakinra for the treatment of COVID-19.
• The Panel recommends against the use of canakinumab for the treatment of COVID-19, except
in a clinical trial (BIIa).
Rationale
In the SAVE-MORE trial, 594 hospitalized patients who had moderate or severe COVID-19 pneumonia
and plasma-soluble urokinase plasminogen activator receptor (suPAR) levels ≥6 ng/mL were randomized
to receive either anakinra or placebo. The study found that patients who received anakinra had a lower
risk of clinical progression of COVID-19 than those who received placebo.4 CORIMUNO-ANA-1, a
randomized controlled trial that compared the use of anakinra to usual care in 116 hospitalized patients
who were hypoxemic but did not require high-flow oxygen or ventilation, was stopped early for futility.5
REMAP-CAP, an open-label, adaptive platform, randomized controlled trial that evaluated several
immunomodulators in patients with COVID-19 who required organ support, found that anakinra was not
effective in reducing the combined endpoint of in-hospital mortality and days of organ support.6 Although
the SAVE-MORE study suggests that suPAR levels could be used in risk stratification to identify
populations that could benefit from IL-1 inhibition, the laboratory assay that is used to assess suPAR levels
is not currently available in many countries, including the United States. After reviewing the results of the
studies discussed above and taking into consideration the fact that suPAR assays are not widely available
to guide the use of anakinra, the Panel has concluded that there is insufficient evidence to recommend
either for or against the use of anakinra for the treatment of COVID-19 in hospitalized patients.
Finally, CAN-COVID, a randomized controlled trial that evaluated canakinumab in hospitalized patients
with COVID-19 who were hypoxemic but did not require ventilatory support, reported that the use
of canakinumab did not improve the likelihood of survival without invasive mechanical ventilation.7
Because of these results, the Panel recommends against the use of canakinumab for the treatment of
COVID-19, except in a clinical trial (BIIa).

SAVE-MORE
SAVE-MORE was a randomized controlled trial in 594 hospitalized patients with moderate or severe
COVID-19 pneumonia and plasma suPAR levels ≥6 ng/mL. Patients who required noninvasive or
invasive mechanical ventilation were excluded from the study. Patients were randomized 2:1 to receive
anakinra 100 mg subcutaneously once daily for 10 days or placebo. The primary endpoint was clinical
status at Day 28 on the 11-point World Health Organization Clinical Progression Scale (WHO-CPS).4
Results
• Patients who were randomized to receive anakinra had a lower odds of progression of COVID-19
on the WHO-CPS (OR 0.36; 95% CI, 0.26–0.50; P < 0.0001).
• The secondary endpoints also favored anakinra, including the absolute decrease in WHO-CPS
scores from baseline at Days 14 and 28, the absolute decrease in Sequential Organ Failure
Assessment scores from baseline at Day 7, the median time to hospital discharge, and the median
duration of intensive care unit (ICU) stays.
• A smaller proportion of patients in the anakinra arm experienced secondary infections, including
ventilator-associated pneumonias, than in the placebo arm (8.4% vs. 15.9%; P = 0.01).
• Twenty-eight-day mortality was lower among patients who received anakinra than those who
received placebo (3.2% vs. 6.9%; HR 0.45; 95% CI, 0.21–0.98; P = 0.045).
Limitations
• The laboratory assay that is used to assess suPAR levels is not currently available in many
countries, including the United States.
REMAP-CAP
The REMAP-CAP trial is an open-label, adaptive platform trial in which eligible participants are
randomized to several domains, including the Immune Modulation Therapy domain, which consists
of two IL-6 inhibitors, anakinra, interferon beta-1a, and a control group. Participants are eligible for
enrollment if they are within 24 hours of receiving respiratory or cardiovascular organ support in the
ICU and they have suspected or microbiologically confirmed COVID-19.
Anakinra 300 mg was given intravenously (IV) as a loading dose, followed by anakinra 100 mg IV every
6 hours for 14 days until patients were either free from invasive mechanical ventilation for >24 hours
or discharged from the ICU. The primary outcome was measured using an ordinal scale that included
a composite of in-hospital mortality and duration of respiratory and cardiovascular organ support at 21
days; all deaths up to 90 days were assigned the worst outcome. The trial used a Bayesian design that
allowed the authors to compare nonconcurrently randomized interventions across time periods.6
Results
• Of the 2,274 participants who were randomized to one of the arms in the Immune Modulation
Therapy domain, 365 individuals were assigned to receive anakinra and included in the analysis,
406 were assigned to the usual care (control) arm, 943 were assigned to receive tocilizumab, and
483 were assigned to receive sarilumab.
• Of those assigned to receive anakinra, 37% were receiving invasive mechanical ventilation at
study entry compared with 32% of patients in the other arms. The other patients received oxygen
through a high-flow nasal cannula or noninvasive ventilation, with a few exceptions.
• The median number of organ support-free days was similar for patients who received anakinra and

those who received usual care (0 days [IQR 1–15 days] vs. 0 days [IQR -1 to 15 days]). The aOR
for organ support-free days was 0.99 for anakinra (95% CrI, 0.74–1.35), with a 46.6% posterior
probability of superiority to control. Sixty percent of those who were assigned to receive anakinra
survived compared to 63% of those who were assigned to the control arm, with a 43.6% posterior
probability that anakinra was superior to usual care.
• The risk of experiencing serious adverse events was similar between the arms.
Limitations
• Patients were not randomized contemporaneously to receive anakinra or usual care; the treatment
effect was estimated from an overarching model that mostly included patients who were
randomized to receive an IL-6 inhibitor (tocilizumab or sarilumab) or usual care, and patients
who were randomized to receive an IL-6 inhibitor or anakinra. Thus, the estimate of the treatment
effect is not fully protected by randomization.
• This study had an open-label design.
CORIMUNO-ANA-1
The CORIMUNO-ANA-1 trial randomized 116 hospitalized patients with COVID-19 pneumonia 1:1
to receive either usual care plus anakinra (200 mg IV twice a day on Days 1–3, 100 mg IV twice on
Day 4, and 100 mg IV once on Day 5) or usual care alone. Patients were eligible for enrollment if they
had laboratory-confirmed SARS-CoV-2 infection with COVID-19 pneumonia and they required >3 L/
min of supplemental oxygen. Patients who required high-flow oxygen, ventilation, or ICU admission
were excluded. The two coprimary outcomes were the proportion of patients who had died or who
needed noninvasive or invasive mechanical ventilation by Day 4 (score of >5 on the WHO-CPS) and the
proportion who survived without the need for noninvasive or invasive mechanical ventilation (including
high-flow oxygen) by Day 14.5
Results
• There was no difference between the anakinra plus usual care arm and the usual care alone arm in
the two coprimary outcomes: by Day 4, 36% of patients in the anakinra arm had died or required
high-flow oxygen or ventilation compared with 38% in the usual care arm (90% CrI, -17.1 to 12.0,
posterior probability of benefit 61%). By Day 14, 47% of patients in the anakinra arm had died or
required noninvasive or invasive mechanical ventilation compared to 51% in the usual care arm
(median HR 0.97; 90% CrI, 0.62–1.52; posterior probability of benefit 55%).
• Fifty-two percent of patients received corticosteroids at study entry.
• Serious adverse events occurred in 46% of patients in the anakinra arm compared to 38% in the
usual care arm; 11 of 59 patients (18.6%) in the anakinra arm experienced bacterial or fungal
infections compared to 4 of 55 patients (7.3%) who received usual care.
Limitations
• The limitations of this study include the small sample size, narrow eligibility criteria, and the
fact that many patients did not receive current standard-of-care therapy (e.g., corticosteroids,
remdesivir).
CAN-COVID
CAN-COVID was a double-blind, placebo-controlled randomized trial of 454 hospitalized patients with
COVID-19 who were hypoxemic but not mechanically ventilated and had elevated C-reactive protein
(≥ 20 mg/L) or ferritin (≥600 micrograms/L) levels. Patients were randomized 1:1 to receive a single
dose of IV canakinumab (450 mg for a body weight of 40 kg to <60 kg, 600 mg for 60–80 kg, and 750

mg for >80 kg) or placebo. The primary outcome was survival without the need for invasive mechanical
ventilation from Days 3 through 29.7
Results
• There was no statistical difference between the canakinumab arm and placebo arm in the
proportion of patients who survived without invasive mechanical ventilation (88.8% vs. 85.7%; P
= 0.29).
• The number of COVID-19-related deaths at 4 weeks was similar for the two arms (11 of 223
patients [4.9%] in the canakinumab arm vs. 16 of 222 patients [7.2%] in the placebo arm; OR
0.67; 95% CI, 0.30–1.50).
• Forty-one percent of patients in the canakinumab arm and 32% in the placebo arm received
dexamethasone.
• Serious adverse events occurred in 16% of patients who received canakinumab and in 20.6% of
patients who received placebo.
Limitations
• The use of corticosteroids was unbalanced in this study, with more patients receiving
dexamethasone at baseline in the canakinumab arm than in the placebo arm.
• More patients received dexamethasone after the trial was underway in the placebo arm than in the
canakinumab arm (22.5% vs. 14.5%), and more patients received tocilizumab in the placebo arm
than in the canakinumab arm (8.8% vs. 2.2%).
Other small cohort studies, case-control studies, and case series have reported mixed findings with
regard to improvement in outcomes among patients who received anakinra for the treatment of COVID-
19.8-11 The clinical implication of these findings is uncertain due to small sample sizes and unmeasured
confounding factors. Therefore, these studies did not substantially influence the Panel’s current
recommendations for using IL-1 inhibitors.
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating anakinra and canakinumab for the
Adverse Effects
Headache, nausea, vomiting, and liver enzyme elevations can occur with both anakinra and
canakinumab.
Anakinra was not associated with any significant safety concerns when used in clinical trials for the
treatment of sepsis.12-14 Increased rates of infection were reported with prolonged anakinra use in
combination with tumor necrosis factor-alpha blockade, but not with short-term use.15
The data on using IL-1 inhibitors to treat COVID-19 in pregnant patients are currently limited. The
American College of Rheumatology recommends against the use of anakinra during pregnancy.16
Unintentional first-trimester exposure to anakinra is unlikely to be harmful, given the minimal transfer
of monoclonal antibodies across the placenta early in pregnancy.17

Anakinra has been used in the treatment of severely ill children with rheumatologic conditions,
including MAS. The data on the use of anakinra in pediatric patients with acute respiratory distress
syndrome or sepsis are limited. Anakinra is rarely used to treat pediatric patients with acute COVID-19,
and it has been used in approximately 10% of cases of multisystem inflammatory syndrome in children
(MIS-C).18,19 Anakinra is often included in institutional protocols for the treatment of MIS-C in the
United States, and it is mentioned as an option for second-line therapy for refractory MIS-C in national
consensus guidelines.20-22 However, robust data on the effectiveness of anakinra for the treatment of
MIS-C are not currently available. Data on using canakinumab in pediatric patients are limited to use in
patients with periodic fever syndromes and systemic juvenile idiopathic arthritis. There are no data on
its use in pediatric patients with acute COVID-19 or MIS-C. The Panel recommends consulting with a
multidisciplinary team when using immunomodulating therapy (which may include anakinra) in children
with MIS-C (AIII).
References
1. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced
mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior Phase III
trial. Crit Care Med. 2016;44(2):275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26584195.
2. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm
in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. Available at:
3. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at:
4. Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by
soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.
Nat Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480127.
5. CORIMUNO-19 Collaborative Group. Effect of anakinra versus usual care in adults in hospital with
COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet
Respir Med. 2021;9(3):295-304. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33493450.
6. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for
critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain
randomized clinical trial. medRxiv. 2021;Preprint. Available at:
7. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive
mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA.
8. Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe
COVID-19 pneumonia: case series. Ann Rheum Dis. 2020;79(10):1381-1382. Available at:
9. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with
COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet
Rheumatol. 2020;2(6):e325-e331. Available at: https://pubmed.ncbi.nlm.nih.gov/32501454/.
10. Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet
Rheumatol. 2020;2(7):e393-e400. Available at: https://pubmed.ncbi.nlm.nih.gov/32835245/.
11. Kooistra EJ, Waalders NJB, Grondman I, et al. Anakinra treatment in critically ill COVID-19 patients: a
prospective cohort study. Crit Care. 2020;24(1):688. Available at:

12. Fisher CJ, Jr., Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the
treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial.
Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836-1843. Available at:
13. Fisher CJ, Jr., Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor
antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
Crit Care Med. 1994;22(1):12-21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8124953.
14. Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis:
a Phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor
Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115-1124. Available at:
15. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts
(ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases
perspective (soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and
complement factors). Clin Microbiol Infect. 2018;24 Suppl 2:S21-S40. Available at:
17. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and
breastfeeding-part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford).
19. Derespina KR, Kaushik S, Plichta A, et al. Clinical manifestations and outcomes of critically ill children and
adolescents with coronavirus disease 2019 in New York City. J Pediatr. 2020;Published online ahead of print.
20. Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: survey of protocols
for early hospital evaluation and management. J Pediatr. 2021;229:33-40. Available at:
21. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for
multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in
pediatric COVID-19: version 2. Arthritis Rheumatol. 2021;73(4):e13-e29. Available at:
22. Harwood R, Allin B, Jones CE, et al. A national consensus management pathway for paediatric inflammatory
multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi
process. Lancet Child Adolesc Health. 2021;5(2):133-141. Available at:

Table 6g. Characteristics of Immunomodulators
• The information in this table is derived from data on the use of these drugs for FDA-approved indications or in investigational trials, and
it is supplemented with data on their use in patients with COVID-19, when available.
• For dose modifications for patients with organ failure or those who require extracorporeal devices, please refer to product labels or EUAs,
when available.
• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment
of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.
• The potential additive, antagonistic, or synergistic effects and the safety of using certain combination therapies for the treatment of
COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.
• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the drug-specific sections of the Guidelines,
to Therapeutic Management of Nonhospitalized Adults With COVID-19, and Therapeutic Management of Hospitalized Adults With
COVID-19.
Monitoring Drug-Drug Interaction Comments and Links to Clinical

Drug Name Dosing Regimens Adverse Events
Parameters Potential Trials
Corticosteroid (Systemic)
Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Dexamethasone Dose for COVID-19: • Hyperglycemia • Blood glucose • Moderate CYP3A4 inducer • If DEX is not available, an
(Systemic) • DEX 6 mg IV or PO • Secondary infections • BP • CYP3A4 substrate alternative corticosteroid (e.g.,
once daily for up to 10 • Reactivation of latent prednisone, methylprednisolone,
• Signs and hydrocortisone) can be used.
days or until hospital infections (e.g., HBV, symptoms of
discharge, whichever HSV, strongyloidiasis, new infection • The approximate total daily
comes first1 TB) dose equivalencies for these
glucocorticoids to DEX 6 mg (PO or
• Cases of disseminated IV) are:
strongyloidiasis have
been reported in • Prednisone 40 mg
patients with COVID-19 • Methylprednisolone 32 mg
during treatment with • Hydrocortisone 160 mg
corticosteroids and
tocilizumab. • A list of clinical trials is available:
Dexamethasone

Monitoring Comments and Links to Clinical
Drug Name Dosing Regimens Adverse Events Drug-Drug Interaction Potential
Parameters Trials
Corticosteroid (Systemic), continued

• Psychiatric
disturbances
• Avascular necrosis
• Adrenal insufficiency
• Increased BP
• Peripheral edema
• Myopathy
(particularly if used
with NMBAs)
Kinase Inhibitors
Janus Kinase Inhibitors
Baricitinib and tofacitinib: Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Ruxolitinib: Not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Baricitinib2 FDA-Approved Doses for • Lymphoma and • CBC with • Dose modification is • See the FDA label2 and EUA3 for
COVID-19 for Adults Aged other malignancies differential recommended when dosing guidance for patients with:
≥18 Years2 • Thrombosis • Renal function administering concurrently with • ALC <200 cells/µL
eGFR ≥60 mL/min/1.73 m : 2 a strong OAT3 inhibitor.
• GI perforation • Liver enzymes • ANC <500 cells/µL
• Baricitinib 4 mg PO once • Treatment- • New infections • If increases in ALT or AST are
daily related changes observed and DILI is suspected,
eGFR 30 to <60 mL/min/1.73 in lymphocytes, interrupt baricitinib treatment
m2: neutrophils, Hgb, until the diagnosis of DILI is
liver enzymes excluded.
• Baricitinib 2 mg PO once
daily • HSV reactivation • Baricitinib tablets can be taken
orally or crushed, dispersed
eGFR 15 to <30 mL/min/1.73 • Herpes zoster in water, and given via a
m2: • Serious cardiac- gastrostomy tube.2
• Baricitinib 1 mg PO once related events (e.g.,
MI, stroke) • A list of clinical trials is available:
daily Baricitinib
eGFR <15 mL/min/1.73 m2: Availability:
• Not recommended • Baricitinib is approved by the FDA
for the treatment of COVID-19 for
adults aged ≥18 years and is

Monitoring Comments and Links to
Parameters Clinical Trials
Kinase Inhibitors, continued

Janus Kinase Inhibitors, continued
FDA EUA Dose for Children a vailable through an FDA
Aged 9–17 Years:3 EUA for children aged
• Same as adults 2–17 years who require
supplemental oxygen, NIV,
FDA EUA Doses for Children MV, or ECMO.3
Aged 2 to <9 Years3
eGFR ≥60 mL/min/1.73m2:
daily
eGFR 30 to <60 mL/
min/1.73m2:
daily
eGFR <30 mL/min/1.73m2:
• Not recommended
Duration of Therapy:
• Up to 14 days or until
hospital discharge
Ruxolitinib Dose for FDA-Approved • Thrombocytopenia • CBC with • Requires dose modification when • May require dose
Indications: •A nemia differential administered with strong CYP3A4 modification in patients
• Ruxolitinib 5 mg–20 mg PO • N • Liver enzymes inhibitor with hepatic impairment,
eutropenia moderate or severe
twice daily • New infections • Avoid use with fluconazole doses
• Liver enzyme >200 mg. renal impairment, or
Dose for COVID-19 in elevations thrombocytopenia
Clinical Trials: • Risk of infection • A list of clinical trials is
• Ruxolitinib 5 mg PO twice • Dizziness available: Ruxolitinib
daily for 14 days4
• Headache
• Diarrhea
• CPK elevation
• Herpes zoster

Kinase Inhibitors, continued

Janus Kinase Inhibitors, continued
Tofacitinib Dose for COVID-19 in • Thrombotic events • CBC with • Requires dose modification • Avoid use in patients with
Clinical Trials: (e.g., PE, DVT, arterial differential when administered with strong ALC <500 cells/mm3, ANC
• Tofacitinib 10 mg PO thrombosis) • Liver enzymes CYP3A4 inhibitors or when <1,000 cells/mm3, or Hgb <9
twice daily for up to 14 • Anemia used with a moderate CYP3A4 grams/dL.
• New infections inhibitor that is coadministered
days or until hospital • Risk of infection • May require dose
discharge5 with a strong CYP2C19 inhibitor. modification in patients with
• GI perforation • Coadministration with strong moderate or severe renal
• Diarrhea CYP3A4 inducers is not impairment or moderate
• Headache recommended. hepatic impairment.
• Herpes zoster • A list of clinical trials is
available: Tofacitinib
• Lipid elevations
• Liver enzyme elevations
• Lymphoma and other
malignancies
• Serious cardiac-related
events (e.g., MI, stroke)
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Sarilumab6 Dose for COVID-19 in • Neutropenia, • HSR • Elevated IL-6 may downregulate • Sarilumab is not
Clinical Trials: thrombocytopenia • Infusion reactions CYP enzymes; thus, use of recommended in patients
• Single dose of sarilumab • GI perforation sarilumab may lead to increased with ALT or AST >1.5
• Neutrophils metabolism of drugs that are times the upper limit of the
400 mg IV 7
• HSR • PLT CYP substrates. reference range, ANC <2,000
• Increased liver enzymes • Liver enzymes • The effects of sarilumab on CYP cells/mm3, or PLT <150,000
• HBV reactivation enzymes may persist for weeks cells/mm3.6
• Infusion-related reaction after the drug is stopped. • Treatment with sarilumab
may mask signs of acute
inflammation or infection by
suppressing fever and CRP
levels.

Interleukin-6 Inhibitors, continued

Anti-Interleukin-6 Receptor Monoclonal Antibodies, continued
available: Sarilumab
Availability:
• The IV formulation of
sarilumab is not approved by
the FDA, but in a clinical trial,
a single SUBQ dose (using
the prefilled syringe, not the
prefilled pen) of sarilumab
400 mg was reconstituted in
100 cc 0.9% NaCl and given
as an IV infusion over 1 hour.
• Sarilumab infusion should
be used within 4 hours of
preparation; it can be stored
at room temperature until
administered.
Tocilizumab8 FDA EUA Doses for • Infusion-related • HSR • Inhibition of IL-6 may lead • Tocilizumab is not
COVID-19 in Hospitalized reaction • Infusion reactions to increased metabolism of recommended in patients
Patients Aged ≥2 Years • HSR coadministered drugs that are with ALT or AST >10 times
• Neutrophils CYP450 substrates. the upper limit of the
Body Weight ≥30 kg: • GI perforation • PLT • The effects of tocilizumab on reference range, ANC <1,000
• Tocilizumab 8 mg/kg • Hepatotoxicity cells/mm3, or PLT <50,000
(maximum 800 mg) by IV • Liver enzymes CYP enzymes may persist for
• Treatment-related weeks after the drug is stopped. cells/mm3.9
infusion over 1 hour
changes on • The SUBQ formulation of
• Per the EUA, if clinical signs laboratory tests for tocilizumab is not intended
or symptoms worsen or do neutrophils, PLT, for IV administration.
not improve following the lipids, and liver
first infusion, 1 additional • A list of clinical trials is
enzymes available: Tocilizumab
dose may be administered
≥8 hours after the first • HBV reactivation
Availability:
dose. • Secondary infections
• IV tocilizumab, which has
been approved for non-

Monitoring Drug-Drug Interaction Comments and Links to Clinical
Parameters Potential Trials
Interleukin-6 Inhibitors, continued

Anti-Interleukin-6 Receptor Monoclonal Antibodies, continued
Body Weight <30 kg: • Cases of disseminated OVID-19 indications, is available
C
• Tocilizumab 12 mg/kg by strongyloidiasis commercially and through an
IV infusion over 1 hour have been reported FDA EUA for the treatment of
in patients with COVID-19 in hospitalized adults
• Per the EUA, if clinical COVID-19 during and pediatric patients aged
signs or symptoms treatment with ≥2 years who are receiving
worsen or do not improve tocilizumab and systemic corticosteroids and
following the first infusion, corticosteroids. require supplemental oxygen,
1 additional dose may be NIV, MV, or ECMO. The EUA does
administered ≥8 hours not authorize the use of SUBQ
after the first dose. administration of tocilizumab for
the treatment of COVID-19.9
Anti-Interleukin-6 Monoclonal Antibody
Not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Siltuximab FDA-Approved Dose for • Infusion-related • Neutrophils • Elevated IL-6 may • Siltuximab is not recommended
Multicentric Castleman reaction • HSR downregulate CYP enzymes; in patients with ANC <1,000
Disease: • HSR use of siltuximab may lead cells/mm3, Hgb >17 g/dL, or PLT
• Infusion reactions to increased metabolism <75,000 cells/mm3.10
• Siltuximab 11 mg/kg by IV • GI perforation
infusion over 1 hour every of drugs that are CYP • Treatment with siltuximab may
3 weeks10 • Neutropenia substrates. mask signs of acute inflammation
• HTN • The effects of siltuximab on or infection by suppressing fever
Dose for COVID-19:
• Dizziness CYP enzymes may persist and CRP levels.
• Dose and duration for weeks after therapy is
• Rash • A list of clinical trials is available:
unknown stopped. Siltuximab
• Pruritus
• Hyperuricemia

Colchicine
Colchicine Dose for COVID-19 in • Diarrhea • CBC • P-gp and CYP3A4 substrate • Use of colchicine should
COLCORONA Trial: • Nausea • Renal function • The risk of myopathy may be avoided in patients with
• Colchicine 0.5 mg twice be increased with the severe renal insufficiency.
• Vomiting • Hepatic function Patients with moderate renal
daily for 3 days, then once concomitant use of certain
daily for 27 days11 • Cramping HMG-CoA reductase inhibitors insufficiency who receive the
• Abdominal pain (e.g., atorvastatin, lovastatin, drug should be monitored
Dose for COVID-19 in for AEs.
• B
loating simvastatin) due to potential
COLCOVID Trial:
competitive interactions • A list of clinical trials is
• Colchicine 1.5 mg PO • Loss of appetite
mediated by P-gp and available: Colchicine
followed by 0.5 mg PO • Neuromyotoxicity CYP3A4 pathways.
within 2 hours of initial (rare)13 Availability:
• Fatal colchicine toxicity has
dose, then twice daily for • Blood dyscrasias (rare) • In the COLCORONA and
been reported in individuals
14 days or until hospital COLCOVID trials, 0.5 mg
with renal or hepatic
discharge, whichever colchicine tablets were used
impairment who used
comes first 12
for dosing; in the United
colchicine in conjunction
States, colchicine is available
with P-gp inhibitors or strong
as 0.6 mg tablets.
CYP3A4 inhibitors.
Corticosteroids (Inhaled)
Budesonide Dose for COVID-19 in • Secondary infections • Signs of AEs • CYP3A4 substrate • A list of clinical trials is
(Inhaled) Clinical Trials: • Oral thrush involving the oral •D o not use with strong available: Inhaled Budesonide
• Budesonide 800 mcg oral • Systemic AEs (less mucosa or throat, CYP3A4 inhibitors.
inhalation twice daily until including thrush
common)
symptom resolution or for • Signs of systemic
up to 14 days14,15 corticosteroid
effects (e.g., adrenal
suppression)

Corticosteroids (Inhaled), continued

Ciclesonide Dose for COVID-19 in • Secondary infections • Signs of AEs • CYP3A4 substrate • A list of clinical trials is
(Inhaled) Clinical Trials: • Oral thrush involving the oral • Strong CYP3A4 inhibitors available: Ciclesonide
• Ciclesonide 160 mcg as mucosa or throat, are expected to have less
• Systemic AEs (less including thrush
2 MDI inhalations twice common) of an effect on ciclesonide
daily for 30 days16 • Signs of systemic exposure than they have on
corticosteroid budesonide exposure.
effects (e.g.,
adrenal
suppression)
Fluvoxamine
Fluvoxamine Doses for COVID-19 in • Nausea • Hepatic function • CYP2D6 substrate • Fluvoxamine may enhance
Clinical Trials: • Diarrhea • Drug interactions • Fluvoxamine inhibits anticoagulant effects
• Fluvoxamine 50 mg twice • Dyspepsia several CYP isoenzymes of antiplatelets and
• Withdrawal anticoagulants; consider
daily symptoms during (CYP1A2, CYP2C9,
• Asthenia CYP3A4, CYP2C19, additional monitoring
• Fluvoxamine 100 mg twice dose tapering when these drugs are
daily • I
nsomnia CYP2D6)
used concomitantly with
• Fluvoxamine 100 mg 3 • Somnolence • Coadministration of fluvoxamine.
times daily • Sweating tizanidine, thioridazine,
alosetron, or pimozide • The use of MAOIs
• Suicidal ideation (rare) concomitantly with
with fluvoxamine is
contraindicated. fluvoxamine or within 14 days
of treatment with fluvoxamine
is contraindicated.
available: Fluvoxamine

Anakinra FDA-Approved Dose for • Neutropenia (particularly • CBC with • Use with TNF- • Anakinra for IV administration
Rheumatoid Arthritis: when used concomitantly differential blocking agents is not is not an approved
• Anakinra 100 mg SUBQ once with other agents that can • Liver enzymes recommended due formulation in the United
daily cause neutropenia) to increased risk of States.17
• Renal function; infection.
• Anaphylaxis and reduce dose if CrCl • A list of clinical trials is
Doses for COVID-19 in Clinical
angioedema <30 mL/min. available: Anakinra
Trials:
• Headache
• Dose and duration vary by
study. • Nausea
• Has also been used as IV • Diarrhea
infusion. • Sinusitis
• Arthralgia
• Flu-like symptoms
• Abdominal pain
• Injection site reactions
Canakinumab FDA-Approved Dose for • HSR • HSR • Binding of canakinumab • Canakinumab for IV
Systemic JIA: • Neutropenia • CBC with to IL-1 may increase administration is not an
• Canakinumab 4 mg/kg differential formation of CYP approved formulation in the
• Nasopharyngitis enzymes and alter United States.18
(maximum 300 mg) SUBQ • Liver enzymes
every 4 weeks 18 • D
iarrhea metabolism of drugs • A list of clinical trials is
• Respiratory tract that are CYP substrates. available: Canakinumab
infections • Use with TNF-
• Bronchitis blocking agents is not
recommended due to
• Gastroenteritis
potential increased risk
• Pharyngitis of infection.
• Musculoskeletal pain
• Vertigo
• Abdominal pain
• Injection site reactions

Non-SARS-CoV-2 Specific Immunoglobulin

Primarily used for the treatment of multisystem inflammatory syndrome in children (MIS-C). Currently under investigation in clinical trials.
Non-SARS- • Dose varies based on • Allergic reactions, including • Transfusion- • Not a substrate of CYP • A list of clinical trials is
CoV-2 Specific indication and formulation. anaphylaxis related reactions available: Intravenous
Immunoglobulin • Renal failure • Vital signs at Immunoglobulin
• Thrombotic events baseline and
during and after
• Aseptic meningitis syndrome infusion
• Hemolysis • Renal function;
• TRALI discontinue
• Transmission of infectious treatment
pathogens if function
deteriorates.
• AEs may vary by formulation.
• AEs may be increased with
high dose or rapid infusion
or in patients with underlying
conditions.
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BP =
blood pressure; CBC = complete blood count; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive protein; CYP = cytochrome P450; DEX
= dexamethasone; DILI = drug-induced liver injury; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular
filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal; HBV = hepatitis B virus; Hgb = hemoglobin; HSR =
hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IL = interleukin; IV = intravenous; JIA = juvenile idiopathic arthritis; MAOI = monoamine
oxidase inhibitor; MDI = metered dose inhaler; MI= myocardial infarction; MV = mechanical ventilation; NaCl = sodium chloride; NIV = noninvasive ventilation;
NMBA = neuromuscular blocking agents; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; PE = pulmonary embolism; P-gp=
P-glycoprotein; PLT = platelet count; PO = orally; SUBQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung
injury
References
1. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with
severe respiratory complications of COVID-19. 2020. Available at: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-
to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed August 3, 2022.
2. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2022/207924s006lbl.pdf.

3. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of baricitinib. 2022. Available at: https://www.
fda.gov/media/143823/download.
4. Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled
trial. J Allergy Clin Immunol. 2020;146(1):137-146. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
5. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415.
6. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
7. REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the
REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at:
8. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
9. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Actemra (tocilizumab). 2021. Available at:
10. Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
11. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a Phase 3, randomised,
double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at:
12. Diaz R, Orlandini A, Castellana N, et al. Effect of colchicine vs usual care alone on intubation and 28-day mortality in patients hospitalized with
COVID-19: a randomized clinical trial. JAMA Netw Open. 2021;4(12):e2141328. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34964849.
13. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
14. Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label,
randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
15. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK
(PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855. Available at:
16. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with
symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med. 2022;182(1):42-49. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/34807241.
17. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/

18. Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/

Antithrombotic Therapy in Patients with
COVID-19
Chronic Anticoagulant and Antiplatelet Therapy
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that hospitalized patients with COVID-19 who
are receiving anticoagulant or antiplatelet therapy for underlying medical conditions continue this treatment unless
significant bleeding develops, or other contraindications are present (AIII).
Screening and Evaluation for Venous Thromboembolism
• In patients with COVID-19 who have no signs or symptoms of venous thromboembolism (VTE), there is currently
insufficient evidence to recommend either for or against routine VTE screening, regardless of the patient’s coagulation
markers.
• For hospitalized patients with COVID-19 who experience rapid deterioration of pulmonary, cardiac, or neurological
function or sudden, localized loss of peripheral perfusion, the Panel recommends evaluating the patients for
thromboembolic disease (AIII).
Anticoagulant Treatment for Thrombosis
• The Panel recommends that when diagnostic imaging is not possible, patients with COVID-19 who are highly
suspected to have thromboembolic disease be managed with therapeutic anticoagulation (AIII).
• The Panel recommends that patients with COVID-19 who require extracorporeal membrane oxygenation or
continuous renal replacement therapy or who have thrombosis related to catheters or extracorporeal filters be treated
with antithrombotic therapy as per the standard institutional protocols for those without COVID-19 (AIII).
Antithrombotic Therapy for Nonhospitalized Patients Without Evidence of Venous Thromboembolism
• In nonhospitalized patients with COVID-19, the Panel recommends against the use of anticoagulants and antiplatelet
therapy (aspirin or P2Y12 inhibitors) for the prevention of VTE or arterial thrombosis unless the patient has other
indications for the therapy or is participating in a clinical trial (AIIa).
• The Panel recommends against routinely continuing VTE prophylaxis for patients with COVID-19 after hospital
discharge, except in a clinical trial (AIII).
• For patients who are at high risk for VTE and low risk for bleeding, there is insufficient evidence to recommend either
for or against continuing anticoagulation after hospital discharge unless another indication for VTE prophylaxis exists.
Antithrombotic Therapy for Hospitalized, Nonpregnant Adults Without Evidence of Venous Thromboembolism
• The Panel recommends against using anticoagulant or antiplatelet therapy to prevent arterial thrombosis outside of
the usual standard of care for patients without COVID-19 (AIII).
• In hospitalized patients, low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is preferred over
oral anticoagulants, because these 2 types of heparin have shorter half-lives and the effect can be reversed quickly,
can be administered intravenously or subcutaneously, and have fewer drug-drug interactions (AIII).
• When heparin is used, LMWH is preferred over UFH.
For adults who require low-flow oxygen and do not require intensive care unit (ICU)-level care:
• The Panel recommends using a therapeutic dose of heparin for patients with D-dimer levels above the upper limit of
normal, who require low-flow oxygen, and who do not have an increased bleeding risk (CIIa).
• Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 are a platelet count <50 x
109/L, hemoglobin <8 g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required
an emergency department visit or hospitalization, history of a bleeding disorder, or an inherited or active acquired
bleeding disorder. This list is based on the exclusion criteria from clinical trials; patients with these conditions have
an increased risk of bleeding.
• In patients without VTE who have begun a therapeutic dose of heparin, treatment should continue for 14 days or until
hospital discharge, whichever comes first.

• The Panel recommends using a prophylactic dose of heparin for patients who are not receiving a therapeutic dose of
heparin, unless a contraindication exists (AIIb).
• The Panel recommends against the use of a therapeutic dose of oral anticoagulants for VTE prophylaxis or
prevention of COVID-19 progression, except in a clinical trial (AIIa).
• There is currently insufficient evidence to recommend either for or against the use of thrombolytics for COVID-19.
• The Panel recommends against the use of antiplatelet therapy to prevent COVID-19 progression or death in
noncritically ill patients (BIIa).
For adults who require ICU-level care, including those receiving high-flow oxygen:
• The Panel recommends using a prophylactic dose of heparin as VTE prophylaxis, unless a contraindication exists
(AI).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg once daily) or a
therapeutic dose of anticoagulation for VTE prophylaxis, except in a clinical trial (BI).
• For patients who start on a therapeutic dose of heparin in a non-ICU setting due to COVID-19 and then transfer to the
ICU, the Panel recommends switching from the therapeutic dose to a prophylactic dose of heparin, unless VTE is
confirmed (BIII).
• There is insufficient evidence for the Panel to recommend either for or against antiplatelet therapy in critically ill
Hospitalized Children
• For hospitalized children with COVID-19, indications for VTE prophylaxis should be the same as those for children
without COVID-19 (BIII).
Special Considerations During Pregnancy and Lactation
• The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet therapies for underlying
conditions continue these medications after they receive a diagnosis of COVID-19 (AIII).
• The Panel recommends using a prophylactic dose of anticoagulation for pregnant patients hospitalized for
manifestations of COVID-19, unless otherwise contraindicated (BIII).
• Because pregnant patients have not been included in most clinical trials evaluating therapeutic anticoagulation in
the setting of COVID-19, there is currently insufficient evidence to recommend either for or against therapeutic
anticoagulation for pregnant patients with COVID-19 without evidence of VTE.
• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not routinely recommended for pregnant
patients (BIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be
individualized, with consideration of concomitant VTE risk factors.
• The use of anticoagulation therapy during labor and delivery requires specialized care and planning. It should be
managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions (AIII).
• UFH, LMWH, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the
newborn; therefore, they can be used by breastfeeding individuals who require VTE prophylaxis or treatment (AIII).
Association Between COVID-19 and Thromboembolism

COVID-19 has been associated with inflammation and a prothrombotic state, with increases in fibrin,
fibrin degradation products, fibrinogen, and D-dimer levels.1,2 In some studies, elevations in these
markers have been associated with worse clinical outcomes.3,4
Studies have reported varying incidences of venous thromboembolism (VTE) in patients with
COVID-19. A meta-analysis of studies of hospitalized patients with COVID-19 treated with VTE
prophylaxis found an overall VTE prevalence of 14.1% (95% CI, 11.6–16.9).5 The VTE prevalence

was higher in studies that used ultrasound screening (40.3%; 95% CI, 27.0–54.3) than in studies that
did not (9.5%; 95% CI, 7.5–11.7). In randomized controlled trials conducted prior to the pandemic, the
incidence of VTE in hospitalized patients without COVID-19 who received VTE prophylaxis ranged
from 0.3% to 1% for symptomatic VTE and from 2.8% to 5.6% for VTE overall.6-8 The VTE incidence
in randomized trials in critically ill patients without COVID-19 who received a prophylactic dose of
anticoagulants ranged from 5% to 16%, and a prospective cohort study of critically ill patients with
sepsis reported a VTE incidence of 37%.9-12
Guidelines about the use of antithrombotic therapy in patients with COVID-19 have been released by
multiple organizations, including the American College of Chest Physicians,13 American Society of
Hematology,14 Anticoagulation Forum,15 International Society on Thrombosis and Haemostasis,16 Italian
Society for Haemostasis and Thrombosis,17 National Institute for Health and Care Excellence (NICE),18
and Royal College of Physicians.19
The guidelines referenced above agree that hospitalized, nonpregnant patients with COVID-19 should
receive, at a minimum, a prophylactic dose of anticoagulation to prevent VTE. The NICE guideline
recommendation states, “Consider a treatment dose of a low molecular weight heparin (LMWH) for
young people and adults with COVID-19 who need low-flow oxygen and who do not have an increased
bleeding risk.” Results from clinical trials that assess the safety and efficacy of different anticoagulant
doses and strategies have provided further information on antithrombotic strategies for patients with
COVID-19.
Chronic Anticoagulant or Antiplatelet Therapy

The COVID-19 Treatment Guidelines Panel (the Panel) recommends that hospitalized patients with
COVID-19 who are receiving anticoagulant or antiplatelet therapy for underlying medical conditions
continue this treatment unless significant bleeding develops, or other contraindications are present
(AIII). Outpatients with COVID-19 who are receiving warfarin and are in isolation and unable to have
international normalized ratio monitoring may be candidates for switching to direct oral anticoagulant
therapy, except in settings where substitution would be clinically inappropriate, such as for patients
with a mechanical heart valve, a ventricular assist device, valvular atrial fibrillation, or antiphospholipid
antibody syndrome or who are lactating.
Screening and Evaluation for Venous Thromboembolism

VTE guidelines for patients without COVID-19 have recommended against routine screening
ultrasounds in critically ill patients because no study has shown that this strategy reduces the rate of
subsequent symptomatic thromboembolic complications.20 Although the incidence of thromboembolic
events, especially pulmonary emboli, can be high among hospitalized patients with COVID-19,
no published data demonstrate the clinical utility of using lower extremity ultrasound as routine
surveillance for deep vein thrombosis in this population.
• In patients with COVID-19 who have no signs or symptoms of VTE, there is currently insufficient
evidence to recommend either for or against routine VTE screening, regardless of the patient’s
coagulation markers.
• For hospitalized patients with COVID-19 who experience rapid deterioration of pulmonary,
cardiac, or neurological function or sudden, localized loss of peripheral perfusion, the Panel
recommends evaluating the patients for thromboembolic disease (AIII).
Managing Antithrombotic Therapy in Patients With COVID-19

The Panel recommends that when diagnostic imaging is not possible, patients with COVID-19 who are

highly suspected to have thromboembolic disease be managed with therapeutic anticoagulation (AIII).
The Panel recommends that patients with COVID-19 who require extracorporeal membrane oxygenation
(ECMO) or continuous renal replacement therapy or who have thrombosis related to catheters or
extracorporeal filters be treated with antithrombotic therapy as per the standard institutional protocols
for those without COVID-19 (AIII).
Selection of Anticoagulant or Antiplatelet Drugs

Whenever anticoagulant or antiplatelet therapy is used, potential drug-drug interactions with other
concomitant drugs must be considered. The University of Liverpool has collated a list of drug
interactions. In hospitalized, critically ill patients, LMWH or unfractionated heparin (UFH) is
preferred over oral anticoagulants, because these 2 types of heparin have shorter half-lives and the effect
can be reversed quickly, can be administered intravenously or subcutaneously, and have fewer drug-drug
interactions (AIII).
Management of Nonhospitalized Patients

The ACTIV-4b placebo-controlled, randomized trial evaluated the efficacy of aspirin versus prophylactic
(2.5 mg) or therapeutic (5 mg) doses of apixaban to prevent thromboembolic events, hospitalization,
and death in outpatients with COVID-19 aged >40 years. The trial was stopped in June 2021 due to
a low event rate (1 patient each in the placebo, aspirin, and apixaban 2.5 mg arms and 2 patients in
the apixaban 5 mg arm) after randomization of 657 symptomatic outpatients. The median time from
randomization to study treatment was 3 days, and 22 participants were hospitalized for COVID-19 prior
to initiation of study drug.21 It is not known whether patients with previous VTE events or inherited
thrombophilias were included in this trial. For nonhospitalized patients with COVID-19, the Panel
recommends against the use of anticoagulants and antiplatelet therapy for the prevention of VTE or
arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical
trial (AIIa).
Management of Hospitalized Patients

Several studies have evaluated the risks and benefits of prophylactic or therapeutic doses of
anticoagulants in patients with COVID-19. Observational studies and clinical trials have examined the
effects of anticoagulation on mortality, progression of COVID-19, thrombosis, and bleeding. Some of
these studies are outlined below (visit ClinicalTrials.gov for a current list of trials). Observational studies
are included here only when evidence from clinical trials is not available.
Prophylactic-Dose of Anticoagulation Versus No Anticoagulation—Observational Cohort
An observational study of 4,297 veterans hospitalized with COVID-19 evaluated the benefit of
prophylactic anticoagulation. A prophylactic dose of anticoagulation was administered to 3,627 patients
with COVID-19 within 24 hours of hospital admission. An inverse probability of treatment weighted
analysis showed a cumulative 30-day mortality of 14% among veterans who received prophylactic
anticoagulation and 19% among patients who were not treated with anticoagulation (HR 0.73; 95% CI,
0.66–0.81). Participants treated with the prophylactic dose did not have a significant difference in risk
of bleeding that required transfusion when compared with participants who were not treated (HR 0.87;
95% CI, 0.71–1.05). Overall, the study demonstrated that patients with COVID-19 may benefit from a
prophylactic dose of anticoagulation.22
Therapeutic Versus Prophylactic Doses of Heparin in Hospitalized Patients Who Do Not Require
Intensive Care Unit-Level Care
Several randomized controlled trials have evaluated the role of therapeutic doses of heparin in reducing

VTE events or mortality in patients hospitalized for COVID-19.
Three open-label randomized controlled trials (the large ATTACC/ACTIV-4a/REMAP-CAP
multiplatform trial and the smaller RAPID and HEP-COVID trials) compared therapeutic doses of
heparin to prophylactic or intermediate doses of the anticoagulant in selected hospitalized patients who
did not require intensive care. Clinical data for these trials are summarized in Table 5a. The inclusion
and exclusion criteria for these studies varied, but most included a need for supplemental oxygen and no
risk of a major bleeding event. In the larger multiplatform trial, therapeutic doses of heparin increased
organ support-free days but did not significantly affect mortality or length of hospitalization when
compared with prophylactic doses of heparin.23
The RAPID trial enrolled patients with elevated D-dimer levels and hypoxemia. The patients were
randomized to receive therapeutic or prophylactic doses of heparin. There was no statistically significant
difference between the arms for the primary endpoint, which was a composite of intensive care unit
(ICU) admission, noninvasive or mechanical ventilation, or death by Day 28. However, the therapeutic
dose of heparin reduced all-cause death, a secondary outcome.24
The HEP-COVID trial enrolled patients who required supplemental oxygen and had a D-dimer value
>4 times the upper limit of normal (ULN) or a sepsis-induced coagulopathy score of ≥4. There were
significantly fewer occurrences of the primary endpoint of VTE, arterial thromboembolism, or all-cause
death within 32 days of randomization in the therapeutic LMWH arm than in the prophylactic LMWH
arm, but there was no difference between arms for the outcome of death within 32 days.25 Results from
smaller randomized trials, single-center studies, and observational studies have also been published.
Given the results of the ATTACC/ACTIV-4a/REMAP-CAP, RAPID, and HEP-COVID trials conducted
among hospitalized, nonpregnant adults with COVID-19 who did not require ICU-level care and without
evidence of VTE:
• The Panel recommends using a therapeutic dose of heparin for patients with D-dimer levels
above the ULN who require low-flow oxygen and who do not have an increased bleeding risk
(CIIa).
• Based on clinical trial exclusion criteria, contraindications for use of therapeutic
anticoagulation for patients with COVID-19 are a platelet count <50 x 109/L, hemoglobin <8
g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required an
emergency department visit or hospitalization, history of a bleeding disorder, or an inherited or
active, acquired bleeding disorder.
• LMWH is preferred over UFH because of its decreased administrative burden and because
LMWH was the predominant form of heparin used in the clinical trials for COVID-19.
• In patients without VTE who have begun a therapeutic dose of heparin, treatment should continue
for 14 days or until hospital discharge, whichever comes first.
• Patients with predicted hospitalizations of <72 hours were excluded from the multiplatform trial.
The risk/benefit ratio of therapeutic doses of anticoagulation for short hospital stays is not known.
• The Panel recommends using a prophylactic dose of heparin for patients who do not meet the
criteria for receiving therapeutic heparin or are not receiving a therapeutic dose of heparin for
other reasons, unless a contraindication exists (AIIb).
• The Panel recommends against the use of a therapeutic dose of oral anticoagulants for VTE
prophylaxis or prevention of COVID-19 progression, except in a clinical trial (AIIa).
• There is currently insufficient evidence to recommend either for or against the use of
thrombolytics for COVID-19.

Prophylactic Versus Intermediate or Therapeutic Doses of Heparin in Hospitalized Patients Who
Require Intensive Care Unit-Level Care
Several randomized controlled trials have evaluated the role of therapeutic doses of heparin in reducing
VTE events or mortality in patients in the ICU setting. Clinical data for these trials are summarized in
Table 5a.
For the composite endpoint of adjudicated VTE, arterial thrombosis, ECMO, or all-cause mortality, the
INSPIRATION trial found no difference between patients in the ICU treated with an intermediate dose
of anticoagulation (enoxaparin 1 mg/kg daily) and those who received a prophylactic dose (45.7% vs.
44.1%; OR 1.06; 95% CI, 0.76–1.48). Major bleeding occurred in 2.5% of patients in the intermediate-
dose anticoagulation arm compared with 1.4% of patients who received the prophylactic dose. Overall,
there was no significant benefit of receiving an intermediate dose of anticoagulation for patients with
COVID-19 in the ICU.26
A multiplatform randomized control trial (REMAP-CAP/ACTIV-4a/ATTACC) compared the
effectiveness of a therapeutic dose of heparin or LMWH with usual care in reducing the number of
organ support-free days among critically ill patients with COVID-19.27 All 3 trials were stopped for
futility. Heparin doses in the usual care arm varied. The median number of organ support-free days was
3 days (IQR -1 to 16) for patients who received a therapeutic dose of anticoagulation and 4 days (IQR -1
to 16) for patients who received usual care. The likelihood of survival to hospital discharge did not differ
between arms (63% therapeutic arm vs. 65% usual care arm; aOR 0.84; 95% CrI, 0.64–1.11). Major
bleeding occurred in 4% of participants receiving therapeutic anticoagulation and in 2% of participants
receiving usual care. Therapeutic doses of heparin showed no significant benefit for patients with
COVID-19 admitted to the ICU.
Given the results of these trials, for hospitalized, nonpregnant adults with COVID-19 who require ICU
level-care and who do not have documented or suspected VTE:
• The Panel recommends using a prophylactic dose of heparin as VTE prophylaxis, unless a
contraindication exists (AI).
• For patients who start on a therapeutic dose of heparin in a non-ICU setting due to COVID-19
and then transfer to the ICU, the Panel recommends switching from the therapeutic dose to a
prophylactic dose of heparin, unless VTE is confirmed (BIII).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg daily)
or a therapeutic dose of anticoagulation for VTE prophylaxis, except in a clinical trial (BI).
Rivaroxaban Versus Usual Care in Hospitalized Patients With Elevated D-Dimer Levels
The ACTION trial randomized adults hospitalized with COVID-19 and elevated D-dimer levels (defined
as above the laboratory ULN) to receive rivaroxaban 20 mg daily for 30 days or usual care28 (see Table
5a for a summary of clinical data for this trial). No statistical difference was found for the composite
endpoint of time to death, hospitalization duration, and oxygen use duration (hierarchical analysis; win
ratio 0.86; 95% CI, 0.59–1.22) or for the individual components. The probability of clinically relevant
nonmajor bleeding was greater with rivaroxaban (5% rivaroxaban arm vs. 1% usual care arm; relative
risk 5.23; 95% CI, 1.54–17.77), but for major bleeding events the difference between arms was not
significant (3% rivaroxaban arm vs. 1% usual care arm; relative risk 2.45; 95% CI, 0.78–7.73).
Given the lack of benefit and the increased risk of bleeding events, the Panel recommends against the
use of a therapeutic dose of oral anticoagulation for VTE prophylaxis and prevention of COVID-19
progression, except in a clinical trial (AIIa).

Antiplatelet Therapy Versus Usual Care in Hospitalized Patients
Multiple retrospective cohort studies suggested reduced in-hospital mortality in patients treated
with aspirin either before or within 24 hours of admission.29-31 Results from those studies have been
summarized in meta-analysis.32 These epidemiologic studies used propensity scoring or adjustment for
confounders, but indication bias could not be fully removed. Thus, randomized controlled trials are
needed to further define the role of aspirin and other antiplatelet therapy as an adjunctive treatment in
the management of COVID-19.
The RECOVERY trial randomized 7,351 hospitalized adults with COVID-19 to usual care plus
aspirin 150 mg per day and 7,541 patients to usual care only (see Table 5b).33 At enrollment, 33% of
the patients required noninvasive or mechanical ventilation. Mortality at 28 days was 17% in both
arms (rate ratio 0.96; 95% CI, 0.89–1.04). Results were similar in all prespecified subgroups. Among
participants not receiving mechanical ventilation at baseline, there was no difference in progression
to mechanical ventilation or death (21% aspirin arm vs. 22% usual care arm; rate ratio 0.96; 95% CI,
0.90–1.03). Among those treated with aspirin, the incidence of thrombotic events was lower (4.6% vs.
5.3%; absolute difference 0.6%; SE 0.4%), and the incidence of major bleeding events was higher (1.6%
vs. 1.0%; absolute difference 0.6%; SE 0.2%). Overall, in this large trial of hospitalized patients with
COVID-19, aspirin was associated with increased bleeding events and did not reduce mortality.
The ACTIV-4a trial evaluated P2Y12 inhibitor therapy plus a therapeutic dose of heparin versus
therapeutic heparin alone in hospitalized patients with COVID-19. In this study, enrollment in the
noncritically ill cohort was stopped due to futility because the combination therapy did not improve
the number of organ support-free days.34 Trial limitations include an open-label design, use of different
P2Y12 inhibitors, and a relatively small trial size.
Based on the findings from the ACTIV-4a and RECOVERY trials, the Panel recommends against the
use of antiplatelet therapy to prevent COVID-19 progression or death in noncritically ill patients (BIIa).
The REMAP-CAP study team conducted an open-label, adaptive randomized controlled trial of aspirin
(n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (n = 529) in critically ill patients
with COVID-19 (see Table 5b).35 Treatment was continued for 14 days or until hospital discharge,
whichever came first. The aspirin and P2Y12 inhibitor arms were pooled for analysis because the
criteria for equivalence were met. The trial was stopped due to futility, as the median of organ support-
free days did not differ between the antiplatelet and control arms (7 days [IQR 1–16 days]; 95.7%
posterior probability of futility). Survival to hospital discharge was numerically, but not statistically,
different between the arms (antiplatelet arm, 723 of 1,011 participants [71.5%] vs. control arm, 354 of
521 participants [67.9%]; median aOR, 1.27; 95% CrI, 0.99–1.62). A significantly larger proportion
of participants in the antiplatelet arm than in the control arm had survived at 90 days (median aHR
1.22; 95% CrI, 1.06–1.40). Antiplatelet therapy was associated with increased major bleeding (2.1%
in antiplatelet arm vs. 0.4% in control arm; aOR 2.97; 95% CrI, 1.23–8.28; adjusted absolute risk
difference 0.8%; 95% CrI, 0.1%–2.7%).
In summary, in the RECOVERY trial, aspirin therapy was not associated with reduced mortality in the
subgroups of patients requiring noninvasive or mechanical ventilation at baseline. In the REMAP-CAP
trial, 90-day survival was greater among critically ill patients with COVID-19 who received antiplatelet
therapy, but there was no difference between the antiplatelet and control arms in the number of organ
support-free days. In both studies, antiplatelet therapy was associated with an increased risk of bleeding.
Because of these results, there is insufficient evidence for the Panel to recommend either for or against
antiplatelet therapy in critically ill patients with COVID-19. Participation in clinical trials is encouraged.

Thrombolytic Therapy
Clinical trials are evaluating the use of thrombolysis on mortality and the progression of COVID-19
illness. There is currently insufficient evidence to recommend either for or against the use of
thrombolytic agents for VTE prophylaxis for hospitalized patients with COVID-19 outside of a clinical
trial.
Hospitalized Children
A recent meta-analysis of publications on COVID-19 in children did not discuss VTE.36 Indications for
VTE prophylaxis in hospitalized children with COVID-19 should be the same as those for hospitalized
children without COVID-19 (BIII).
Patients Discharged From the Hospital

For high-VTE-risk patients without COVID-19, post-discharge prophylaxis has been shown to be
beneficial. The Food and Drug Administration approved the use of rivaroxaban 10 mg daily for 31 to
39 days in these patients.37,38 Inclusion criteria for the trials that studied post-discharge VTE prophylaxis
included:
• A VTE risk score of ≥4 on the modified International Medical Prevention Registry on Venous
Thromboembolism (IMPROVE) tool,39 or
• A VTE risk score ≥2 on the modified IMPROVE tool40 and a D-dimer level >2 times ULN.37
The MICHELLE trial randomized 320 patients with COVID-19 who had an IMPROVE score of ≥4 or a
score of 2 to 3 with a D-dimer >500 ng/mL to rivaroxaban 10 mg orally daily or no anticoagulation for
35 days.41 The primary outcome was symptomatic VTE, fatal pulmonary embolism, symptomatic arterial
thromboembolism, cardiovascular death, or asymptomatic VTE detected by screening imaging at day
35. Five patients (3%) treated with rivaroxaban and 15 patients (9%) who did not receive anticoagulation
experienced a thrombotic event (relative risk 0.33; 95% CI, 0.13–0.90). One patient who received
rivaroxaban and 10 patients who did not receive anticoagulation experienced symptomatic events. No
major bleeding events occurred, and 2 patients had clinically relevant, nonmajor bleeding in each arm.
The open-label design and the inclusion of asymptomatic events detected by screening ultrasound and
computed tomography may have biased the results. In addition, two-thirds of the screened patients did
not meet trial eligibility, which limits generalizability.
The Panel recommends against routinely continuing VTE prophylaxis for patients with COVID-19
after hospital discharge, except in a clinical trial (AIII). For patients who are at high risk for VTE and
low risk for bleeding, there is insufficient evidence to recommend either for or against continuing
anticoagulation after hospital discharge unless another indication for VTE prophylaxis exists. The
decision to prescribe post-discharge VTE prophylaxis for patients with COVID-19 should include
consideration of an individual patient’s risk factors for VTE, bleeding risks, and feasibility. Participation
in clinical trials is encouraged.
Special Considerations During Pregnancy and Lactation

Because pregnancy is a hypercoagulable state, the risk of thromboembolism is greater in pregnant
individuals than in nonpregnant individuals.42 It is not yet known whether COVID-19 increases this
risk. In several cohort studies of pregnant women with COVID-19 in the United States and Europe,
VTE was not reported as a complication even among women with severe disease, although the receipt
of prophylactic or therapeutic anticoagulation varied across the studies.43-45 The American College
of Obstetricians and Gynecologists (ACOG) advises that, although there are no data for or against

thromboprophylaxis in the setting of COVID-19 in pregnancy, VTE prophylaxis can reasonably be
considered for pregnant individuals hospitalized with COVID-19, particularly for those who have severe
disease.46 If there are no contraindications to use, the Society for Maternal-Fetal Medicine recommends
prophylactic heparin or LMWH in critically ill or mechanically ventilated pregnant patients.47 Several
professional societies, including the American Society of Hematology and ACOG, have guidelines that
specifically address the management of VTE in the context of pregnancy.48,49 If delivery is imminent,
or if there are other risks for bleeding, the risk of bleeding may outweigh the potential benefit of VTE
prophylaxis in pregnancy.
Outside of pregnancy, D-dimer levels have been used to stratify VTE risk. However, physiologic
increases in D-dimer levels may occur during pregnancy, making elevated D-dimer values an unreliable
predictor that should not be used to evaluate VTE risk during pregnancy in the setting of COVID-19.50-52
In general, the preferred anticoagulants for use during pregnancy are heparin compounds. Because of its
reliability and ease of administration, LMWH is recommended rather than UFH for the prevention and
treatment of VTE in pregnancy.49 Direct-acting anticoagulants are not routinely recommended during
pregnancy because of a lack of safety data for pregnant individuals.48 The use of warfarin to prevent or
treat VTE should be avoided in pregnant individuals regardless of their COVID-19 status, especially
during the first trimester due to the concern for teratogenicity.
Specific recommendations for pregnant or lactating individuals with COVID-19 include:
• The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet
therapies for underlying conditions continue these medications after they receive a diagnosis of
COVID-19 (AIII).
• The Panel recommends using a prophylactic dose of anticoagulation for pregnant patients
hospitalized for manifestations of COVID-19, unless otherwise contraindicated (BIII).
• Because pregnant patients have not been included in most clinical trials evaluating therapeutic
anticoagulation in the setting of COVID-19, there is currently insufficient evidence to recommend
either for or against therapeutic anticoagulation for pregnant patients with COVID-19 without
evidence of VTE.
• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not routinely
recommended for pregnant patients (BIII). Decisions to continue VTE prophylaxis in the pregnant
or postpartum patient after discharge should be individualized, with consideration of concomitant
VTE risk factors.
• The use of anticoagulation therapy during labor and delivery requires specialized care and
planning. It should be managed in pregnant patients with COVID-19 in a similar way as in
pregnant patients with other conditions (AIII).
• UFH, LMWH, and warfarin do not accumulate in breast milk and do not induce an anticoagulant
effect in the newborn; therefore, they can be used by breastfeeding individuals who require VTE
prophylaxis or treatment (AIII).
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24. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin
on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with COVID-19
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prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with
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prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or
mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized
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41. Ramacciotti E, Barile Agati L, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge
thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre,
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Table 7a. Antithrombotic Therapy: Selected Clinical Data
antithrombotic therapy. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

ATTACC/ACTIV-4a/REMAP-CAP: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Noncritically Ill, Hospitalized Patients With COVID-19 in 9
Countries1
• Hospitalized with laboratory-confirmed SARS- • Median age 59 years; 59% men; median BMI 30 • Open-label study
CoV-2 infection without need for HFNC oxygen, • 52% with HTN; 30% with DM; 11% with CVD • Anticoagulation dose varied in SOC
NIV, MV, vasopressors, or inotropes arm (27% received intermediate-dose
• 66% required low-flow oxygen
Key Exclusion Criteria: thromboprophylaxis).
• D-dimer:
• Discharge expected ≤72 hours • Studies had different criteria for ICU care and
• 48.4% <2 times ULN expected hospital LOS.
• Requirement for therapeutic anticoagulation or • 28.4% ≥2 times ULN
dual antiplatelet therapy • Only enrolled 17% of screened patients
• 23.1% unknown
• High bleeding risk Interpretation:
• 62% on corticosteroids; 36% on RDV
Interventions: • Therapeutic heparin increased organ support-
Primary Outcomes: free days and decreased the number of
• Therapeutic UFH or LMWH for 14 days or until
• Organ support-free days: therapeutic anticoagulation patients requiring organ support.
discharge, whichever comes first (n = 1,190)
superior to SOC (aOR 1.27; 95% CrI, 1.03–1.58; 99% • Therapeutic heparin did not significantly
• SOC (n = 1,054) posterior probability) affect hospital LOS or the number of major
Primary Endpoint: • Survival until hospital discharge without organ support: thrombosis events or deaths.
• Organ support-free days at Day 21, evaluated on 4% absolute difference favoring therapeutic anticoagulation • Major bleeds occurred 1% more frequently in
an ordinal scale arm (95% CrI, 0.5–7.2) therapeutic arm than in SOC arm.
Key Secondary Endpoints: • Outcome consistent across D-dimer stratum
• Survival until hospital discharge Secondary Outcomes:
• Hospital LOS • Survival until hospital discharge: 92% in both arms
• Thrombosis or major bleeding • Hospital LOS: no difference between arms (aOR 1.03; 95%
CrI, 0.94–1.13)
• Thrombosis: 1% in therapeutic arm vs. 2% in SOC arm
• Major bleeding: 2% in therapeutic arm vs. 1% in SOC arm

RAPID: Open-Label RCT of Therapeutic Heparin in Moderately Ill, Hospitalized Patients With COVID-19 in 6 Countries2
• Hospitalized with COVID-19 and D-dimer ≥2 • Median age 60 years; 57% men; mean BMI 30 • Open-label study
times ULN or any elevated D-dimer level and • 48% with HTN; 34% with DM; 7% with CVD • Only enrolled 12% of screened patients
SpO2 ≤93% on room air
• 91% had hypoxia; 6% received HFNC oxygen Interpretation:
• Hospitalized <5 days
• D-dimer: • Compared to prophylactic heparin, therapeutic
Key Exclusion Criteria: • 49% <2 times ULN heparin reduced mortality (a secondary endpoint)
• Indication for therapeutic anticoagulation • 51% ≥2 times ULN but had no effects on the composite primary
• Dual antiplatelet therapy endpoint of ICU admissions or the need for NIV or
• 69% on corticosteroids MV, or death up to 28 days.
• High bleeding risk
Primary Outcome: • Major bleeding and VTE events were not different
Interventions: • ICU admission, NIV or MV, or death: 16% in in the therapeutic and prophylactic arms.
• Therapeutic UFH or LMWH for 28 days or until therapeutic arm vs. 22% in prophylactic arm (OR 0.69;
discharge or death (n = 228) 95% CI, 0.43–1.10)
• Prophylactic UFH or LMWH for 28 days or until Secondary Outcomes:
discharge or death (n = 237)
• All-cause death: 2% in therapeutic arm vs. 8% in
Primary Endpoint: prophylactic arm (OR 0.22; 95% CI, 0.07–0.65)
• Composite of ICU admission, NIV or MV, or • Mean organ support-free days: 26 days in therapeutic
death up to 28 days arm vs. 24 days in prophylactic arm (OR 1.41; 95% CI,
Key Secondary Endpoints: 0.9–2.21)
• All-cause death • No difference between arms for VTE (1% in therapeutic
arm vs. 3% in prophylactic arm) or major bleeding (1%
• Mean organ support-free days in therapeutic arm vs. 2% in prophylactic arm)
• VTE • Mean hospital-free days alive: 20 days in therapeutic
• Major bleeding event arm vs. 18 days in prophylactic arm (OR 1.09; 95% CI,
• Mean hospital-free days alive 0.79–1.50)

HEP-COVID: Open-Label RCT of Therapeutic Heparin in High-Risk, Hospitalized Patients With COVID-19 in the United States3
• Hospitalized with supplemental oxygen • Median age 67 years; 54% men; mean BMI 30 • Open-label study
• D-dimer >4 times ULN or sepsis-induced • 60% with HTN; 37% with DM; 7% with CVD • Only enrolled 2% of screened patients
coagulopathy score of ≥4 • 64% received oxygen via nasal cannula; 15% received Interpretation:
• Hospitalized <72 hours high-flow oxygen or NIV; 5% received MV
• Compared to usual care, therapeutic LMWH
Key Exclusion Criteria: • 80% on corticosteroids reduced the incidence of VTE, ATE, and death.
• Indication for therapeutic anticoagulation Primary Outcomes: • For patients not in the ICU, therapeutic LMWH
• Dual antiplatelet therapy • Composite of VTE, ATE, and death within 32 days: 29% significantly reduced thrombotic events and did
in therapeutic arm vs. 42% in usual care arm (relative not increase major bleeding.
• High bleeding risk
risk 0.68; 95% CI, 0.49–0.96)
• CrCl <15 mL/min
• Death: 19% in therapeutic arm vs. 25% in usual care
Interventions: arm (relative risk 0.78; 95% CI, 0.49–1.23)
• Therapeutic LMWH until hospital discharge or • Thrombotic events: 11% in therapeutic arm vs.
primary endpoint met (n = 129) 29% in usual care arm (relative risk 0.37; 95% CI,
• Usual care of prophylactic or intermediate-dose 0.21–0.66
LMWH until hospital discharge or primary • Non-ICU stratum composite of VTE, ATE, or death
endpoint met (n = 124) within 32 days: 17% in therapeutic arm vs. 36% in
Primary Endpoint: usual care arm (relative risk 0.46; 95% CI, 0.27–0.81)
• Composite of VTE, ATE, or death of any cause Safety Outcomes:
within 32 days of randomization • Major bleeding: 5% in therapeutic arm vs. 2% in usual
Key Safety Endpoint: care arm (relative risk 2.88, 95% CI, 0.59–14.02)
• Major bleeding • Non-ICU stratum major bleeding: 2% in both arms

ACTION: Open-Label RCT of Therapeutic Oral Anticoagulation (Rivaroxaban) in Hospitalized Patients With COVID-19 in Brazil4
• Hospitalized for COVID-19 with elevated D-dimer • Median age 57 years; 60% men; mean BMI 30 • Open-label study
level • 49% with HTN; 24% with DM; 5% with coronary • Only enrolled 18% of screened patients
• Symptoms for ≤14 days disease • Longer duration of anticoagulation in the
Key Exclusion Criteria: • Critically ill: 7% in therapeutic arm; 5% in usual care rivaroxaban arm (30 days) than the prophylactic
arm anticoagulation arm (mean duration = 8 days)
• Indication for therapeutic anticoagulation
• 75% required oxygen: 60% low-flow oxygen; 8% HFNC Interpretation:
• CrCl <30 mL/min
oxygen; 1% NIV; 6% MV
• P2Y12 inhibitor therapy or aspirin >100 mg • When compared with usual care, therapeutic
• 83% on corticosteroids rivaroxaban did not reduce mortality, hospital
• High bleeding risk duration, oxygen use duration, or thrombosis.
Primary Outcomes:
Interventions: • Patients who received therapeutic rivaroxaban had
• Composite of time to death, hospital duration, and
• Therapeutic anticoagulation for 30 days: oxygen use duration: no difference between arms (win more clinically relevant nonmajor bleeding than
rivaroxaban 15 mg or 20 mg daily; if clinically ratio 0.86; 95% CI, 0.59–1.22) those who received usual care.
unstable, enoxaparin 1 mg/kg twice daily or UFH • The longer duration of therapy in the rivaroxaban
(n = 311) Secondary Outcomes:
arm may have influenced the difference in
• Usual care prophylactic anticoagulation with • No difference between therapeutic and prophylactic bleeding events.
enoxaparin or UFH during hospitalization (n = arms:
304) • Mortality: 11% vs. 8%
Primary Endpoint: • Thrombosis: 7% vs. 10%
• Hierarchical composite of time to death, hospital • Any bleeding: 12% in therapeutic arm vs. 3% in usual
duration, and oxygen use duration through Day care arm
30 • Major bleeding: 3% in therapeutic arm vs. 1% in usual
Key Secondary Endpoints: care arm
• Thrombosis, with and without all-cause death • Clinically relevant, nonmajor bleeding: 5% in
therapeutic arm vs. 1% in usual care arm
• Mortality
• Bleeding events

REMAP-CAP/ACTIV-4a/ATTACC: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Critically Ill, Hospitalized Patients With COVID-19 in 20
Countries5
• Hospitalized with severe COVID-19 and receiving • Median age 60 years; 70% men; median BMI 30 • Open-label study
HFNC oxygen, NIV, MV, ECMO, vasopressors, or • 24% with chronic respiratory disease; 33% with DM; • Anticoagulation dose varied in usual care arm
inotropes 10% with chronic kidney disease; 8% with severe CVD (i.e., 51% intermediate, 2% subtherapeutic, 5%
• Hospitalized <72 hours (ACTIV-4a, ATTACC) or • 32% required HFNC oxygen; 38% required NIV; 29% therapeutic).
<14 days (REMAP-CAP) required MV • Inclusion criteria for hospital LOS and ICU-level
Key Exclusion Criteria: • 18% on vasopressors; 82% on corticosteroids; 32% care differed across trials.
• Discharge expected within 72 hours on RDV • Trial stopped for futility.
• Requirement for therapeutic anticoagulation or Primary Outcome: Interpretation:
dual antiplatelet therapy • Median organ support-free days at Day 21: 4 days • In patients requiring ICU care, therapeutic heparin
• High bleeding risk therapeutic arm vs. 5 days usual care arm (aOR 0.83; did not reduce the duration of organ support or
95% CrI, 0.67–1.03; 99.9% posterior probability of mortality.
Interventions:
futility; OR < 1.2) • Although the differences were nonsignificant,
• Therapeutic UFH or LMWH for 14 days or until
Secondary Outcomes: patients who received therapeutic anticoagulation
discharge, whichever comes first (n = 534)
had more bleeding events and fewer thrombotic
• Usual care (n = 564) • No difference between therapeutic and usual care
events than patients who received usual care.
arms:
Primary Endpoint:
• Survival to hospital discharge: 63% vs. 65% (aOR
• Organ support-free days at Day 21 0.84; 95% CrI, 0.64–1.11)
Key Secondary Endpoints: • Thrombosis: 6% vs. 10%
• Survival to hospital discharge • Major thrombotic events or death: 41% both arms
• Any thrombosis • Major bleeding events: 4% vs. 2% (aOR 1.48; 95%
• Composite of major thrombotic events or death CrI, 0.75–3.04)
• Bleeding events

INSPIRATION: Open-Label RCT of Intermediate-Dose Versus Prophylactic-Dose Anticoagulant in Patients in Intensive Care With COVID-19 in Iran6
• Admitted to ICU • Median age 62 years; 58% men; median BMI 27 • Open-label study
• Hospitalized <7 days • 44% with HTN; 28% with DM; 14% with coronary • Not all patients received ICU-level care.
artery disease
Key Exclusion Criteria: Interpretation:
• 32% required NIV; 20% required MV
• Life expectancy <24 hours • Intermediate-dose anticoagulation did not
• 23% on vasopressors; 93% on corticosteroids; 60% significantly reduce VTE and ATE, the need for
• Indication for therapeutic anticoagulation
on RDV ECMO, or mortality.
• Overt bleeding
Primary Outcome: • Although the difference was nonsignificant,
Interventions: patients who received intermediate-dose
• Composite adjudicated acute VTE, ATE, ECMO, or
• Intermediate-dose anticoagulation: enoxaparin 1 all-cause mortality: 46% in therapeutic arm vs. 44% in anticoagulation had more bleeding events than
mg/kg daily (n = 276) prophylactic arm (OR 1.06; 95% CI, 0.76–1.48) patients who received usual care.
• Prophylactic-dose anticoagulation (n = 286) Secondary Outcomes:
Primary Endpoint: • No difference between therapeutic and prophylactic
• Composite of adjudicated acute VTE, ATE, ECMO, arms:
or all-cause mortality within 30 days • All-cause mortality: 43% vs. 41%
Key Secondary Endpoints: • VTE: 3% both arms
• All-cause mortality • Major bleeding and clinically relevant nonmajor
• VTE bleeding: 6.3% vs. 3.1% (OR 2.02; 95% CI, 0.89–
4.61)
• Bleeding event
Key: ATE = arterial thromboembolism; BMI = body mass index; CrCl = creatinine clearance; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO =
extracorporeal membrane oxygenation; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; LMWH = low-molecular-weight heparin; LOS
= length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; RCT = randomized controlled trial;
RDV = remdesivir; SOC = standard of care; SpO2 = oxygen saturation; UFH = unfractionated heparin; ULN = upper limit of normal; VTE = venous thromboembolism
References
1. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic anticoagulation with heparin in noncritically ill
patients with COVID-19. N Engl J Med. 2021;385(9):790-802. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351721.
2. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive
care unit admission in moderately ill patients with COVID-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. Available

3. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose
heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med.
4. Lopes RD, de Barros ESPGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19
and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263.
5. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients
with COVID-19. N Engl J Med. 2021;385(9):777-789. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351722.
6. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on
thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit:
the INSPIRATION randomized clinical trial. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.

Table 7b. Antiplatelet Therapy: Selected Clinical Data
antiplatelet therapy. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

ACTIV-4a: Open-Label, Adaptive RCT of Adding a P2Y12 Inhibitor to Anticoagulant Therapy in Noncritically Ill Hospitalized Patients With COVID-19 in Brazil,
Italy, Spain, and the United States1
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 53 years; 42% women; 62% White • Open-label study
• Any 1 of the following: • HTN: 43% in P2Y12 inhibitor arm vs. 55% in usual • Study stopped early for futility
• D-dimer level ≥2 times ULN care arm • Different P2Y12 inhibitors used
• Aged 60–84 years • 65% on glucocorticoids; 52% on RDV; 3% on IL-6 • Median duration of P2Y12 inhibitor use was 6
inhibitors; 14% on aspirin days, which may not be sufficient to observe
• Aged <60 years with oxygen requirement >2
L/min, HTN, DM, eGFR <60 mL/min, CVD, or • Median duration of P2Y12 inhibitor treatment: 6 days effects.
BMI ≥35 • 63% received ticagrelor; 37% received clopidogrelInterpretation:
Key Exclusion Criteria: Primary Outcomes: • Among hospitalized patients with COVID-19 who
• Required HFNC oxygen ≥20 L/min, NIV, MV, • Median number of organ support-free days: 21 in were not critically ill, adding a P2Y12 inhibitor to
ECMO, vasopressors, or inotropes both arms (aOR 0.83; 95% CrI, 0.55–1.25; posterior a therapeutic dose of heparin did not increase the
probability of futility 96%) number of organ support-free days.
• >72 hours since hospital admission
• Major bleeding events: 6 patients (2.0%) in P2Y12 • Major bleeding events occurred infrequently
Interventions: during the study. The number of patients who
inhibitor arm vs. 2 (0.7%) in usual care arm (aOR 3.31;
• Therapeutic dose of heparin plus P2Y12 inhibitor 95% CI, 0.64–17.2; P = 0.15) experienced a major bleeding event was not
for 14 days or until discharge (n = 293) significantly different between the arms.
Secondary Outcome:
• Therapeutic dose of heparin (usual care arm) (n
= 269) • Major thrombotic event or death by Day 28: 6.1% in
P2Y12 inhibitor arm vs. 4.5% in usual care arm (aOR
Primary Endpoints: 1.42; 95% CI, 0.64–3.13)
• Number of organ support-free days by Day 21
• Major bleeding event by Day 28
• Major thrombotic event or death by Day 28

RECOVERY: Open-Label RCT of Aspirin in Hospitalized Patients With COVID-19 in Indonesia, Nepal, and the United Kingdom2
• Clinically suspected or laboratory-confirmed • Mean age 59 years; 62% men; 75% White • Because of open-label design, reporting of
SARS-CoV-2 infection • 97% had laboratory-confirmed SARS-CoV-2 infection thrombotic and major bleeding events may have
influenced treatment allocation.
Key Exclusion Criteria: • At baseline:
• Hypersensitivity to aspirin • 33% on NIV or MV Interpretation:
• Recent history of major bleeding events • 34% on intermediate- or therapeutic-dose LMWH • In hospitalized patients with COVID-19, the use
of aspirin was not associated with reductions in
• Currently receiving aspirin or another antiplatelet • 60% on standard-dose LMWH 28-day mortality or the risk of progressing to MV
treatment • 7% received no thromboprophylaxis or death.
Interventions: • 94% on corticosteroids; 26% on RDV; 13% on
• Aspirin 150 mg once daily until discharge (n = tocilizumab; 6% on baricitinib
7,351) Primary Outcome:
• SOC alone (n = 7,541) • All-cause mortality at 28 days: 17% in both arms (rate
Primary Endpoint: ratio 0.96; 95% CI, 0.89–1.04; P = 0.35)
• All-cause mortality at 28 days Secondary Outcomes:
Key Secondary Endpoints: • Progression to MV or death at 28 days: 21% in aspirin
• Progression to MV or death at 28 days arm vs. 22% in SOC arm (risk ratio 0.96; 95% CI,
0.90–1.03)
• Major bleeding or thrombotic events at 28 days
• Major bleeding events at 28 days: 1.6% in aspirin arm
vs. 1.0% in SOC arm (P = 0.0028)
• Thrombotic events: 4.6% in aspirin arm vs. 5.3% in
SOC arm (P = 0.07)

REMAP-CAP: Open-Label, Adaptive RCT of Antiplatelet Therapy in Critically Ill Patients With COVID-19 in 8 Countries in Europe and Asia3
• Clinically suspected or laboratory-confirmed • Mean age 57 years; 34% women; 77% White • Open-label study
SARS-CoV-2 infection • At baseline, 98% on LMWH: • Different P2Y12 inhibitors used
• Within 48 hours of ICU admission • 19% on low-dose LMWH • Trial stopped for futility. Because equivalence for
Key Exclusion Criteria: • 59% on intermediate-dose LMWH aspirin and P2Y12 inhibitor arms was reached,
these arms were pooled for analyses.
• Bleeding risk sufficient to contraindicate • 12% therapeutic-dose LMWH
antiplatelet therapy • 98% on steroids; 21% on RDV; 44% on tocilizumab; Interpretation:
• CrCl <30 mL/min 11% on sarilumab • In critically ill patients with COVID-19, the use of
• Receiving antiplatelet therapy or NSAID • In P2Y12 inhibitor arm, 88.5% received clopidogrel, aspirin or a P2Y12 inhibitor did not reduce the
1.3% received ticagrelor, 1.3% received prasugrel, and number of organ support-free days or in-hospital
Interventions: mortality.
8.8% received an unknown P2Y12 inhibitor
• 1 of the following plus anticoagulation for 14 • Patients in pooled antiplatelet arm had more major
days or until hospital discharge, whichever came Primary Outcome: bleeding events than those in the control arm, but
first: • Data from aspirin and P2Y12 inhibitor arms were they had improved survival over 90 days.
• Aspirin 75–100 mg once daily (n = 565) pooled and reported as “pooled antiplatelet arm” in
final analysis:
• P2Y12 inhibitor (n = 455)
• Median number of organ support-free days: 7 in
• No antiplatelet therapy (control arm) (n = 529)
pooled antiplatelet arm and control arm (aOR 1.02;
Primary Endpoint: 95% CrI, 0.86–1.23; posterior probability of futility
• Number of organ support-free days by Day 21 96%)
Key Secondary Endpoints: Secondary Outcomes:
• Survival to hospital discharge • Survival to hospital discharge: 71.5% in pooled
antiplatelet arm vs. 67.9% in control arm (median-
• Survival to Day 90
adjusted OR 1.27; 95% CrI, 0.99–1.62; adjusted
• Major bleeding event by Day 14 absolute difference 5%; 95% CrI, -0.2% to 9.5%; 97%
posterior probability of efficacy)
• Survival to Day 90: 72% in pooled antiplatelet arm vs.
68% in control arm (HR with pooled antiplatelets 1.22;
95% CrI, 1.06–1.40; 99.7% posterior probability of
efficacy)
• Major bleeding event by Day 14: 21 (2.1%) in pooled
antiplatelet arm vs. 2 (0.4%) in control arm (aOR 2.97;
95% CrI, 1.23–8.28; posterior probability of harm
99.4%)

Key: BMI = body mass index; CrCl = creatinine clearance; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation;
eGFR = estimated glomerular filtration rate; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; IL = interleukin; LMWH = low-molecular-
weight heparin; MV = mechanical ventilation; NIV = noninvasive ventilation; NSAID = nonsteroidal anti-inflammatory drug; the Panel = the COVID-19 Treatment
Guidelines Panel; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; ULN = upper limit of normal
References
1. Berger JS, Kornblith LZ, Gong MN, et al. Effect of P2Y12 inhibitors on survival free of organ support among non-critically ill hospitalized patients
with COVID-19: a randomized clinical trial. JAMA. 2022;327(3):227-236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35040887.
2. RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label,
platform trial. Lancet. 2022;399(10320):143-151. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34800427.
3. REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, et al. Effect of antiplatelet therapy on survival and
organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1247-1259. Available at:

Supplements
Vitamin C
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or
against the use of vitamin C for the treatment of COVID-19.
Vitamin D
• There is insufficient evidence for the Panel to recommend either for or against the use of vitamin D for the treatment
of COVID-19.
Zinc
• There is insufficient evidence for the Panel to recommend either for or against the use of zinc for the treatment of
COVID-19.
• The Panel recommends against using zinc supplementation above the recommended dietary allowance for the
prevention of COVID-19, except in a clinical trial (BIII).

In addition to the antiviral medications and the immune-based therapies that are discussed elsewhere in
the COVID-19 Treatment Guidelines, adjunctive therapies are frequently used in the prevention and/or
treatment of COVID-19 or its complications. Some of these agents are being studied in clinical trials.
Some clinicians advocate for the use of vitamin and mineral supplements to treat respiratory viral
infections. Ongoing studies are evaluating the use of vitamin and mineral supplements for both the
treatment and prevention of SARS-CoV-2 infection.
The following sections describe the underlying rationale for using adjunctive therapies and summarize
the existing clinical trial data. Other adjunctive therapies will be added as new evidence emerges.

Vitamin C
Vitamin C (ascorbic acid) is a water-soluble vitamin that is thought to have beneficial effects in
patients with severe and critical illnesses. It is an antioxidant and free radical scavenger that has anti-
inflammatory properties, influences cellular immunity and vascular integrity, and serves as a cofactor in
the generation of endogenous catecholamines.1,2 Because humans may require more vitamin C in states
of oxidative stress, vitamin C supplementation has been evaluated in numerous disease states, including
serious infections and sepsis. Because SARS-CoV-2 infection may cause sepsis and acute respiratory
distress syndrome (ARDS), the potential role of high doses of vitamin C in ameliorating inflammation
and vascular injury in patients with COVID-19 is being studied.
Recommendation for Non-Critically Ill Patients With COVID-19

recommend either for or against the use of vitamin C for the treatment of COVID-19 in non-critically
ill patients.
Rationale
Because patients who are not critically ill with COVID-19 are less likely to experience oxidative stress
or severe inflammation, the role of vitamin C in this setting is unknown.
Clinical Data on Vitamin C in Outpatients With COVID-19

Oral Ascorbic Acid Versus Zinc Gluconate Versus Both Agents Versus Standard of Care
In an open-label clinical trial that was conducted at two sites in the United States, outpatients with
laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of oral ascorbic
acid 8,000 mg, zinc gluconate 50 mg, both agents, or standard of care.3 The primary end point was the
number of days required to reach a 50% reduction in the patient’s symptom severity score. The study
was stopped early by an operational and safety monitoring board due to futility after 40% of the planned
520 participants were enrolled (n = 214).
Patients who received standard of care achieved a 50% reduction in their symptom severity scores at
a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic acid arm, 5.9
days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the arm that received
both agents (overall P = 0.45). Nonserious adverse effects occurred more frequently in patients who
received supplements than in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in
the zinc gluconate arm, and 32.1% in the arm that received both agents experienced nonserious adverse
effects compared with 0% of patients in the standard of care arm (overall P < 0.001). The most common
nonserious adverse effects in this study were gastrointestinal events.
The limitations of this study include the small sample size and the lack of a placebo control. In
outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of
the two supplements did not significantly decrease the number of days required to reach a 50% reduction
in a symptom severity score compared with standard of care.

Recommendation for Critically Ill Patients With COVID-19
• There is insufficient evidence for the Panel to recommend either for or against the use of vitamin
C for the treatment of COVID-19 in critically ill patients.
Rationale
There are no controlled trials that have definitively demonstrated a clinical benefit for vitamin C in
critically ill patients with COVID-19, and the available observational data are inconclusive. Studies of
vitamin C regimens in sepsis patients and ARDS patients have reported variable efficacy and few safety
concerns.
Clinical Data on Vitamin C in Critically Ill Patients

Intravenous Vitamin C Alone in Patients With COVID-19
A pilot clinical trial in China randomized 56 adults with COVID-19 in the intensive care unit to receive
intravenous (IV) vitamin C 24 g per day or placebo for 7 days. The study was terminated early due to a
reduction in the number of cases of COVID-19 in China. Overall, the study found no differences between
the arms in mortality, the duration of mechanical ventilation, or the change in median sequential organ
failure assessment (SOFA) scores. The study reported improvements in oxygenation (as measured by the
ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2]) from baseline to
Day 7 in the treatment arm that were statistically greater than those observed in the placebo arm (+20.0 vs.
-51.9; P = 0.04).4
Intravenous Vitamin C Alone in Patients Without COVID-19

A small, three-arm pilot study compared two regimens of IV vitamin C to placebo in 24 critically ill
patients with sepsis. Over the 4-day study period, patients who received vitamin C 200 mg/kg per
day and those who received vitamin C 50 mg/kg per day had lower SOFA scores and lower levels of
proinflammatory markers than patients who received placebo.5
In a randomized controlled trial in critically ill patients with sepsis-induced ARDS (n = 167), patients
who received IV vitamin C 200 mg/kg per day for 4 days had SOFA scores and levels of inflammatory
markers that were similar to those observed in patients who received placebo. However, 28-day
mortality was lower in the treatment group (29.8% vs. 46.3%; P = 0.03), coinciding with more days
alive and free of the hospital and the intensive care unit.6 A post hoc analysis of the study data reported a
difference in median SOFA scores between the treatment group and placebo group at 96 hours; however,
this difference was not present at baseline or 48 hours.7
Intravenous Vitamin C Plus Thiamine With or Without Hydrocortisone in Critically Ill

Patients Without COVID-19
Two small studies that used historic controls reported favorable clinical outcomes (i.e., reduced mortality,
reduced risk of progression to organ failure, and improved radiographic findings) in patients with
sepsis or severe pneumonia who received a combination of vitamin C, thiamine, and hydrocortisone.8,9
Subsequently, several randomized trials in which patients received vitamin C and thiamine (with or without
hydrocortisone) to treat sepsis and septic shock showed that this combination conferred benefits for certain
clinical parameters. However, no survival benefit was reported. Two trials observed reductions in organ
dysfunction (as measured by change in SOFA score on Day 3)10,11 or the duration of shock12 without an
effect on clinical outcomes. Three other trials, including a large trial of 501 sepsis patients, found no
differences in any physiologic or outcome measures between the treatment and placebo groups.13-15

See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of vitamin C in patients with
COVID-19.
Other Considerations
It is important to note that high circulating concentrations of vitamin C may affect the accuracy of point-
of-care glucometers.16,17
References
1. Wei XB, Wang ZH, Liao XL, et al. Efficacy of vitamin C in patients with sepsis: an updated meta-analysis.
Eur J Pharmacol. 2020;868:172889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31870831.
2. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung
injury. Crit Care Med. 2011;39(6):1454-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21358394.
3. Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care
on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z
randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at:
4. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann
Intensive Care. 2021;11(1):5. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33420963.
5. Fowler AA, 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with
severe sepsis. J Transl Med. 2014;12:32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24484547.
6. Fowler AA, 3rd, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of
inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI
7. Fowler AA, 3rd, Fisher BJ, Kashiouris MG. Vitamin C for sepsis and acute respiratory failure-reply. JAMA.
8. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the
treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238.
9. Kim WY, Jo EJ, Eom JS, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with
severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after
cohort study. J Crit Care. 2018;47:211-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30029205.
10. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone
on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized
clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31950979.
11. Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis
and septic shock: a randomized controlled trial. Chest. 2020;158(1):174-182. Available at:
12. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation
using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest.
13. Hwang SY, Ryoo SM, Park JE, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-
centre, double-blinded randomized, controlled study. Intensive Care Med. 2020;46(11):2015-2025. Available
14. Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury
in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642-650. Available at:

15. Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on
ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA.
16. Hager DN, Martin GS, Sevransky JE, Hooper MH. Glucometry when using vitamin C in sepsis: a note of
caution. Chest. 2018;154(1):228-229. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30044741.
17. Food and Drug Administration. Blood glucose monitoring devices. 2019. Available at:
https://www.fda.gov/medical-devices/in-vitro-diagnostics/blood-glucose-monitoring-devices. Accessed March
26, 2021.

Vitamin D
Recommendation
• There is insufficient evidence to recommend either for or against the use of vitamin D for the
prevention or treatment of COVID-19.
Rationale
Vitamin D is critical for bone and mineral metabolism. Because the vitamin D receptor is expressed
on immune cells such as B cells, T cells, and antigen-presenting cells, and because these cells can
synthesize the active vitamin D metabolite, vitamin D also has the potential to modulate innate and
adaptive immune responses.1
Vitamin D deficiency (defined as a serum concentration of 25-hydroxyvitamin D ≤20 ng/mL) is
common in the United States, particularly among persons of Hispanic ethnicity and Black race. These
groups are also overrepresented among cases of COVID-19 in the United States.2 Vitamin D deficiency
is also more common in older patients and patients with obesity and hypertension; these factors have
been associated with worse outcomes in patients with COVID-19. In observational studies, low vitamin
D levels have been associated with an increased risk of community-acquired pneumonia in older adults3
and children.4
Vitamin D supplements may increase the levels of T regulatory cells in healthy individuals and patients
with autoimmune diseases; vitamin D supplements may also increase T regulatory cell activity.5 In a
meta-analysis of randomized clinical trials, vitamin D supplementation was shown to protect against
acute respiratory tract infection.6 However, in two double-blind, placebo-controlled, randomized clinical
trials, administering high doses of vitamin D to critically ill patients with vitamin D deficiency (but
not COVID-19) did not reduce the length of the hospital stay or the mortality rate when compared to
placebo.7,8 High levels of vitamin D may cause hypercalcemia and nephrocalcinosis.9
The rationale for using vitamin D is based largely on immunomodulatory effects that could potentially
protect against COVID-19 infection or decrease the severity of illness. Ongoing observational studies
are evaluating the role of vitamin D in preventing and treating COVID-19. Some investigational trials on
the use of vitamin D in people with COVID-19 are being planned or are already accruing participants.
These trials will administer vitamin D alone or in combination with other agents to participants with
and without vitamin D deficiency. The latest information on these clinical trials can be found on
ClinicalTrials.gov.
Clinical Data
Randomized Clinical Trial of Vitamin D Versus Placebo in Patients With Moderate to Severe
COVID-19
In a double-blind, placebo-controlled randomized trial that was conducted at two sites in Brazil, 240
hospitalized patients with moderate to severe COVID-19 received either a single dose of 200,000
international units of vitamin D3 or placebo.10 Moderate to severe COVID-19 was defined as patients
with a positive result on a SARS-CoV-2 polymerase chain reaction test (or compatible computed
tomography scan findings) and a respiratory rate >24 breaths/min, oxygen saturation <93% on room air,

or risk factors for complications. The primary outcome in this study was the length of the hospital stay.
The median length of stay was not significantly different between the vitamin D3 arm (7.0 days [IQR
4.0–10.0 days]) and the placebo arm (7.0 days [IQR 5.0–13.0 days]; P = 0.59, log-rank test). No
significant differences were observed between the arms in the percentages of patients who were admitted
to the intensive care unit, who required mechanical ventilation, or who died during hospitalization.
It should be noted that this study had a small sample size and enrolled participants with a variety of
comorbidities and concomitant medications. The time between symptom onset and randomization was
relatively long, with patients randomized at a mean of 10.3 days after symptom onset. In this study, a
single, high dose of vitamin D3 did not significantly reduce the length of stay for hospitalized patients
with COVID-19.
References
1. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-886. Available at:
2. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res.
3. Lu D, Zhang J, Ma C, et al. Link between community-acquired pneumonia and vitamin D levels in older
patients. Z Gerontol Geriatr. 2018;51(4):435-439. Available at:
4. Science M, Maguire JL, Russell ML, Smieja M, Walter SD, Loeb M. Low serum 25-hydroxyvitamin D level
and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392-397.
5. Fisher SA, Rahimzadeh M, Brierley C, et al. The role of vitamin D in increasing circulating T regulatory cell
numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy
volunteers: a systematic review. PLoS One. 2019;14(9):e0222313. Available at:
6. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory
tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
7. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill
patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520-
8. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde AA, et al. Early high-dose
vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med. 2019;381(26):2529-2540. Available
9. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press;
2011.
10. Murai IH, Fernandes AL, Sales LP. Effect of a single high dose of vitamin D3 on hospital length of stay in
patients with moderate to severe COVID-19: a randomized clinical trial. 2021; Published online ahead of
print. Available at: https://pubmed.ncbi.nlm.nih.gov/33595634/.

Zinc
Recommendations
recommend either for or against the use of zinc for the treatment of COVID-19.
• The Panel recommends against using zinc supplementation above the recommended dietary
allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Rationale
Increased intracellular zinc concentrations efficiently impair replication in a number of RNA viruses.1
Zinc has been shown to enhance cytotoxicity and induce apoptosis when used in vitro with a zinc
ionophore (e.g., chloroquine). Chloroquine has also been shown to enhance intracellular zinc uptake
in vitro.2 The relationship between zinc and COVID-19, including how zinc deficiency affects the
severity of COVID-19 and whether zinc supplements can improve clinical outcomes, is currently under
investigation.3 Zinc levels are difficult to measure accurately, as zinc is distributed as a component of
various proteins and nucleic acids.4
Several clinical trials are currently investigating the use of zinc supplementation alone or in combination
with hydroxychloroquine for the prevention and treatment of COVID-19 (see ClinicalTrials.gov for
more information about ongoing studies). The recommended dietary allowance for elemental zinc is
11 mg daily for men and 8 mg for nonpregnant women.5 The doses used in registered clinical trials for
patients with COVID-19 vary between studies, with a maximum dose of zinc sulfate 220 mg (50 mg of
elemental zinc) twice daily. However, there is currently insufficient evidence to recommend either for or
against the use of zinc for the treatment of COVID-19.
Long-term zinc supplementation can cause copper deficiency with subsequent reversible hematologic
defects (i.e., anemia, leukopenia) and potentially irreversible neurologic manifestations (i.e.,
myelopathy, paresthesia, ataxia, spasticity).6,7 The use of zinc supplementation for durations as short as
10 months has been associated with copper deficiency.4 In addition, oral zinc can decrease the absorption
of medications that bind with polyvalent cations.5 Because zinc has not been shown to have a clinical
benefit and may be harmful, the Panel recommends against using zinc supplementation above the
recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Clinical Data
Randomized Clinical Trial of Zinc Plus Hydroxychloroquine Versus Hydroxychloroquine
Alone in Hospitalized Patients With COVID-19
In a randomized clinical trial that was conducted at three academic medical centers in Egypt, 191
patients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either zinc 220
mg twice daily plus hydroxychloroquine or hydroxychloroquine alone for a 5-day course. The primary
endpoints were recovery within 28 days, the need for mechanical ventilation, and death. The two arms
were matched for age and gender.8
Results
• There were no significant differences between the two arms in the percentages of patients who

recovered within 28 days (79.2% in the hydroxychloroquine plus zinc arm vs. 77.9% in the
hydroxychloroquine only arm; P = 0.969), the need for mechanical ventilation (P = 0.537), or
overall mortality (P = 0.986).
• The only risk factors for mortality were age and the need for mechanical ventilation.
Limitations
• This study had a relatively small sample size.
Interpretation
A moderately sized randomized clinical trial failed to find a clinical benefit for the combination of zinc
and hydroxychloroquine.
Open-Label, Randomized Trial of Zinc Versus Ascorbic Acid Versus Zinc Plus Ascorbic Acid
Versus Standard of Care in Outpatients With COVID-19
In an open-label clinical trial that was conducted at two sites in the United States, outpatients with
laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of zinc
gluconate 50 mg, ascorbic acid 8,000 mg, both agents, or standard of care. The primary end point was
the number of days required to reach a 50% reduction in the patient’s symptom severity score. The study
was stopped early by an operational and safety monitoring board due to futility after 40% of the planned
520 participants were enrolled (n = 214).9
Results
• Participants who received standard of care achieved a 50% reduction in their symptom severity
scores at a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic
acid arm, 5.9 days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the
arm that received both agents (overall P = 0.45).
• Nonserious adverse effects occurred more frequently in patients who received supplements than
in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in the zinc gluconate arm,
and 32.1% in the arm that received both agents experienced nonserious adverse effects compared
with 0% of patients in the standard of care arm (overall P < 0.001). The most common nonserious
adverse effects in this study were gastrointestinal events.
Limitations
• The study had a small sample size.
• There was no placebo control.
Interpretation
In outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination
of the two supplements did not significantly decrease the number of days required to reach a 50%
reduction in a symptom severity score compared with standard of care.
Observational Study of Zinc Supplementation in Hospitalized Patients

A retrospective study enrolled 242 patients with polymerase chain reaction-confirmed SARS-CoV-2
infection who were admitted to Hoboken University Medical Center. One hundred and ninety-six
patients (81.0%) received a total daily dose of zinc sulfate 440 mg (100 mg of elemental zinc); of those,
191 patients (97%) also received hydroxychloroquine. Among the 46 patients who did not receive
zinc, 32 patients (70%) received hydroxychloroquine. The primary outcome was days from hospital
admission to in-hospital mortality, and the primary analysis explored the causal association between zinc
therapy and survival.10

Results
• There were no significant differences in baseline characteristics between the arms. In the zinc arm,
73 patients (37.2%) died compared with 21 patients (45.7%) in the control arm. In the primary
analysis, which used inverse probability weighting (IPW), the effect estimate of zinc therapy was
an additional 0.84 days of survival (95% CI, -1.51 days to 3.20 days; P = 0.48).
• In a multivariate Cox regression analysis with IPW, the use of zinc sulfate was not significantly
associated with a change in the risk of in-hospital mortality (aHR 0.66; 95% CI, 0.41–1.07; P =
0.09).
• Older age, male sex, and severe or critical COVID-19 were significantly associated with an
increased risk of in-hospital mortality.
Limitations
• This is a retrospective study; patients were not randomized to receive zinc supplementation or to
receive no zinc.
Interpretation
This single-center, retrospective study failed to find a mortality benefit in patients who received zinc
supplementation.
Multicenter, Retrospective Cohort Study That Compared Hospitalized Patients Who Received
Zinc Plus Hydroxychloroquine to Those Who Did Not
This study has not been peer reviewed.
This multicenter, retrospective cohort study of hospitalized adults with SARS-CoV-2 infection who
were admitted to four New York City hospitals between March 10 and May 20, 2020, compared patients
who received zinc plus hydroxychloroquine to those who received treatment that did not include this
combination.11
Results
• The records of 3,473 patients were reviewed.
• The median patient age was 64 years; 1,947 patients (56%) were male, and 522 patients (15%)
were mechanically ventilated.
• Patients who received an interleukin-6 inhibitor or remdesivir were excluded from the analysis.
• A total of 1,006 patients (29%) received zinc plus hydroxychloroquine, and 2,467 patients (71%)
received hydroxychloroquine without zinc.
• During the study, 545 patients (16%) died. In univariate analyses, mortality rates were
significantly lower among patients who received zinc plus hydroxychloroquine than among those
who did not (12% vs. 17%; P < 0.001). Similarly, hospital discharge rates were significantly
higher among patients who received zinc plus hydroxychloroquine than among those who did not
(72% vs. 67%; P < 0.001).
• In a Cox regression analysis that adjusted for confounders, treatment with zinc plus
hydroxychloroquine was associated with a significantly reduced risk of in-hospital death (aHR
0.76; 95% CI, 0.60–0.96; P = 0.023). Treatment with zinc alone (n = 1,097) did not affect
mortality (aHR 1.14; 95% CI, 0.89–1.44; P = 0.296), and treatment with hydroxychloroquine
alone (n = 2,299) appeared to be harmful (aHR 1.60; 95% CI, 1.22–2.11; P = 0.001).
• There were no significant interactions between zinc plus hydroxychloroquine and other COVID-
19-specific medications.

Limitations
• This is a retrospective review; patients were not randomized to receive zinc plus
hydroxychloroquine or to receive other treatments.
• The authors do not have data on whether patients were taking zinc and/or hydroxychloroquine
prior to study admission.
• The arms were not balanced; recipients of zinc plus hydroxychloroquine were more likely to be
male, Black, or to have a higher body mass index and diabetes. Patients who received zinc plus
hydroxychloroquine were also treated more often with corticosteroids and azithromycin and less
often with lopinavir/ritonavir than those who did not receive this drug combination.
Interpretation
In this preprint, the use of zinc plus hydroxychloroquine was associated with decreased rates of
in-hospital mortality, but neither zinc alone nor hydroxychloroquine alone reduced mortality. Treatment
with hydroxychloroquine alone appeared to be harmful.
References
1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits
coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of
these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176. Available at:
2. Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One.
3. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune
system is an important factor to protect against viral infections. Nutrients. 2020;12(4). Available at:
4. Hambridge K. The management of lipohypertrophy in diabetes care. Br J Nurs. 2007;16(9):520-524. Available
5. National Institutes of Health. Office of Dietary Supplements. Zinc fact sheet for health professionals. 2020.
Available at: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/.
6. Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H. Copper deficiency anemia: review article. Ann Hematol.
7. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006;81(10):1371-1384.
8. Abd-Elsalam S, Soliman S, Esmail ES, et al. Do zinc supplements enhance the clinical efficacy of
hydroxychloroquine?: a randomized, multicenter trial. Biol Trace Elem Res. 2020;Published online ahead of
9. Thomas S, Patel D, Bittel B. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on
symptom length and reduction among ambulatory patients with SARS-CoV-2 Infection: the COVID a to z
randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at:
10. Yao JS, Paguio JA, Dee EC, et al. The minimal effect of zinc on the survival of hospitalized patients with
COVID-19: an observational study. Chest. 2021;159(1):108-111. Available at:
11. Frontera JA, Rahimian JO, Yaghi S, et al. Treatment with zinc is associated with reduced in-hospital mortality
among COVID-19 patients: a multi-center cohort study. Res Sq. 2020;Preprint. Available at:

Considerations for Using Concomitant
Medications in Patients With COVID-19
• Patients with COVID-19 who are receiving concomitant medications (e.g., angiotensin-converting enzyme [ACE]
inhibitors, angiotensin receptor blockers [ARBs], HMG-CoA reductase inhibitors [statins], systemic or inhaled
corticosteroids, nonsteroidal anti-inflammatory drugs, acid-suppressive therapy) for underlying medical conditions
should not discontinue these medications during acute management of COVID-19 unless discontinuation is
otherwise warranted by their clinical condition (AIIa for ACE inhibitors and ARBs; AIII for other medications).
• The COVID-19 Treatment Guidelines Panel recommends against using medications off-label to treat COVID-19 if they
have not been shown to be safe and effective for this indication in a clinical trial (AIII).

Individuals with underlying medical conditions, such as cardiovascular disease, pulmonary disease,
diabetes, and malignancy, and those who receive chronic immunosuppressive therapy are at higher risk
of severe illness with COVID-19. These patients are often prescribed medications to treat their
underlying medical conditions.
Early in the pandemic, some of these medications, such as angiotensin converting enzyme (ACE)
inhibitors, angiotensin receptor blockers (ARBs),1 HMG-CoA reductase inhibitors (statins),2,3 and H-2
receptor antagonists,4 were hypothesized to offer potential as COVID-19 therapeutic agents. Others,
such as nonsteroidal anti-inflammatory agents (NSAIDs), were postulated to have negative impacts.5
Currently, there is no evidence that discontinuing medication for underlying medical conditions offers
a clinical benefit for patients with COVID-19.6-8 For example, the Food and Drug Administration stated
that there is no evidence linking the use of NSAIDs with worsening of COVID-19 and advised patients
to use them as directed.9 Additionally, the American Heart Association, the Heart Failure Society of
America, and the American College of Cardiology issued a joint statement that renin-angiotensin-
aldosterone system antagonists, such as ACE inhibitors and ARBs, should be continued as prescribed in
those with COVID-19.10
Therefore, patients with COVID-19 who are treated with concomitant medications for an underlying
medical condition should not discontinue these medications during acute management of COVID-19
unless discontinuation is otherwise warranted by their clinical condition (AIII). For patients with
COVID-19 who require nebulized medications, precautions should be taken to minimize the potential
for transmission of SARS-CoV-2 in the home and in health care settings.11,12
The COVID-19 Treatment Guidelines Panel recommends against using medications off-label to
treat COVID-19 if they have not been shown to be safe and effective for this indication in a clinical
trial (AIII). Clinicians should refer to the Therapies section of the Guidelines for information on the
medications that have been studied as potential therapeutic options for patients with COVID-19.
When prescribing medications to treat COVID-19, clinicians should always assess the patient’s current
medications for potential drug-drug interactions and/or additive adverse effects.13 The decision to
continue or change a patient’s medications should be individualized based on their specific clinical
condition.

References
1. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers: what is the evidence? JAMA. 2020;323(18):1769-1770. Available at:
2. Lee KCH, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis. 2020;96:615-617.
3. Kashour T, Halwani R, Arabi YM, et al. Statins as an adjunctive therapy for COVID-19: the biological and
clinical plausibility. Immunopharmacol Immunotoxicol. 2021;43(1):37-50. Available at:
4. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized patients with
COVID-19. Am J Gastroenterol. 2020;115(10):1617-1623. Available at:
5. Yousefifard M, Zali A, Zarghi A, Madani Neishaboori A, Hosseini M, Safari S. Non-steroidal anti-
inflammatory drugs in management of COVID-19; a systematic review on current evidence. Int J Clin Pract.
6. Lopes RD, Macedo AVS, de Barros E Silva PGM, et al. Effect of discontinuing vs continuing angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in
patients admitted with COVID-19: a randomized clinical trial. JAMA. 2021;325(3):254-264. Available at:
7. Cohen JB, Hanff TC, William P, et al. Continuation versus discontinuation of renin-angiotensin system
inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet
8. Bauer A, Schreinlechner M, Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system
inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label
trial. Lancet Respir Med. 2021;9(8):863-872. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34126053.
9. Food and Drug Administration. FDA advises patients on use of non-steroidal anti-inflammatory drugs
(NSAIDs) for COVID-19. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-
advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19. Accessed October 26, 2021.
10. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA statement addresses concerns re: using RAAS
antagonists in COVID-19. J Card Fail. 2020;26(5):370. Available at:
11. Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19
pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.
12. Sethi S, Barjaktarevic IZ, Tashkin DP. The use of nebulized pharmacotherapies during the COVID-19
pandemic. Ther Adv Respir Dis. 2020;14:1753466620954366. Available at:
13. University of Liverpool. COVID-19 drug interactions. 2021. Available at:
https://www.covid19-druginteractions.org/. Accessed November 1, 2021.

Special Considerations in People Who Are
Immunocompromised
Prevention of COVID-19
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for all people who are
moderately or severely immunocompromised (AIII).
• All close contacts of people who are immunocompromised are strongly encouraged to be up to date on vaccination
against COVID-19 (AIII). Vaccinating household members, close contacts, and health care providers who provide care
for patients who are immunocompromised is important to protect these patients from infection.
• The Panel recommends using tixagevimab plus cilgavimab (Evusheld) as SARS-CoV-2 pre-exposure prophylaxis
(PrEP) for adults and adolescents who do not have SARS-CoV-2 infection or recent exposure to an individual with
SARS-CoV-2 infection and who are moderately to severely immunocompromised and may have an inadequate
immune response to COVID-19 vaccination (BIIb).
• There is insufficient evidence for the Panel to recommend either for or against the use of SARS-CoV-2 serologic
testing to assess for immunity or to guide clinical decisions about using COVID-19 vaccines or anti-SARS-CoV-2
monoclonal antibodies (mAbs) as PrEP in certain people.
General Management of Patients With COVID-19 Who Are Immunocompromised
• The Panel recommends that decisions regarding stopping or reducing the doses of immunosuppressive drugs
in patients with COVID-19 be made in consultation with the appropriate specialists; clinicians should consider
factors such as the underlying disease, the specific immunosuppressants being used, the potential for drug-drug
interactions, and the severity of COVID-19 (BIII).
Therapeutic Management of Nonhospitalized Patients With COVID-19 Who Are Immunocompromised
• The Panel recommends prompt treatment with antivirals or anti-SARS-CoV-2 mAbs for nonhospitalized patients with
mild to moderate COVID-19 who are immunocompromised (AIII). Specific recommendations are outlined in the text.
Therapeutic Management of Hospitalized Patients With COVID-19 Who Are Immunocompromised
• For most patients with COVID-19 who are immunocompromised, the Panel recommends using antiviral drugs,
anti-SARS-CoV-2 mAbs, and immunomodulatory therapies at the doses and durations that are recommended for the
general population (AIII).
• In some cases, immunomodulatory drug regimens may need to be adjusted to reduce the risk of drug-drug
interactions, overlapping toxicities, and secondary infections.
• There is insufficient evidence to guide clinical recommendations on using combination therapies (e.g., an antiviral
drug plus an anti-SARS-CoV-2 mAb) or extending the duration of treatment beyond the duration authorized by the
Food and Drug Administration.
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer COVID-19
convalescent plasma (CCP) in patients with COVID-19 who are immunocompromised. Some clinicians would
consider the use of CCP in patients who, in their clinical judgment, have severe or progressive COVID-19 and
an inadequate response to therapy. In these cases, clinicians should attempt to administer high-titer CCP from a
vaccinated donor who recently recovered from COVID-19 likely caused by a similar SARS-CoV-2 variant as the
patient.
• For people who are immunocompromised and have mild to moderate COVID-19 but are hospitalized for reasons
other than COVID-19, the Panel recommends promptly initiating treatment with an antiviral drug or an anti-SARS-
CoV-2 mAb (AIII).

Approximately 3% of Americans have immunocompromising conditions.1 People who are
immunocompromised are a heterogeneous population, and the severity of COVID-19 can vary
significantly in this group. Some individuals who are immunocompromised may have a higher risk of
hospitalization, complications, or death, and some may have outcomes that are comparable to those in
the general population.
This section pertains to people who are moderately or severely immunocompromised, which includes
those who:
• Are receiving active treatment for solid tumor and hematologic malignancies.
• Have hematologic malignancies (e.g., chronic lymphocytic lymphoma, non-Hodgkin lymphoma,
plasma cell dyscrasias) and are known to have poor responses to COVID-19 vaccines or an
increased risk of severe COVID-19, regardless of the treatment status for the hematologic
malignancy.
• Received a solid-organ transplant or an islet transplant and are receiving immunosuppressive
therapy.
• Received chimeric antigen receptor T cell (CAR T-cell) therapy or a hematopoietic stem cell
transplant (HCT) and are within 2 years of transplantation or are receiving immunosuppressive
therapy.
• Have a moderate or severe primary immunodeficiency (e.g., severe combined immunodeficiency,
DiGeorge syndrome, Wiskott-Aldrich syndrome, combined variable immunodeficiency disease).
• Have advanced or untreated HIV infection (defined as people with HIV and CD4 T lymphocyte
[CD4] cell counts <200 cells/mm3, a history of an AIDS-defining illness without immune
reconstitution, or clinical manifestations of symptomatic HIV).
equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites,
transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified
as severely immunosuppressive, and biologic agents that are immunosuppressive or
immunomodulatory.
Data are evolving on the clinical outcomes of COVID-19 in people who are immunocompromised.
Analyses have found a higher risk of hospitalization or death from COVID-19 in those with a variety
of immunocompromising conditions, including rheumatic diseases, hematological malignancies,
solid organ transplants, and HIV.2-7 Factors that increase the risk of severe COVID-19 in the general
population, such as older age, chronic kidney disease, cardiovascular disease, and other comorbidities,
are significant drivers of risk in immunocompromised individuals. Moreover, some immunodeficiencies
seem to increase the risk above and beyond traditional risk factors. For example, there is evidence that
individuals who make autoantibodies to type I interferons, proteins critical to the protective immune
response against viral infections, have a higher risk of severe COVID-19.8 Similarly, certain classes
of medications, such as T cell-depleting or T cell-suppressing agents (e.g., antithymocyte globulin,
calcineurin inhibitors, mycophenolate mofetil, belatacept) or B cell-depleting agents (e.g., rituximab,
ocrelizumab, obinutuzumab), have been associated with more severe COVID-19 outcomes.9,10
Prolonged shedding of SARS-CoV-2 has been reported in patients who are immunocompromised. A
systematic review found that replication-competent virus could be detected for a median of 20 days in
these patients, compared to 11 days in the general population.11 Prolonged viral shedding may affect
SARS-CoV-2 testing strategies and isolation durations for this group of patients.12 Moreover, case
reports suggest that prolonged infections can create evolutionary pressure for the emergence of variants
that resist therapies or evade vaccine-induced immunity.13-15 There is currently insufficient evidence

to guide clinical recommendations on using combinations of antiviral drugs and/or anti-SARS-CoV-2
monoclonal antibodies (mAbs) for the treatment of COVID-19. There are also no data to support
extending the duration of COVID-19 therapies beyond the durations authorized or approved by the Food
and Drug Administration (FDA).
When there are no logistical or supply constraints, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends prescribing therapies for the prevention or treatment of COVID-19 to any eligible individual
as recommended in these Guidelines. However, at times during the pandemic, logistical or supply
constraints have limited the availability of therapies. In those cases, the Panel recommends prioritizing the
treatment of patients with COVID-19 who are at the highest risk of clinical progression (see Prioritization
of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There Are
Logistical or Supply Constraints). Providers should use their clinical judgment when prioritizing patients
for treatment, including assessing a patient’s immunocompromised status, age, and comorbidities.
The sections below outline the Panel’s rationale for the recommendations on preventing and managing
COVID-19 in people who are immunocompromised. Some of the special considerations for patients
who are immunocompromised include the timing of COVID-19 vaccination, the use of pre-exposure
prophylaxis (PrEP), the management of immunosuppressive medications, and the strategies for treating
COVID-19.
Vaccination
The Panel recommends COVID-19 vaccination for all people who are moderately or severely
immunocompromised (AIII). Vaccination is the most effective way to prevent serious outcomes and
death from SARS-CoV-2 infection, although there are certain special considerations for the timing of
vaccination and vaccine responses in people who are immunocompromised. Authorized and approved
COVID-19 vaccines in the United States are not live-virus vaccines, and they can be safely administered
to patients who are immunocompromised.16
The pivotal clinical trials that evaluated the safety and efficacy of the COVID-19 vaccines excluded
people who were severely immunocompromised; therefore, the data for this population are less robust.17,18
Observational data suggest that serological responses to vaccines may be blunted in patients who are
immunocompromised.19,20 Nevertheless, vaccination is still recommended, as it may confer partial
protection, including protection from vaccine-induced, cell-mediated immunity.4 See the Centers for
Disease Control and Prevention (CDC) webpage COVID-19 Vaccines for People Who Are Moderately or
Severely Immunocompromised for the current COVID-19 vaccination schedule for this population.
Vaccination of Close Contacts
All close contacts of people who are immunocompromised are strongly encouraged to be up to date on
vaccination against COVID-19 (AIII). Vaccinating household members, close contacts, and health care
workers who provide care to patients who are immunocompromised is important to protect these patients
from infection. There is evidence that vaccinated individuals who are infected with SARS-CoV-2 have
lower viral loads than unvaccinated individuals, and COVID-19 vaccines are associated with a reduction
in the number of SARS-CoV-2 infections not only among vaccinated individuals but also among their
household contacts.21-26
Vaccine Timing and Anti-SARS-CoV-2 Monoclonal Antibodies
Nonhospitalized patients who are immunocompromised may have received anti-SARS-CoV-2 mAbs
for the treatment of COVID-19. Vaccines can be administered at any time after anti-SARS-CoV-2 mAb

treatment.27 When tixagevimab plus cilgavimab (Evusheld) is being used as PrEP, it should not be
administered until at least 2 weeks after vaccination.27 The use of these anti-SARS-CoV-2 mAbs as PrEP
is not a substitute for vaccination.
Vaccine Timing and Immunosuppressive Therapies
If possible, the COVID-19 vaccination series should be completed at least 2 weeks before initiating
or resuming immunosuppressive therapies. The timing of the vaccination series should be determined
based on the patient’s current or planned immunosuppressive therapies, as well as the patient’s
medical condition and predicted response to the vaccine. Guidance about the timing of COVID-19
vaccination in solid organ transplant, HCT, and cellular immunotherapy candidates can be found in
Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell Transplant, and Cellular
Immunotherapy Candidates, Donors, and Recipients. HCT and CAR T-cell recipients who received
doses of COVID-19 vaccines prior to or during treatment with an HCT or CAR T-cell therapy should be
revaccinated with a primary vaccine series at least 3 months after the transplant or CAR T-cell therapy.28
The American Society of Hematology and the National Comprehensive Cancer Network have specific
guidance about the timing of COVID-19 vaccination around cancer chemotherapy,28,29 and the American
College of Rheumatology also provides guidance for temporarily stopping immunosuppressive regimens
during vaccination.30
The Panel recommends using tixagevimab plus cilgavimab as SARS-CoV-2 PrEP for adults
and adolescents who do not have SARS-CoV-2 infection or recent exposure to an individual with
SARS-CoV-2 infection and who are moderately to severely immunocompromised and may have an
inadequate immune response to COVID-19 vaccination (BIIb). Information on dosing is available in
Prevention of SARS-CoV-2 Infection.
The FDA Emergency Use Authorization (EUA) for tixagevimab plus cilgavimab identifies a broad
group of immunocompromised individuals who are eligible for PrEP.31 Data suggest that some of
these individuals are at particularly high risk of inadequate vaccine responses and progression to
severe COVID-19 if infected. These individuals include, but are not limited to, those with hematologic
malignancies who are receiving active treatment, those who are within 1 year of receiving B cell-
depleting agents (e.g., rituximab, ocrelizumab, obinutuzumab, epratuzumab), CAR T-cell therapy
recipients, solid organ transplant recipients who are receiving immunosuppressive therapy, those with
severe combined immunodeficiencies, and those with HIV and low CD4 counts.4,9,32-36
Serologic Testing to Guide Vaccination or Pre-Exposure Prophylaxis Strategies

There is currently insufficient evidence for the Panel to recommend either for or against the use
of SARS-CoV-2 serologic testing to assess for immunity or to guide clinical decisions about using
COVID-19 vaccines or anti-SARS-CoV-2 mAbs for PrEP. More than 80 SARS-CoV-2 serologic tests,
including quantitative, semiquantitative, neutralizing antibody, and point-of-care tests, have been
issued EUAs by the FDA to aid in detecting antibodies to SARS-CoV-2.37 However, these tests are
not currently authorized for routine use in making individual medical decisions, and their ability to
assess a person’s level of immunity or protection from SARS-CoV-2 infection has not been evaluated.38
Most of these tests have not been calibrated to a reference standard, limiting the comparability and
reproducibility of results from different tests.
Management of Patients With COVID-19 Who Are Immunocompromised

Adjusting Chronic Immunosuppressive Therapies

The Panel recommends that decisions regarding stopping or reducing the doses of immunosuppressive
drugs in patients with COVID-19 be made in consultation with the appropriate specialists; clinicians
should consider factors such as the underlying disease, the specific immunosuppressants being used, the
potential for drug-drug interactions, and the severity of COVID-19 (BIII).
Early in the clinical course of COVID-19, the disease is primarily driven by the replication of
SARS-CoV-2. Immunosuppressive medications can reduce the host immune responses that suppress
viral replication, increasing the risk of prolonged viral shedding and infection.39,40 Clinicians
should consider adjusting the doses of immunosuppressive medications or substituting certain
immunosuppressive medications, if possible, to improve the patient’s immune response to infection.
When making decisions about stopping or reducing the dose of immunosuppressive drugs, clinicians
should balance the potential benefit of enhancing the patient’s immune response to COVID-19 with the
risk of exacerbating the underlying condition. They should also consider the role of immunomodulation
in the treatment of COVID-19.
Clinicians should be aware that many immunosuppressive drugs, particularly biologic agents, have long
half-lives or prolonged periods of biologic activity. Patients may remain immunosuppressed long after
the drugs are stopped. Care should be taken to not stop glucocorticoids abruptly, since this may result
in adrenal insufficiency. For medications other than glucocorticoids, decisions about dose adjustments
should be made on a case-by-case basis. For example, for some autoimmune diseases, temporary
cessation of immunosuppression is often possible, and restarting medications 7 to 14 days after symptom
resolution may be appropriate.30,41
For solid organ transplant recipients, adjustments to immunosuppressive regimens should be
individualized based on disease severity, the risk of graft rejection, the specific immunosuppressants
being used, the type of transplant, the time since transplantation, the concentration of
immunosuppressants, and the potential for drug-drug interactions.42 See Special Considerations in
Solid Organ Transplant, Hematopoietic Stem Cell Transplant, and Cellular Immunotherapy Candidates,
Donors, and Recipients for more information.
Therapeutic Management of Nonhospitalized Patients With COVID-19

The Panel recommends prompt treatment with antiviral agents or anti-SARS-CoV-2 mAbs for
nonhospitalized patients with mild to moderate COVID-19 who are immunocompromised (AIII).
See Therapeutic Management of Nonhospitalized Adults With COVID-19 to review the Panel’s
recommendations. Some special considerations for using these therapies in people who are
immunocompromised are outlined below.
Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Molnupiravir
In the EPIC-HR trial, ritonavir-boosted nirmatrelvir, when compared with placebo, reduced the risk
of hospitalization or death in nonhospitalized, unvaccinated adults who had laboratory-confirmed
SARS-CoV-2 infection and a high risk of progressing to severe COVID-19.43 However, as the trial
enrolled very few participants who were immunocompromised, the efficacy of using this drug in this
population is unknown.
Because ritonavir-boosted nirmatrelvir is the only highly effective oral antiviral for the treatment of
COVID-19, it should be considered for patients who are immunocompromised if there are no potential
drug-drug interactions or if the potential interactions can be safely managed. Clinicians should be aware
of drug-drug interactions that may be life- or organ-threatening (see Drug-Drug Interactions Between
Ritonavir-Boosted Nirmatrelvir [Paxlovid] and Concomitant Medications).44 Notably, calcineurin
inhibitors (e.g., tacrolimus, cyclosporine A) and mammalian target of rapamycin (mTOR) drugs

(e.g., sirolimus, everolimus) have important drug-drug interactions with ritonavir. For this reason,
the American Society of Transplantation recommends preferentially using other therapies, such as
anti-SARS CoV-2 mAbs or remdesivir, over ritonavir-boosted nirmatrelvir in people who are taking
calcineurin inhibitors or mTOR inhibitors.45
Ritonavir can inhibit the metabolism of many cancer-directed therapies and should only be given after
consulting with specialty pharmacists and other appropriate specialists. Case reports have described
reoccurring COVID-19 symptoms and positive SARS-CoV-2 test results in some patients who have
completed treatment with ritonavir-boosted nirmatrelvir.46 There is currently no evidence to support
routinely administering longer courses or a second course of ritonavir-boosted nirmatrelvir. People
with COVID-19 who are immunocompromised should not delay or avoid taking ritonavir-boosted
nirmatrelvir due to concerns about the rebound of symptoms after treatment completion (see Ritonavir-
Boosted Nirmatrelvir [Paxlovid]).
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death in nonhospitalized
patients with COVID-19, when compared with placebo.47 The MOVe-OUT trial enrolled very few
participants who were immunocompromised.48 Although the different treatment options have not been
directly compared in clinical trials, the available evidence suggests that molnupiravir has a lower
efficacy than the other options (see Molnupiravir). Other COVID-19 therapies should be prioritized over
molnupiravir in patients who are immunocompromised.
Remdesivir
Remdesivir was studied in nonhospitalized patients with mild to moderate COVID-19 who were at high
risk of progressing to severe disease, and it was shown to be highly effective in reducing the risk of
hospitalization and death.49 However, this trial included few participants who were immunocompromised
(see Table 4a). Because remdesivir requires an intravenous infusion for 3 consecutive days, there
may be logistical constraints to administering this drug in many settings, but it can be considered for
patients who are immunocompromised if other options, such as ritonavir-boosted nirmatrelvir, are not
appropriate or available.
Clinical trials have demonstrated that anti-SARS-CoV-2 mAb therapy can reduce the risk of
hospitalization or death in high-risk patients with COVID-19.50-53 However, because these trials only
enrolled a few patients who were immunocompromised, there is not enough data to determine the
efficacy of using anti-SARS-CoV-2 mAbs in this population. Nevertheless, given that a reduced humoral
immune response to infection is seen in many patients who are immunocompromised, anti-SARS-CoV-2
mAbs are expected to be effective. Anti-SARS-CoV-2 mAb therapy should be considered for patients
who are immunocompromised, especially if significant drug-drug interactions preclude use of ritonavir-
boosted nirmatrelvir42 or logistical constraints prevent the use of remdesivir.
There is insufficient evidence to guide clinical recommendations on using combinations of anti-SARS-
CoV-2 mAbs and antiviral drugs. Because the neutralizing activities of some anti-SARS-CoV-2 mAbs
may be diminished against certain SARS-CoV-2 variants of concern (VOCs), clinicians should refer to
Anti-SARS-CoV-2 Monoclonal Antibodies for guidance on the use of anti-SARS-CoV-2 mAbs against
specific circulating VOCs.
COVID-19 convalescent plasma (CCP) in patients with COVID-19 who are immunocompromised.
The FDA has issued an EUA that allows the use of high-titer CCP for the treatment of COVID-19
in outpatients or inpatients who are immunocompromised or who are receiving immunosuppressive

treatment.54 However, the evidence generated from well-designed clinical trials that evaluated the use of
CCP for the treatment of nonhospitalized patients is conflicting; these trials enrolled few, if any, patients
who were immunocompromised.55-58
Some clinicians would consider using CCP in patients who, in their clinical judgment, have severe or
progressive COVID-19 and an inadequate response to therapy. In these cases, to the extent possible,
clinicians should attempt to administer high-titer CCP from a vaccinated donor who recently recovered
from COVID-19 likely caused by a similar SARS-CoV-2 variant as the patient.
Therapeutic Management of Patients Who Are Hospitalized for COVID-19

For most patients with COVID-19 who are immunocompromised, the Panel recommends using antiviral
drugs, anti-SARS-CoV-2 mAbs, and immunomodulatory therapies at the doses and durations that
are recommended for the general population (AIII). See Therapeutic Management of Hospitalized
Adults With COVID-19 for more information. The optimal management strategies and treatments for
COVID-19 in hospitalized patients who are immunocompromised are unknown, since these individuals
were either excluded from or poorly represented in major clinical trials. Nevertheless, clinical
experience suggests that many patients who are immunocompromised have the expected responses to
standard therapies for COVID-19.
Remdesivir
The optimal duration of treatment with remdesivir in patients who are immunocompromised is
unknown. Case reports suggest that the drug can suppress, but does not always eliminate, viral
replication in this population.59,60 Some clinicians may choose to extend the course of antiviral
therapy past 5 to 10 days in patients who are immunocompromised, given the risk of prolonged
viral replication. Similarly, although remdesivir has not been shown to confer a benefit in patients
with more severe respiratory impairment due to COVID-19 (i.e., those who require high-flow nasal
cannula [HFNC] oxygen, noninvasive ventilation [NIV], or mechanical ventilation), clinicians may
consider using remdesivir along with immunomodulatory therapy in this population of patients who are
immunocompromised, given the concerns about prolonged viral replication.
Corticosteroids
The RECOVERY trial reported a survival benefit for dexamethasone in inpatients with COVID-19 who
were receiving oxygen, HFNC oxygen, NIV, or mechanical ventilation; however, specific data regarding
the subgroup of patients who were immunocompromised is not available.61
Patients who are immunocompromised may experience delayed development of favorable adaptive
responses and a prolonged period of viral replication, as discussed above. For patients who are
immunocompromised, who are receiving minimal levels of conventional oxygen, and who are earlier
in the course of COVID-19 (e.g., those with <10 days of symptoms), the preferred approach may be
emphasizing supportive care, using antiviral therapy, and avoiding corticosteroids. This strategy may
reduce the duration of viral replication and the risk of secondary infections. Dexamethasone should be
added if the patient has escalating oxygen requirements.
For patients who are immunocompromised and who were on chronic corticosteroids prior to
hospitalization, the optimal dose of dexamethasone for the treatment of COVID-19 is unknown. The
recommended dose of dexamethasone is 6 mg, which is equivalent to 40 mg of prednisone. This is
the minimum dose of steroid that should be used. Maintenance doses of corticosteroids should be
discontinued while a patient is receiving dexamethasone, and they should be resumed as soon as
possible after recovery from COVID-19 or after completion of the course of dexamethasone.

Immunomodulators
Randomized trials have shown that adding interleukin (IL)-6 inhibitors and Janus Kinase (JAK)
inhibitors to dexamethasone improves clinical outcomes in patients with severe or critical COVID-19.
These trials generally excluded patients who were immunocompromised or only included small
numbers of these patients.62-64 The use of these agents may provide a clinical benefit to patients who
are immunocompromised that is similar to the benefit seen in the general population. However, it is not
clear whether augmenting immunomodulation in this population increases the risk of serious bacterial,
invasive fungal, or parasitic infections.
For most patients who are immunocompromised, adding IL-6 or JAK inhibitors to dexamethasone
is reasonable for those who are hypoxemic and experiencing clinical progression, which follows the
Panel’s recommendations for the general population (see Therapeutic Management of Hospitalized
Adults With COVID-19). However, clinicians should consult with the appropriate specialists to ensure
that the risks of additional immunosuppression, including the risks of serious infections, do not outweigh
the benefits of additional immunosuppression and that the patient is closely monitored for infections.
CCP in hospitalized patients with COVID-19 who are immunocompromised. Three key randomized
trials that evaluated the use of CCP for the treatment of COVID-19—RECOVERY, CONCOR-1, and
REMAP-CAP—reported no evidence of benefit from CCP in hospitalized patients with COVID-19.
However, most of the patients enrolled in these trials were not immunocompromised.65-67 A prespecified
subgroup analysis of 126 critically ill REMAP-CAP participants who were immunocompromised
suggested that CCP might offer a potential benefit of improved survival and more organ support-free
days in this subgroup, but these results were not statistically significant. Observational data from case
reports, case series, and retrospective case-control studies also suggest a potential benefit of CCP in
patients who are immunocompromised due to hematologic malignancy, common variable immune
deficiency, agammaglobulinemia, or receipt of a solid organ transplant.68-83
Some clinicians would consider using CCP in patients who, in their clinical judgment, have severe or
progressive COVID-19 and an inadequate response to therapy. In these cases, to the extent possible,
clinicians should attempt to administer high-titer CCP from a vaccinated donor who recently recovered
from COVID-19 likely caused by a similar SARS-CoV-2 variant as the patient.
Therapeutic Management of Patients Who Are Hospitalized for Reasons Other Than
COVID-19
People who are immunocompromised and have COVID-19 but were hospitalized for conditions other
than COVID-19 should receive the same treatments as nonhospitalized patients (BIII). See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for more information.
Therapeutic Management of Hospitalized Patients With Prolonged SARS-CoV-2 Viral

Replication
In the absence of evidence, some Panel members would consider using additional treatments in
hospitalized patients who are immunocompromised and have ongoing, severe symptoms attributed to
viral replication despite the use of other therapies (i.e., remdesivir), because humoral immune responses
may be diminished or absent in this population. These treatments may include using anti-SARS-CoV-2
mAbs (under Emergency Investigational New Drug provisions, if available) that have activity against
dominant circulating variants or using high-titer CCP collected from vaccinated donors who were
infected with SARS-CoV-2 within the past 6 months.

The optimal management of individuals who are immunocompromised, hospitalized with symptomatic
COVID-19, and have prolonged periods of significant viral replication despite the receipt of remdesivir
and appropriate immunomodulatory drugs is unknown. Data from the RECOVERY trial of casirivimab
plus imdevimab versus placebo suggest that hospitalized patients with COVID-19 who have not
developed a humoral immune response (as measured by serologic testing for SARS-CoV-2) received a
survival benefit from anti-SARS-CoV-2 mAb therapy.84
Special Considerations for Pregnant Individuals Who Are Immunocompromised

Multiple studies have found that pregnant individuals have an increased risk of severe COVID-19
compared to age-matched controls, with increased rates of intensive care unit admission, mechanical
ventilation, extracorporeal membrane oxygenation, and death.85-87 Although hormonally mediated
immunomodulation occurs during pregnancy, pregnancy is not a state of systemic immunosuppression.
Changes in the immune response to certain infectious pathogens during pregnancy may increase the
severity of respiratory illness in pregnant individuals. Physiologic changes, such as reduced pulmonary
residual capacity, may also contribute to respiratory disease severity.88-91 Pregnant people who have
underlying immunocompromising conditions or are receiving immunosuppressive medications likely
have an even higher risk of severe disease. This patient group should be prioritized for the prevention
and treatment of COVID-19.
Prevention
The Panel recommends administering COVID-19 vaccines to pregnant individuals according to
the guidelines from the CDC and the Advisory Committee on Immunization Practices (ACIP) (AI).
COVID-19 vaccination is strongly recommended for pregnant individuals due to their increased
risk for severe disease.92,93 Vaccination is especially important for pregnant people with concomitant
risk factors such as underlying immunocompromising conditions (including those who are receiving
immunosuppressive medications), as the risk for severe disease is likely additive.86 Pregnant individuals
who otherwise meet the criteria for PrEP with tixagevimab plus cilgavimab should not have this
therapy withheld due to their pregnancy status (AIII).
Treatment
Although pregnant patients have been excluded from the majority of the clinical trials that evaluated
the use of COVID-19 therapeutics, pregnant patients with COVID-19 can be treated the same as
nonpregnant patients, with a few exceptions. Pregnant patients who are immunocompromised or who
have other risk factors likely have an even higher risk for severe COVID-19 and should be prioritized
for treatment. Providers should refer to the Panel’s recommendations in Therapeutic Management
of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized Adults
With COVID-19. Pregnant people who are immunocompromised comprise a heterogeneous group
of patients, ranging from those who are mildly immunocompromised to those who are severely
immunocompromised. The Panel recommends forming a collaborative, multidisciplinary team to make
decisions regarding the evaluation and management of pregnant patients, including the involvement of
a transplant or specialty provider, an obstetrician or maternal-fetal medicine specialist, a pediatrics or
neonatology specialist, and pharmacy services.
Special Considerations for Children Who Are Immunocompromised

Although the overall risk of critical illness and death related to COVID-19 is lower in children than
adults, severe disease does occur, particularly in children with risk factors such as moderate to severe
immunocompromising conditions. See Special Considerations in Children for a discussion of the
risk factors for severe COVID-19 in children, and see Therapeutic Management of Nonhospitalized

Children With COVID-19 for the Panel’s framework for assessing a child’s risk of progression to severe
COVID-19 based on vaccination status, comorbidities, and age.
Prevention
The Panel recommends vaccinating all eligible children against COVID-19 as soon as possible
according to the guidelines from the CDC and ACIP (AI). In addition, PrEP with tixagevimab
plus cilgavimab is authorized by the FDA for children aged ≥12 years and weighing ≥40 kg and
recommended by the Panel for those who do not have SARS-CoV-2 infection or recent exposure to an
individual with SARS-CoV-2 infection and who are moderately to severely immunocompromised and
may have an inadequate immune response to COVID-19 vaccination (BIIb).
Treatment
Most children with mild to moderate COVID-19 will not progress to more severe illness and can be
managed with supportive care alone (AIII). Few children, if any, including children aged <18 years who
are immunocompromised, have been enrolled in clinical trials of treatments for COVID-19. Therefore,
clinicians should be cautious when applying recommendations based on adult data to children.
Clinicians need to consider the potential risks and benefits of therapy, the severity of the patient’s
disease, and underlying risk factors. See Therapeutic Management of Hospitalized Children With
COVID-19 and Therapeutic Management of Nonhospitalized Children With COVID-19 for the Panel’s
treatment recommendations in these scenarios.
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Lymphoma. 2021;62(6):1490-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33461387.
80. Fung M, Nambiar A, Pandey S, et al. Treatment of immunocompromised COVID-19 patients with
convalescent plasma. Transpl Infect Dis. 2021;23(2):e13477. Available at:
81. Thompson MA, Henderson JP, Shah PK, et al. Association of convalescent plasma therapy with survival in
patients with hematologic cancers and COVID-19. JAMA Oncol. 2021:1167-1175. Available at:
82. Sanz C, Nomdedeu M, Pereira A, et al. Efficacy of early transfusion of convalescent plasma with high-titer
SARS-CoV-2 neutralizing antibodies in hospitalized patients with COVID-19. Transfusion. 2022;62(5):974-
83. Hueso T, Godron AS, Lanoy E, et al. Convalescent plasma improves overall survival in patients with B-cell
lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis. Leukemia.
84. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital
with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet.
86. Ellington S, Strid P, Tong VT, et al. Characteristics of women of reproductive age with laboratory-confirmed
SARS-CoV-2 infection by pregnancy status—United States, January 22–June 7, 2020. MMWR Morb Mortal
87. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal
outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ.
88. Denney JM, Nelson EL, Wadhwa PD, et al. Longitudinal modulation of immune system cytokine
profile during pregnancy. Cytokine. 2011;53(2):170-177. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/21123081.
89. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014;370(23):2211-2218.
90. Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic
review of the literature. Am J Obstet Gynecol. 2011;205(1):10-18. Available at:

91. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among
pregnant women in the United States. JAMA. 2010;303(15):1517-1525. Available at:
92. Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html.
93. American College of Obstetricians and Gynecologists. Practice advisory: COVID-19 vaccination
considerations for obstetric-gynecologic care. 2022. Available at: https://www.acog.org/clinical/clinical-
guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19.

Special Considerations in Adults and Children
With Cancer
• COVID-19 vaccination remains the most effective way to prevent SARS-CoV-2 infection and should be considered
the first line of prevention. The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination
as soon as possible for everyone who is eligible (AI), including patients with active cancer and patients who are
receiving treatment for cancer (AIII).
• Because vaccine response rates may be lower in people with cancer, specific guidance on administering vaccines
to these individuals is provided by the Centers for Disease Control and Prevention’s Advisory Committee on
Immunization Practices. The Panel recommends following the most current COVID-19 vaccination schedule for
people with cancer.
• Vaccinating household members, close contacts, and health care providers who provide care to patients with cancer
is important to protect these patients from infection. All close contacts are strongly encouraged to get vaccinated
against COVID-19 as soon as possible (AIII).
• Patients with cancer are at high risk of progressing to serious COVID-19, and they may be eligible to receive anti-
SARS-CoV-2 monoclonal antibodies as pre-exposure prophylaxis (PrEP).
• The Panel recommends performing diagnostic molecular or antigen testing for SARS-CoV-2 in patients with cancer
who develop signs and symptoms that suggest acute COVID-19 (AIII). The Panel also recommends performing
diagnostic molecular testing in asymptomatic patients prior to procedures that require anesthesia and before
initiating cytotoxic chemotherapy and long-acting biologic therapy (BIII).
• The recommendations for treating COVID-19 in patients with cancer are the same as those for the general population
(AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of
Hospitalized Adults With COVID-19 for more information.
• Clinicians should pay careful attention to potential overlapping toxicities and drug-drug interactions between drugs
that are used to treat COVID-19 (e.g., ritonavir-boosted nirmatrelvir [Paxlovid], dexamethasone) and cancer-directed
therapies, prophylactic antimicrobials, and other medications (AIII).
• Clinicians who are treating COVID-19 in patients with cancer should consult a hematologist or oncologist before
adjusting cancer-directed medications (AIII).
• Decisions about administering cancer-directed therapy to patients with acute COVID-19 and those who are recovering
from COVID-19 should be made on a case-by-case basis; clinicians should consider the indication for chemotherapy,
the goals of care, and the patient’s history of tolerance to the treatment (BIII).

People who are being treated for cancer may be at increased risk of severe COVID-19, and clinical
outcomes of COVID-19 are generally worse in people with cancer than in people without cancer.1-4 A
meta-analysis of 46,499 patients with COVID-19 showed that all-cause mortality (risk ratio 1.66; 95%
CI, 1.33–2.07) was higher in patients with cancer, and that patients with cancer were more likely to be
admitted to intensive care units (risk ratio 1.56; 95% CI, 1.31–1.87).5 A patient’s risk of
immunosuppression and susceptibility to SARS-CoV-2 infection depend on the type of cancer, the
treatments administered, and the stage of disease (e.g., patients who are actively being treated compared
to those in remission). In a study that used data from the COVID-19 and Cancer Consortium Registry,
patients with cancer who were in remission or who had no evidence of disease had a lower risk of death
from COVID-19 than those who were receiving active treatment.6 It is unclear whether cancer survivors

have an increased risk for severe COVID-19 and its complications compared to people without a history
of cancer.
Many organizations have outlined recommendations for treating patients with cancer during the
COVID-19 pandemic, such as:
• National Comprehensive Cancer Network (NCCN)
• American Society of Hematology
• American Society of Clinical Oncology
• Society of Surgical Oncology
• American Society for Radiation Oncology
• International Lymphoma Radiation Oncology Group
This section of the COVID-19 Treatment Guidelines complements these sources and focuses on testing
for SARS-CoV-2, managing COVID-19 in patients with cancer, and managing cancer-directed therapies
during the COVID-19 pandemic. The optimal management and therapeutic approach to COVID-19 in
this population has not yet been defined.
COVID-19 Vaccination in Patients With Cancer

The clinical trials that evaluated the COVID-19 vaccines that have received Emergency Use
Authorizations (EUAs) and/or approvals from the Food and Drug Administration (FDA) excluded
severely immunocompromised patients. The Center for Disease Control and Prevention’s (CDC)
Advisory Committee on Immunization Practices notes that the COVID-19 vaccines that are authorized
for use in the United States are not live vaccines; therefore, they can be safely administered to
immunocompromised people.7 Given the effectiveness of the COVID-19 vaccines in the general
population and the increased risk of severe COVID-19 and mortality in patients with cancer, the
COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for patients
with active cancer and patients who are receiving treatment for cancer (AIII). Observational data suggest
that the serological responses to vaccines may be blunted in immunocompromised patients; however,
vaccination is still recommended for these patients, because it may provide partial protection, including
protection from vaccine-induced, cell-mediated immunity.8,9 See the CDC website COVID-19 Vaccines
for People who are Moderately or Severely Immunocompromised for the current COVID-19 vaccination
schedule for these individuals. Given the effectiveness of COVID-19 vaccines, the Panel recommends
COVID-19 vaccination as soon as possible for everyone who is eligible (AI), including individuals who
have immunodeficiency or are on immunosuppressive medications (AIII).
Vaccinating household members, close contacts, and health care providers who provide care to patients
with cancer is important to protect these patients from infection. All close contacts are strongly
encouraged to get vaccinated as soon as possible (AIII). There is evidence that vaccinated individuals
who are infected with SARS-CoV-2 have lower viral loads than unvaccinated individuals10,11 and that
COVID-19 vaccines reduce the incidence of SARS-CoV-2 infections not only among vaccinated
individuals but also among their household contacts.12-14
The mRNA vaccines contain polyethylene glycol (PEG), and the Johnson & Johnson (J&J)/Janssen
vaccine contains polysorbate. For patients who experience severe anaphylactic reactions to PEG-
asparaginase, consider performing allergy testing for PEG prior to vaccination with either of the mRNA
vaccines, or consider using the J&J/Janssen vaccine with precautions.15-17
When determining the timing of COVID-19 vaccination in patients with cancer, clinicians should

consider the following factors:
• If possible, patients who are planning to receive chemotherapy should complete vaccination for
COVID-19 at least 2 weeks before starting chemotherapy.18,19
• In patients with hematologic malignancy who are undergoing intensive chemotherapy (e.g.,
induction chemotherapy for acute myelogenous leukemia), vaccination should be delayed until
neutrophil recovery.20
• Hematopoietic stem cell and chimeric antigen receptor T cell recipients can be offered COVID-19
vaccination starting at least 3 months after therapy.19,20
It is unknown whether the immune response to COVID-19 vaccination can increase the risk of graft-
versus-host disease. No immune-related adverse events were reported after COVID-19 vaccination in
two studies of patients with cancer who received immune checkpoint inhibitors.21,22
Decreased immunologic responses to COVID-19 vaccination have been reported in patients who
were receiving treatment for solid tumors and hematologic malignancies.9,23 The type of therapy has
been shown to influence the patient’s response to vaccination. For example, people with chronic
lymphocytic leukemia who were treated with Bruton’s tyrosine kinase inhibitors or venetoclax with
or without anti-CD20 antibodies had extremely low response rates (16.0% and 13.6%, respectively).23
In comparison, approximately 80% to 95% of patients with solid tumors showed immunologic
responses.9,24,25 Several observational studies support the use of a third vaccine dose in patients with
cancer, even though vaccine failure may still occur.26-28 See the CDC website COVID-19 Vaccines for
People who are Moderately or Severely Immunocompromised for guidance on vaccine dosing.
the first line of prevention. However, some individuals, including some patients with cancer, cannot or
may not mount an adequate protective response to COVID-19 vaccines. These patients are at high risk
of progressing to severe COVID-19 and may be eligible to receive the anti-SARS-CoV-2 monoclonal
antibodies tixagevimab plus cilgavimab (Evusheld) as pre-exposure prophylaxis (PrEP). See Prevention
of SARS-CoV-2 Infection for more information.
Testing for SARS-CoV-2 in Patients With Cancer

The Panel recommends performing diagnostic molecular or antigen testing for SARS-CoV-2 in patients
with cancer who develop signs and symptoms that suggest acute COVID-19 (AIII).
Patients with cancer who are receiving chemotherapy are at risk of developing neutropenia. The NCCN
Guidelines for Hematopoietic Growth Factors categorizes cancer treatment regimens based on the
patient’s risk of developing neutropenia.29 A retrospective study suggests that patients with cancer and
neutropenia have a higher mortality rate if they develop COVID-19.30 Studies have reported an increased
risk of poor clinical outcomes for patients with COVID-19 in the setting of neutropenia and/or during
the perioperative period.31,32 Because of this, the Panel recommends performing diagnostic molecular
testing for SARS-CoV-2 in asymptomatic patients prior to procedures that require anesthesia and before
initiating cytotoxic chemotherapy and long-acting biologic therapy (BIII).
General Guidance on Medical Care for Patients With Cancer During the COVID-19
Pandemic
Patients with cancer frequently engage with the health care system to receive treatment and supportive
care for cancer and/or treatment-related complications. Telemedicine can minimize the need for

in-person services and reduce the risk of SARS-CoV-2 exposure. Telemedicine may improve access
to providers for medically or socially vulnerable populations, but it could worsen disparities if these
populations have limited access to technology. Nosocomial transmission of SARS-CoV-2 to patients and
health care workers has been reported.33-35 Health care providers and patients should take precautions
to reduce the risk of SARS-CoV-2 exposure and infection, including wearing a mask, maintaining a
distance of 6 feet from others, and practicing good hand hygiene.36
Decisions about treatment regimens, surgery, and radiation therapy for the underlying malignancy
should be made on a case-by-case basis, and clinicians should consider the biology of the cancer,
the need for hospitalization, the number of clinic visits required, and the anticipated degree of
immunosuppression. Additional factors that should be considered include the following:
• If possible, avoid treatment delays for curable cancers that have been shown to have worse
outcomes when treatment is delayed (e.g., pediatric acute lymphoblastic leukemia).
• When deciding between equally effective treatment regimens, regimens that can be administered
orally or those that require fewer infusions are preferred.37
• The potential risks of drug-related lung toxicity (e.g., from using bleomycin or PD-1 inhibitors)
must be balanced with the clinical efficacy of alternative regimens or the risk of delaying care.38
• Preventing neutropenia can decrease the risk of neutropenic fever and the need for emergency
department evaluation and hospitalization. Granulocyte colony-stimulating factor (G-CSF) should
be given with chemotherapy regimens that have intermediate (10% to 20%) or high (>20%) risks
of febrile neutropenia.39
• Cancer treatment regimens that do not affect the outcomes of COVID-19 in patients with cancer
may not need to be altered. In a prospective observational study, receipt of immunotherapy,
hormonal therapy, or radiotherapy in the month prior to SARS-CoV-2 infection was not associated
with an increased risk of mortality among patients with cancer and COVID-19.40
• Radiation therapy guidelines suggest increasing the dose per fraction and reducing the number of
daily treatments to minimize the number of hospital visits.41,42
Blood supply shortages will likely continue during the COVID-19 pandemic due to social distancing,
cancellation of blood drives, and infection among donors. The FDA has proposed revising the donor
criteria to increase the number of eligible donors.43 In patients with cancer, stricter transfusion thresholds
for blood products (e.g., red blood cells, platelets) in asymptomatic patients should be considered. At
this time, there is no evidence that COVID-19 can be transmitted through blood products.44
Febrile Neutropenia
Patients with cancer and febrile neutropenia should undergo diagnostic molecular or antigen testing
for SARS-CoV-2 and evaluation for other infectious agents. They should also be given empiric
antibiotics, as outlined in the NCCN Guidelines.45 Low-risk febrile neutropenia patients should be
treated at home with oral antibiotics or intravenous infusions of antibiotics to limit nosocomial exposure
to SARS-CoV-2. Patients with high-risk febrile neutropenia should be hospitalized per standard of
care.45 Empiric antibiotics should be continued per standard of care in patients who test positive for
SARS-CoV-2. Clinicians should also continuously evaluate neutropenic patients for emergent infections.
Treating COVID-19 and Managing Chemotherapy in Patients With Cancer and

COVID-19
Retrospective studies suggest that patients with cancer who were admitted to the hospital with
SARS-CoV-2 infection have a high case-fatality rate, with higher rates observed in patients with

hematologic malignancies than in those with solid tumors.46,47
The recommendations for treating COVID-19 in patients with cancer are the same as those for the
general population (AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and
Therapeutic Management of Hospitalized Adults With COVID-19 for more information. Patients with
cancer are at high risk of progressing to severe COVID-19, and they may be eligible to receive anti-
SARS-CoV-2 therapies in the outpatient setting if they develop mild to moderate COVID-19.
The use of dexamethasone has been associated with a lower mortality rate in patients with COVID-19
who require supplemental oxygen or mechanical ventilation.48 In patients with cancer, dexamethasone
is commonly used to prevent chemotherapy-induced nausea, as a part of tumor-directed therapy, and
to treat inflammation associated with brain metastasis. The side effects of dexamethasone are expected
to be the same in patients with cancer as in those without cancer. If possible, treatments that are not
currently recommended for SARS-CoV-2 infection should be administered as part of a clinical trial,
since the safety and efficacy of these agents have not been well-defined in patients with cancer.
Tocilizumab or baricitinib used in combination with dexamethasone is recommended for some
patients with severe or critical COVID-19 who exhibit rapid respiratory decompensation (see
Therapeutic Management of Hospitalized Adults With COVID-19).49-51 The risks and benefits of
using dexamethasone in combination with tocilizumab or baricitinib in patients with cancer who
recently received chemotherapy is unknown. Because dexamethasone, tocilizumab, and baricitinib are
immunosuppressive agents, patients who receive these medications should be closely monitored for
secondary infections.
Therapeutic anticoagulation for patients with cancer who are hospitalized for COVID-19 should be
managed similarly to anticoagulation for other hospitalized patients. Patients with platelet counts
<50,000 cells/µL should not receive therapeutic anticoagulation to treat COVID-19. Clinicians should
follow hospital protocols for managing anticoagulation in patients with thrombocytopenia.
The NCCN recommends against using G-CSF and granulocyte-macrophage colony-stimulating factor
in patients with cancer and acute COVID-19 who do not have bacterial or fungal infections to avoid
the hypothetical risk of increasing inflammatory cytokine levels and pulmonary inflammation.52,53
Secondary infections (e.g., invasive pulmonary aspergillosis) have been reported in critically ill patients
with COVID-19.54,55
Decisions about administering cancer-directed therapy to patients with acute COVID-19 and those who
are recovering from COVID-19 should be made on a case-by-case basis; clinicians should consider the
indication for chemotherapy, the goals of care, and the patient’s history of tolerance to the treatment
(BIII). The optimal time to initiate or restart cancer-directed therapies after the infection has resolved
is unclear. If possible, clinicians should withhold treatment until COVID-19 symptoms have resolved.
Prolonged viral shedding may occur in patients with cancer,2 although it is unknown how this relates
to infectious virus and how it impacts outcomes. Therefore, there is no role for repeat testing in those
recovering from COVID-19, and the decision to restart cancer treatments in this setting should be made
on a case-by-case basis. Clinicians who are treating COVID-19 in patients with cancer should consult a
hematologist or oncologist before adjusting cancer-directed medications (AIII).
Medication Interactions
The use of antiviral or immune-based therapies to treat COVID-19 can present additional challenges
in patients with cancer. Clinicians should pay careful attention to potential overlapping toxicities and
drug-drug interactions between drugs that are used to treat COVID-19 and cancer-directed therapies,
prophylactic antimicrobials, corticosteroids, and other medications (AIII).

A 5-day course of ritonavir-boosted nirmatrelvir (Paxlovid) is 1 of the preferred therapies for treating
mild to moderate COVID-19 in nonhospitalized patients who are at risk for disease progression.
However, this regimen has the potential for significant and complex drug-drug interactions with
concomitant medications, primarily due to the ritonavir component of the combination. Boosting
with ritonavir, a strong cytochrome P450 (CYP) 3A inhibitor, is required to increase the exposure of
nirmatrelvir to a concentration that is effective against SARS-CoV-2. Ritonavir may also increase
concentrations of certain concomitant medications, including certain chemotherapeutic agents and
immunotherapies that are used to treat cancer. Significant increases in the concentrations of these drugs
may lead to serious and sometimes life-threatening drug toxicities. Additionally, ritonavir is an inhibitor,
inducer, and substrate of various other drug-metabolizing enzymes and/or drug transporters.
Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s
concomitant medications. Clinicians should refer to resources such as the Liverpool COVID-19 Drug
Interactions website, Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and
Concomitant Medications, and the FDA EUA fact sheet for ritonavir-boosted nirmatrelvir for guidance
on identifying and managing potential drug-drug interactions. If significant interactions prohibit the
concomitant use of ritonavir-boosted nirmatrelvir, another COVID-19 treatment option should be used.
Dexamethasone is commonly used as an antiemetic for patients with cancer and is recommended for the
treatment of certain patients with COVID-19 (see Therapeutic Management of Hospitalized Adults With
COVID-19). Dexamethasone is a weak to moderate CYP3A4 inducer; therefore, interactions with any
CYP3A4 substrates need to be considered.
Special Considerations in Children

Preliminary published reports suggest that pediatric patients with cancer may have milder manifestations
of COVID-19 than adult patients with cancer, although larger studies are needed.56-58 Guidance on
managing children with cancer during the COVID-19 pandemic is available from an international group
that received input from the International Society of Paediatric Oncology, the Children’s Oncology
Group, St. Jude Global, and Childhood Cancer International.59 Two publications provide guidance
on managing specific malignancies and supportive care and a summary of web links from groups of
experts that are relevant to the care of pediatric oncology patients during the COVID-19 pandemic.59,60
Special considerations for using antiviral drugs in immunocompromised children, including those with
malignancy, are available in a multicenter guidance statement.61
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45. National Comprehensive Cancer Network. NCCN best practices guidance: management of COVID-19
infection in patients with cancer. 2021. Available at: https://www.nccn.org/docs/default-source/covid-19/2021-
covid-infectious-disease-management.pdf?sfvrsn=63f70c30_7.
46. Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York
Hospital System. Cancer Discov. 2020;10(7):935-941. Available at:
47. Meng Y, Lu W, Guo E, et al. Cancer history is an independent risk factor for mortality in hospitalized
COVID-19 patients: a propensity score-matched analysis. J Hematol Oncol. 2020;13(1):75. Available at:
52. Nawar T, Morjaria S, Kaltsas A, et al. Granulocyte-colony stimulating factor in COVID-19: Is it stimulating
more than just the bone marrow? Am J Hematol. 2020;95(8):E210-E213. Available at:
53. National Comprehensive Cancer Network. NCCN hematopoietic growth factors: short-term recommendations
specific to issues with COVID-19 (SARS-CoV-2). 2020. Available at: https://www.iononline.com/-/media/
assets/ion/pdf/covid19-resources/nccn_hgf_covid-19_19may20.pdf.

54. van Arkel ALE, Rijpstra TA, Belderbos HNA, et al. COVID-19-associated pulmonary aspergillosis. Am J
Respir Crit Care Med. 2020;202(1):132-135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32396381.
55. Alanio A, Delliere S, Fodil S, Bretagne S, Megarbane B. Prevalence of putative invasive pulmonary
aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 2020;8(6):e48-e49. Available at:
56. Hrusak O, Kalina T, Wolf J, et al. Flash survey on severe acute respiratory syndrome coronavirus-2 infections
in paediatric patients on anticancer treatment. Eur J Cancer. 2020;132:11-16. Available at:
57. Andre N, Rouger-Gaudichon J, Brethon B, et al. COVID-19 in pediatric oncology from French pediatric
oncology and hematology centers: high risk of severe forms? Pediatr Blood Cancer. 2020;67(7):e28392.
58. de Rojas T, Perez-Martinez A, Cela E, et al. COVID-19 infection in children and adolescents with cancer in
Madrid. Pediatr Blood Cancer. 2020;67(7):e28397. Available at:
59. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19 pandemic: a rapid global response for
children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St. Jude Global. Pediatr
Blood Cancer. 2020;67(7):e28409. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32400924.
60. Bouffet E, Challinor J, Sullivan M, et al. Early advice on managing children with cancer during the
COVID-19 pandemic and a call for sharing experiences. Pediatr Blood Cancer. 2020;67(7):e28327. Available

Special Considerations in Solid Organ Transplant,
Hematopoietic Stem Cell Transplant, and Cellular
Immunotherapy Candidates, Donors, and Recipients
Vaccination for COVID-19
• COVID-19 vaccination remains the most effective way to prevent SARS-CoV-2 infection and should be considered
the first line of prevention. Given the effectiveness of COVID-19 vaccines in the general population and the increased
risk of worse clinical outcomes of COVID-19 in transplant and cellular immunotherapy candidates and recipients, the
COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for these patients (AIII).
• Because vaccine response rates may be lower in moderately or severely immunocompromised patients, specific
guidance on administering vaccines to these individuals is provided by the Centers for Disease Control and
Prevention’s Advisory Committee on Immunization Practices. The Panel recommends following the current COVID-19
vaccination schedule for these patients.
• Vaccinating household members, close contacts, and health care providers who provide care to transplant and
cellular immunotherapy candidates and recipients is important to protect these patients from infection. All close
contacts are strongly encouraged to get vaccinated against COVID-19 as soon as possible (AIII).
• All potential organ and stem cell donors are encouraged to get vaccinated against COVID-19 (AI).
• Some transplant candidates or recipients cannot or may not mount an adequate protective response to COVID-19
vaccines. These patients are eligible to receive the anti-SARS-CoV-2 monoclonal antibodies tixagevimab plus
cilgavimab (Evusheld) as pre-exposure prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for more
information.
Potential Transplant and Cellular Immunotherapy Candidates
• The Panel recommends performing diagnostic molecular or antigen testing for SARS-CoV-2 for all potential solid
organ transplant, hematopoietic stem cell transplant (HCT), and cellular immunotherapy candidates with signs and
symptoms that suggest acute COVID-19 (AIII).
• The Panel recommends following the guidance from medical professional organizations that specialize in providing
care for solid organ transplant, HCT, or cellular immunotherapy recipients when performing diagnostic molecular or
antigen testing for SARS-CoV-2 in these patients (AIII).
• If SARS-CoV-2 is detected or if infection is strongly suspected, transplantation should be deferred, if possible (BIII).
• The optimal management and therapeutic approach to COVID-19 in these populations is unknown. At this time, the
procedures for evaluating and managing COVID-19 in transplant candidates are the same as those for nontransplant
candidates (AIII).
Potential Transplant Donors
• The Panel recommends assessing all potential solid organ transplant and HCT donors for signs and symptoms of
COVID-19 according to guidance from medical professional organizations (AIII).
• The Panel recommends performing diagnostic molecular or antigen testing for SARS-CoV-2 if symptoms are
present (AIII).
• If SARS-CoV-2 is detected or if infection is strongly suspected, donation should be deferred (BIII).
Transplant and Cellular Immunotherapy Recipients With COVID-19
• Clinicians should follow the guidelines for evaluating and managing COVID-19 in nontransplant patients when treating
transplant and cellular immunotherapy recipients (AIII). See Therapeutic Management of Hospitalized Adults With
COVID-19 and Therapeutic Management of Nonhospitalized Adults With COVID-19 for more information.
• Immunocompromised patients with mild to moderate COVID-19 are at high risk of progressing to severe disease and
should receive anti-SARS-CoV-2 therapies for treatment.

• Clinicians who are treating COVID-19 in transplant and cellular immunotherapy patients should consult a transplant
specialist before adjusting immunosuppressive medications (AIII).
• When treating COVID-19, clinicians should pay careful attention to potential overlapping toxicities and drug-drug
interactions between drugs that are used to treat COVID-19 (e.g., ritonavir-boosted nirmatrelvir [Paxlovid]) and
immunosuppressants, prophylactic antimicrobials, or other medications (AIII).
Introduction
Treating COVID-19 in solid organ transplant, hematopoietic stem cell transplant (HCT), and cellular
immunotherapy recipients can be challenging due to the presence of coexisting medical conditions,
the potential for transplant-related cytopenias, and the need for chronic immunosuppressive therapy
to prevent graft rejection and graft-versus-host disease. Transplant recipients may also have a higher
risk of exposure to SARS-CoV-2 given their frequent contact with the health care system. Since
immunosuppressive agents modulate several aspects of the host’s immune response, the severity of
COVID-19 could potentially be affected by the type and intensity of the immunosuppressive effect of the
agent, as well as by specific combinations of immunosuppressive agents. Some transplant recipients have
medical comorbidities that have been associated with more severe cases of COVID-19 and a greater risk
of mortality, which makes the impact of transplantation on disease severity difficult to assess.
The International Society for Heart and Lung Transplantation, the American Society of Transplantation
(AST), the American Society for Transplantation and Cellular Therapy (ASTCT), and the European
Society for Blood and Marrow Transplantation (EBMT) provide guidance for clinicians who are caring
for transplant recipients with COVID-19 and guidance on screening potential donors and transplant or
cellular immunotherapy candidates. In addition, the American Society of Hematology offers guidance
regarding COVID-19 vaccination for transplant and cellular immunotherapy recipients. This section
of the COVID-19 Treatment Guidelines complements these sources and focuses on considerations
for managing COVID-19 in solid organ transplant, HCT, and cellular immunotherapy recipients.
The optimal management and therapeutic approach to COVID-19 in these populations is unknown.
At this time, the procedures for evaluating and managing COVID-19 in transplant recipients are the
same as those for nontransplant patients (AIII). See Therapeutic Management of Hospitalized Adults
With COVID-19 and Therapeutic Management of Nonhospitalized Adults With COVID-19 for more
information. The risks and benefits of each medication that is used to treat COVID-19 may be different
for transplant patients and nontransplant patients.
COVID-19 Vaccination in Solid Organ Transplant, Hematopoietic Stem Cell

Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients
The clinical trials that evaluated the safety and efficacy of the COVID-19 vaccines excluded severely
immunocompromised patients.1-3 The Center for Disease Control and Prevention’s (CDC) Advisory
Committee on Immunization Practices notes that the currently authorized or approved COVID-19
vaccines are not live vaccines; therefore, they can be safely administered to immunocompromised
people.4 However, solid organ transplant recipients have reduced immunological antibody responses
following a primary 2-dose or 3-dose series of the mRNA COVID-19 vaccines.5-8
Given the effectiveness of COVID-19 vaccines in the general population and the increased risk of worse

clinical outcomes of COVID-19 in transplant and cellular immunotherapy recipients, the COVID-19
Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for potential transplant and
cellular immunotherapy candidates and recipients (AIII). See the CDC website COVID-19 Vaccines for
People Who Are Moderately or Severely Immunocompromised for the current COVID-19 vaccination
schedule for all populations, including transplant and cellular immunotherapy recipients.
When determining the timing of COVID-19 vaccination in solid organ transplant, HCT, and cellular
immunotherapy recipients, clinicians should consider the following factors:
• Ideally, solid organ transplant candidates should receive COVID-19 vaccines while they are
awaiting transplant.
• In general, vaccination should be completed at least 2 weeks prior to a solid organ transplant or
started 1 month after a solid organ transplant.
• In certain situations, it may be appropriate to delay vaccination until 3 months after a solid
organ transplant, such as when T cell- or B cell-ablative therapy (with antithymocyte globulin or
rituximab) is used at the time of transplant.9
• At this time, reducing the dose of immunosuppressants and withholding immunosuppressants
prior to vaccination are not recommended.
• COVID-19 vaccines can be offered as early as 3 months after a patient receives HCT or chimeric
antigen receptor T cell therapy, although the efficacy of the vaccines may be reduced compared to
the efficacy observed in the general population.10-12 Patients who are scheduled to receive cytotoxic
or B cell-depleting therapies should complete their COVID-19 vaccination prior to initiation or
between cycles of cytotoxic or B cell-depleting therapies, if possible.
• After completing COVID-19 vaccination, immunocompromised persons should be advised to
continue to exercise precautions to reduce their risk of SARS-CoV-2 exposure and infection (e.g.,
they should wear a mask, maintain a distance of 6 feet from others, and avoid crowds and poorly
ventilated spaces).13
There is insufficient evidence for the Panel to recommend either for or against the use of SARS-CoV-2
serologic testing to assess for immunity or to guide clinical decisions about using COVID-19 vaccines.
It is currently unknown whether revaccination offers a clinical benefit for people who received
COVID-19 vaccines during treatment with immunosuppressive drugs.
Vaccinating household members, close contacts, and health care providers who provide care to
transplant and cellular immunotherapy candidates and recipients is important to protect these patients
from infection. All close contacts are strongly encouraged to get vaccinated against COVID-19 as soon
as possible (AIII). There is evidence that vaccinated individuals who are infected with SARS-CoV-2
have lower viral loads than unvaccinated individuals14,15 and that COVID-19 vaccines reduce the
incidence of SARS-CoV-2 infections not only among vaccinated individuals but also among their
household contacts.16-18 All potential organ and stem cell donors are encouraged to get vaccinated against
COVID-19 (AI).
the first line of prevention. However, some individuals, including some transplant candidates and
recipients, cannot or may not mount an adequate protective response to COVID-19 vaccines. These
patients are at high risk of progressing to severe COVID-19 and may be eligible to receive the anti-
SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus cilgavimab (Evusheld) as pre-exposure

prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for more information.
Assessing SARS-CoV-2 Infection in Transplant and Cellular Immunotherapy

Candidates and Donors
The risk of transmission of SARS-CoV-2 from donors to candidates is unknown. The probability that a
donor or candidate may have SARS-CoV-2 infection can be estimated by considering the epidemiologic
risk, obtaining a clinical history, and testing with molecular techniques. No current testing strategy is
sensitive enough or specific enough to totally exclude active infection.
Assessing Transplant and Cellular Immunotherapy Candidates

The Panel recommends performing diagnostic molecular or antigen testing for SARS-CoV-2 for all
potential solid organ transplant candidates with signs and symptoms that suggest acute COVID-19 (AIII).
All potential solid organ transplant candidates should be assessed for exposure to COVID-19 and clinical
symptoms that are compatible with COVID-19 before they are called in for transplantation and should
undergo diagnostic molecular testing for SARS-CoV-2 shortly before a solid organ transplant (AIII).
Clinicians should perform diagnostic testing for SARS-CoV-2 in all HCT and cellular immunotherapy
candidates who exhibit symptoms. All candidates should also undergo diagnostic molecular testing for
SARS-CoV-2 shortly before HCT or cellular immunotherapy (AIII).
Assessing Donors
Living solid organ donors should be counseled on strategies to prevent infection and be monitored for
exposures and symptoms in the 14 days prior to a scheduled transplant.19 Living donors should undergo
SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing with a sample collected
from the respiratory tract within 3 days of donation. Deceased donors should be tested for SARS-CoV-2
infection using an RT-PCR assay of a sample taken from the upper respiratory tract within 72 hours of
death; ideally, the test should be performed as close to organ recovery as possible. Deceased donors can
be considered for donation if the results are negative. Lower respiratory sampling for COVID-19 testing
is required for potential lung transplant donors by the United Network for Organ Sharing.20
The Panel recommends following the guidance from medical professional organizations and assessing
all potential HCT donors for exposure to COVID-19 and clinical symptoms that are compatible with
COVID-19 before donation (AIII). HCT donors should practice good hygiene and avoid crowded places
and large gatherings during the 28 days prior to donation.21 Recommendations for screening HCT donors
are outlined in the ASTCT and EBMT guidelines.
If SARS-CoV-2 Infection Is Detected or Strongly Suspected

If SARS-CoV-2 is detected or if infection is strongly suspected in a potential solid organ transplant
candidate, transplant should be deferred, if possible. The optimal disease-free interval before
transplantation is not known. When deciding on the appropriate timing for the transplant, clinicians
should consider both the risk of viral transmission and the risks to the candidate if the transplant is
deferred, such as the potential progression of the underlying disease and the risk of death. This decision
should be continually reassessed as conditions evolve.
Donors for solid organ transplants who test positive for SARS-CoV-2 are medically ineligible for
donation.22 Current guidelines recommend deferring transplants or immunotherapy procedures, including
peripheral blood stem cell mobilization, bone marrow harvest, T cell collection, and conditioning/
lymphodepletion, in HCT and cellular immunotherapy candidates who test positive for SARS-CoV-2
or who have clinical symptoms that are consistent with infection. Final decisions should be made on a

case-by-case basis while weighing the risks of delaying or altering therapy for the underlying disease.
Transplant Recipients With COVID-19

Solid organ transplant recipients who are receiving immunosuppressive therapy should be considered to
be at increased risk for severe COVID-19.23,24 A national survey of 88 U.S. transplant centers conducted
between March 24 and 31, 2020, reported that 148 solid organ transplant recipients received a diagnosis
of SARS-CoV-2 infection (69.6% were kidney recipients, 15.5% were liver recipients, 8.8% were heart
recipients, and 6.1% were lung recipients).25 COVID-19 was mild in 54% of recipients and moderate in
21% of recipients, and 25% of recipients were critically ill. Initial reports of transplant recipients who
were hospitalized with COVID-19 suggest mortality rates of up to 28%.26-30
Risk of Graft Rejection

There are concerns that COVID-19 itself may increase the risk for acute rejection. Acute cellular
rejection should not be presumed in solid organ transplant recipients without biopsy confirmation,
regardless of whether the individual has COVID-19. Similarly, immunosuppressive therapy should be
initiated in recipients with or without COVID-19 who have rejection confirmed by a biopsy.23
There are limited data on the incidence and clinical characteristics of SARS-CoV-2 infection in HCT31
and cellular immunotherapy recipients.32 Recent data from the Center for International Blood and
Marrow Transplant Research demonstrated a mortality rate of approximately 30% within a month of
COVID-19 diagnosis among a cohort of 318 HCT recipients.33 This mortality rate was observed in
both allogeneic and autologous recipients. Older age (≥50 years), male sex, and receipt of a COVID-19
diagnosis within 12 months of transplantation were associated with a higher risk of mortality among
allogeneic recipients. In autologous recipients, patients with lymphoma had a higher risk of mortality
than patients who had plasma cell disorder or myeloma.
A smaller study demonstrated a slightly lower mortality rate among HCT and cellular immunotherapy
recipients than earlier reports. This study found that the number of comorbidities, the presence of
infiltrates on initial chest imaging, and neutropenia were predictors for increased disease severity.34
Additional factors that have been used to determine the clinical severity of other respiratory viral
infections include the degree of cytopenia, the intensity of the conditioning regimen, the graft source, the
degree of mismatch, and the need for further immunosuppression to manage graft-versus-host disease.
Prolonged viral shedding has been described in solid organ transplant and HCT recipients; this can have
implications for preventing infection and for the timing of therapeutic interventions.35
Treating COVID-19 in Transplant Recipients

Currently, remdesivir is the only antiviral drug that is approved by the Food and Drug Administration
for the treatment of COVID-19 in both nonhospitalized and hospitalized patients. Outpatient transplant
recipients who are immunosuppressed or who have certain underlying comorbidities are candidates for
several other therapeutic agents that are available through Emergency Use Authorizations (EUAs). See
Therapeutic Management of Nonhospitalized Adults With COVID-19 for more information.
When treating hospitalized patients with mild to moderate, symptomatic COVID-19, clinicians should
consider administering the therapeutics used in nonhospitalized patients with similar disease severity.
Data from a large randomized controlled trial found that a short course of dexamethasone (6 mg once
daily for up to 10 days) improved survival in hospitalized people with severe COVID-19 who were
mechanically ventilated or who required supplemental oxygen.36 Tocilizumab or baricitinib used in
combination with dexamethasone is recommended for some patients with severe or critical COVID-19
who exhibit rapid respiratory decompensation (see Therapeutic Management of Hospitalized Adults

With COVID-19).36-38 Because dexamethasone, tocilizumab, and baricitinib are immunosuppressive
agents, patients who receive these medications should be closely monitored for secondary infections.
Therapeutic anticoagulation for transplant recipients who are hospitalized for COVID-19 should be
managed similarly to anticoagulation for other hospitalized patients. Patients with platelet counts
<50,000 cells/µL should not receive therapeutic anticoagulation to treat COVID-19. Clinicians should
follow hospital protocols for managing anticoagulation in patients with thrombocytopenia.
The Panel’s recommendations for the use of remdesivir, dexamethasone, tocilizumab, baricitinib, and
anticoagulation in hospitalized patients with COVID-19 can be found in Therapeutic Management of
Hospitalized Adults With COVID-19.
Concomitant Medications
Clinicians should pay special attention to the potential for drug-drug interactions and overlapping
toxicities between treatments for COVID-19 and concomitant medications, such as immunosuppressants
that are used to prevent allograft rejection, antimicrobials that are used to prevent opportunistic
infections, and other medications. Dose modifications may be necessary for drugs that are used
to treat COVID-19 in transplant recipients with pre-existing organ dysfunction. Adjustments to
the immunosuppressive regimen should be individualized based on disease severity, the specific
immunosuppressants used, the type of transplant, the time since transplantation, the drug concentration,
and the risk of graft rejection.27 Clinicians who are treating COVID-19 in transplant patients should
consult a transplant specialist before adjusting immunosuppressive medications (AIII).
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus) and mammalian target of rapamycin (mTOR)
inhibitors (e.g., everolimus, sirolimus), which are commonly used to prevent allograft rejection, have
a narrow therapeutic index. Medications that inhibit or induce cytochrome P450 (CYP) enzymes or
P-glycoprotein may put patients who receive these drugs at risk of clinically significant drug-drug
interactions, increasing the need for therapeutic drug monitoring and the need to assess for signs of
toxicity or rejection.39
A 5-day course of ritonavir-boosted nirmatrelvir (Paxlovid) is 1 of the preferred therapies for treating
mild to moderate COVID-19 in nonhospitalized patients who are at risk for disease progression.
However, this regimen has the potential for significant and complex drug-drug interactions with
concomitant medications, primarily due to the ritonavir component of the combination. Boosting
with ritonavir, a strong CYP3A inhibitor, is required to increase the exposure of nirmatrelvir to a
concentration that is effective against SARS-CoV-2. Ritonavir may also increase concentrations of
certain concomitant medications, including calcineurin and mTOR inhibitors, during the treatment
course and for ≥3 days after ritonavir is discontinued. Significant increases in the concentrations of these
drugs may lead to serious and sometimes life-threatening drug toxicities.
For nonhospitalized transplant patients who are receiving calcineurin or mTOR inhibitors as part of their
antirejection regimen, AST recommends either an anti-SARS-CoV-2 mAb or remdesivir as the first-line
therapy.40 If these drugs are not available or feasible to use, ritonavir-boosted nirmatrelvir may be used
with caution. Ritonavir-boosted nirmatrelvir should only be used when close monitoring of the patient
is possible, and clinicians should consult with transplant specialists during the treatment course. General
guidance for coadministering ritonavir-boosted nirmatrelvir with concomitant medications includes
temporarily withholding certain immunosuppressive agents (e.g., tacrolimus, everolimus, sirolimus) or
reducing the dosage of certain immunosuppressive agents (e.g., cyclosporine), monitoring the patient
closely for toxicities, and performing therapeutic drug monitoring (if possible) during and after the

treatment course of ritonavir-boosted nirmatrelvir.40,41
Some small case series have reported real-life success in using these recommendations to manage
patients;42,43 however, cases of significant toxicities due to supratherapeutic tacrolimus concentrations
have also been reported.44 The reintroduction or dose modification of calcineurin and mTOR inhibitors
in patients who have completed a course of ritonavir-boosted nirmatrelvir should be guided by
therapeutic drug monitoring. Clinicians should also consult with a specialist who has experience with
dose management. Clinicians should take additional precautions when treating transplant recipients who
are also receiving other concomitant medications (e.g., certain triazole antifungals) that may interact
with ritonavir, the immunosuppressants, or both. The extent and significance of multiple drug-drug
interactions are much more complex and unpredictable.
Clinicians should refer to resources such as the Liverpool COVID-19 Drug Interactions website,
Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant
Medications, and the EUA fact sheet for ritonavir-boosted nirmatrelvir for guidance on identifying and
managing potential drug-drug interactions. If significant interactions prohibit the concomitant use of
ritonavir-boosted nirmatrelvir, another COVID-19 treatment option should be used.
Among the drugs that are commonly used to treat hospitalized patients with COVID-19, dexamethasone
is a moderate inducer of CYP3A4, and interleukin-6 inhibitors may lead to increased metabolism of
CYP substrates. Clinicians should closely monitor the serum concentrations of calcineurin and mTOR
inhibitors when these drugs are used.
Additional details about the adverse effects and drug-drug interactions of antiviral medications, anti-
SARS-CoV-2 antibody products, and immune-based therapies for COVID-19 are noted in Tables 4d, 5c,
and 6g.
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on%20Oral%20Antiviral%20Therapy%20for%20COVID%20Jan%204%20%282%29.pdf.
41. Lange NW, Salerno DM, Jennings DL, et al. Nirmatrelvir/ritonavir use: managing clinically significant
drug-drug interactions with transplant immunosuppressants. Am J of Transplant. 2022;Published online ahead
of print. Available at: https://pubmed.ncbi.nlm.nih.gov/35015924.

42. Salerno DM, Jennings DL, Lange NW, et al. Early clinical experience with nirmatrelvir/ritonavir for the
treatment of COVID-19 in solid organ transplant recipients. Am J Transplant. 2022;Published online ahead of
43. Wang AX, Koff A, Hao D, Tuznik NM, Huang Y. Effect of nirmatrelvir/ritonavir on calcineurin inhibitor
levels: early experience in four SARS-CoV-2 infected kidney transplant recipients. Am J Transplant.
2022;Published online ahead of print. Available at: https://pubmed.ncbi.nlm.nih.gov/35158412.
44. Rose DT, Gandhi SM, Bedard RA, et al. Supratherapeutic tacrolimus concentrations with nirmatrelvir/
ritonavir in solid organ transplant recipients requiring hospitalization: a case series using rifampin for reversal.
Open Forum Infect Dis. 2022;Accepted manuscript. Available at:
https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac238/6585265.

Special Considerations in People With HIV
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that people with HIV receive COVID-19 vaccines
regardless of their CD4 T lymphocyte (CD4) cell count or HIV viral load, because the potential benefits outweigh the
potential risks (AIII).
• The Advisory Committee on Immunization Practices recommends that people with advanced or untreated HIV who
received a 2-dose series of an mRNA COVID-19 vaccine should receive a third dose of that vaccine at least 28 days
after the second dose. Advanced HIV is defined as people with CD4 counts <200 cells/mm3, a history of an AIDS-
defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV.
• People with advanced or untreated HIV who do not have SARS-CoV-2 infection and who have not been recently
exposed to SARS-CoV-2 are eligible to receive the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus
cilgavimab as pre-exposure prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for details.
• Two anti-SARS-CoV-2 mAb combinations, bamlanivimab plus etesevimab and casirivimab plus imdevimab, have
received Emergency Use Authorizations from the Food and Drug Administration for post-exposure prophylaxis (PEP).
However, the Panel recommends against their use in patients with COVID-19, including in people with HIV, because
the Omicron variant is currently the dominant SARS-CoV-2 variant in the United States, and it is not susceptible to
these anti-SARS-CoV-2 mAbs (AIII).
Diagnosis of COVID-19
• The Panel recommends using the same approach for diagnosing SARS-CoV-2 infection in people with HIV as in
people without HIV (AIII).
Management of COVID-19
• Recommendations for the triage, management, and treatment of COVID-19 in people with HIV are generally the same
as those for the general population (AIII).
• Nonhospitalized people with HIV and mild to moderate COVID-19 may be eligible to receive anti-SARS-CoV-2 therapy
(e.g., ritonavir-boosted nirmatrelvir [Paxlovid], bebtelovimab, remdesivir, molnupiravir). However, in situations where
there are logistical or supply constraints for administering these drugs, priority should be given to those with very
advanced HIV (e.g., those with CD4 counts <50 cells/mm3) (AIII). See the Panel’s statement on patient prioritization
for outpatient therapies for details.
• People with HIV who are taking ritonavir-based or cobicistat-based antiretroviral therapy (ART) can receive ritonavir-
boosted nirmatrelvir to treat COVID-19 without altering or interrupting their ART (i.e., they can continue using the
ritonavir or cobicistat dose that is associated with their ART in addition to the dose of ritonavir that is used with
nirmatrelvir).
• In people with advanced HIV and suspected or documented COVID-19, HIV-associated opportunistic infections
should also be considered in the differential diagnosis of febrile illness (AIII).
• When starting treatment for COVID-19 in patients with HIV, clinicians should pay careful attention to potential
drug-drug interactions and overlapping toxicities among COVID-19 treatments, antiretroviral (ARV) medications,
antimicrobial therapies, and other medications (AIII).
• People with HIV should be offered the opportunity to participate in clinical trials that are evaluating agents for the
prevention and treatment of SARS-CoV-2 infection.
Management of HIV
• People with HIV who develop COVID-19, including those who require hospitalization, should continue their ART and
opportunistic infection treatment and prophylaxis whenever possible (AIII).
• Clinicians who are treating COVID-19 in people with HIV should consult an HIV specialist before adjusting or
switching ARV medications (AIII).

• An ARV regimen should not be switched or adjusted (i.e., by adding ARV drugs to the regimen) for the purpose of
preventing or treating SARS-CoV-2 infection (AIII).
• Clinicians should consult an HIV specialist to determine the optimal time to initiate ART in people who present with
COVID-19 and a new diagnosis of HIV.
Introduction
Approximately 1.2 million people in the United States are living with HIV. Most of these individuals
are in care, and many are on antiretroviral therapy (ART) and have well-controlled disease.1 Similar
to COVID-19, HIV disproportionately affects racial and ethnic minorities and people of lower
socioeconomic status in the United States;2 these demographic groups also appear to have a higher risk
of poor outcomes with COVID-19. In the general population, the individuals who are at the highest
risk of severe COVID-19 include those aged >60 years; those who are pregnant; those who have
received solid organ transplants; and those with comorbidities, such as cancer, obesity, diabetes mellitus,
cardiovascular disease, pulmonary disease, a history of smoking, chronic kidney disease, or chronic liver
disease.3 Many people with HIV have 1 or more comorbidities that may put them at increased risk for a
more severe course of COVID-19.
Information on SARS-CoV-2/HIV coinfection is evolving rapidly. The sections below outline the current
state of knowledge regarding preventing and diagnosing SARS-CoV-2 infection in people with HIV,
the treatment and clinical outcomes in people with HIV who develop COVID-19, and the management
of HIV during the COVID-19 pandemic. In addition to these Guidelines, the Department of Health
and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents has developed the
Guidance for COVID-19 and People With HIV.
Clinical Outcomes of COVID-19 in People With HIV

Data are emerging on the clinical outcomes of COVID-19 in people with HIV. In some of the initial
case series of people with COVID-19 in Europe and the United States, no significant differences were
observed in the clinical outcomes of COVID-19 between people with HIV and people who did not have
HIV.4-11
In contrast, more recent reports suggest worse outcomes for patients with HIV and COVID-19, including
increased COVID-19 mortality rates in cohort studies in the United States, the United Kingdom,
and South Africa.12-18 HIV was independently associated with an increased risk of severe and critical
COVID-19 in a large World Health Organization platform trial that included data from 24 countries.19 In
a multicenter cohort study of 286 patients with HIV and COVID-19 in the United States, lower CD4 T
lymphocyte (CD4) cell counts (i.e., <200 cells/mm3) were associated with a higher risk for the composite
endpoint of intensive care unit admission, mechanical ventilation, or death. This increased risk was
observed even in patients who had achieved virologic suppression of HIV.15 In a large observational
cohort study of people with HIV and COVID-19 in the United States, those with CD4 counts <350 cells/
mm3 were more likely to be hospitalized, require ventilation, or die. Higher levels of viremia were also
associated with worse outcomes.18 In another study of 175 patients with HIV and COVID-19, a low CD4
count or a low CD4 nadir was associated with poor outcomes.16 In a cohort study conducted in New
York, people with HIV and COVID-19 had higher rates of hospitalization and mortality than people with
COVID-19 who did not have HIV.17

Prevention of COVID-19 in People With HIV
The COVID-19 Treatment Guidelines Panel (the Panel) recommends using the same approach for
advising persons with HIV on the strategies to prevent SARS-CoV-2 infection that is used for people
without HIV (AIII). There is currently no clear evidence that any antiretroviral (ARV) medications can
prevent SARS-CoV-2 infection.
People with HIV should receive COVID-19 vaccines, regardless of their CD4 count or HIV viral load,
because the potential benefits outweigh the potential risks (AIII). People with HIV were included in the
clinical trials of the 2 mRNA vaccines and the adenovirus vector vaccine that are currently available
through Emergency Use Authorizations (EUAs) and/or approval from the Food and Drug Administration
(FDA);20-22 however, few studies have evaluated the safety and efficacy of these vaccines in people with
HIV. Typically, people with HIV who are on ART and who have achieved virologic suppression respond
well to licensed vaccines. Preliminary data from studies that used COVID-19 vaccines in people with HIV
confirm that people who are on ART and have normal CD4 counts have good immunologic responses to
the vaccines.23-25
On August 12, 2021, the FDA changed the EUAs for the 2 mRNA vaccines to allow a third dose of an
mRNA vaccine to be administered at least 28 days after the second dose to people with advanced or
untreated HIV. Advanced HIV is defined as people with CD4 counts <200 cells/mm3, a history of an
AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV.
People with HIV should also receive booster doses of the COVID-19 vaccines as recommended by the
Advisory Committee on Immunization Practices.
People with advanced or untreated HIV who are not infected or recently exposed to SARS-CoV-2 are
eligible to receive the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus cilgavimab as
pre-exposure prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for details.
Two anti-SARS-CoV-2 mAb combinations, bamlanivimab plus etesevimab and casirivimab plus
imdevimab, have received FDA EUAs for post-exposure prophylaxis (PEP). However, the Panel
recommends against their use in patients with COVID-19, including in people with HIV, because the
Omicron variant is currently the dominant variant in the United States, and it is not susceptible to these
anti-SARS-CoV-2 mAbs (AIII).
Diagnostic and Laboratory Testing for COVID-19 in People With HIV

Diagnosis of COVID-19 in People With HIV
The Panel recommends using the same approach for diagnosing SARS-CoV-2 infection in people with
HIV as in those without HIV (AIII). See Testing for SARS-CoV-2 Infection for more information.
There is currently no evidence that the performance characteristics of nucleic acid amplification tests
(NAATs) and antigen tests differ in people with and without HIV when diagnosing acute SARS-CoV-2
infection. The Panel recommends against the use of serologic testing as the sole basis for diagnosis of
acute SARS-CoV-2 infection (AIII). However, if diagnostic serologic testing is performed in a patient
with HIV, the results should be interpreted with caution because cross-reactivity between antibodies to
SARS-CoV-2 and HIV has been reported.26
Correlation of CD4 Count in People With HIV and COVID-19

The normal range for CD4 counts in healthy adults is about 500 to 1,600 cells/mm3. People with HIV
who have a CD4 count of ≥500 cells/mm3 have similar cellular immune function to those without HIV.
In people with HIV, a CD4 count <200 cells/mm3 meets the definition for AIDS. For patients on ART,
the hallmark of treatment success is plasma HIV RNA below the level of detection by a polymerase

chain reaction assay. Lymphopenia is a common laboratory finding in patients with COVID-19; in
patients with HIV, clinicians should note that CD4 counts obtained during acute COVID-19 may not
accurately reflect the patient’s HIV disease stage.
There have been some reports of people with advanced HIV who have presented with COVID-19 and
another coinfection, including Pneumocystis jirovecii pneumonia.27,28 In patients with advanced HIV
who have suspected or laboratory-confirmed SARS-CoV-2 infection, clinicians should consider a
broader differential diagnosis for clinical symptoms and consider consulting an HIV specialist (AIII).
Clinical Presentation of COVID-19 in People With HIV

It is currently unknown whether people with HIV have a higher incidence of SARS-CoV-2 infection or
a higher rate of progression to symptomatic disease than the general population. Approximately 50%
of people with HIV in the United States are aged >50 years,29 and many have comorbidities that are
associated with more severe cases of COVID-19. These comorbidities include hypertension, diabetes
mellitus, cardiovascular disease, a history of smoking, chronic lung disease, chronic liver disease, and
cancer.30
There are a number of case reports and case series that describe the clinical presentation of COVID-19
in people with HIV.4-11,31,32 These studies indicate that the clinical presentation of COVID-19 is similar in
people with and without HIV. Most of the published reports describe populations in which most of the
individuals with HIV are on ART and have achieved virologic suppression. Consequently, the current
understanding of the impact of COVID-19 in those with advanced HIV who have low CD4 counts or
persistent HIV viremia is limited.
Management of COVID-19 in People With HIV

Recommendations for the triage and management of COVID-19 in people with HIV are the same as
those for the general population (AIII).
The treatment of COVID-19 in persons with HIV is the same as for those without HIV (AIII).
Nonhospitalized people with HIV and mild to moderate COVID-19 may be eligible to receive
the therapies that are currently recommended for treatment (see Therapeutic Management of
Nonhospitalized Adults With COVID-19). However, in situations where there are logistical or supply
constraints for administering these therapies, priority should be given to those with advanced HIV
(AIII).
When starting treatment for COVID-19 in patients with HIV, clinicians should pay careful attention
to potential drug-drug interactions and overlapping toxicities among COVID-19 treatments,
ARV medications, antimicrobial therapies, and other medications (AIII). Therapeutic options for
nonhospitalized patients with HIV include ritonavir-boosted nirmatrelvir (Paxlovid), intravenous
remdesivir, bebtelovimab, and molnupiravir (see Therapeutic Management of Nonhospitalized Adults
With COVID-19). Drug-drug interactions are a special concern with ritonavir-boosted nirmatrelvir (see
the Panel’s statement on the drug-drug interactions for ritonavir-boosted nirmatrelvir). People with HIV
who are taking ritonavir-based or cobicistat-based ART can receive the 5-day course of ritonavir-boosted
nirmatrelvir to treat COVID-19 without altering or interrupting their ART (i.e., they can continue using
the ritonavir or cobicistat dose that is associated with their ART in addition to the dose of ritonavir that
is used with nirmatrelvir). Before prescribing ritonavir-boosted nirmatrelvir for a patient who is not
already on a ritonavir-based or cobicistat-based regimen, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medicines and herbal supplements, and evaluate
the potential for drug-drug interactions. Clinicians should utilize resources such as the EUA fact sheet
for ritonavir-boosted nirmatrelvir and the Liverpool COVID-19 Drug Interactions website for additional

guidance on identifying and managing drug-drug interactions.
In hospitalized patients, the appropriate treatment strategy depends on disease severity (see Therapeutic
Management of Hospitalized Adults With COVID-19). Both tocilizumab and dexamethasone, which
are recommended for some patients with severe or critical COVID-19, are immunosuppressive agents.
The safety of using these drugs in immunocompromised patients, including those with advanced HIV,
has not been studied. Therefore, patients with advanced HIV who are receiving these drugs should be
closely monitored for secondary infections. Dexamethasone is a dose-dependent inducer of cytochrome
P450 3A4 and could potentially lower the levels of certain coadministered ARV drugs. More than a
single dose of dexamethasone is not recommended for patients who are receiving rilpivirine as part of
their ARV regimen. Clinicians should consult an HIV specialist before administering dexamethasone to
these patients. It is currently unknown whether administering ≤10 days of dexamethasone impacts the
clinical efficacy of other ARV drugs. Patients with HIV who are receiving dexamethasone as treatment
for COVID-19 should follow up with their HIV providers to assess their virologic response.
Although some ARV drugs were studied for the prevention and treatment of COVID-19, no agents have
been shown to be effective.
People with HIV should be offered the opportunity to participate in clinical trials of vaccines and potential
treatments for COVID-19. A variety of immunomodulatory therapies are prescribed empirically or
administered as part of a clinical trial to treat severe COVID-19. The data on whether these medications
are safe to use in patients with HIV are lacking. If a medication has been shown to reduce the mortality of
patients with COVID-19 in the general population, it should also be used to treat COVID-19 in patients
with HIV, unless data indicate that the medication is not safe or effective in this population.
Managing HIV in People With COVID-19

Whenever possible, ART and opportunistic infection prophylaxis should be continued in a patient
with HIV who develops COVID-19, including in those who require hospitalization (AIII). Treatment
interruption may lead to rebound viremia, and, in some cases, the emergence of drug resistance. If the
appropriate ARV drugs are not on the hospital’s formulary, administer medications from the patient’s
home supplies, if available.
Clinicians who are treating COVID-19 in people with HIV should consult an HIV specialist before
adjusting or switching a patient’s ARV medications. An ARV regimen should not be switched
or adjusted (i.e., by adding ARV drugs to the regimen) for the purpose of preventing or treating
SARS-CoV-2 infection (AIII). Many drugs, including some ARV agents (e.g., lopinavir/ritonavir,
boosted darunavir, tenofovir disoproxil fumarate/emtricitabine), have been or are being evaluated in
clinical trials or are prescribed off-label to treat or prevent SARS-CoV-2 infection. To date, lopinavir/
ritonavir and darunavir/cobicistat have not been found to be effective (see Lopinavir/Ritonavir and
Other HIV Protease Inhibitors).33,34 Two retrospective studies have suggested that tenofovir disoproxil
fumarate/emtricitabine may play a role in preventing SARS-CoV-2 acquisition or hospitalization or
death associated with COVID-19; however, the significance of these findings is unclear, as neither study
adequately controlled for confounding variables such as age and comorbidities.12,32
For patients who are taking an investigational ARV medication as part of their ARV regimen,
arrangements should be made with the investigational study team to continue the medication, if possible.
For critically ill patients who require tube feeding, some ARV medications are available in liquid
formulations, and some ARV pills may be crushed. Clinicians should consult an HIV specialist and/
or pharmacist to assess the best way to continue an effective ARV regimen for a patient with a feeding
tube. Information may be available in the drug product label or in this document from Toronto General

Hospital.
For people who present with COVID-19 and have either a new diagnosis of HIV or a history of HIV
but are not taking ART, the optimal time to start or restart ART is currently unknown. For people with
HIV who have not initiated ART or who have been off therapy for >2 weeks before presenting with
COVID-19, the Panel recommends consulting an HIV specialist about initiating or reinitiating ART as
soon as clinically feasible. If ART is initiated, maintaining treatment and linking patients to HIV care
upon hospital discharge is critical. If an HIV specialist is not available, clinical consultation is available
by phone through the National Clinician Consultation Center, Monday through Friday, 9 am to 8 pm EST.
References
1. Harris NS, Johnson AS, Huang YA, et al. Vital signs: status of human immunodeficiency virus testing, viral
suppression, and HIV preexposure prophylaxis—United States, 2013-2018. MMWR Morb Mortal Wkly Rep.
2. Meyerowitz EA, Kim AY, Ard KL, et al. Disproportionate burden of coronavirus disease 2019 among racial
minorities and those in congregate settings among a large cohort of people with HIV. AIDS. 2020;34(12):1781-
3. Centers for Disease Control and Prevention. COVID-19 information for specific groups of people. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html. Accessed January
24, 2022.
4. Gervasoni C, Meraviglia P, Riva A, et al. Clinical features and outcomes of patients with human
immunodeficiency virus with COVID-19. Clin Infect Dis. 2020;71(16):2276-2278. Available at:
5. Harter G, Spinner CD, Roider J, et al. COVID-19 in people living with human immunodeficiency virus: a case
series of 33 patients. Infection. 2020;48(5):681-686. Available at:
6. Karmen-Tuohy S, Carlucci PM, Zervou FN, et al. Outcomes among HIV-positive patients hospitalized with
COVID-19. J Acquir Immune Defic Syndr. 2020;85(1):6-10. Available at:
7. Patel VV, Felsen UR, Fisher M, et al. Clinical outcomes and inflammatory markers by HIV serostatus and
viral suppression in a large cohort of patients hospitalized with COVID-19. J Acquir Immune Defic Syndr.
8. Shalev N, Scherer M, LaSota ED, et al. Clinical characteristics and outcomes in people living with human
immunodeficiency virus hospitalized for coronavirus disease 2019. Clin Infect Dis. 2020;71(16):2294-2297.
9. Sigel K, Swartz T, Golden E, et al. Coronavirus 2019 and people living with human immunodeficiency virus:
outcomes for hospitalized patients in New York City. Clin Infect Dis. 2020;71(11):2933-2938. Available at:
10. Stoeckle K, Johnston CD, Jannat-Khah DP, et al. COVID-19 in hospitalized adults with HIV. Open Forum
Infect Dis. 2020;7(8):ofaa327. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32864388.
11. Vizcarra P, Perez-Elias MJ, Quereda C, et al. Description of COVID-19 in HIV-infected individuals: a single-
centre, prospective cohort. Lancet HIV. 2020;7(8):e554-e564. Available at:
12. Western Cape Department of Health in collaboration with the National Institute for Communicable Diseases,
South Africa. Risk factors for coronavirus disease 2019 (COVID-19) death in a population cohort study from
the Western Cape Province, South Africa. Clin Infect Dis. 2021;73(7):e2005-e2015. Available at:

13. Bhaskaran K, Rentsch CT, MacKenna B, et al. HIV infection and COVID-19 death: a population-based cohort
analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
Lancet HIV. 2021;8(1):e24-e32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33316211.
14. Geretti AM, Stockdale AJ, Kelly SH, et al. Outcomes of coronavirus disease 2019 (COVID-19) related
hospitalization among people with human immunodeficiency virus (HIV) in the ISARIC World Health
Organization (WHO) clinical characterization protocol (UK): a prospective observational study. Clin Infect
Dis. 2021;73(7):e2095-e2106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33095853.
15. Dandachi D, Geiger G, Montgomery MW, et al. Characteristics, comorbidities, and outcomes in a multicenter
registry of patients with human immunodeficiency virus and coronavirus disease 2019. Clin Infect Dis.
16. Hoffmann C, Casado JL, Harter G, et al. Immune deficiency is a risk factor for severe COVID-19 in
people living with HIV. HIV Med. 2021;22(5):372-378. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33368966.
17. Tesoriero JM, Swain CE, Pierce JL, et al. COVID-19 outcomes among persons living with or without
diagnosed HIV infection in New York State. JAMA Netw Open. 2021;4(2):e2037069. Available at:
18. Sun J, Patel RC, Zheng Q, et al. COVID-19 disease severity among people with HIV infection or solid organ
transplant in the United States: a nationally-representative, multicenter, observational cohort study. medRxiv.
2021;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34341798.
19. Bertagnolio S, Thwin SS, Silva R, et al. Clinical characteristics and prognostic factors in people living
with HIV hospitalized with COVID-19: findings from the WHO Global Clinical Platform. Presented
at: International AIDS Society. 2021. Virtual. Available at: https://theprogramme.ias2021.org/Abstract/
Abstract/2498.
22. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination
providers): emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus
disease 2019 (COVID-19). 2022. Available at: https://www.fda.gov/media/146304/download.
23. Levy I, Wieder-Finesod A, Litchevsky V, et al. Immunogenicity and safety of the BNT162b2 mRNA
COVID-19 vaccine in people living with HIV-1. Clin Microbiol Infect. 2021;27(12):1851-1855. Available at:
24. Woldemeskel BA, Karaba AH, Garliss CC, et al. The BNT162b2 mRNA vaccine elicits robust humoral and
cellular immune responses in people living with HIV. Clin Infect Dis. 2021;Published online ahead of print.
25. Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine
against SARS-CoV-2 in HIV infection: a single-arm substudy of a Phase 2/3 clinical trial. Lancet HIV.
26. Tan SS, Chew KL, Saw S, Jureen R, Sethi S. Cross-reactivity of SARS-CoV-2 with HIV chemiluminescent
assay leading to false-positive results. J Clin Pathol. 2021;74(9):614. Available at:
27. Blanco JL, Ambrosioni J, Garcia F, et al. COVID-19 in patients with HIV: clinical case series. Lancet HIV.
28. Coleman H, Snell LB, Simons R, Douthwaite ST, Lee MJ. Coronavirus disease 2019 and Pneumocystis
jirovecii pneumonia: a diagnostic dilemma in HIV. AIDS. 2020;34(8):1258-1260. Available at:

29. Centers for Disease Control and Prevention. HIV surveillance report: estimated HIV incidence and prevalence
in the United States 2014–2018. 2020. Available at: https://www.cdc.gov/hiv/pdf/library/reports/surveillance/
cdc-hiv-surveillance-supplemental-report-vol-25-1.pdf.
30. Kong AM, Pozen A, Anastos K, Kelvin EA, Nash D. Non-HIV comorbid conditions and polypharmacy among
people living with HIV age 65 or older compared with HIV-negative individuals age 65 or older in the United
States: a retrospective claims-based analysis. AIDS Patient Care STDS. 2019;33(3):93-103. Available at:
31. Byrd KM, Beckwith CG, Garland JM, et al. SARS-CoV-2 and HIV coinfection: clinical experience from
Rhode Island, United States. J Int AIDS Soc. 2020;23(7):e25573. Available at:
32. Del Amo J, Polo R, Moreno S, et al. Incidence and severity of COVID-19 in HIV-positive persons receiving
antiretroviral therapy: a cohort study. Ann Intern Med. 2020;173(7):536-541. Available at:
33. Recovery Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19
34. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19.
Open Forum Infect Dis. 2020;7(7):ofaa241. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32671131.

Influenza and COVID-19
Last Updated: October 27, 2021
Influenza Vaccination
• People with acute COVID-19 should receive an inactivated influenza vaccine (BIII). For more information on
administering influenza vaccines to these patients, see Interim Guidance for Routine and Influenza Immunization
Services During the COVID-19 Pandemic from the Centers for Disease Control and Prevention (CDC).
• Clinicians should consider deferring influenza vaccination for symptomatic COVID-19 patients until these patients
have completed their COVID-19 isolation period and are no longer moderately or severely ill.
• People with SARS-CoV-2 infection who are not moderately or severely ill (including those who are asymptomatic)
should seek influenza vaccination when they no longer require isolation. They can be vaccinated sooner if they are
in a health care setting for other reasons.
• An influenza vaccine and a COVID-19 vaccine may be administered concurrently at different injection sites (see the
recommendations from CDC and the Advisory Committee on Immunization Practices).
Diagnosis of Influenza and COVID-19 When Influenza Viruses and SARS-CoV-2 Are Cocirculating
• Only testing can distinguish between SARS-CoV-2 and influenza virus infections and identify SARS-CoV-2 and
influenza virus coinfection.
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends testing for both viruses in all hospitalized patients
with acute respiratory illness (AIII).
• The Panel recommends influenza testing in addition to SARS-CoV-2 testing in outpatients with acute respiratory
illness if the results will change the clinical management strategy for the patient (e.g., administering antiviral
treatment for influenza) (BIII).
• Clinicians should consider testing patients for other pathogens based on their specific clinical circumstances.
Additional testing is especially important for patients with influenza who have a high risk of acquiring bacterial
superinfections.
• See the CDC Information for Clinicians on Influenza Virus Testing and the Infectious Diseases Society of America
(IDSA) Clinical Practice Guidelines for more information.
Antiviral Treatment of Influenza When Influenza Viruses and SARS-CoV-2 Are Cocirculating
• Antiviral treatment of influenza is the same in all patients with or without SARS-CoV-2 coinfection (AIII).
• For information on using antiviral drugs to treat influenza in hospitalized and nonhospitalized patients, see the CDC
and IDSA recommendations.
• The Panel recommends that hospitalized patients with suspected influenza be started on empiric treatment for
influenza with oseltamivir as soon as possible and without waiting for influenza test results (AIIb).
• Antiviral treatment for influenza can be stopped when influenza has been ruled out by the results of a nucleic
acid detection assay in upper respiratory tract specimens for nonintubated patients and in both upper and lower
respiratory tract specimens for intubated patients.
Introduction
Influenza activity in the United States during the 2021 to 2022 influenza season is difficult to predict, and
activity may vary depending on location and the measures taken by individual communities to mitigate
the spread of SARS-CoV-2.1 Influenza activity worldwide has been very low since the early spring of

2020, including in the United States during the 2020 to 2021 season.2,3 Clinicians should monitor local
influenza and SARS-CoV-2 activities during influenza season to inform the evaluation and management
of patients with acute respiratory illness. This can be done by tracking local and state public health
surveillance data, assessing the results of testing performed at health care facilities, and reviewing the
Centers for Disease Control and Prevention (CDC) Weekly U.S. Influenza Surveillance Report.
Influenza Vaccination
For Patients With Acute COVID-19 or Those Who Are Recovering From COVID-19
The Advisory Committee on Immunization Practices (ACIP) recommends offering an influenza vaccine
to all persons aged ≥6 months in the United States by the end of October.4 People with acute COVID-19
should receive an inactivated influenza vaccine (BIII).
There are currently no available data on the safety, immunogenicity, or efficacy of influenza vaccines
in patients with mild COVID-19 or those who are recovering from COVID-19. Therefore, the optimal
timing for influenza vaccination in these patients is unknown. The safety and efficacy of vaccinating
persons who have mild illnesses from other etiologies have been documented.5 Clinicians should consider
deferring influenza vaccination for symptomatic COVID-19 patients until these patients have completed
their COVID-19 isolation period and are no longer moderately or severely ill. People with SARS-CoV-2
infection who are not moderately or severely ill (including those who are asymptomatic) should seek
influenza vaccination when they no longer require isolation. They can be vaccinated sooner if they are
in a health care setting for other reasons (see Interim Guidance for Routine and Influenza Immunization
Services During the COVID-19 Pandemic from CDC for more detailed recommendations).
It is not known whether administering dexamethasone or other immunomodulatory therapies to patients
with severe COVID-19 will affect the immune response to an influenza vaccine. Nevertheless, as long as
influenza viruses are circulating, people with COVID-19 should receive an influenza vaccine once they
have substantially improved or recovered from COVID-19. See the influenza vaccine recommendations
from CDC, ACIP, and the American Academy of Pediatrics.
Coadministration of COVID-19 Vaccines and Influenza Vaccines

Although there are currently no data on the coadministration of COVID-19 vaccines and influenza
vaccines, these vaccines may be administered concurrently at different injection sites. Providers and
patients should be aware of the potential for increased reactogenicity when administering both vaccines
concurrently (see the recommendations from CDC and ACIP).
Clinical Presentation of Influenza Versus COVID-19

The signs and symptoms of uncomplicated, clinically mild influenza overlap with those of mild
COVID-19. Ageusia and anosmia can occur with both diseases, but these symptoms are more
common with COVID-19 than with influenza. Fever is not always present in patients with either
disease, particularly in patients who are immunosuppressed or elderly. Complications of influenza and
COVID-19 can be similar, but the onset of influenza complications and severe disease typically occurs
within a week of illness onset whereas the onset of severe COVID-19 usually occurs in the second week
of illness. Because of the overlap in signs and symptoms, when SARS-CoV-2 and influenza viruses are
cocirculating, diagnostic testing for both viruses is needed to distinguish between SARS-CoV-2 and
influenza virus and to identify coinfection in people with an acute respiratory illness. Coinfection with
influenza and SARS-CoV-2 has been described in case reports and case series.6-10

Testing for SARS-CoV-2 and Influenza
When influenza viruses and SARS-CoV-2 are cocirculating in the community, SARS-CoV-2 testing
and influenza testing should be performed in all patients who are hospitalized with an acute respiratory
illness (see Testing for SARS-CoV-2 Infection) (AIII). SARS-CoV-2 testing should also be performed in
outpatients with suspected COVID-19, and influenza testing can be considered if the results will change
the clinical management strategy for the patient (e.g., administering antiviral treatment for influenza)
(BIII). Several multiplex molecular assays and multiplex antigen assays that detect SARS-CoV-2 and
influenza A and B viruses have received Food and Drug Administration Emergency Use Authorizations
or De Novo classifications and can provide results in 15 minutes to 8 hours using a single respiratory
specimen.11,12 For more information, see the CDC Information for Clinicians on Influenza Virus Testing
and the recommendations from the Infectious Diseases Society of America (IDSA) on the use of
influenza tests and the interpretation of testing results.13
Treating Influenza With Antiviral Agents

Antiviral treatment for influenza is the same for all patients regardless of SARS-CoV-2 coinfection
(AIII). When SARS-CoV-2 and influenza viruses are cocirculating in the community, patients who
require hospitalization and are suspected of having either or both viral infections should receive
influenza antiviral treatment with oseltamivir as soon as possible and without waiting for influenza
testing results (AIIb). Oseltamivir has no activity against SARS-CoV-214 or known interactions with
remdesivir or other therapeutics for COVID-19. The standard dose of oseltamivir is well absorbed even
in critically ill patients. For patients who cannot tolerate oral or enterically administered oseltamivir
(e.g., because of gastric stasis, malabsorption, or gastrointestinal bleeding), intravenous peramivir
is an option.13 There are no data on peramivir activity against SARS-CoV-2. See the CDC Influenza
Antiviral Medications: Summary for Clinicians for clinical algorithms for using antiviral agents in
patients with suspected or laboratory-confirmed influenza, including pregnant people and other people
who are at high risk for influenza complications. The IDSA Clinical Practice Guidelines also provide
recommendations on using antiviral agents to treat influenza, and the American Academy of Pediatrics
provides recommendations on the antiviral treatment of influenza in children.
When the result of an influenza nucleic acid detection assay from an upper respiratory tract specimen is
negative in a patient who is receiving antiviral treatment for influenza:
• In a patient who is not intubated: Antiviral treatment for influenza can be stopped.
• In a patient who is intubated: Antiviral treatment for influenza should be continued, and if a lower
respiratory tract specimen (e.g., endotracheal aspirate) can be safely obtained, it should be tested
using an influenza nucleic acid detection assay. If the lower respiratory tract specimen is also
negative, influenza antiviral treatment can be stopped.
COVID-19 Treatment Considerations for Hospitalized Patients With Suspected or

Confirmed Influenza Virus Coinfection
• Corticosteroids, which are used for the treatment of patients with severe COVID-19, may prolong
influenza viral replication and viral RNA detection and may be associated with poor outcomes
for influenza.13,15 Currently, no data are available on the use of corticosteroids in patients with
SARS-CoV-2 and influenza virus coinfection. However, because dexamethasone has demonstrated
substantial benefits for patients with COVID-19 who require supplemental oxygen, the benefits of
using corticosteroids in patients with severe SARS-CoV-2 and influenza virus coinfection likely
outweigh any potential harms.

• Remdesivir does not have activity against influenza viruses. There are no known drug interactions
between remdesivir and oseltamivir. Therefore, remdesivir may be used safely when indicated
in patients with COVID-19 and suspected or laboratory-confirmed influenza who are receiving
oseltamivir treatment.
• Although severe influenza may be associated with a dysregulated innate immune response, there
are no data on the use of immunomodulatory therapies, such as interleukin-6 inhibitors (e.g.,
tocilizumab, sarilumab) or Janus Kinase inhibitors (e.g., baricitinib, tofacitinib), for the treatment
of severe influenza. There are also no data on the effect these therapies may have on influenza
viral replication. Because these immunomodulators have demonstrated a clinical benefit in certain
COVID-19 patients, clinicians should consider engaging in a shared decision-making process
on use of these drugs with patients who have been diagnosed with COVID-19 and who have
suspected or laboratory-confirmed influenza.
• The co-occurrence of community-acquired secondary bacterial pneumonia and COVID-19
appears to be infrequent and may be more common in people who also have influenza; however,
this inference is based on limited data.16-18 Typical bacterial causes of community-acquired
pneumonia with severe influenza are Staphylococcus aureus (methicillin-resistant S. aureus
[MRSA] and methicillin-susceptible S. aureus [MSSA]), Streptococcus pneumoniae, and group A
Streptococcus.13
• Patients with COVID-19 who develop new respiratory symptoms with or without fever or
respiratory distress and who do not have a clear diagnosis should be evaluated for the possibility
of nosocomial influenza.
References
1. Qi Y, Shaman J, Pei S. Quantifying the impact of COVID-19 non-pharmaceutical interventions on influenza
transmission in the United States. J Infect Dis. 2021;Published online ahead of print. Available at:
2. World Health Organization. Review of global influenza circulation, late 2019 to 2020, and the impact of
the COVID-19 pandemic on influenza circulation. Wkly Epidemiol Rec. 2021;96(25):241-264. Available at:
https://apps.who.int/iris/handle/10665/341995.
3. Olsen SJ, Winn AK, Budd AP, et al. Changes in influenza and other respiratory virus activity during the
COVID-19 pandemic—United States, 2020–2021. MMWR Morb Mortal Wkly Rep. 2021;70(29):1013-1019.
4. Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines:
recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 influenza
season. MMWR Recomm Rep. 2021;70(5):1-28. Available at:
5. Centers for Disease Control and Prevention. Contraindications and precautions. General best practice
guidelines for immunization: best practices guidance of the advisory committee on immunization practices
(ACIP). 2020. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/contraindications.html.
Accessed October 16, 2021.
6. Hashemi SA, Safamanesh S, Ghasemzadeh-Moghaddam H, Ghafouri M, Azimian A. High prevalence of
SARS-CoV-2 and influenza A virus (H1N1) coinfection in dead patients in Northeastern Iran. J Med Virol.
7. Huang BR, Lin YL, Wan CK, et al. Co-infection of influenza B virus and SARS-CoV-2: a case report from
Taiwan. J Microbiol Immunol Infect. 2021;54(2):336-338. Available at:
8. Yue H, Zhang M, Xing L, et al. The epidemiology and clinical characteristics of co-infection of SARS-CoV-2

and influenza viruses in patients during COVID-19 outbreak. J Med Virol. 2020;92(11):2870-2873. Available
9. Cuadrado-Payan E, Montagud-Marrahi E, Torres-Elorza M, et al. SARS-CoV-2 and influenza virus co-
infection. Lancet. 2020;395(10236):e84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32423586.
10. Wu X, Cai Y, Huang X, et al. Co-infection with SARS-CoV-2 and influenza A virus in patient with
pneumonia, China. Emerg Infect Dis. 2020;26(6):1324-1326. Available at:
11. Food and Drug Administration. In vitro diagnostic EUAs—molecular diagnostic tests for SARS-CoV-2.
2021. Available at: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-
authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2. Accessed
October 21, 2021.
12. Food and Drug Administration. In vitro diagnostic EUAs—antigen diagnostic tests for SARS-CoV-2. 2021.
Available at: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-
authorizations-medical-devices/in-vitro-diagnostics-euas-antigen-diagnostic-tests-sars-cov-2. Accessed
October 21, 2021.
13. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of
America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of
seasonal influenza. Clin Infect Dis. 2019;68(6):e1-e47. Available at:
14. Choy KT, Wong AY, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit
SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786. Available at:
15. Zhou Y, Fu X, Liu X, et al. Use of corticosteroids in influenza-associated acute respiratory distress syndrome
and severe pneumonia: a systemic review and meta-analysis. Sci Rep. 2020;10(1):3044. Available at:
16. Vaughn VM, Gandhi T, Petty LA, et al. Empiric antibacterial therapy and community-onset bacterial
co-infection in patients hospitalized with COVID-19: a multi-hospital cohort study. Clin Infect Dis.
17. Adler H, Ball R, Fisher M, Mortimer K, Vardhan MS. Low rate of bacterial co-infection in patients with
COVID-19. Lancet Microbe. 2020;1(2):e62. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32835331.
18. Russell CD, Fairfield CJ, Drake TM, et al. Co-infections, secondary infections, and antimicrobial use in
patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study:
a multicentre, prospective cohort study. Lancet Microbe. 2021;2(8):e354-e365. Available at:

Special Considerations in Pregnancy
Key Considerations
There is current guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and
Gynecologists, and the Society for Maternal-Fetal Medicine on the management of pregnant patients with COVID-19. This
section of the COVID-19 Treatment Guidelines complements that guidance. The following are key considerations regarding
the management of COVID-19 in pregnancy:
• Pregnant people should be counseled about the increased risk for severe disease from SARS-CoV-2 infection and
receive recommendations on ways to protect themselves and their families from infection.
• If hospitalization for COVID-19 is indicated for a pregnant patient, care should be provided in a facility that can
conduct maternal and fetal monitoring, when appropriate.
• Management of COVID-19 in pregnant patients should include:
• Fetal and uterine contraction monitoring based on gestational age, when appropriate
• Individualized delivery planning
• A multispecialty, team-based approach that may include consultation with obstetric, maternal-fetal medicine,
infectious disease, pulmonary-critical care, and pediatric specialists, as appropriate
• In general, the therapeutic management of pregnant patients with COVID-19 should be the same as for
nonpregnant patients. The COVID-19 Treatment Guidelines Panel recommends against withholding treatment
for COVID-19 and SARS-CoV-2 vaccination from pregnant or lactating individuals because of theoretical safety
concerns (AIII). For details regarding therapeutic recommendations and pregnancy considerations, see General
Management of Nonhospitalized Patients With Acute COVID-19 and the individual drug sections.
• Pregnant or lactating patients with COVID-19 and their clinical teams should discuss the use of investigational drugs
or drugs that are approved for other indications as treatments for COVID-19. During this shared decision-making
process, the patient and the clinical team should consider the safety of the medication for the pregnant or lactating
individual and the fetus and the severity of maternal disease. For detailed guidance on using COVID-19 therapeutic
agents during pregnancy, please refer to the pregnancy considerations subsections found in the Antiviral Therapy and
Immunomodulators sections of these Guidelines.
• The decision to feed the infant breast milk while the patient is receiving therapeutic agents for COVID-19 should
be a collaborative effort between the patient and the clinical team, including infant care providers. The patient and
the clinical team should discuss the potential benefits of the therapeutic agent and evaluate the potential impact of
pausing lactation on the future of breast milk delivery to the infant.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak 

Epidemiology of COVID-19 in Pregnancy

Early in the pandemic, reports of COVID-19 disease acquired during pregnancy were limited to case
series or studies that did not compare pregnant patients to age-matched, nonpregnant controls, and these
reports were largely reassuring. Subsequent data have indicated that while the overall risk of severe
illness is low, COVID-19 is associated with more severe disease in pregnant people than in nonpregnant
people.1 There is also an increased risk of poor obstetric outcomes among pregnant people with
COVID-19, such as preterm birth.2,3
In November 2020, the Centers for Disease Control and Prevention (CDC) released surveillance data on
outcomes in approximately 400,000 reproductive-aged women with symptomatic, laboratory-confirmed

COVID-19.1 After adjusting for age, race/ethnicity, and underlying medical conditions, pregnant women
had significantly higher rates of intensive care unit (ICU) admission (10.5 vs. 3.9 cases per 1,000
cases; adjusted risk ratio [aRR] 3.0; 95% CI, 2.6–3.4), mechanical ventilation (2.9 vs. 1.1 cases per
1,000 cases; aRR 2.9; 95% CI, 2.2–3.8), extracorporeal membrane oxygenation (0.7 vs. 0.3 cases per
1,000 cases; aRR 2.4; 95% CI, 1.5–4.0), and death (1.5 vs. 1.2 cases per 1,000 cases; aRR 1.7; 95% CI,
1.2–2.4). The increased risk for severe disease was most significant in women aged 35 to 44 years, who
were almost four times as likely to be mechanically ventilated and twice as likely to die as nonpregnant
women of the same age.
Notably, among Hispanic women, pregnancy was associated with a risk of death that was 2.4 times
higher (95% CI, 1.3–4.3) than the risk observed in nonpregnant Hispanic women. Racial and ethnic
disparities were also seen in other reports. Among 8,207 pregnant women with COVID-19 who were
reported to CDC, the proportion of those who were reported to be Hispanic (46%) and Black (22%)
was higher than the proportion of Hispanic and Black women who gave birth in 2019 (24% and 15%,
respectively), suggesting that pregnant people who are Hispanic or Black may be disproportionately
affected by SARS-CoV-2 infection.4
In an ongoing systematic review that includes 192 studies to date, maternal factors that were associated
with severe disease included increased maternal age (OR 1.83; 95% CI, 1.27–2.63; 3,561 women from 7
studies); a high body mass index (OR 2.37; 95% CI, 1.83–3.07; 3,367 women from 5 studies); any pre-
existing maternal comorbidity, including chronic hypertension and diabetes (OR 1.81; 95% CI, 1.49–2.20;
2,634 women from 3 studies); pre-eclampsia (OR 4.21; 95% CI, 1.27–14.0; 274 women from 4 studies);
and pre-existing diabetes (OR 2.12; 95% CI, 1.62–2.78; 3,333 women from 3 studies).5 Compared with
pregnant women and recently pregnant women without COVID-19, pregnant women with COVID-19
were at a higher risk of any instance of preterm birth (OR 1.47; 95% CI, 1.14–1.91; 8,549 women from
18 studies) and stillbirth (OR 2.84; 95% CI, 1.25–6.45; 5,794 women from 9 studies).
An observational cohort study of all pregnant patients at 33 U.S. hospitals with a singleton gestation and
a positive result on a SARS-CoV-2 virologic test evaluated maternal characteristics and outcomes across
disease severity.6 The data suggested that adverse perinatal outcomes were more common in patients
with severe or critical disease than in asymptomatic patients with SARS-CoV-2 infection, including an
increased incidence of cesarean delivery (59.6% vs. 34.0% of patients; aRR 1.57; 95% CI, 1.30–1.90),
hypertensive disorders of pregnancy (40.4% vs. 18.8%; aRR 1.61; 95% CI, 1.18–2.20), and preterm
birth (41.8% vs. 11.9%; aRR 3.53; 95% CI, 2.42–5.14). The perinatal outcomes for those with mild
to moderate illness were similar to those observed among asymptomatic patients with SARS-CoV-2
infection.
Although vertical transmission of SARS-CoV-2 is possible, current data suggest that it is rare.7 A review
of 101 infants born to 100 women with SARS-CoV-2 infection at a single U.S. academic medical center
found that 2 infants (2%) had indeterminate SARS-CoV-2 polymerase chain reaction (PCR) results,
which were presumed to be positive; however, the infants exhibited no evidence of clinical disease. It is
reassuring that the majority of the infants received negative PCR results after rooming with their mothers
and breastfeeding directly (the mothers in this study practiced appropriate hand and breast hygiene).
Managing COVID-19 in Pregnancy

Pregnant people should be counseled about the increased risk for severe disease from SARS-CoV-2
and the measures they can take to protect themselves and their families from infection. These measures
include practicing physical distancing, washing their hands regularly, and wearing a face covering (if
indicated). If the patient is not vaccinated, they should be counseled about wearing a face covering
and getting vaccinated against SARS-CoV-2 infection. CDC, the American College of Obstetricians

and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine highlight the importance
of accessing prenatal care. ACOG provides a list of frequently asked questions on using telehealth to
deliver antenatal care, when appropriate.
ACOG has developed an algorithm to evaluate and manage pregnant outpatients with suspected or
laboratory-confirmed SARS-CoV-2 infection. As in nonpregnant patients, SARS-CoV-2 infection in
pregnant patients can present as asymptomatic/presymptomatic disease or with a wide range of clinical
manifestations, from mild symptoms that can be managed with supportive care at home to severe disease
and respiratory failure that requires ICU admission. As in other patients, the illness severity, underlying
comorbidities, and clinical status of pregnant patients with symptoms that are compatible with COVID-19
should be assessed to determine whether in-person evaluation for potential hospitalization is needed.
If hospitalization is indicated, care should be provided in a facility that can conduct maternal and fetal
monitoring, when appropriate. The management of COVID-19 in the pregnant patient may include:
• Fetal and uterine contraction monitoring based on gestational age, when appropriate
• Individualized delivery planning
• A multispecialty, team-based approach that may include consultation with obstetric, maternal-fetal
medicine, infectious disease, pulmonary-critical care, and pediatric specialists, as appropriate.
In general, the recommendations for managing COVID-19 in nonpregnant patients also apply to
pregnant patients.
Therapeutic Management of COVID-19 in the Setting of Pregnancy

Potentially effective treatments for COVID-19 should not be withheld from pregnant people because of
theoretical concerns related to the safety of using those therapeutic agents in pregnancy (AIII).
Pregnant or lactating patients with COVID-19 and their clinical teams should discuss the use of
investigational drugs or drugs that are approved for other indications as treatments for COVID-19.
During this shared decision-making process, the patient and the clinical team should consider the safety
of the medication for the pregnant or lactating individual and the fetus and the severity of maternal
disease. For detailed guidance on the use of COVID-19 therapeutic agents during pregnancy, please
refer to the pregnancy considerations subsections found in the Antiviral Therapy and Immunomodulators
sections of these Guidelines.
The use of anti-SARS-CoV-2 monoclonal antibodies can be considered in pregnant people with
COVID-19, especially in those who have additional risk factors for severe disease. There is no
pregnancy-specific data on the use of monoclonal antibodies; however, other immunoglobulin G
products have been safely used in pregnancy when their use is indicated. Therefore, these products
should not be withheld in the setting of pregnancy.
To date, most SARS-CoV-2-related clinical trials have excluded individuals who are pregnant and
lactating; in cases where lactating and pregnant individuals have been included in studies, only a small
number have been enrolled. This limitation makes it difficult to make evidence-based recommendations
on the use of SARS-CoV-2 therapies in these vulnerable patients and potentially limits their COVID-19
treatment options. When possible, pregnant and lactating individuals should not be excluded from
clinical trials of therapeutic agents or vaccines for SARS-CoV-2 infection.
Timing of Delivery
ACOG provides detailed guidance on the timing of delivery and the risk of vertical transmission of

SARS-CoV-2.
In most cases, the timing of delivery should be dictated by obstetric indications rather than maternal
diagnosis of COVID-19. For women who had suspected or confirmed COVID-19 early in pregnancy
who recover, no alteration to the usual timing of delivery is indicated.
Post-Delivery
The majority of studies have not demonstrated the presence of SARS-CoV-2 in breast milk; therefore,
breastfeeding is not contraindicated for people with laboratory-confirmed or suspected SARS-CoV-2
infection.8 Precautions should be taken to avoid transmission to the infant, including practicing good
hand hygiene, wearing face coverings, and performing proper pump cleaning before and after breast
milk expression.
The decision to feed the infant breast milk while the patient is receiving therapeutic agents for
COVID-19 should be a joint effort between the patient and the clinical team, including infant care
providers. The patient and the clinical team should discuss the potential benefits of the therapeutic agent
and evaluate the potential impact of pausing lactation on the future of breast milk delivery to the infant.
Specific guidance on the post-delivery management of infants born to mothers with known or suspected
SARS-CoV-2 infection, including breastfeeding recommendations, is provided by CDC and the
American Academy of Pediatrics, as well as the Special Considerations in Children section in these
Guidelines.
SARS-CoV-2 Vaccine in Pregnancy

A study that used data from three vaccine safety reporting systems in the United States reported that
the frequency of adverse events among 35,691 vaccine recipients who identified as pregnant was
similar to the frequency observed among nonpregnant patients. Local injection site pain, nausea, and
vomiting were reported slightly more frequently in pregnant people than in nonpregnant people. Other
systemic reactions were reported more frequently among nonpregnant vaccine recipients, but the overall
reactogenicity profile was similar for pregnant and nonpregnant patients. Surveillance data from 3,958
pregnant patients who were enrolled in CDC’s v-safe Vaccine Pregnancy Registry showed that, among
827 people who completed their pregnancies, there were no obvious safety signals among obstetric
or neonatal outcomes when rates of pregnancy loss (spontaneous abortion or stillbirth), preterm birth,
congenital anomalies, infants who were small for gestational age, and neonatal death were compared
to historic incidences in the peer-reviewed literature.9 ACOG has published practice guidance on using
COVID-19 vaccines in pregnant and lactating people, including a guide to assist clinicians during risk
and benefit conversations with pregnant patients.
References
2. Ko JY, DeSisto CL, Simeone RM, et al. Adverse pregnancy outcomes, maternal complications, and severe
illness among U.S. delivery hospitalizations with and without a COVID-19 diagnosis. Clin Infect Dis.
3. Woodworth KR, Olsen EO, Neelam V, et al. Birth and infant outcomes following laboratory-confirmed
SARS-CoV-2 infection in pregnancy—SET-NET, 16 jurisdictions, March 29–October 14, 2020. MMWR Morb

4. Ellington S, Strid P, Tong VT, et al. Characteristics of women of reproductive age with laboratory-confirmed
SARS-CoV-2 infection by pregnancy status—United States, January 22–June 7, 2020. MMWR Morb Mortal
5. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal
outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ.
6. Metz TD, Clifton RG, Hughes BL, et al. Disease severity and perinatal outcomes of pregnant patients with
coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2021;137(4):571-580. Available at:
7. Dumitriu D, Emeruwa UN, Hanft E, et al. Outcomes of neonates born to mothers with severe acute
respiratory syndrome coronavirus 2 infection at a large medical center in New York City. JAMA Pediatr.
gyns-obstetrics. Accessed February 8, 2021.
9. Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary findings of mRNA COVID-19 vaccine safety in
pregnant persons. N Engl J Med. 2021;384(24):2273-2282. Available at:

Appendix A, Table 1. COVID-19 Treatment
Guidelines Panel Members
Name Affiliation
Co-Chairs
Roy M. Gulick, MD, MPH Weill Cornell Medicine, New York, NY
H. Clifford Lane, MD National Institutes of Health, Bethesda, MD
Henry Masur, MD National Institutes of Health, Bethesda, MD
Executive Secretary
Alice K. Pau, PharmD National Institutes of Health, Bethesda, MD
Members
Judith Aberg, MD Icahn School of Medicine at Mount Sinai, New York, NY
Adaora Adimora, MD, MPH University of North Carolina School of Medicine, Chapel Hill, NC
Jason Baker, MD, MS Hennepin Healthcare/University of Minnesota, Minneapolis, MN
Lisa Baumann Kreuziger, MD, MS Versiti/Medical College of Wisconsin, Milwaukee, WI
Roger Bedimo, MD, MS University of Texas Southwestern/Veterans Affairs North Texas Health Care System,
Dallas, TX
Pamela S. Belperio, PharmD Department of Veterans Affairs, Los Angeles, CA
Anoopindar Bhalla, MD Children’s Hospital Los Angeles/University of Southern California, Los Angeles, CA
Stephen V. Cantrill, MD Denver Health, Denver, CO
Kathleen Chiotos, MD, MSCE Children’s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA
Craig Coopersmith, MD Emory University School of Medicine, Atlanta, GA
Eric Daar, MD Harbor-UCLA Medical Center, Torrance, CA
Amy L. Dzierba, PharmD New York-Presbyterian Hospital, New York, NY
Gregory Eschenauer, PharmD University of Michigan, Ann Arbor, MI
Laura Evans, MD, MSc University of Washington, Seattle, WA
John J. Gallagher, DNP, RN University of Pittsburgh Medical Center, Pittsburgh, PA
Rajesh Gandhi, MD Massachusetts General Hospital/Harvard Medical School, Boston, MA
David V. Glidden, PhD University of California San Francisco, San Francisco, CA
Steve Grapentine, PharmD University of California San Francisco, San Francisco, CA
Birgit Grund, PhD University of Minnesota, Minneapolis, MN
Erica J. Hardy, MD, MMSc Warren Alpert Medical School of Brown University, Providence, RI
Lauren Henderson, MD, MMSc Boston Children’s Hospital/Harvard Medical School, Boston, MA
Carl Hinkson, MSRC Providence Health & Services, Everett, WA
Brenna L. Hughes, MD, MSc Duke University School of Medicine, Durham, NC
Steven Johnson, MD University of Colorado School of Medicine, Aurora, CO
Marla J. Keller, MD Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
Arthur Kim, MD Massachusetts General Hospital/Harvard Medical School, Boston, MA
Jeffrey L. Lennox, MD Emory University School of Medicine, Atlanta, GA
Mitchell M. Levy, MD Warren Alpert Medical School of Brown University, Providence, RI
Jonathan Li, MD, MMSc Brigham and Women’s Hospital/Harvard Medical School, Boston, MA
Gregory Martin, MD, MSc Emory University School of Medicine, Atlanta, GA
Susanna Naggie, MD, MHS Duke University School of Medicine, Durham, NC

Name Affiliation
Members, continued
Andrew T. Pavia, MD University of Utah School of Medicine, Salt Lake City, UT
Grant Schulert, MD, PhD Cincinnati Children’s Hospital Medical Center/University of Cincinnati
College of Medicine, Cincinnati, OH
Nitin Seam, MD National Institutes of Health, Bethesda, MD
Steven Q. Simpson, MD University of Kansas Medical Center, Kansas City, KS
Renee Stapleton, MD, PhD University of Vermont Larner College of Medicine, Burlington, VT
Susan Swindells, MBBS University of Nebraska Medical Center, Omaha, NE
Pablo Tebas, MD University of Pennsylvania, Philadelphia, PA
Phyllis Tien, MD, MSc University of California, San Francisco/San Francisco VA Healthcare
System, San Francisco, CA
Alpana A. Waghmare, MD Seattle Children’s Hospital, Seattle, WA
Jinoos Yazdany, MD, MPH University of California, San Francisco, San Francisco, CA
Community Members
Danielle M. Campbell, MPH University of California, Los Angeles, Los Angeles, CA
Carly Harrison LupusChat, New York, NY
Pharmacology Consultants
Sarita Boyd, PharmD Food and Drug Administration, Silver Spring, MD
Jomy George, PharmD National Institutes of Health, Bethesda, MD
Kimberly Scarsi, PharmD University of Nebraska Medical Center, Omaha, NE
Ex Officio Members, U.S. Government Representatives
Timothy Burgess, MD Department of Defense, Bethesda, MD
Demetre Daskalakis, MD, MPH Centers for Disease Control and Prevention, Atlanta, GA
Derek Eisnor, MD Biomedical Advanced Research and Development Authority, Washington, DC
Joseph Francis, MD, MPH Department of Veterans Affairs, Washington, DC
Virginia Sheikh, MD, MHS Food and Drug Administration, Silver Spring, MD
Timothy M. Uyeki, MD, MPH Centers for Disease Control and Prevention, Atlanta, GA
U.S. Government Support Team
John T. Brooks, MD Centers for Disease Control and Prevention, Atlanta, GA
Richard T. Davey, Jr., MD National Institutes of Health, Bethesda, MD
Laurie K. Doepel, BA National Institutes of Health, Bethesda, MD
Alison Han, MD (Co-Team Coordinator) National Institutes of Health, Bethesda, MD
Elizabeth S. Higgs, MD, DTM&H, MIA National Institutes of Health, Bethesda, MD
Martha C. Nason, PhD (Biostatistics Support) National Institutes of Health, Bethesda, MD
Michael Proschan, PhD (Biostatistics National Institutes of Health, Bethesda, MD
Support)
Renee Ridzon, MD National Institutes of Health, Bethesda, MD
Kanal Singh, MD, MPH (Co-Team Coordinator) National Institutes of Health, Bethesda, MD
Assistant Executive Secretaries
Page Crew, PharmD, MPH National Institutes of Health, Bethesda, MD
Safia Kuriakose, PharmD Frederick National Laboratory for Cancer Research, in support of NIAID,
Frederick, MD
Andrea M. Lerner, MD, MS National Institutes of Health, Bethesda, MD

Appendix A, Table 2. COVID-19 Treatment
Guidelines Panel Financial Disclosure for Companies
Related to COVID-19 Treatment or Diagnostics
Reporting Period: April 1, 2021, to March 31, 2022 Financial Disclosure

Panel Member
Company Relationship
Judith Aberg, MD Atea Pharmaceuticals Research support
Emergent BioSolutions Research support
Gilead Sciences Research support
GSK Advisory board, research support
GSK/ViiV Healthcare Advisory board, research support
Janssen Research support
Merck & Co. Advisory board, research support
Pfizer Research support
Regeneron Research support
Adaora Adimora, MD, MPH Gilead Sciences Research support, consultant
Jason Baker, MD, MS Humanigen Research support
Lisa Baumann Kreuziger, MD, MS 3M Stockholder, spouse is an employee
Versiti Employee
Roger Bedimo, MD, MS Gilead Sciences Advisory board
GSK/ViiV Healthcare Advisory board
Janssen Advisory board
Pamela S. Belperio, PharmD None N/A
Anoopindar Bhalla, MD None N/A
John T. Brooks, MD None N/A
Timothy Burgess, MD AstraZeneca Research support
Danielle M. Campbell, MPH Gilead Sciences Advisory board
GSK/ViiV Healthcare Attendee at the community stakeholder meeting
Stephen V. Cantrill, MD None N/A
Kathleen Chiotos, MD, MSCE None N/A
Craig Coopersmith, MD None N/A
Page Crew, PharmD, MPH None N/A
Eric Daar, MD Gilead Sciences Consultant, research support
GSK/ViiV Healthcare Consultant, research support
Merck & Co. Consultant, research support
Demetre Daskalakis, MD, MPH None N/A
Richard T. Davey, Jr., MD None N/A
Laurie K. Doepel, BA None N/A
Amy L. Dzierba, PharmD None N/A
Derek Eisnor, MD None N/A

Financial Disclosure
Panel Member
Gregory Eschenauer, PharmD None N/A
Laura Evans, MD, MSc None N/A
Joseph Francis, MD, MPH None N/A
John J. Gallagher, DNP, RN None N/A
Rajesh Gandhi, MD None N/A
David V. Glidden, PhD None N/A
Steve Grapentine, PharmD None N/A
Birgit Grund, PhD None N/A
Roy M. Gulick, MD, MPH None N/A
Alison Han, MD None N/A
Erica J. Hardy, MD, MMSc None N/A
Carly Harrison AstraZeneca Advisory board, consultant
Aurinia Pharmaceuticals Advisory board, stockholder
UCB Advisory board, consultant
Lauren Henderson, MD, MMSc Adaptive Biotechnologies Consultant
Bristol Myers Squibb Research support
Pfizer External panel for grant reviews
Sobi Advisory board, consultant, research support
Skygenic Consultant, spouse is an employee
Elizabeth S. Higgs, MD, DTM&H, None N/A
MIA
Carl Hinkson, MSRC None N/A
Brenna L. Hughes, MD, MSc None N/A
Steven Johnson, MD GSK/ViiV Healthcare Advisory board
Marla J. Keller, MD None N/A
Arthur Kim, MD Kintor Pharmaceutical Data and safety monitoring board chair/member
Safia Kuriakose, PharmD None N/A
H. Clifford Lane, MD None N/A
Jeffrey L. Lennox, MD None N/A
Andrea M. Lerner, MD, MS None N/A
Mitchell M. Levy, MD None N/A
Jonathan Li, MD, MMSc None N/A
Gregory Martin, MD, MSc Genentech Data and safety monitoring board chair/member
Grifols Research grants review panel
Henry Masur, MD None N/A

Financial Disclosure
Panel Member
Susanna Naggie, MD, MHS AbbVie Research support, funding via NIH-supported
trial
Bristol Myers Squibb Event adjudication committee
FHI 360 Event adjudication committee
Pardes Biosciences Consultant
Silverback Therapeutics Consultant
Vir Biotechnology Advisory board, stockholder, stock options
Martha C. Nason, PhD None N/A
Alice K. Pau, PharmD None N/A
Andrew T. Pavia, MD GSK Advisory board
Michael Proschan, PhD None N/A
Renee Ridzon, MD None N/A
Grant Schulert, MD, PhD Novartis Honoraria
Nitin Seam, MD None N/A
Virginia Sheikh, MD, MHS None N/A
Steven Q. Simpson, MD None N/A
Kanal Singh, MD, MPH None N/A
Renee Stapleton, MD, PhD Altimmune Data and safety monitoring board chair
CSL Behring Consultant
Susan Swindells, MBBS GSK/ViiV Healthcare Research support
Pablo Tebas, MD Gilead Sciences Consultant
GSK/ViiV Healthcare Consultant
Merck & Co. Consultant
Phyllis Tien, MD, MSc Eli Lilly Research support
Merck & Co. Research support
Timothy M. Uyeki, MD, MPH None N/A
Alpana A. Waghmare, MD AlloVir Research support
Ansun Biopharma Research support
Deverra Therapeutics Data and safety monitoring board member
KYORIN Pharmaceutical Co. Advisory board
Pfizer Research support
Vir Biotechnology Research support
Jinoos Yazdany, MD, MPH AstraZeneca Consulting and research support related to lupus
Aurinia Consulting related to lupus drug
Bristol Myers Squibb Research support
Pfizer Consultant, lecture presenter

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