C Ovid 19 Treatment Guidelines

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

Treatment Guidelines
Credit NIAID-RML
Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 1/6/2022
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/).

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Table of Contents
What’s New in the Guidelines................................................................................................... 5
The COVID-19 Treatment Guidelines Panel’s Statement on Tixagevimab Plus
Cilgavimab (Evusheld) for Pre-Exposure Prophylaxis for SARS-CoV-2 Infection.................... 10
The COVID-19 Treatment Guidelines Panel’s Statement on Anticoagulation in
Hospitalized Patients With COVID-19...................................................................................... 13
The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-19................................................... 16
The COVID-19 Treatment Guidelines Panel’s Statement on Potential Drug-Drug Interactions
Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications................ 24
The COVID-19 Treatment Guidelines Panel’s Interim Statement on Patient Prioritization
for Outpatient Anti-SARS-CoV-2 Therapies or Preventive Strategies When There Are
Logistical or Supply Constraints.............................................................................................. 28
Introduction............................................................................................................................. 31
Overview of COVID-19............................................................................................................ 34
Testing for SARS-CoV-2 Infection....................................................................................... 39
Prevention of SARS-CoV-2 Infection.................................................................................. 45
Clinical Spectrum of SARS-CoV-2 Infection....................................................................... 54
Clinical Management Summary.............................................................................................. 63
General Management of Nonhospitalized Patients with Acute COVID-19......................... 66
Therapeutic Management of Nonhospitalized Adults With COVID-19............................... 73
Therapeutic Management of Hospitalized Adults With COVID-19..................................... 79
Care of Critically Ill Adult Patients With COVID-19................................................................ 92
General Considerations...................................................................................................... 94
Infection Control............................................................................................................... 102
Hemodynamics................................................................................................................. 105
Oxygenation and Ventilation............................................................................................. 109
Acute Kidney Injury and Renal Replacement Therapy..................................................... 117
Pharmacologic Interventions............................................................................................ 118
Extracorporeal Membrane Oxygenation........................................................................... 119
Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19.. 121
Remdesivir........................................................................................................................ 123
Table 2a. Remdesivir: Selected Clinical Data.............................................................. 127
Chloroquine or Hydroxychloroquine and/or Azithromycin................................................ 132
Table 2b. Chloroquine or Hydroxychloroquine and/or Azithromycin:
Selected Clinical Data ................................................................................................ 136
Interferons......................................................................................................................... 146
Table 2c. Interferons: Selected Clinical Data .............................................................. 148
COVID-19 Treatment Guidelines 2

Ivermectin......................................................................................................................... 154
Table 2d. Ivermectin: Selected Clinical Data............................................................... 159
Lopinavir/Ritonavir and Other HIV Protease Inhibitors..................................................... 168
Nitazoxanide..................................................................................................................... 173
Table 2e. Nitazoxanide: Selected Clinical Data........................................................... 175
Table 2f. Characteristics of Antiviral Agents..................................................................... 178
Anti-SARS-CoV-2 Antibody Products.................................................................................. 182
Anti-SARS-CoV-2 Monoclonal Antibodies........................................................................ 183
Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data.............. 192
Convalescent Plasma....................................................................................................... 195
Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data............................ 202
Immunoglobulins: SARS-CoV-2-Specific......................................................................... 209
Table 3c. Characteristics of SARS-CoV-2 Antibody-Based Products.............................. 210
Cell-Based Therapy Under Evaluation for the Treatment of COVID-19.............................. 214
Immunomodulators Under Evaluation for the Treatment of COVID-19.............................. 217
Colchicine......................................................................................................................... 218
Corticosteroids.................................................................................................................. 223
Table 4a. Systemic Corticosteroids: Selected Clinical Data........................................ 230
Table 4b. Inhaled Corticosteroids: Selected Clinical Data........................................... 236
Fluvoxamine...................................................................................................................... 240
Table 4c. Fluvoxamine: Selected Clinical Data............................................................ 243
Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors...................................... 246
Table 4d. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors:
Selected Clinical Data................................................................................................. 249
Immunoglobulins: Non-SARS-CoV-2-Specific................................................................. 253
Interleukin-1 Inhibitors...................................................................................................... 255
Interleukin-6 Inhibitors...................................................................................................... 261
Table 4e. Interleukin-6 Inhibitors: Selected Clinical Data............................................ 267
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s Tyrosine Kinase Inhibitors......... 274
Table 4f. Characteristics of Immunomodulators............................................................... 282
Antithrombotic Therapy in Patients with COVID-19............................................................ 294
Supplements.......................................................................................................................... 303
Vitamin C........................................................................................................................... 304
Vitamin D........................................................................................................................... 307
Zinc................................................................................................................................... 309
Considerations for Using Concomitant Medications in Patients With COVID-19.............. 313
COVID-19 and Special Populations...................................................................................... 315

Special Considerations in Pregnancy............................................................................... 316

Special Considerations in Children................................................................................... 321
Special Considerations in Adults and Children With Cancer............................................ 332
Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell
Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients............... 341
Special Considerations in People With HIV...................................................................... 349
Influenza and COVID-19................................................................................................... 356
Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Members............................. 361
Appendix A, Table 2. Panel on COVID-19 Treatment Guidelines Financial Disclosure
for Companies Related to COVID-19 Treatment or Diagnostics......................................... 363

What’s New in the Guidelines

Last Updated: January 5, 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 the Introduction for additional details on the Guidelines
development process).
Major revisions to the Guidelines within the last month are as follows:
January 5, 2022
The COVID-19 Treatment Guidelines Panel’s Statement on Tixagevimab Plus Cilgavimab
(Evusheld) for Pre-Exposure Prophylaxis for SARS-CoV-2 Infection
On December 8, 2021, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus
cilgavimab (Evusheld). The EUA allows this combination to be used as pre-exposure prophylaxis (PrEP)
in certain individuals who, if infected, are at high risk of progressing to severe COVID-19.
The Panel recommends using tixagevimab plus cilgavimab 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 (BIIa); or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a documented
history of severe reactions to a COVID-19 vaccine or any of its components (AIIa).
The statement includes a list of moderately or severely immunocompromising conditions that will
qualify an individual to receive tixagevimab plus cilgavimab as SARS-CoV-2 PrEP under the EUA. It
also includes a detailed discussion of the clinical data that support the recommendations.
The COVID-19 Treatment Guidelines Panel’s Statement on Anticoagulation in Hospitalized

Patients With COVID-19
Several randomized controlled trials have evaluated the role of therapeutic doses of heparin in reducing
venous thromboembolism or mortality in patients hospitalized for COVID-19. This statement includes
the Panel’s recommendations on the use of anticoagulation therapy in hospitalized, nonpregnant adults
with COVID-19 who are receiving supplemental oxygen. These recommendations are presented
according to whether the patient is receiving intensive care unit level of care.
The statement includes additional recommendations on the use of anticoagulation therapy in pregnant
adults with COVID-19 and discusses the clinical data supporting the Panel’s recommendations.

December 30, 2021

The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-19
The FDA recently issued EUAs that allow 2 oral antiviral agents to be used as treatments for COVID-19
in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to
serious disease: ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir. This statement contains
the Panel’s recommendations for treating these nonhospitalized patients using the currently available
therapies.
The Panel’s recommendations take into account the efficacies of these drugs and the high prevalence
of the B.1.1.529 (Omicron) variant of concern (VOC). When resources are limited, therapy should be
prioritized for patients who are at the highest risk of progressing to severe COVID-19 (see the Panel’s
statement on patient prioritization for outpatient therapies).
The Panel’s current outpatient treatment recommendations are as follows (in order of preference):
• Paxlovid (nirmatrelvir 300 mg plus ritonavir 100 mg) orally twice daily for 5 days
• Sotrovimab 500 mg administered as a single intravenous (IV) infusion
• Remdesivir 200 mg IV on Day 1 followed by remdesivir 100 mg IV on Days 2 and 3
• Molnupiravir 800 mg orally twice daily for 5 days
The statement includes additional considerations for using these treatments and a detailed discussion of
the clinical data that support the recommendations.
The COVID-19 Treatment Guidelines Panel’s Statement on Potential Drug-Drug Interactions

Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications
On December 22, 2021, the FDA issued an EUA for ritonavir-boosted nirmatrelvir (Paxlovid) for the
treatment of patients with mild to moderate COVID-19. The dose in patients with normal renal function
is nirmatrelvir 300 mg (two 150 mg tablets) plus ritonavir 100 mg (one 100 mg tablet) orally twice daily
for 5 days. Boosting with ritonavir, a strong cytochrome P450 3A4 inhibitor, is required to increase the
exposure of nirmatrelvir to a concentration that is effective against SARS-CoV-2.
This statement highlights the critical importance of evaluating a patient’s medication regimens for
potentially serious drug-drug interactions before prescribing ritonavir-boosted nirmatrelvir (Paxlovid).
The statement provides suggested resources (i.e., an EUA fact sheet and the Liverpool COVID-19 Drug
Interactions website) to identify potential drug-drug interactions between ritonavir-boosted nirmatrelvir
(Paxlovid) and concomitant medications and outlines potential strategies to manage any interactions.
The statement includes a table that lists drugs that are contraindicated or should not be coadministered
with ritonavir-boosted nirmatrelvir (Paxlovid).
December 23, 2021

The COVID-19 Treatment Guidelines Panel’s Statement on the Use of Anti-SARS-CoV-2
Monoclonal Antibodies or Remdesivir for the Treatment of COVID-19 in Nonhospitalized
Patients When Omicron Is the Predominant Circulating Variant
The Omicron VOC has become the dominant variant in many parts of the United States. Omicron
has markedly reduced susceptibility to the anti-SARS-CoV-2 mAbs bamlanivimab plus etesevimab
and casirivimab plus imdevimab. However, sotrovimab, another mAb, is expected to retain activity
against the variant. Intravenous remdesivir is approved by the FDA for the treatment of COVID-19 in

hospitalized patients. A 3-day regimen of remdesivir has been studied in nonhospitalized patients and
resulted in a significant reduction in hospitalizations and deaths compared to placebo. Remdesivir is
expected to retain activity against the Omicron VOC.
With the rapid rise in the prevalence of the Omicron VOC, it is anticipated there will be a limited supply
of therapeutic agents that are active against the variant (e.g., sotrovimab and small molecule antiviral
agents, once they become available) for patients who are at high risk of progression to severe COVID-19
and who might benefit from these therapies.
In this statement, the Panel issues interim recommendations for the use of anti-SARS-CoV-2 mAbs and
remdesivir in nonhospitalized patients with COVID-19. The Panel will update these recommendations as
additional options for COVID-19 outpatient treatment become available.
The COVID-19 Treatment Guidelines Panel’s Interim Statement on Patient Prioritization for
Outpatient Anti-SARS-CoV-2 Therapies or Preventive Strategies When There Are Logistical
or Supply Constraints
With the increase in cases of COVID-19 and the emergence of the Omicron VOC, logistical or supply
constraints may make it impossible to offer available outpatient therapeutics to all eligible patients.
When these constraints limit the availability of anti-SARS-CoV-2 mAbs or small molecule antiviral
drugs, the Panel recommends that patients at highest risk of clinical progression should be prioritized to
receive these therapies. This statement provides the Panel’s recommendations on patient prioritization
based on 4 key patient elements: age, vaccination status, immune status, and clinical risk factors.
December 16, 2021

Key Updates to the Guidelines
Therapeutic Management of Hospitalized Adults With COVID-19
Figure 2 and the text of this section have been updated with changes to the Panel’s recommendations
for patients who require supplemental oxygen but who are not on high-flow oxygen, noninvasive
ventilation, or mechanical ventilation.
Key changes include:
• The Panel has clarified that the recommendation for using remdesivir without dexamethasone
applies to patients who are early in their disease course and who require minimal supplemental
oxygen.
• The rating for the recommendation on using dexamethasone plus remdesivir has been changed
from BIII to BIIb based on data from observational studies.
• A new recommendation has been added to this section:
• For patients on dexamethasone who have rapidly increasing oxygen needs and systemic
inflammation, add a second immunomodulatory drug (e.g., baricitinib, tocilizumab) (CIIa).
Anti-SARS-CoV-2 Monoclonal Antibodies
This section has been updated to incorporate information on the newly authorized use of bamlanivimab
plus etesevimab as treatment or post-exposure prophylaxis (PEP) for children aged <12 years who are at
risk of serious COVID-19.
The text and Table A also now include information on the Omicron variant and its potential impact
on the anti-SARS-CoV-2 mAbs that are currently authorized to treat mild to moderate COVID-19 in
nonhospitalized patients.

Convalescent Plasma
The Panel has simplified the recommendations in this section:
• The Panel recommends against the use of COVID-19 convalescent plasma for the treatment of
COVID-19 in hospitalized patients without impaired humoral immunity (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of
COVID-19 convalescent plasma for the treatment of COVID-19 in:
• Nonhospitalized patients without impaired humoral immunity; and
• Nonhospitalized or hospitalized patients with impaired humoral immunity.
The rationale for the Panel’s recommendations and the clinical data table in this section have been
reorganized and updated to incorporate the recently published results of certain trials.
Interferons
This section has been moved from the Immunomodulators section to the Antiviral Therapy section
based on the proposed antiviral activities of interferons against SARS-CoV-2. The Panel has added
new information on the use of interferons, including recently published data from clinical trials. The
Panel’s recommendations have been revised, and a new clinical data table (Table 2c) has been added to
the Guidelines to summarize the findings from key clinical studies that provide the basis for the Panel’s
recommendations.
Colchicine
This section has been updated to incorporate results from the PRINCIPLE trial, an open-label,
randomized adaptive platform trial that evaluated the use of colchicine in nonhospitalized patients with
COVID-19. After reviewing the results of this trial and previous clinical trials, the Panel has revised the
recommendation regarding the use of colchicine in nonhospitalized patients with COVID-19; the Panel
now recommends against the use of colchicine in this patient population, except in a clinical trial (BIIa).
Fluvoxamine
The Panel has added a discussion on the results of the TOGETHER trial, a placebo-controlled,
randomized adaptive platform trial of fluvoxamine in nonhospitalized patients with COVID-19 that
was conducted in Brazil. The Panel also noted that STOP COVID 2, a randomized controlled trial
of fluvoxamine versus placebo that was conducted in the United States, recently stopped enrollment
because of futility. Based on the current evidence, the Panel continues to find that there is insufficient
evidence to recommend either for or against the use of fluvoxamine for the treatment of nonhospitalized
patients with COVID-19. A new clinical data table (Table 4c) has been added to the Guidelines to
summarize the findings from key clinical studies that provide the basis for the Panel’s recommendations.
Other Updates to the Guidelines

Overview of COVID-19
This section has been updated with information regarding the Omicron variant.
Remdesivir
The clinical data table for this section now includes results from the DisCoVeRy trial. In addition, new
references that address the use of remdesivir in children and pregnant people have been added to the
section, and the information regarding the use of remdesivir in patients with renal impairment has been
updated and clarified.

Interleukin-6 Inhibitors
This section has been updated to incorporate results from the REMDACTA trial, a double-blind,
placebo-controlled, randomized trial that evaluated the use of tocilizumab in combination with
remdesivir in patients who were hospitalized with severe COVID-19 pneumonia.
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s Tyrosine Kinase Inhibitors
The results from an additional cohort of critically ill patients that was enrolled into the COV-BARRIER
trial have been added to this section. This study evaluated the role of baricitinib in treating hospitalized
patients with COVID-19 pneumonia. Due to the small sample size of this additional study cohort, the
results did not warrant a change to the Panel’s recommendation.
Minor updates have been made to the following Guidelines sections:
• Prevention of SARS-CoV-2 Infection
• Corticosteroids

The COVID-19 Treatment Guidelines Panel’s Statement on

Tixagevimab Plus Cilgavimab (Evusheld) for Pre-Exposure
Prophylaxis for SARS-CoV-2 Infection
Vaccination remains the most effective way to prevent SARS-CoV-2 infection, and it should be
considered the first line of prevention. However, some individuals cannot or may not mount an adequate
immune response to COVID-19 vaccines. Others may not have been fully vaccinated because of
documented adverse reactions to the available vaccines or their components.
Based on the results of PROVENT, a large randomized controlled trial (ClinicalTrials.gov Identifier
NCT04625725), the Food and Drug Administration (FDA) issued an Emergency Use Authorization
(EUA) on December 8, 2021, for the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab
plus cilgavimab (Evusheld).1 The EUA allows this combination to be used as pre-exposure prophylaxis
(PrEP) in certain individuals who, if infected, are at high risk of progressing to severe COVID-19. These
mAbs are SARS-CoV-2 spike protein-directed attachment inhibitors that bind to nonoverlapping regions
of the receptor binding domain of the SARS-CoV-2 spike protein. A modification in the Fc region gives
these anti-SARS-CoV-2 mAbs prolonged half-lives; as a result, they may be able to protect a recipient
from SARS-CoV-2 infection for up to 6 months. This combination of mAbs appears to have activity
against the B.1.617.2 (Delta) variant. Although preliminary in vitro data suggest that the B.1.1.529
(Omicron) variant remains susceptible to this combination, more data are needed to fully assess the
activity of this regimen in situations where the Omicron variant is circulating at high levels.1-3
Recommendations
The COVID-19 Treatment Guidelines Panel recommends using tixagevimab plus cilgavimab 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 (BIIa); or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a documented
history of severe adverse reactions to a COVID-19 vaccine or any of its components (AIIa).
If supplies of tixagevimab plus cilgavimab are limited, priority should be given to those who are at
the highest risk for severe COVID-19 (see the Panel’s statement on prioritizing patients for outpatient
therapies when there are logistical or supply constraints).
Using tixagevimab plus cilgavimab as SARS-CoV-2 PrEP is NOT AUTHORIZED by the FDA in
unvaccinated individuals for whom COVID-19 vaccination is recommended.
The individuals who qualify as having moderate to severe immunocompromising conditions under this
EUA are those who:
• Are receiving active treatment for solid tumors and hematologic malignancies.
• Received a solid organ transplant and are taking immunosuppressive therapy.
• Received a 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
cell counts <200/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 administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-
related immunosuppressive drugs, cancer chemotherapeutic agents that are classified as
severely immunosuppressive, tumor-necrosis blockers, and other biologic agents that are
immunosuppressive or immunomodulatory (e.g., B cell-depleting agents).
Additional Information
• Each package of Evusheld includes a vial of tixagevimab and a vial of cilgavimab, each containing
a single 150 mg/1.5 mL dose (100 mg/mL concentration per vial). These doses are administered as
2 consecutive intramuscular (IM) injections.
• People who continue to meet the criteria for the use of tixagevimab plus cilgavimab for PrEP and
who remain in a setting with ongoing SARS-CoV-2 circulation can be redosed every 6 months.
• If a person has received a COVID-19 vaccine, tixagevimab plus cilgavimab should be
administered ≥2 weeks after vaccination.
Clinical Trial Data

PROVENT is an ongoing, double-blind, Phase 3 randomized controlled trial that evaluated the use of
tixagevimab plus cilgavimab for SARS-CoV-2 PrEP. 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, 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 history of confirmed SARS-CoV-2 infection or who were antibody positive at screening.
The analyzed population included the participants who received a negative reverse transcription
polymerase chain reaction (RT-PCR) result at baseline. Participants were given either tixagevimab 150
mg plus cilgavimab 150 mg as 2 consecutive IM injections (n = 3,441) or 2 placebo IM injections (n
= 1,731). The primary endpoint was symptomatic SARS-CoV-2 infection and a positive SARS-CoV-2
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. 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 groups. RT-PCR-confirmed symptomatic SARS-CoV-2 infection that occurred prior to
unblinding or vaccination was reported in 8 participants (0.2%) in the tixagevimab plus cilgavimab arm
and in 17 participants (1.0%) in the placebo arm, representing a 77% reduction in the incidence of RT-
PCR-confirmed symptomatic SARS-CoV-2 infection in the tixagevimab plus cilgavimab arm (95% CI,
46% to 90%; P < 0.001). A post hoc analysis performed after a median follow-up period of 6.5 months
showed a similar reduction in the event rate between the study arms.
Thirty-five percent of the 3,461 tixagevimab plus cilgavimab recipients and 34% of the 1,736 placebo
recipients experienced adverse events. Serious adverse events were reported in 1% of participants in
both arms, with 1 participant from the tixagevimab plus cilgavimab arm reporting an anaphylactic
reaction that resolved with epinephrine therapy. Most adverse events were mild (73%) or moderate

(24%), with similar incidences for mild and moderate adverse events between the arms. Serious cardiac
adverse events occurred in 0.6% of participants in the tixagevimab plus cilgavimab arm and 0.2%
of participants in the placebo arm. All participants who experienced a cardiac event had cardiac risk
factors and/or a history of cardiac disease at baseline. There was no clear temporal pattern between these
cardiac events and administration of the mAbs.
Additional Considerations
• Tixagevimab and cilgavimab have only been studied in clinical trials as a 1-time combination
therapy; therefore, no safety or efficacy data exist for repeat dosing.
• The median follow-up time during the PROVENT trial was 83 days; therefore, the long-term
duration of protection is not well defined.
• Tixagevimab plus cilgavimab is authorized for use as PrEP for a population that was not well
represented in the PROVENT trial (i.e., a very small proportion of the participants in the trial were
immunocompromised).
• The PROVENT trial has not been published.
• There are no data on the effectiveness of tixagevimab and cilgavimab in preventing infection from
the Omicron variant.
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld
(tixagevimab co-packaged with cilgavimab). 2021. Available at:
https://www.fda.gov/media/154701/download.
2. Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
Nature. 2021;Advance article preview. Available at: https://www.nature.com/articles/d41586-021-03827-2.
3. Cameroni E, Saliba C, Bowen JE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron
antigenic shift. bioRxiv. 2021;Preprint. Available at:
https://www.biorxiv.org/content/10.1101/2021.12.12.472269v1.


Anticoagulation in Hospitalized Patients With COVID-19
Background
COVID-19 has been associated with inflammation and a prothrombotic state accompanied by increases
in fibrinogen and D-dimer.1,2 In some studies, elevations in these markers have been associated
with worse clinical outcomes.3,4 Hospitalized patients with COVID-19 are at high risk for venous
thromboembolism (VTE).5 At a minimum, hospitalized COVID-19 patients should receive prophylactic
doses of anticoagulants, such as low molecular weight heparin (LMWH) or unfractionated heparin, for
the duration of their hospitalization.
Recommendations
Based on the collective data from randomized controlled trials on the use of anticoagulation in patients
with COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) provides the following
recommendations.
For Hospitalized, Nonpregnant Adults Who Require Low-Flow Oxygen and Are Not
Receiving Intensive Care Unit Level of Care
• The Panel recommends using therapeutic-dose heparin for patients who have a D-dimer above
the upper limit of normal (ULN), require low-flow oxygen, and have no increased bleeding risk
(CIIa). LMWH is preferred over unfractionated heparin.
• Based on clinical trial exclusion criteria, contraindications for therapeutic anticoagulation
for COVID-19 due to an increased bleeding risk are as follows: platelet count <50 x 109/L,
hemoglobin <8 g/dL, need for dual antiplatelet therapy, known bleeding within the last 30 days
requiring an emergency room visit or hospitalization, known history of a bleeding disorder, or
an inherited or active acquired bleeding disorder.
• In patients without a VTE who are started on therapeutic-dose heparin, treatment should continue
for 14 days or until hospital discharge, whichever comes first.
• The Panel recommends using prophylactic-dose heparin (LMWH or unfractionated heparin) for
patients who are not administered therapeutic heparin unless a contraindication exists (AIIb).
• The Panel recommends against the use of therapeutic-dose oral anticoagulants for VTE
prophylaxis or prevention of COVID-19 progression in hospitalized patients, except in a clinical
trial (AIIa).
For Hospitalized, Nonpregnant Adults Who Are Receiving Intensive Care Unit Level of Care
(Including Patients Who Are Receiving High-Flow Oxygen)
• The Panel recommends using prophylactic-dose heparin as VTE prophylaxis unless a
contraindication exists (AI).
• The Panel recommends against the use of intermediate-dose (e.g., enoxaparin 1 mg/kg daily)
and therapeutic-dose anticoagulation for VTE prophylaxis, except in a clinical trial (BI).
• For patients who start on therapeutic-dose heparin while on low-flow oxygen due to COVID-19
and then transfer to the intensive care unit (ICU), the Panel recommends switching from
therapeutic to prophylactic-dose heparin unless a VTE is confirmed (BIII).

For Hospitalized Pregnant Adults

• The Panel recommends using prophylactic-dose anticoagulation for pregnant patients
hospitalized for manifestations of COVID-19 unless otherwise contraindicated (see below) (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 in the
absence of a known VTE.2
Rationale
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. In the ICU setting, these studies
showed that therapeutic heparin did not reduce mortality but may have a higher risk of bleeding events;
therefore, this approach is not recommended.6
Three open-label randomized controlled trials (a large 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 ICU care. The entry criteria for these
studies varied, but typically they included need for supplemental oxygen, elevated D-dimer level, and
no risk of major bleeding event. In the larger multiplatform trial, therapeutic heparin showed an increase
in organ support-free days but no difference in mortality or length of hospitalization compared to
prophylactic heparin.7 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 outcome, a composite of ICU
admission, noninvasive or invasive ventilation, or death at Day 28, but therapeutic heparin reduced
mortality at 28 days, a secondary outcome.8 The HEP-COVID trial enrolled patients who required
supplemental oxygen and had a D-dimer >4 times ULN or a sepsis-induced coagulopathy score of ≥4.
The occurrence of the primary outcome of VTE, arterial thromboembolism, or all-cause death at Day 30
was significantly lower in the therapeutic LMWH arm than in the prophylactic LMWH arm, but there
was no difference in mortality at Day 30 between the arms.9 Results from smaller randomized trials,
single-center studies, and observational studies have also been published.
Based on the available study data, the Panel recommends using therapeutic-dose heparin for patients
who have a D-dimer above the ULN, require low-flow oxygen, and have no increased bleeding risk
(CIIa). The rating reflects the fact that, although the 3 randomized controlled trials showed benefit of
therapeutic heparin in hospitalized patients, their inclusion criteria and beneficial outcomes differed.
The RAPID and HEP-COVID trials each required a specified D-dimer elevation for enrollment, but the
multiplatform trial did not. Beneficial outcomes ranged from reduction in the primary outcome of organ
support-free days without a mortality benefit in the multiplatform trial, to no change in the primary
composite outcome of ICU admission, noninvasive or invasive ventilation, or death at Day 28, but a
reduction in the secondary outcome of mortality at 28 days in the RAPID trial.8 The HEP-COVID trial
showed improvement in the composite outcome of thrombosis and death. Event rates were significantly
higher in HEP-COVID than in the other trials, highlighting the difference in their inclusion criteria. In
addition, it should be noted that <20% of screened patients enrolled into the studies; therefore, these
findings may not be generalizable to all hospitalized patients with COVID-19.
References
1. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
Clin Chem Lab Med. 2020;58(7):1116-1120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32172226.

2. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers,
and health systems during the COVID-19 pandemic. J Am Coll Cardiol. 2020;75(18):2352-2371. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32201335.
3. 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.
4. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. Available at:
5. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a
systematic review and meta-analysis. Res Pract Thromb Haemost. 2020;4(7):1178-1191. Available at:
6. 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.
7. 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.
8. 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:
9. 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.


Therapies for High-Risk, Nonhospitalized Patients With Mild
to Moderate COVID-19
Last Updated: December 30, 2021
Prior to mid-December 2021, the anti-SARS-CoV-2 monoclonal antibodies (mAbs) bamlanivimab plus
etesevimab, casirivimab plus imdevimab, and sotrovimab were the only therapies recommended by the
COVID-19 Treatment Guidelines Panel (the Panel) for nonhospitalized patients with mild to moderate
COVID-19 who are at high risk of progressing to severe disease. Since then, the B.1.1.529 (Omicron)
variant of concern (VOC) has become the dominant variant in many parts of the United States.1 This
variant, which has numerous mutations in the spike protein, is predicted to have markedly reduced
susceptibility to bamlanivimab plus etesevimab and casirivimab plus imdevimab. Because sotrovimab is
the only available anti-SARS-CoV-2 mAb that is anticipated to have activity against the Omicron VOC,
the Panel recently added a 3-day course of intravenous (IV) remdesivir as another treatment option for
this group of patients (see the Panel’s statement in an archived version of the Guidelines).
On December 22 and 23, 2021, the Food and Drug Administration (FDA) issued Emergency Use
Authorizations (EUAs) that allow 2 new oral antiviral agents to be used in this patient population:
ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir.
Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Nirmatrelvir (PF-07321332) 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.2
It has demonstrated antiviral activity against all coronaviruses that are known to infect humans.3
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 ranges.
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.4,5
Molnupiravir has potent antiviral activity against SARS-CoV-2.4 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 results that were equivocal; 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.6 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.
Purpose of This Statement

The purpose of this statement is to provide clinicians with guidance on the use of ritonavir-boosted
nirmatrelvir (Paxlovid), sotrovimab, remdesivir, and molnupiravir for the treatment of nonhospitalized
patients with COVID-19 who are at high risk of progressing to severe disease. These recommendations

are based on the results of clinical trials for ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir, and
molnupiravir, and on the results of clinical trials and laboratory assessments of the activity of the anti-
SARS-CoV-2 mAb products that are currently available through EUAs for COVID-19 treatment.
It should be noted that a number of factors affect the selection of the best treatment option for a
specific patient. These factors include, but are not limited to, the clinical efficacy of the treatment
option, the availability of the treatment option, the feasibility of administering parenteral medications
(i.e., sotrovimab, remdesivir), the potential for significant drug-drug interactions (i.e., the interactions
associated with using ritonavir-boosted nirmatrelvir [Paxlovid]), and the regional prevalence of the
Omicron VOC.
All these anti-SARS-CoV-2 therapeutics, which were evaluated initially in unvaccinated individuals,
provide the greatest 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 those
who are vaccinated but who are not expected to mount an adequate immune response to the vaccine.
When there are logistical or supply constraints that make it impossible to offer the available therapy to
all eligible patients, patient triage will be necessary. Please see the Panel’s statement on prioritizing the
use of outpatient therapies when there are logistical or supply constraints.
Recommendations
For nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease
progression,7 the Panel recommends using 1 of the following therapeutics (listed in order of preference):
• Nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days, initiated as
soon as possible and within 5 days of symptom onset in those aged ≥12 years and weighing ≥40
kg (AIIa).
• Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug-drug interactions,
primarily due to the ritonavir component of the combination.
• Before prescribing ritonavir-boosted nirmatrelvir (Paxlovid), clinicians should carefully
review the patient’s concomitant medications, including over-the-counter medications and
herbal supplements, to evaluate potential drug-drug interactions. See the Panel’s statement on
the drug-drug interactions for ritonavir-boosted nirmatrelvir (Paxlovid) for details.
• Sotrovimab 500 mg as a single IV infusion, administered as soon as possible and within 10 days
of symptom onset in those aged ≥12 years and weighing ≥40 kg who live in areas with a high
prevalence of the Omicron VOC (AIIa).
• If the Delta VOC still represents a significant proportion of infections in the region and other
options are not available or are contraindicated, patients can be offered bamlanivimab plus
etesevimab or casirivimab plus imdevimab, with the understanding that this treatment would be
ineffective if they are infected with the Omicron VOC.
• Sotrovimab 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.
• Remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3,
initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and
weighing ≥40 kg (BIIa).
• Because remdesivir requires IV infusion for 3 consecutive days, there may be logistical
constraints to administering remdesivir in many settings.

• Remdesivir is currently approved by the FDA for use in hospitalized individuals, and outpatient
treatment would be an off-label indication.
• 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.
• Molnupiravir 800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days
of symptom onset in those aged ≥18 years ONLY when none of the above options can be used
(CIIa).
• 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 those who 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.
• There are no data on the use of molnupiravir in patients who have received COVID-19
vaccines, and the risk-to-benefit ratio is likely to be less favorable because of the lower efficacy
of this drug.
Rationale
Multiple therapeutic agents are now available for nonhospitalized patients with mild to moderate
COVID-19 who are at high risk of disease progression. The Panel favors the use of ritonavir-boosted
nirmatrelvir (Paxlovid) in most high-risk, nonhospitalized patients with mild to moderate COVID-19. If
ritonavir-boosted nirmatrelvir (Paxlovid) is not available or cannot be used because of drug interactions,
then the Panel recommends using sotrovimab. If sotrovimab is not available, then the Panel recommends
using remdesivir. Molnupiravir should only be administered when the other 3 options are either not
available or cannot be used.
There are currently no clinical trial data that compare the clinical efficacy of these 4 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 the Panel’s recommendations is discussed below.

In the EPIC-HR trial, ritonavir-boosted nirmatrelvir (Paxlovid) reduced the risk of hospitalization or
death by 88% compared to placebo in nonhospitalized adults with laboratory-confirmed SARS-CoV-2
infection.8 This efficacy is comparable to the efficacies reported for sotrovimab (i.e., 85% relative
reduction),9 and remdesivir (i.e., 87% relative reduction)10 and greater than the efficacy reported for
molnupiravir (i.e., 30% relative reduction).11
Ritonavir-boosted nirmatrelvir (Paxlovid) is expected to be active against the Omicron VOC, although
in vitro and in vivo data are currently limited. Because of the potential for significant drug-drug
interactions with concomitant medications, this regimen may not be a safe choice for all patients (see the
Panel’s statement on these drug-drug interactions for details).
Sotrovimab
Several anti-SARS-CoV-2 mAb products (i.e., bamlanivimab plus etesevimab, casirivimab plus
imdevimab, and sotrovimab) have received EUAs from the FDA for the treatment of nonhospitalized

patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. In the
clinical trials for these agents, anti-SARS-CoV-2 mAbs reduced the risk of hospitalization or death by
70% to 85% compared to placebo.
The Omicron VOC has become the dominant variant in many parts of the United States1 and is predicted
to have markedly reduced susceptibility to bamlanivimab plus etesevimab and casirivimab plus
imdevimab. In vitro studies indicate that sotrovimab remains active against the Omicron VOC.12
Remdesivir
Remdesivir has been studied in nonhospitalized patients with mild to moderate COVID-19 who are
at high risk of progressing to severe disease. The PINETREE trial showed that 3 consecutive days of
IV remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death compared to
placebo.10
Remdesivir is expected to be active against the Omicron VOC, although in vitro and in vivo data
are currently limited. Because remdesivir requires IV infusion for 3 consecutive days, there may be
logistical constraints to administering remdesivir in many settings, but it is an option if ritonavir-boosted
nirmatrelvir (Paxlovid) and sotrovimab are not available.
Remdesivir is currently approved by the FDA for use in hospitalized individuals, and outpatient
treatment would be an off-label indication.
Molnupiravir
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared
to placebo.6 Even though the different treatment options have not been directly compared in clinical
trials, the Panel recommends using molnupiravir only when ritonavir-boosted nirmatrelvir (Paxlovid),
sotrovimab, and remdesivir are not available or cannot be given, because molnupiravir has lower
efficacy than the other options.
Molnupiravir is expected to be active against the Omicron VOC, although in vitro and in vivo data are
currently limited.
General Considerations
• For guidance on determining which individuals may receive the greatest benefit from therapy
when there are logistical or supply constraints, see the Panel’s statement on prioritizing the use of
outpatient therapies.
• The time from symptom onset may influence which treatment options should be used, as outlined
in the Recommendations section above.
• There are no data on the use of combination antiviral therapies, or on the combination 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 combination therapy has a role in the
treatment of SARS-CoV-2 infection.
• If a patient requires hospitalization after starting treatment, the full treatment course of ritonavir-
boosted nirmatrelvir (Paxlovid), remdesivir, or molnupiravir can be completed at the health care
provider’s discretion.
• These agents 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.

Additional Considerations When Using Ritonavir-Boosted Nirmatrelvir (Paxlovid)

and Molnupiravir
• Nirmatrelvir must be administered with ritonavir to achieve sufficient therapeutic plasma
concentrations.
• Ritonavir-boosted nirmatrelvir (Paxlovid) has numerous drug-drug interactions and the potential
to cause serious or life-threatening adverse effects. Before prescribing ritonavir-boosted
nirmatrelvir (Paxlovid), clinicians should review the patients’ medication list to assess the
risk of drug-drug interactions. See the Panel’s statement on the drug-drug interactions for
ritonavir-boosted nirmatrelvir (Paxlovid) for details.
• Patients should complete the 5-day treatment course of ritonavir-boosted nirmatrelvir (Paxlovid).
It is unknown whether a shorter course is less effective or whether a shorter course is associated
with the emergence of nirmatrelvir-resistant mutations.
• 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 would not withhold ritonavir-boosted nirmatrelvir
(Paxlovid) from a pregnant patient if the potential benefits outweighed the potential risks.
• Ritonavir-boosted nirmatrelvir (Paxlovid) is authorized for use in pediatric patients aged ≥12 years
and weighing ≥40 kg. The safety and efficacy of using ritonavir-boosted nirmatrelvir (Paxlovid) in
pediatric patients has not been established in clinical trials.
• The dose should be reduced to nirmatrelvir 150 mg and 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 (Paxlovid) is not recommended in patients
with an eGFR of <30 mL/min until more data are available.
• Ritonavir-boosted nirmatrelvir (Paxlovid) is not recommended in patients with 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.
• The most common adverse effects of ritonavir-boosted nirmatrelvir (Paxlovid) are dysgeusia,
diarrhea, hypertension, and myalgia.
Molnupiravir
• Patients should complete the 5-day treatment course of molnupiravir. It is unknown whether a
shorter course is less effective or whether a shorter course is associated with the emergence of
molnupiravir-resistant mutations.
• 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.
• Men of reproductive potential who are sexually active with individuals of childbearing potential
should 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 due to
concerns about fetal toxicity that are based on data from animal studies. However, when preferred

therapies are not available, pregnant people who are at high risk of progressing to severe disease
may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly
those who 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.
• Based on the lack of data on the use of molnupiravir in lactating people and the potential for
adverse effects in the infant from molnupiravir exposure, the current recommendation is to avoid
feeding an infant breast milk during molnupiravir treatment and for 4 days after the final dose.
Pumping and discarding breast milk to maintain supply during this time is recommended.
• 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.
• 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.
• The most common adverse effects of molnupiravir are diarrhea, nausea, and dizziness.
Clinical Trial Data

The EPIC-HR study was a multinational, randomized trial that compared the use of ritonavir-boosted
nirmatrelvir (Paxlovid) given orally twice daily for 5 days to placebo in nonhospitalized adults with
mild to moderate COVID-19 who were at high risk of clinical progression. Eligible participants were
randomized within 5 days of symptom onset, were unvaccinated, and had at least 1 risk factor for
progression to severe disease.8 Patients were excluded if they used medications that are highly dependent
upon CYP3A4 for clearance or are strong inducers of CYP3A4. The primary composite outcome was
COVID-19-related hospitalization or death from any cause through Day 28 among the participants who
were randomized within 3 days of symptom onset.
A total of 2,246 participants enrolled in the trial. The mean age was 46 years, 51% of the participants
were men, and 72% were White. Forty-seven percent of the participants tested negative for
SARS-CoV-2 antibodies, and 66% started study treatment within 3 days of symptom onset.
Participants 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 and all-cause deaths
occurred by Day 28 in 5 of 697 participants (0.72%) in the ritonavir-boosted nirmatrelvir (Paxlovid)
arm and in 44 of 682 participants (6.45%) in the placebo arm. Among the 2,085 participants 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 participants (0.8%) in the ritonavir-boosted nirmatrelvir
(Paxlovid) arm and in 66 of 1,046 participants (6.3%) in the placebo arm (88% relative risk reduction;
-5.62% estimated absolute reduction; 95% CI, -7.21% to -4.03%; P < 0.0001). There were no deaths in
the ritonavir-boosted nirmatrelvir (Paxlovid) arm and 12 deaths in the placebo arm.
Among the 2,224 participants who were included in the EPIC-HR safety analysis set (i.e., those who
received at least 1 dose of either ritonavir-boosted nirmatrelvir [Paxlovid] or placebo), the adverse
events that occurred more frequently in ritonavir-boosted nirmatrelvir (Paxlovid) recipients than in
placebo recipients were dysgeusia (6% vs. <1%) and diarrhea (3% vs. 2%). Fewer ritonavir-boosted
nirmatrelvir (Paxlovid) recipients discontinued the study drug due to an adverse event than placebo
recipients (2% vs. 4%).

Sotrovimab
The data that support the EUA for sotrovimab are from the Phase 3 COMET-ICE trial, which included
outpatients aged >18 years with mild to moderate COVID-19 who were at high risk of progressing to
severe COVID-19 and were within 5 days of symptom onset. The primary endpoint of the study was the
proportion of participants who were hospitalized for ≥24 hours or who died from any cause by Day 29.
Endpoint events occurred in 3 of 291 participants (1%) in the sotrovimab arm and in 21 of 292 participants
(7%) in the placebo arm (P = 0.002), resulting in a 6% absolute reduction and an 85% relative reduction
(95% CI, 44% to 96%) in the risk of hospitalization or death among those who received sotrovimab.9,13
Remdesivir
The PINETREE study was a randomized, placebo-controlled trial in nonhospitalized patients with
COVID-19 who were at high risk of clinical progression and were within 7 days of symptom onset.
Nonhospitalized participants were randomized to receive 3 days of IV remdesivir or placebo. The trial was
stopped early for administrative reasons.
At treatment initiation, the median duration of symptoms was 5 days. By Day 28, the primary endpoint had
occurred in 2 of 279 remdesivir recipients (0.7%) and in 15 of 283 placebo recipients (5.3%), resulting in a
4.6% absolute reduction and an 87% relative reduction in the risk of hospitalization or death among those
who received remdesivir (HR 0.13; 95% CI, 0.03–0.59; P = 0.008).10
Molnupiravir
MOVe-OUT was a multinational, Phase 3, randomized trial that compared the use of molnupiravir 800
mg administered orally every 12 hours for 5 days to placebo. The participants were nonhospitalized,
unvaccinated, nonpregnant adults with mild to moderate COVID-19 who were at high risk of clinical
progression to severe COVID-19 and who were within 5 days of symptom onset.11 The primary composite
outcome was all-cause hospitalizations (defined as hospital stays that lasted >24 hours) and deaths by Day
29.
In an interim analysis that included 50% of the target accrual population, hospitalization or death occurred
in 28 of 385 participants (7.3%) in the molnupiravir arm and in 53 of 377 participants (14.1%) in the
placebo arm by Day 29 (adjusted difference of -6.8%; 95% CI, -11.3% to -2.4%; P = 0.001).11
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/Latino, 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).6 There was 1 death in the molnupiravir arm, and there
were 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.
The difference in the efficacy of molnupiravir that was observed between participants in the interim
analysis and those enrolled after the interim analysis has not been fully explained.
References
10. Centers for Disease Control and Prevention. COVID data tracker: variant proportions. 2021. Available at:
https://covid.cdc.gov/covid-data-tracker/#variant-proportions. Accessed December 29, 2021.

11. 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:
12. 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:
13. 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:
14. 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.
15. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for
molnupiravir. 2021. Available at: https://www.fda.gov/media/155054/download.
16. 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 December 27, 2021.
17. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Paxlovid.
2021. Available at: https://www.fda.gov/media/155050/download.
18. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early treatment for COVID-19 with SARS-CoV-2 neutralizing
antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950. Available at:
19. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in
outpatients. N Engl J Med. 2021. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2116846.
20. 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. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34914868.
21. Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831
and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. 2021;Preprint.
Available at: https://www.biorxiv.org/content/10.1101/2021.03.09.434607v10.
22. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of
sotrovimab. 2021. Available at: https://www.fda.gov/media/149534/download.


Potential Drug-Drug Interactions Between Ritonavir-Boosted
Nirmatrelvir (Paxlovid) and Concomitant Medications
On December 22, 2021, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for ritonavir-boosted nirmatrelvir (Paxlovid) for the treatment of patients with
mild to moderate COVID-19 who are within 5 days of symptom onset and at high risk of progression to
severe disease.1,2 The dose for patients with normal renal function is nirmatrelvir 300 mg (two 150 mg
tablets) plus ritonavir 100 mg (one 100 mg tablet) orally twice daily for 5 days. For more information,
see the COVID-19 Treatment Guidelines Panel’s (the Panel) statement on treatment options for
nonhospitalized patients with mild to moderate COVID-19.
Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug-drug interaction
potential, 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 is an FDA-approved drug that has been
used for more than 2 decades as a pharmacologic boosting agent for certain anti-HIV medications;
therefore, there is a large body of literature describing its use with other drugs and its potential for
serious and sometimes life-threatening drug-drug interactions. Clinicians who are not experienced
in prescribing ritonavir-boosted drugs should refer to resources such as the EUA fact sheet for
ritonavir-boosted nirmatrelvir (Paxlovid) and the Liverpool COVID-19 Drug Interactions website
for additional guidance. Consultation with an expert (e.g., clinical pharmacist, HIV specialist, and/or
the patient’s specialist provider[s], if applicable) should also be considered.
Ritonavir is an inhibitor, inducer, and substrate of various drug-metabolizing enzymes and/or drug
transporters. Most notably, as a strong inhibitor of CYP3A, it may increase concentrations of certain
concomitant medications, thereby increasing the potential for significant drug toxicities. CYP3A
inhibition by ritonavir typically resolves 3 to 5 days after the drug is discontinued. When ritonavir is
used for a treatment duration of 5 days, its induction properties are less likely to be clinically relevant
than when the drug is used chronically for HIV. In addition, both nirmatrelvir and ritonavir are substrates
of CYP3A; thus, administration of this treatment with or immediately after discontinuing medications
that are strong inducers of CYP3A4 (e.g., rifampin) can lead to significant reductions in nirmatrelvir and
ritonavir concentrations, which may decrease nirmatrelvir’s effectiveness against SARS-CoV-2.
Assess for Potential Drug-Drug Interactions

• Before prescribing ritonavir-boosted nirmatrelvir (Paxlovid), clinicians should carefully
review concomitant medications, including over-the-counter medicines and herbal
supplements, to evaluate the potential for drug-drug interactions.
• The EUA fact sheet for ritonavir-boosted nirmatrelvir (Paxlovid) and the Liverpool COVID-19
Drug Interactions website are useful for identifying and managing drug-drug interactions.
• Drug classes of particular concern are those that include drugs that are prone to concentration-
dependent toxicities, including (but not limited to) certain antiarrhythmics, oral anticoagulants,
immunosuppressants, anticonvulsants, antineoplastics, and neuropsychiatric drugs.
• If a significant drug-drug interaction is identified, clinicians should consider the risks and benefits
of using ritonavir-boosted nirmatrelvir (Paxlovid). Expert consultation (e.g., with a clinical
pharmacist, HIV specialist, and/or the patient’s specialist provider[s], if applicable) should be
considered, especially for patients receiving highly specialized therapies, such as antineoplastics,

neuropsychiatric drugs, and certain immunosuppressants.

• Potential management strategies to facilitate the use of ritonavir-boosted nirmatrelvir (Paxlovid)
may differ depending on the magnitude and significance of the interaction. Potential strategies
include:
• Dose adjustment of the concomitant medication
• Use of an alternative to the concomitant medication
• Increased monitoring for potential adverse reactions to the concomitant medication
• In some instances, temporary withholding of the concomitant medication
• The dose of ritonavir-boosted nirmatrelvir (Paxlovid) should not be adjusted to avoid or mitigate a
drug-drug interaction with a concomitant medication.
• Patients should be informed of ritonavir-boosted nirmatrelvir’s (Paxlovid) drug-drug interaction
potential. If a drug-drug interaction is identified, the patient should be informed and advised of the
signs and symptoms of potential adverse effects.
• These strategies should be considered for the 5-day duration of ritonavir-boosted nirmatrelvir
(Paxlovid) treatment and for at least 3 to 5 days after treatment completion, and for potentially
longer if ritonavir-boosted nirmatrelvir (Paxlovid) is administered with an interacting concomitant
medication that has a long half-life.
• In settings where these management strategies are not feasible or where the effectiveness of
ritonavir-boosted nirmatrelvir (Paxlovid) may be compromised, consider using alternative
COVID-19 therapies (see the Panel’s statement on treatment options for nonhospitalized patients
with mild to moderate COVID-19 for more information).
• The EUA for ritonavir-boosted nirmatrelvir (Paxlovid) suggests that individuals who use products
containing ethinyl estradiol for contraception should use a backup, nonhormonal contraceptive
method because ritonavir-boosted nirmatrelvir (Paxlovid) has the potential to decrease ethinyl
estradiol levels. However, the enzyme-inducing effects of ritonavir-boosted nirmatrelvir
(Paxlovid) that would lead to lower hormone exposure are not expected to be clinically significant
during 5 days of therapy and, therefore, would not be expected to decrease contraceptive
effectiveness. In addition, ethinyl estradiol is always combined with a progestin for contraception.
Progestin concentrations are expected to remain similar or increase when ritonavir-boosted
nirmatrelvir (Paxlovid) is used concomitantly with combined hormonal contraception, which
maintains the effectiveness of the oral contraceptive.
Medications That Are Contraindicated or Should Not Be Coadministered With

This table is a guide and not a comprehensive list of all possible drugs that may interact or should
not be coadministered with ritonavir-boosted nirmatrelvir (Paxlovid). For example, many drugs
that may require dose adjustment or increased monitoring when coadministered with ritonavir-
boosted nirmatrelvir (Paxlovid) are not listed in this table. The EUA fact sheet for ritonavir-boosted
nirmatrelvir (Paxlovid) and the Liverpool COVID-19 Drug Interactions website should be used to
identify and manage drug-drug interactions. Before prescribing ritonavir-boosted nirmatrelvir (Paxlovid)
for patients receiving highly specialized drugs, such as antineoplastics, consultation with the appropriate
specialist providers is recommended.
Deviation from these recommendations may be appropriate in certain clinical scenarios.
Providers should exercise clinical judgment when assessing the risks and benefits of ritonavir-boosted
nirmatrelvir (Paxlovid) and determine the most appropriate strategy for managing drug-drug interactions

between ritonavir-boosted nirmatrelvir (Paxlovid) and concomitant medications. This is particularly

important in the outpatient setting, where close monitoring may not be feasible. Expert consultation
should be considered.
In situations where drug-drug interaction risks cannot be mitigated or where the effectiveness of
ritonavir-boosted nirmatrelvir (Paxlovid) may be compromised, consider using alternative COVID-19
therapies (see the Panel’s statement on treatment options for nonhospitalized patients with mild to
moderate COVID-19 for more information).
Before prescribing ritonavir-boosted nirmatrelvir

(Paxlovid), determine whether the patient is receiving
any of the medications listed.
Prescribe an alternative COVID-19 therapy for patients
• If the patient is receiving any of these medications,
who are receiving any of the medications listed.
withhold the medication if clinically appropriate.
• If withholding is not clinically appropriate, use an
alternative concomitant medication or COVID-19 therapy.a
• Amiodarone • Alfuzosin
• Apalutamide • Alprazolam
• Bosentan • Atorvastatin
• Carbamazepine • Avanafil
• Cisapride • Clonazepam
• Clopidogrel • Codeine
• Clozapine • Cyclosporineb
• Colchicine in patients with renal and/or hepatic impairment • Diazepam
• Disopyramide • Everolimusb
• Dofetilide • Fentanyl
• Dronedarone • Hydrocodone
• Eplerenone • Lomitapide
• Ergot derivatives • Lovastatin
• Flecainide • Meperidine (pethidine)
• Flibanserin • Midazolam (oral)
• Glecaprevir/pibrentasvir • Oxycodone
• Ivabradine • Piroxicam
• Lumateperone • Propoxyphene
• Lurasidone • Rosuvastatin
• Mexiletine • Salmeterol
• Phenobarbital • Sildenafil for erectile dysfunction
• Phenytoin • Silodosin
• Pimozide • Simvastatin
• Propafenone • Sirolimusb
• Quinidine • Suvorexant
• Ranolazine • Tacrolimusb
• Rifampin • Tadalafil for erectile dysfunction
• Rifapentine • Tamsulosin
• Rivaroxaban • Tramadol
• Sildenafil for pulmonary hypertension • Triazolam
• St. John’s wort • Vardenafil
• Tadalafil for pulmonary hypertension
• Ticagrelor
• Vorapaxar
a
E xpert consultation may be considered. In some cases, dose reduction of the concomitant medication may be an
appropriate management strategy.

b
efore prescribing ritonavir-boosted nirmatrelvir (Paxlovid) for a patient receiving this immunosuppressant, the patient’s
B
specialist provider(s) should be consulted, given the significant drug-drug interaction potential between ritonavir and the
narrow therapeutic index agent and because close monitoring may not be feasible.
Acknowledgments
The Panel would like to express their appreciation to the following clinical pharmacology experts for
their contributions to this statement:
Sarita Boyd, PharmD, of the Food and Drug Administration, Jomy George, PharmD, of the National
Institutes of Health, and Kimberly Scarsi, PharmD, of the University of Nebraska
References
1. 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: December 27, 2021.
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for paxlovid.

The COVID-19 Treatment Guidelines Panel’s Interim

Statement on Patient Prioritization for Outpatient Anti-
SARS-CoV-2 Therapies or Preventive Strategies When
There Are Logistical or Supply Constraints
The COVID-19 Treatment Guidelines Panel (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 are of greatest 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.
With the increase in cases of COVID-19 and the emergence of the Omicron (B.1.1.529) variant of
concern, there may be logistical or supply constraints that make it impossible to offer the available
therapy to all eligible patients, making patient triage necessary.
The purpose of this interim statement is to provide guidance on which individuals might receive the
greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention. 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 over post-exposure prophylaxis (PEP) of SARS-CoV-2 infection.
• 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 pre-exposure prophylaxis (PrEP) for severely
immunocompromised individuals over moderately immunocompromised individuals (see
Immunocompromising Conditions below).
It is anticipated there may be limitations that make it difficult to provide therapeutic agents (e.g., anti-
SARS-CoV-2 monoclonal antibodies [mAbs] that are active against Omicron, small molecule antiviral
agents) to all who are at high risk of progression to severe COVID-19 and might benefit from these
therapies. In this situation, the Panel’s opinion on how to prioritize high-risk ambulatory patients for
these interventions is provided below. For more specific guidance, see the Panel’s Statement on using
mAbs in nonhospitalized patients when Omicron is the predominant circulating variant.
Prioritization of Patients at Highest Risk of Progression to Severe COVID-19

When logistical or supply constraints limit the availability of anti-SARS-CoV-2 mAbs or small molecule
antivirals, 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 or PEP in a specific situation.
Prioritization schemes should consider how to equitably distribute these scarce resources to populations
that may include individuals who may have less knowledge of and/or access to these therapies. The
availability and distribution of recommended therapies should be monitored to ensure that access to the

products is equitable.
Patient Prioritization for Treatment

The Panel prioritized the following risk groups for anti-SARS-CoV-2 mAb 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 CDC webpage Underlying Medical Conditions Associated with High
Risk for Severe COVID-19.
Tier Risk Groups

• 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
1 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).
• Unvaccinated individuals at risk of severe disease not included in Tier 1 (anyone aged ≥65 years or anyone
2
aged <65 years with clinical risk factors)
• Vaccinated individuals at high risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years with
clinical risk factors)
3
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients in this situation within this tier should be prioritized for treatment.
• Vaccinated individuals at risk of severe disease (anyone aged ≥65 years or anyone aged <65 with clinical
risk factors)
4
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients in this situation within this tier should be prioritized for treatment.
Patient Prioritization for Pre-Exposure Prophylaxis

Tixagevimab plus cilgavimab (Evusheld) 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 (Evusheld) 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 speaking,
those who qualify for PrEP because of allergy to the vaccine or contraindication to vaccination are less
likely to suffer severe consequences, unless they are also moderately to severely immunocompromised.
Immunocompromising Conditions
The Centers for Disease Control and Prevention (CDC) website COVID-19 Vaccines for Moderately or
Severely Immunocompromised People provides a list of moderate and severe immunocompromising
conditions.
If these anti-SARS-CoV-2 agents cannot be provided to all moderately to severely immunocompromised
individuals because of logistical constraints or supply limitations, the Panel suggests prioritizing
their use for those 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 patients:
• Patients who are within 1 year of receiving B-cell depleting therapies (e.g., rituximab,
ocrelizumab, ofatumumab, alemtuzumab)

• Patients receiving Bruton 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 with recent treatment for acute rejection with T or B cell
depleting agents
• Patients with severe combined immunodeficiencies
• Patients with untreated HIV who have a CD4 T lymphocyte cell count <50 cells/mm3
If supplies are extremely limited, the Panel suggests prioritizing those who are more severely
immunocompromised (see above list) and who also have additional risk factors for severe disease for the
outpatient therapies.
Clinical Risk Factors

Some of the most important risk factors for severe COVID-19 include (listed alphabetically) age (risk
increases with each decade after age 50),1 cancer, cardiovascular disease, chronic kidney disease, chronic
lung disease, diabetes, immunocompromising conditions or receipt of immunosuppressive medications,
obesity (body mass index ≥30), pregnancy, and sickle cell disease. 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 High Risk for Severe COVID-19. Of note, the likelihood of developing
severe COVID-19 increases when a person has multiple comorbidities.2
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, as listed above. Children who are
aged <1 year or with obesity, moderate to severe immunosuppression, or those with complex chronic
disease and medical complexity with respiratory technology dependence are at substantially increased
risk of severe disease.3
The FDA Emergency Use Authorizations (EUAs) provide a broad list of medical conditions or other
factors as criteria for use of anti-SARS-CoV-2 agents as treatment or PEP. See the individual EUAs for
the full list of these medical conditions and other factors.
References
1. 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.
2. Rosenthal N, Cao Z, Gundrum J, Sianis J,Safo S. Risk factors associated with in-hospital mortality in a US
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
3. 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:

Introduction
Last Updated: July 8, 2021
The COVID-19 Treatment Guidelines have been 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 will be updated frequently as published data and other
authoritative information become available.
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 development of treatment guidelines. Panel members include representatives from
federal agencies, health care and 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 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 evolving 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
Panel members; this applies to recommendations for treatments, recommendations 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 considered
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.
Aspects of the data that are considered can include, but are not limited to, the source of the data, the type
of study (e.g., randomized controlled trial, prospective or retrospective cohort study, case series), 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 two 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 (see Table 1).
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: Optional 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 published research on COVID-19. The Panel also relies heavily on experience with other diseases,
supplemented with 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 from clinical trials or large cohort
studies that demonstrate the clinical or virologic efficacy of a therapy in patients with COVID-19,
with the potential benefits outweighing the potential risks.
[blank] for the treatment of COVID-19 (no rating). This statement is used when the collective
results from clinical trials and/or observational cohorts do not provide the evidence needed to
support a recommendation due to too few or conflicting data.
• 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.

• The Panel recommends against the use of [blank] for the treatment of COVID-19 (rating).
This recommendation is used in cases when the available data clearly show a safety concern and/
or the data show no benefit for the treatment of COVID-19.
Evolving Knowledge on Treatment for COVID-19

Currently, remdesivir, an antiviral agent, is the only Food and Drug Administration-approved drug
for the treatment of COVID-19. An array of drugs 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 (EUAs), Emergency Investigational New Drug
(EIND) 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.
A large volume of data and publications from randomized controlled trials, observational cohorts, and
case series are emerging at a very rapid pace, some in peer-reviewed journals, others as manuscripts that
have not yet been peer reviewed, and, in some cases, 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 December 14, 2021, more than 270 million cases of COVID-19—caused by SARS-CoV-2
infection—have been reported globally, including more than 5.3 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 those who were hospitalized was 6 times higher among those with reported medical
conditions (45.4%) than among those without medical conditions (7.6%). The mortality rate was highest
in those aged >70 years, regardless of the presence of chronic medical conditions. Among those with
available data on health conditions, 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 and 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 increases 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
may increase the risk of reinfection or decrease the efficacy of vaccines.18 There is already 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
Since December 2020, several variants have been identified that have now been assigned Greek letter
designations by the World Health Organization (WHO). SARS-CoV-2 variants are designated as
variants of concern (VOC) if they display certain characteristics, such as increased transmissibility or
virulence. In addition, vaccines and/or therapeutics may have decreased effectiveness against VOC, and

the mutations found in these variants may interfere with diagnostic test targets. The designation variant
of interest (VOI) is used for important variants that have not yet been fully characterized; however, the
designations and definitions for these variants differ between organizations.20,21 In September 2021,
the Centers for Disease Control and Prevention (CDC) added a new designation for variants: variants
being monitored (VBM). This refers to variants for which the data indicate a potential or clear impact on
approved or authorized medical countermeasures, or variants that have been 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. As such, these variants do not pose a significant and
imminent risk to public health in the United States.
The B.1.617.2 (Delta) variant, which was first identified in India and has been designated a VOC,
is the dominant variant in the United States since the summer of 2021. The Delta variant is more
infectious than other variants, leading to increased transmissibility.22 The B.1.1.529 (Omicron) variant
was designated a VOC in November 2021. It has become the predominant variant in parts of Africa,
and cases of COVID-19 caused by the Omicron variant have been reported across the globe. Early
evidence suggests that the Omicron variant may spread more easily than other variants, but data are
limited on the severity of disease caused by this variant.23 The B.1.1.7 (Alpha) variant that was first
seen in the United Kingdom is more infectious and may be more virulent than earlier variants.24-26 The
B.1.351 (Beta) variant that was originally identified in South Africa has spread to many other countries,
including the United States. The P.1 (Gamma) variant was originally identified in Manaus, Brazil, and
has also emerged in the United States. These variants, which were previously designated as VOC, are
now classified as VBM. Other VBM in the United States include the B.1.427/B.1.429 (Epsilon) variants
that were originally identified in California, the B.1.526 (Iota) variant that was originally identified in
New York, and the B.1.617.1 (Kappa) variant that was first identified in India. For a detailed discussion
on the susceptibility of certain VOC, VOI , and VBM to available anti-SARS-CoV-2 mAbs, please see
Anti-SARS-CoV-2 Monoclonal Antibodies.
The data on the emergence, spread, and clinical relevance of these new variants is 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, CoVariants.org, and WHO’s Tracking SARS-CoV-2 Variants provide
regular updates on the data for SARS-CoV-2 variants. The COVID-19 Treatment Guidelines Panel
reviews the 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.6,27,28 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 [SpO2] ≤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 multiorgan dysfunction or failure).29 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-19.30 Imaging may be normal early in infection and can
be abnormal in the absence of symptoms.30
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,31,32 dermatologic,33 hematologic,34 hepatic,35 neurologic,36,37 renal,38,39 and other complications.
Thromboembolic events also occur in patients with COVID-19, with the highest risk occurring in
critically ill patients.40
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).41,42 Please see Special
Considerations in Children for more information.
References
1. Johns Hopkins. COVID-19 Dashboard by the Center for Science and Engineering. 2021. Available at:
https://coronavirus.jhu.edu/map.html. Accessed October 18, 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. 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. Coronavirus disease 2019 (COVID-19): cases in U.S. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html. Accessed November
25, 2020.
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.
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.
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 (coronavirus disease): people with certain medical

conditions. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-

with-medical-conditions.html. Accessed September 16, 2021.
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. Available at:
13. Gross CP, Essien UR, Pasha S, Gross JR, Wang SY, Nunez-Smith M. Racial and ethnic disparities in
population-level COVID-19 mortality. J Gen Intern Med. 2020;35(10):3097-3099. Available at:
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.
2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-ethnicity.html.
Accessed November 24, 2020.
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. World Health Organization. Tracking SARS-CoV-2 variants. 2021. Available at: https://www.who.int/en/
activities/tracking-SARS-CoV-2-variants/. Accessed October 18, 2021.
21. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html.
Accessed April 5, 2021.
22. Centers for Disease Control and Prevention. Delta variant: what we know about the science. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. Accessed September 16, 2021.
23. Centers for Disease Control and Prevention. Omicron variant: what you need to know. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/variants/omicron-variant.html. Accessed December 14, 2021.
24. 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).
25. 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.
26. Murugan NA, Javali PS, Pandian CJ, Ali MA, Srivastava N, Jeyaraman J. Computational investigation of
increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7. bioRxiv. 2021;Preprint. Available at:
27. 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:

28. 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. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/32150748.
29. 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:
30. 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:
31. 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.
32. 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:
33. 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:
34. 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:
35. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastrointestinal and liver manifestations of COVID-19.
J Clin Exp Hepatol. 2020;10(3):263-265. Available at:
36. Whittaker A, Anson M, Harky A. Neurological manifestations of COVID-19: a systematic review and current
update. Acta Neurol Scand. 2020;142(1):14-22. Available at:
37. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699-702. Available at:
38. 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.
39. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with
COVID-19 in China. Kidney Int. 2020;98(1):219-227. Available at:
40. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease:
implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll
Cardiol. 2020;75(23):2950-2973. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32311448.
41. 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:
42. 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:

Testing for SARS-CoV-2 Infection

Last Updated: April 21, 2021
Summary Recommendations
• To diagnose acute infection of SARS-CoV-2, the COVID-19 Treatment Guidelines Panel (the Panel) recommends
using a nucleic acid amplification test (NAAT) with a sample collected from the upper respiratory tract (i.e., a
nasopharyngeal, nasal, or oropharyngeal specimen) (AIII).
• For intubated and mechanically ventilated adults who are suspected to have COVID-19 but who do not have a
confirmed diagnosis:
• The Panel recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial
upper respiratory tract sample is negative (BII).
• The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage samples
when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 (BII).
• A NAAT should not be repeated in an asymptomatic person 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 who have received an initial diagnosis of infection; therefore,
a NAAT should be considered for persons 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 the use of serologic (i.e., antibody) testing as the sole basis for diagnosis of acute
SARS-CoV-2 infection (AIII).
• The Panel recommends against the use of serologic (i.e., antibody) testing to determine whether a person is immune
to SARS-CoV-2 infection (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
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, as well as 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.
Ideally, diagnostic testing should also be performed for people who are likely to be at repeated risk
of exposure to SARS-CoV-2, such as health care workers and first responders. Testing should also be
considered for individuals who spend time in heavily populated environments (e.g., teachers, students,
food industry workers) and for travelers. Testing requirements may vary by state, local, and employer
policies. Travelers may need evidence of a recent negative test result to enter some states or countries;
such documentation may be an acceptable alternative to quarantine upon arrival.
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),1 but no
diagnostic test has been approved by the FDA.
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.2
Lower respiratory tract samples have a higher yield than upper tract samples, but they are often not
obtained because of concerns about aerosolization of the virus during sample collection procedures.
Some tests that have received EUAs can also be performed on saliva specimens. Studies are currently
evaluating the use of other sample types, including stool samples.
Some tests that have received EUAs allow for self-collection of specimens at home, but these specimens

must be sent to a laboratory for processing. In addition, some tests allow trained personnel to collect and
test specimens in nonclinical settings, such as in the home or in nursing or assisted living facilities. This
allows real-time antigen results to be obtained on site.
Nucleic Acid Amplification Testing for SARS-CoV-2 Infection

Reverse transcriptase 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 a variety of additional platforms (e.g., reverse transcriptase loop-
mediated isothermal amplification [RT-LAMP]). 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’ genome that is assessed
by that test.3 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 one 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.4
Many commercial NAATs that use RT-PCR rely on multiple targets to detect the virus, such that even if
a mutation impacts one of the targets, the other RT-PCR targets will still work.5 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 B.1.1.7 variant that
has been associated with increased transmission carries 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.3
SARS-CoV-2 poses several diagnostic challenges, including potentially discordant shedding of virus
from the upper versus the 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.6-12 For intubated or mechanically ventilated patients with clinical signs and symptoms that
are consistent with COVID-19 pneumonia, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial
upper respiratory tract sample is negative (BII). The Panel recommends obtaining endotracheal aspirates
over bronchial wash or bronchoalveolar lavage (BAL) samples when collecting lower respiratory tract
samples to establish a diagnosis of COVID-19 (BII).
BAL and sputum induction are aerosol-generating procedures that should be performed only after
careful consideration of the risk of exposing staff to infectious aerosols. Endotracheal aspiration appears
to carry a lower risk of aerosol-generation than BAL, and some experts consider the sensitivity and
specificity of endotracheal aspirates and BAL specimens comparable in detecting SARS-CoV-2.

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.13,14 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.15,16 Furthermore, both virologic studies and contact tracing of high-risk contacts show a low risk
for SARS-CoV-2 transmission after these intervals.17,18 Based on these results, the Centers for Disease
Control and Prevention (CDC) recommends that NAATs should not be repeated 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 (AIII).19 If there are concerns that an immunocompromised health care worker may still
be infectious >20 days from the onset of SARS-CoV-2 infection, consultation with local employee health
services regarding return-to-work testing policies is advised.
SARS-CoV-2 reinfection has been reported in people who have received an initial diagnosis of infection;
therefore, a NAAT should be considered for persons 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, it should be noted that persons infected with SARS-CoV-2 may have a negative
result on an initial NAAT and then have a positive result on a subsequent test due to intermittent detection
of viral RNA and not due to reinfection.13 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 RT-PCR-based tests,
but they have 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. Advantages of antigen-based tests are
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 where preventing transmission is critical.
Antigen-based tests also allow for repeat testing to quickly identify persons with SARS-CoV-2 infection.
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 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-19.20
The CDC testing algorithm recommends additional NAATs 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 who is asymptomatic receives a positive result. 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 or storing test cartridges/cards inappropriately)

• Test interference due to human antibodies (e.g., rheumatoid factor or other nonspecific antibodies)
• 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),21-26 the Panel does not recommend 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.1 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 for SARS-CoV-2, 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). Serologic assays that have FDA EUAs should be used for
public health and clinical use. 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 of tests detect neutralizing antibodies from recent or prior SARS-CoV-2 infection. It is
unknown whether one type of test is more clinically meaningful than the other.
• Serologic assays may detect IgM, IgG, IgA, and/or total antibodies, or a combination of IgM and
IgG antibodies. Serologic assays that detect IgG and total antibodies have 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 Panel recommends against the use of serologic testing to determine whether a person is immune to
SARS-CoV-2 infection (AIII).
If SARS-CoV-2 antibodies are detected during a serologic test, the results should be interpreted with
caution for the following reasons:
• It is unclear how long antibodies persist following infection; and
• It is unclear whether the presence of antibodies confers protective immunity against future infection.
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, confirmatory testing using a distinct
antibody assay, ideally one that uses a different antigenic target (e.g., the nucleocapsid phosphoprotein

if the first assay targeted the spike protein), can substantially improve the probability that persons with
positive test results are antibody positive.
Assuming that the test is reliable, serologic tests that identify recent or prior SARS-CoV-2 infection may
be used to:
• Differentiate SARS-CoV-2 antibody responses to natural infection from vaccine-induced antibody
responses to the SARS-CoV-2 spike protein antigen. Because nucleocapsid protein is not a
constituent of vaccines that are currently available through EUAs or in late-stage clinical trials,
serologic tests that detect antibodies by recognizing nucleocapsid protein can be used to distinguish
antibody responses to natural infection from vaccine-induced antibody responses.
• Determine who may be eligible to donate convalescent plasma
• Estimate the proportion of the population that has been exposed to SARS-CoV-2
Based on current knowledge, serologic tests should not be used to (AIII):
• Make decisions about how to group persons in congregate settings (e.g., schools, dormitories,
correctional facilities)
• Determine whether persons may return to the workplace
• Assess for prior infection solely to determine whether to vaccinate an individual
• Assess for immunity to SARS-CoV-2 following vaccination, except in clinical trials
References
1. Food and Drug Administration. Coronavirus disease 2019 (COVID-19) emergency use authorizations for
medical devices. 2020. Available at: https://www.fda.gov/medical-devices/emergency-situations-medical-
devices/emergency-use-authorizations. Accessed February 4, 2021.
2. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical
specimens from persons for coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/lab/guidelines-clinical-specimens.html. Accessed February 4, 2021.
3. Food and Drug Administration. Genetic variants of SARS-CoV-2 may lead to false negative results with
molecular tests for detection of SARS-CoV-2—letter to clinical laboratory staff and health care providers. 2021.
Available at: https://www.fda.gov/medical-devices/letters-health-care-providers/genetic-variants-sars-cov-2-
may-lead-false-negative-results-molecular-tests-detection-sars-cov-2. Accessed March 15, 2021.
4. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse
transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med.
5. Centers for Disease Control and Prevention. Science brief: emerging SARS-CoV-2 variants. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html.
Accessed March 15, 2021.
6. Chan PK, To WK, Ng KC, et al. Laboratory diagnosis of SARS. Emerg Infect Dis. 2004;10(5):825-831.
7. Tang P, Louie M, Richardson SE, et al. Interpretation of diagnostic laboratory tests for severe acute respiratory
syndrome: the Toronto experience. CMAJ. 2004;170(1):47-54. Available at:
8. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Respiratory tract samples, viral load, and genome fraction
yield in patients with Middle East respiratory syndrome. J Infect Dis. 2014;210(10):1590-1594. Available at:
9. Centers for Disease Control and Prevention. Overview of testing for SARS-CoV-2 (COVID-19). 2020.

Available at: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html. Accessed February 4,

2021.
10. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical
specimens from persons under investigation (PUIs) for Middle East respiratory syndrome coronavirus
(MERS-CoV)–Version 2.1. 2019. Available at: https://www.cdc.gov/coronavirus/mers/guidelines-clinical-
specimens.html. Accessed February 4, 2021.
11. Hase R, Kurita T, Muranaka E, Sasazawa H, Mito H, Yano Y. A case of imported COVID-19 diagnosed by
PCR-positive lower respiratory specimen but with PCR-negative throat swabs. Infect Dis (Lond). 2020:1-4.
12. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA.
13. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19
patients. Clin Infect Dis. 2020;71(16):2249-2251. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306036.
14. Rhee C, Kanjilal S, Baker M, Klompas M. Duration of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infectivity: when is it safe to discontinue isolation? Clin Infect Dis. 2020;Published online
ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33029620.
15. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a
skilled nursing facility. N Engl J Med. 2020;382(22):2081-2090. Available at:
16. Bullard J, Dust K, Funk D, et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis.
17. Cheng HY, Jian SW, Liu DP, et al. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan
and risk at different exposure periods before and after symptom onset. JAMA Intern Med. 2020;180(9):1156-
1163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32356867.
18. Korean Disease Control and Prevention Agency. Findings from investigation and analysis of re-positive cases
[press release]. 2020. Available at: https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030.
19. Centers for Disease Control and Prevention. Duration of isolation and precautions for adults with COVID-19.
2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Accessed January
7, 2021.
20. Centers for Disease Control and Prevention. Interim guidance for antigen testing for SARS-CoV-2. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html.
Accessed January 7, 2021.
21. Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease
(COVID-19). Clin Infect Dis. 2020;71(15):778-785. Available at:
22. Haveri A, Smura T, Kuivanen S, et al. Serological and molecular findings during SARS-CoV-2 infection: the
first case study in Finland, January to February 2020. Euro Surveill. 2020;25(11). Available at:
23. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med.
24. Okba NMA, Muller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody
responses in coronavirus disease patients. Emerg Infect Dis. 2020;26(7):1478-1488. Available at:
25. Xiang F, Wang X, He X, et al. Antibody detection and dynamic characteristics in patients with COVID-19.
Clin Infect Dis. 2020;71(8):1930-1934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306047.
26. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease
2019. Clin Infect Dis. 2020;71(16):2027-2034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32221519.

Prevention of SARS-CoV-2 Infection

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination 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 1 of the following anti-SARS-CoV-2 monoclonal antibodies (listed alphabetically) as
post-exposure prophylaxis (PEP) for people who are at high risk of progressing to severe COVID-19 if infected with
SARS-CoV-2 AND who have the vaccination status AND exposure history outlined in the text below:
• Bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an intravenous (IV) infusion (BIII); or
• Casirivimab 600 mg plus imdevimab 600 mg administered as subcutaneous injections (AI) or an IV infusion (BIII).
• The Panel recommends against the use of hydroxychloroquine for SARS-CoV-2 PEP (AI).
• The Panel recommends against the use of other drugs for SARS-CoV-2 PEP, except in a clinical trial (AIII).
• The Panel recommends against the use of any drugs for SARS-CoV-2 pre-exposure prophylaxis (PrEP), except in a
clinical trial (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 further
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
Vaccination is highly effective in preventing SARS-CoV-2 infection. Anti-SARS-CoV-2 monoclonal
antibodies (mAbs) may also be effective as post-exposure prophylaxis (PEP) for certain groups of
people who are at risk of progression to serious COVID-19 and who have not been fully vaccinated or
who are not expected to mount an adequate immune response to vaccines.
Vaccines
The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for
everyone who is eligible according to CDC’s Advisory Committee on Immunization Practices (AI).

CDC regularly updates the clinical considerations for using the COVID-19 vaccines that are currently
approved by the Food and Drug Administration (FDA) or authorized for use in the United States.4
Currently, 2 mRNA vaccines are available in the United States. The 2-dose series of the BNT162b2
(Pfizer-BioNTech) vaccine was approved by FDA for individuals aged ≥16 years, and it is authorized for
use in individuals aged ≥12 years to <16 years under an Emergency Use Authorization (EUA). Emerging
data suggest that this vaccine may have potential for use in younger individuals. A pediatric formulation
of this vaccine has been authorized for use in children aged 5 to 11 years under an EUA. The 2-dose
series of the mRNA-1273 (Moderna) vaccine has an EUA for individuals aged ≥18 years. The single-dose
human adenovirus type 26 (Ad26) vectored vaccine, Ad26.COV2.S (Johnson & Johnson/Janssen), has an
EUA for individuals aged ≥18 years.
These products have also been authorized for additional doses and booster doses in certain populations.5
Studies that have evaluated the role of heterologous boosters (i.e., using a different vaccine product for
the booster than was used for the primary series) indicate that, regardless of the vaccine used for the
primary series, an additional dose of any of these products boosts antibody levels. The current vaccine
authorizations support this approach. Immunocompromised individuals who have received 2 doses of the
mRNA-1273 or BNT162b2 vaccines are eligible for an additional mRNA vaccine dose 28 days after the
primary series and a booster at 6 months. Some people who have received 2 doses of the mRNA-1273
or BNT162b2 vaccines are eligible for a booster at 6 months. Recipients of the Ad26.COV2.S vaccine
should receive a booster ≥2 months after their primary dose. CDC regularly updates the details on the
timing, dose, and volume for these additional doses and boosters, as well as the recommendations for the
populations that are eligible for these additional doses and boosters.
For people who received anti-SARS-CoV-2 mAbs for the treatment of COVID-19, CDC recommends
deferring COVID-19 vaccination until at least 90 days after therapy. For people who received anti-
SARS-CoV-2 mAbs for PEP, vaccination should be deferred until at least 30 days after PEP. This is a
precautionary measure to accommodate the theoretical possibility that anti-SARS-CoV-2 mAbs may
interfere with vaccine-induced immune responses.4
Adverse Events
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 in adults
who have received the Ad26.COV2.S vaccine.7 Most reports of this rare and serious condition have been
in women aged 18 to 49 years.8 Similar reports from Europe describe thrombocytopenia and venous
thrombosis in patients who received the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine, which
uses a chimpanzee adenoviral vector.9,10 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 the type of thrombosis with thrombocytopenia that
occurs in people who receive the Ad26.COV2.S vaccine. These considerations include information on
administering a nonheparin anticoagulant and intravenous (IV) immunoglobulin to these patients.11,12
Given the rarity of this syndrome and the unique treatment required, consider consulting a hematologist
when treating these patients.
Myocarditis and pericarditis are rarely reported in people who have received COVID-19 vaccines, and
most of the cases that have been reported were very mild and self-limiting. These conditions have occurred
most often in male adolescents and young adults and people who have received mRNA vaccines.13

Guillain-Barré syndrome (GBS), a rare neurologic disorder, has been reported in approximately 12
people per million who received the Ad26.COV2.S vaccine. 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.13
CDC provides regular updates on selected adverse events of COVID-19 vaccines on their website.
Vaccination in Pregnant or Lactating People

Pregnant and lactating individuals were not included in the initial COVID-19 vaccine trials. However,
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. These organizations also recommend vaccination
for people who are trying to become pregnant now or who may become pregnant in the future.14-20
The ACOG publication includes a guide to assist clinicians during conversations about COVID-19
vaccination with pregnant patients.21
Post-Exposure Prophylaxis
Vaccination remains a highly effective way to prevent SARS-CoV-2 infection. However, despite
widespread availability of COVID-19 vaccines, a number of individuals are either not fully vaccinated or
cannot mount adequate responses to the vaccine. Some of these individuals, if infected, are at high risk
of progressing to serious COVID-19. Based on the results of 2 large randomized controlled trials, the
FDA expanded the EUA indication for the anti-SARS-CoV-2 mAbs bamlanivimab plus etesevimab and
casirivimab plus imdevimab to allow these combinations to be used as PEP for selected individuals.22
Recommendations
The Panel recommends using 1 of the following anti-SARS-CoV-2 mAbs (listed alphabetically) as PEP
for people who are at high risk for progressing to severe COVID-19 if infected with SARS-CoV-2 AND
who have the vaccination status AND exposure history outlined in the text below.
• Bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an IV infusion (BIII); or
• Casirivimab 600 mg plus imdevimab 600 mg administered as subcutaneous (SQ) injections (AI)
or an IV infusion (BIII).
Vaccination Status:
• Not fully vaccinated (defined as people who were never vaccinated, those who received the first
dose of a 2-dose series, or those who received the second dose of a 2-dose series or a single-dose
vaccine <2 weeks ago); or
• Fully vaccinated, but not expected to mount an adequate immune response (e.g., those with
immunocompromising conditions, including those who are taking immunosuppressive
medications).
AND
Exposure History to SARS-CoV-2:
• Had a recent exposure to an individual with SARS-CoV-2 infection that is consistent with CDC
close contact criteria; or

• Had a high risk of exposure to an individual with SARS-CoV-2 infection because of a recent
occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (e.g.,
nursing homes, prisons).
The doses should be administered as soon as possible and preferably within 7 days of high-risk exposure
(BIII). The patient should be observed for at least 1 hour after the injections or infusion for anaphylaxis
and infusion-related reactions.
It should be noted that even though the EUA calls for the combination of bamlanivimab 700 mg plus
etesevimab 1,400 mg administered as a single IV infusion, the clinical trial that was used to support
the EUA only studied bamlanivimab monotherapy at a single dose of 4,200 mg (see Anti-SARS-CoV-2
Monoclonal Antibodies).
The EUA for casirivimab plus imdevimab allows for repeat dosing of casirivimab 300 mg plus
imdevimab 300 mg once every 4 weeks using SQ injections or an IV infusion for those who meet the
EUA criteria for PEP and have ongoing exposures. However, there are no data from the COVID-19
Phase 3 Prevention Trial or other studies on the utility of repeat dosing for individuals who continue to
have high-risk exposures. Therefore, the Panel finds that there is insufficient evidence to recommend
either for or against repeat dosing every 4 weeks for those who received PEP and who continue to have
high-risk exposures.
If there are shortages of anti-SARS-CoV-2 mAbs or logistical constraints (e.g., limited space, not
enough staff who can administer therapy), it may be difficult to administer these agents to all eligible
patients. In situations where it is necessary to triage eligible patients, the Panel suggests prioritizing the
treatment of COVID-19 over PEP. For further guidance on prioritizing the use of these mAbs, see this
statement from the Panel.
Clinical Trial Data for Bamlanivimab Monotherapy
BLAZE-2 is a double-blind, Phase 3 randomized trial that enrolled residents and staff of 74 skilled
nursing and assisted living facilities in the United States. Each facility had had at least 1 confirmed index
case of SARS-CoV-2 infection, and the staff and residents had no known history of COVID-19.23 All
participants provided both nasal and nasopharyngeal (NP) swabs for reverse transcription polymerase
chain reaction (RT-PCR)-based diagnostic tests and blood for SARS-CoV-2 antibody testing. Nasal and
NP swabs were obtained weekly for 57 days.
Participants who were found to be RT-PCR and antibody negative were considered the prevention
population. Between August and November 2020, the study randomized 1,175 participants 1:1 to receive
either bamlanivimab monotherapy at a dose of 4,200 mg or placebo by IV infusion. The prevention
population included 484 participants who received bamlanivimab (323 staff and 161 residents) and 482
participants who received placebo (343 staff and 139 residents). The baseline characteristics of the staff
and resident populations were very different; for example, the residents had a median age that was >30
years higher than the staff (76 years vs. 43 years) and had greater risks for disease progression.
In the overall prevention population, 114 participants (11.9%) experienced mild or worse COVID-19
by Day 57. There was a significantly lower incidence of mild or worse COVID-19 in the bamlanivimab
arm than in the placebo arm (8.5% vs. 15.2%; OR 0.43; 95% CI, 0.28–0.68; P < 0.001), with an absolute
risk difference of -6.6 percentage points (95% CI, -10.7 to -2.6). The difference was most significant in
the resident population, where the incidence of mild or worse COVID-19 was 8.8% in the bamlanivimab
arm compared to 22.5% in the placebo arm (OR 0.20; 95% CI, 0.08–0.49; P < 0.001), with an absolute
difference of -13.7 percentage points (95% CI, -21.9 to -5.4). In contrast, the difference between
the bamlanivimab and placebo arms did not achieve statistical significance in the staff prevention
population. Similar findings were observed for the secondary endpoint of the incidence of moderate or

worse COVID-19.
In the prevention population, 198 participants (20.6%) had positive RT-PCR results within 4 weeks
of randomization. The frequency of positive results was significantly lower in the bamlanivimab arm
than in the placebo arm (17.9% vs. 23.3%; OR 0.66; 95% CI, 0.46–0.94; P = 0.02), with an absolute
risk difference of -5.4 percentage points (95% CI, -10.5 to -0.3). The difference was significant for the
resident prevention population but not the staff prevention population. An additional secondary endpoint
in this study was mortality due to COVID-19; a total of 4 participants died, all of whom were residents
who were randomized to receive placebo.
The overall safety population included 1,175 participants. Serious adverse events were reported in
3.7% of bamlanivimab recipients and 3.2% of placebo recipients. Any adverse events were reported in
20.1% of participants in the bamlanivimab arm and 18.9% of those in the placebo arm. The types of
events were balanced across the study arms. Hypersensitivity reactions that occurred within 24 hours of
study product infusion were reported in 3 participants (0.5%) in the bamlanivimab arm and none in the
placebo arm.
Clinical Trial Data for Casirivimab Plus Imdevimab
Casirivimab plus imdevimab was evaluated as PEP in a Phase 3, double-blind randomized placebo-
controlled trial that was conducted at 112 sites in the United States, Romania, and Moldova.24 The
trial enrolled individuals aged ≥12 years who were exposed to a household contact (the index patient)
who had a positive SARS-CoV-2 RT-PCR result from a NP swab specimen that was collected within
the previous 96 hours. Study participants were asymptomatic, had a negative NP RT-PCR result for
SARS-CoV-2, and intended to live with the index patient for the 28-day duration of follow-up.
Participants were randomized 1:1 to receive casirivimab 600 mg plus imdevimab 600 mg or placebo
administered as 4 SQ injections (2.5 mL per injection) at different sites. NP swabs were collected weekly.
The primary efficacy endpoint was the proportion of participants who developed symptomatic, RT-PCR-
confirmed SARS-CoV-2 infection during the 28 days of follow-up. Additional key efficacy endpoints
included asymptomatic infection and the quantity and duration of viral shedding detected by NP swabs.
The primary analysis included 1,505 participants (753 in the casirivimab plus imdevimab arm and 752 in
the placebo arm) who had negative SARS-CoV-2 RT-PCR results at baseline and who were subsequently
found to be serum SARS-CoV-2 antibody negative. The mean age was 42.9 years, 45.9% of participants
were men, and 9.3% of participants were Black or African American and 40.5% were Hispanic/Latino.
The protocol-specified risk factors for progression to severe COVID-19 were present in 30.5% of
participants, with approximately 75% meeting the high-risk criteria in the revised EUA.
The use of casirivimab plus imdevimab resulted in a significant reduction in the risk of symptomatic
SARS-CoV-2 infection when compared with placebo (81.4% risk reduction: 11 of 753 participants
[1.5%] vs. 59 of 752 patients [7.8%]; OR 0.17; P < 0.001). This risk reduction was present throughout
the follow-up period, starting from the first week and continuing through Week 4. Using both
asymptomatic and symptomatic infections as an endpoint, the use of casirivimab plus imdevimab
was associated with a significant reduction in risk compared to placebo (66.4% risk reduction; 36
of 753 participants [4.8%] vs. 107 of 752 participants [14.2%]; OR 0.31; 95% CI, 0.21–0.46; P <
0.0001). Among the subset of participants who were found to be seropositive at baseline (and were
therefore excluded from the primary analysis), only a small number of participants reached the study
endpoints, and there was no significant difference in the number who reached the endpoints between the
casirivimab plus imdevimab arm (1 of 235 patients [0.4%]) and the placebo arm (5 of 222 participants
[2.3%]; OR 0.19; 95% CI, 0.02–1.68; P = 0.14).

Hospitalizations were rare, with no hospitalized participants in the casirivimab plus imdevimab arm
and 4 in the placebo arm. Some participants in the study received casirivimab plus imdevimab before
they received their RT-PCR results; among these participants, those who eventually received positive
RT-PCR results had a shorter duration of viral detection than the participants in the placebo arm (mean
of 1.1 vs. 2.2 weeks). The frequencies of adverse events were similar between the 2 arms.
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-
2.25,26 A small cohort study without a control group suggested that hydroxychloroquine might reduce the
risk of SARS-CoV-2 transmission to close contacts.27 There have been several large trials to determine
whether hydroxychloroquine can reduce the risk of infection after exposure to infected individuals.
These studies used different dosing 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.28-30
Other Drugs for PEP

• 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, 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.31,32
Population data indicated that country-wide, mass-use of prophylactic chemotherapy for parasitic
infections, including the use of ivermectin, was associated with a lower incidence of COVID-19.33 At
this time, few clinical trials have evaluated the safety and efficacy of using ivermectin for SARS-CoV-2
pre-exposure prophylaxis (PrEP) or PEP. Although several studies have reported potentially promising
results, the findings are limited by the design of the studies, their small sample sizes, and the lack of
details regarding the safety and efficacy of ivermectin.
In a descriptive, uncontrolled, interventional study of 33 contacts of patients with laboratory-confirmed
COVID-19, no cases of SARS-CoV-2 infection were identified within 21 days of initiating ivermectin
for PEP.34 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.35
Pre-Exposure Prophylaxis
• The Panel recommends against the use of any drugs for SARS-CoV-2 PrEP, except in a clinical
trial (AIII).
Rationale
At present, there is no known agent that is effective in preventing infection when administered before
exposure to SARS-CoV-2 (i.e., as PrEP). 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. Studies of anti-SARS-CoV-2 mAbs
that target SARS-CoV-2 are also underway. Please check 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 for 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.36
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.37 Neither study
demonstrated any evidence of a reduction in rate of acquiring infection. Both studies reported an increased
frequency of mild adverse events in the treatment group.
References
1. Centers for Disease Control and Prevention. Scientific brief: SARS-CoV-2 transmission. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/sars-cov-2-transmission.html. Accessed
November 16, 2021.
2. 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 September 30,
2021.
3. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): infection control guidance
for healthcare professionals about coronavirus (COVID-19). 2020. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed November 17, 2021.
4. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines
currently approved or authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/
covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed November 17, 2021.
5. Mbaeyi S, Oliver SE, Collins JP, et al. The Advisory Committee on Immunization Practices’ interim
recommendations for additional primary and booster doses of COVID-19 vaccines—United States, 2021.
MMWR Morb Mortal Wkly Rep. 2021;70(44):1545-1552. Available at:
6. Centers for Disease Control and Prevention. Interim considerations: preparing for the potential management of
anaphylaxis after COVID-19 vaccination. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-
product/pfizer/anaphylaxis-management.html. Accessed November 17, 2021.
7. 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). 2021. Available at: https://www.fda.gov/media/146304/download.
8. Centers for Disease Control and Prevention. CDC recommends use of Johnson & Johnson’s Janssen COVID-19
vaccine resume. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/JJUpdate.html.
Accessed September 9, 2021.
9. Pottegard A, Lund LC, Karlstad O, et al. Arterial events, venous thromboembolism, thrombocytopenia, and
bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based
cohort study. BMJ. 2021;373:n1114. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33952445.
10. Taquet M, Husain M, Geddes JR, Luciano S, Harrison PJ. Cerebral venous thrombosis and portal vein
thrombosis: a retrospective cohort study of 537,913 COVID-19 cases. EClinicalMedicine. 2021;39:101061.
11. American Society of Hematology. Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced
thrombotic thrombocytopenia). 2021. Available at: https://www.hematology.org/covid-19/vaccine-induced-
immune-thrombotic-thrombocytopenia. Accessed September 9, 2021.
12. Furie KL, Cushman M, Elkind MSV, Lyden PD, Saposnik G, American Heart Association/American Stroke

Association Stroke Council L. Diagnosis and management of cerebral venous sinus thrombosis with vaccine-
induced immune thrombotic thrombocytopenia. Stroke. 2021;52(7):2478-2482. Available at:
13. Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination.
2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html.
14. Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html.
15. The American College of Obstetricians and Gynecologists. COVID-19 vaccination considerations for
obstetric-gynecologic care. 2021. Available at: https://www.acog.org/clinical/clinical-guidance/practice-
advisory/articles/2020/12/covid-19-vaccination-considerations-for-obstetric-gynecologic-care. Accessed
September 9, 2021.
16. Society for Maternal Fetal Medicine. COVID-19 publications & clinical guidance. 2021. Available at:
https://www.smfm.org/covidclinical. Accessed September 9, 2021.
17. 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:
18. Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA COVID-19 vaccines and risk of spontaneous
abortion. N Engl J Med. 2021;385(16):1533-1535. Available at:
19. Goldshtein I, Nevo D, Steinberg DM, et al. Association between BNT162b2 vaccination and incidence of
SARS-CoV-2 infection in pregnant women. JAMA. 2021;326(8):728-735. Available at:
20. Collier AY, McMahan K, Yu J, et al. Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating
women. JAMA. 2021;325(23):2370-2380. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33983379.
21. The American College of Obstetricians and Gynecologists. Practice advisory: vaccinating pregnant and
lactating patients against COVID-19. 2021. Available at: https://www.acog.org/clinical/clinical-guidance/
practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19. Accessed
November 17, 2021.
REGEN-COV (casirivimab and imdevimab). 2021. Available at:
23. Cohen MS, Nirula A, Mulligan MJ, et al. Effect of bamlanivimab vs placebo on incidence of COVID-19
among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial. JAMA.
24. O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent
COVID-19. N Engl J Med. 2021;385(13):1184-1195. Available at:
25. 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.
26. 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.
27. 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:

28. 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.
29. 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:
30. Mitjà O, Corbacho-Monné 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://pubmed.ncbi.nlm.nih.gov/33289973.
31. 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:
32. 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:
33. 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:
34. Aguirre Chang GF, Figueredo ANT. COVID-19: post-exposure prophylaxis with ivermectin in contacts.
ResearchGate. 2020;Preprint. Available at: https://www.researchgate.net/publication/344781515_COVID-19_
POST-EXPOSURE_PROPHYLAXIS_WITH_IVERMECTIN_IN_CONTACTS_At_Homes_Places_of_
Work_Nursing_Homes_Prisons_and_Others.
35. 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:
36. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-
exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med.
37. 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.

Clinical Spectrum of SARS-CoV-2 Infection

Last Updated: October 19, 2021
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 cardiovascular disease, chronic lung disease,
sickle cell disease, diabetes, cancer, obesity, or chronic kidney disease; 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.
The optimal pulmonary imaging technique has not yet been defined for people with symptomatic
SARS-CoV-2 infection. Initial evaluation for these patients may include a chest X-ray, ultrasound
screening, or, if indicated, a computed tomography scan. An electrocardiogram should be performed if
indicated. Laboratory testing includes 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 may be 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 subsection of each section of 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 that are consistent
with COVID-19 pneumonia.10,11 Increasing the availability of virologic testing for SARS-CoV-2
and reliable serologic assays for SARS-CoV-2 antibodies will help determine the true prevalence of
asymptomatic and presymptomatic infection. See Therapeutic Management of Nonhospitalized Adults
With COVID-19 for recommendations regarding SARS-CoV-2-specific therapy.
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 mildly ill patients 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. If bacterial
pneumonia or sepsis is suspected, administer empiric antibiotic treatment, re-evaluate the patient
daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection. See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for recommendations regarding SARS-CoV-2-
specific therapy.
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 secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, re-evaluate the
patient daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection.

Critical Illness
Critically ill patients may have acute respiratory distress syndrome, septic shock that may represent
virus-induced distributive shock, cardiac dysfunction, an exaggerated inflammatory response, and/or
exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with critical illness
may also experience cardiac, hepatic, renal, central nervous system, or thrombotic disease.
As with any patient in the intensive care unit (ICU), successful clinical management of a patient with
COVID-19 includes treating both the medical condition that initially resulted in ICU admission and
other comorbidities and nosocomial complications. For more information, see Care of Critically Ill Adult
Patients With COVID-19.
Infectious Complications in Patients With COVID-19

Some patients with COVID-19 may have additional infections that are noted 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 With COVID-19: 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.,
treatment with 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 in Patients With COVID-19: 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 more commonly seen in
immunocompromised patients and in patients who are on mechanical ventilation. The majority
of mucormycosis cases have been reported in India and are associated with diabetes mellitus and/
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
As seen with other viral infections, reinfection with SARS-CoV-2 after recovery from prior infection
has been reported.27 The true prevalence of reinfection is not known, although there are concerns that
the frequency of reinfection may increase with the circulation of new variants.28 SARS-CoV-2 can often
be detected from a nasal swab for weeks to months after the initial infection; therefore, repeat testing
to evaluate for reinfection should be considered only for those who have recovered from the initial
infection and present with COVID-19-compatible symptoms with no obvious alternate etiology (AIII).29
Diagnostic testing in this setting is summarized in Testing for SARS-CoV-2 Infection. In addition,
if reinfection is suspected, guidelines for the diagnosis and evaluation of suspected SARS-CoV-2
reinfection are provided by the Centers for Disease Control and Prevention (CDC).30
It has been speculated that reinfection may occur more frequently in those who have a less robust
immune response during the initial infection, as is often reported in those with mild illness. Reinfection
may also occur as initial immune responses wane over time. Nevertheless, one review noted that
SARS-CoV-2 reinfection occurred after previous severe disease in three cases and as early as 3 weeks
after the initial infection was diagnosed.31 A public site that posts a variety of published and unpublished
reports of reinfection notes that reinfection has occurred anywhere from a few weeks to many months
after the initial infection, and it occasionally follows episodes of severe COVID-19.32 Although data
are limited, there is no evidence to suggest that the treatment of suspected or documented SARS-CoV-2
reinfection 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 or Organ Dysfunction After Acute COVID-19

There have been an increasing number of reports of patients who experience persistent symptoms and/or
organ dysfunction after acute COVID-19. Data about the incidence, natural history, and etiology of these
symptoms are emerging. However, these reports have several limitations. For example, there is currently
no agreed-upon case definition for persistent symptoms or organ dysfunction after acute COVID-19. In
addition, most of these reports only included patients who attended post-COVID-19 clinics, and they
often lack comparator groups. No specific treatments for the persistent effects of COVID-19 have yet
been identified, although this COVID-19 rapid guideline proposes general management strategies.
The nomenclature for this phenomenon is evolving, and there is no established clinical terminology to
date. It has been referred to as post-COVID-19 condition, or, colloquially, “long COVID,” and affected
patients have been referred to as “long haulers.” The term “post-acute sequelae of COVID-19” (PASC)
has also been used to describe late sequelae of SARS-CoV-2 infection that include these persistent
symptoms, as well as other delayed syndromes such as MIS-C and multisystem inflammatory syndrome
in adults (MIS-A). To date, no case definition and no specific time frame have been established to define
the syndrome of persistent symptoms and/or organ dysfunction after acute COVID-19. However, CDC
recently proposed defining late sequelae as sequelae that extend >4 weeks after initial infection.33,34 The
Patient-Led Research Collaborative for COVID-19 defines long COVID as a collection of symptoms
that develop during or following a confirmed or suspected case of COVID-19 and that continue for >28
days.35 Incidence rates vary widely, from about 10% in some reports to one cohort study in which 87%
of patients reported at least one persistent symptom.36
Some of the symptoms overlap with the post-intensive care syndrome (PICS) that has been described
in patients without COVID-19, but prolonged symptoms and disabilities after COVID-19 have also
been reported in patients with milder illness, including outpatients (see General Considerations for
information on PICS).37,38

Despite the limitations of the available descriptive data on these persistent symptoms, some
representative studies have suggested that common findings include fatigue, joint pain, chest pain,
palpitations, shortness of breath, cognitive impairment, and worsened quality of life.39,40
CDC conducted a telephone survey of a random sample of 292 adult outpatients who had positive
polymerase chain reaction results for SARS-CoV-2. Among the 274 respondents who were symptomatic
at the time of testing, 35% reported not having returned to their usual state of health 2 weeks or more
after testing; this included 26% of patients aged 18 to 34 years, 32% of those aged 35 to 49 years, and
47% of those aged ≥50 years.38 An age of ≥50 years and the presence of three or more chronic medical
conditions were associated with not returning to usual health within 14 to 21 days. Moreover, one in
five individuals aged 18 to 34 years who did not have chronic medical conditions had not returned to
baseline health when interviewed at a median of 16 days from the testing date.
In a cohort study from Wuhan, China, 1,733 discharged patients with COVID-19 were evaluated for
persistent symptoms at a median of 186 days after symptom onset.41 The most common symptoms
were fatigue or muscle weakness and sleep difficulties (reported among 63% and 26% of participants,
respectively). Anxiety or depression was reported among 23% of patients.
In a longitudinal prospective cohort of mostly outpatients with laboratory-confirmed SARS-CoV-2
infection at the University of Washington, 177 participants completed a follow-up questionnaire
between 3 and 9 months after illness onset.42 Overall, 91% of the respondents were outpatients (150
with mild illness and 11 with no symptoms), and only 9% had moderate or severe disease that required
hospitalization. Among those who reported symptoms, 33% of outpatients and 31% of hospitalized
patients reported at least one 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. The
most common persistent symptoms were loss of sense of smell or taste and fatigue (both reported by
14% of patients).
Persistent symptoms after acute COVID-19 have also been reported in pregnant people.43 Systematic
data on persistent symptoms in children following recovery from the acute phase of COVID-19 are
not currently available, although case reports suggest that children may experience long-term effects
similar to those experienced by adults after clinical COVID-19.44,45 MIS-C is discussed in Special
Considerations in Children.
Fatigue
The prevalence of fatigue among 128 individuals from Ireland who had recovered from the acute phase
of COVID-19 was examined using the Chalder Fatigue Scale (CFQ11). More than half of patients (67
of 128 patients [52.3%]) reported persistent fatigue at a median of 10 weeks after initial symptoms first
appeared. There was no association between illness severity and fatigue.46 An outpatient service that
was developed in Italy for patients recovering from acute COVID-19 reported that 87% of 143 patients
surveyed had persistent symptoms for a mean of 60 days after symptom onset. The most common
symptom was fatigue, which occurred in 53.1% of these patients.36
Cardiopulmonary
A study from the United Kingdom reported that among 100 hospitalized patients with COVID-19 (32
received care in the ICU and 68 received care in hospital wards only), 72% of the ICU patients and 60%
of the ward patients experienced fatigue and breathlessness at 4 to 8 weeks after hospital discharge.
The authors suggested that posthospital rehabilitation may be necessary for some of these patients.39 A
retrospective study from China found that pulmonary function (as measured by spirometry) was still
impaired 1 month after hospital discharge in 31 of 57 patients (54.4%) with COVID-19.47 In a study

from Germany that included 100 patients who had recently recovered from COVID-19, cardiac magnetic
resonance imaging (MRI) performed a median of 71 days after diagnosis revealed cardiac involvement
in 78% of patients and ongoing myocardial inflammation in 60% of patients.48 A retrospective study
from China of 26 patients who had recovered from COVID-19 and who had initially presented with
cardiac symptoms found abnormalities on cardiac MRI in 15 patients (58%).49 This assessment of the
prevalence of cardiac abnormalities in people with PASC should be viewed with caution, however, as
the analysis included only patients with cardiac symptoms.
Neuropsychiatric
Neurologic and psychiatric symptoms have also been reported among patients who have recovered
from acute COVID-19. High rates of anxiety and depression have been reported in some patients using
self-report scales for psychiatric distress.40,50 Younger patients have been reported to experience more
psychiatric symptoms than patients aged >60 years.39,40 Patients may continue to experience headaches,
vision changes, hearing loss, loss of taste or smell, impaired mobility, numbness in extremities, tremors,
myalgia, memory loss, cognitive impairment, and mood changes for up to 3 months after diagnosis of
COVID-19.51-53 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.54
However, the study authors did not report when the tests were administered in relation to the diagnosis
of COVID-19.
More research and more rigorous observational cohort studies are needed to better understand the
pathophysiology and clinical course of post-acute COVID-19 sequelae and to identify management
strategies for patients. More information about ongoing studies can be found at ClinicalTrials.gov.
References
1. Centers for Disease Control and Prevention. COVID-19 (coronavirus disease): people with certain medical
conditions. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-
with-medical-conditions.html. Accessed August 31, 2021.
2. Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with computed tomographic findings and predicts
severe COVID-19 early. J Med Virol. 2020;92(7):856-862. Available at:
3. Berger JS, Kunichoff D, Adhikari S, et al. Prevalence and outcomes of D-dimer elevation in hospitalized
patients with COVID-19. Arterioscler Thromb Vasc Biol. 2020;40(10):2539-2547. Available at:
4. Casas-Rojo JM, Anton-Santos JM, Millan-Nunez-Cortes J, et al. Clinical characteristics of patients
hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Registry. Rev Clin Esp.
5. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19.
2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_
COVID_pos_preg_patients_4-30-20_final.pdf.
6. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for
clinicians. Obstet Gynecol. 2009;114(6):1326-1331. Available at:
7. Anderson BL, Mendez-Figueroa H, Dahlke JD, Raker C, Hillier SL, Cu-Uvin S. Pregnancy-induced changes
in immune protection of the genital tract: defining normal. Am J Obstet Gynecol. 2013;208(4):321 e321-329.

8. 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:
9. 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
10. Zhang R, Ouyang H, Fu L, et al. CT features of SARS-CoV-2 pneumonia according to clinical presentation:
a retrospective analysis of 120 consecutive patients from Wuhan city. Eur Radiol. 2020;30(8):4417-4426.
11. Inui S, Fujikawa A, Jitsu M, et al. Chest CT findings in cases from the cruise ship “Diamond Princess” with
coronavirus disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging. 2020;2(2). Available at:
https://pubs.rsna.org/doi/10.1148/ryct.2020200110.
12. Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between SARS-CoV-2 and other
respiratory pathogens. JAMA. 2020;323(20):2085-2086. Available at:
13. Kubin CJ, McConville TH, Dietz D, et al. Characterization of bacterial and fungal infections in hospitalized
patients with coronavirus disease 2019 and factors associated with health care-associated infections. Open
Forum Infect Dis. 2021;8(6):ofab201. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34099978.
14. Garg N, Lee YI. Reactivation TB with severe COVID-19. Chest. 2020;158(4). Available at:
https://journal.chestnet.org/article/S0012-3692(20)32910-X/fulltext.
15. Rodriguez-Tajes S, Miralpeix A, Costa J, et al. Low risk of hepatitis B reactivation in patients with severe
COVID-19 who receive immunosuppressive therapy. J Viral Hepat. 2021;28(1):89-94. Available at:
16. Aldhaleei WA, Alnuaimi A, Bhagavathula AS. COVID-19 induced hepatitis B virus reactivation: a novel case
from the United Arab Emirates. Cureus. 2020;12(6):e8645. Available at:
17. Xu R, Zhou Y, Cai L, et al. Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1
and varicella zoster virus) in a critically ill patient with COVID-19. Br J Dermatol. 2020;183(6):1145-1147.
18. Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19.
Am J Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642.
19. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive
therapy for SARS-CoV-2 pneumonia. Infection. 2021;49(3):539-542. Available at:
20. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-
related strongyloides hyperinfection. JAMA. 2020;324(7):623-624. Available at:
21. Salmanton-Garcia J, Sprute R, Stemler J, et al. COVID-19-associated pulmonary aspergillosis, March–
August 2020. Emerg Infect Dis. 2021;27(4):1077-1086. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33539721.
22. Chong WH, Neu KP. Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis
(CAPA): a systematic review. J Hosp Infect. 2021;113:115-129. Available at:
23. 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:
24. Yusuf E, Seghers L, Hoek RAS, van den Akker JPC, Bode LGM, Rijnders BJA. Aspergillus in critically ill

COVID-19 patients: a scoping review. J Clin Med. 2021;10(11). Available at:

25. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: a systematic review of cases reported
worldwide and in India. Diabetes Metab Syndr. 2021;15(4):102146. Available at:
26. Pal R, Singh B, Bhadada SK, et al. COVID-19-associated mucormycosis: an updated systematic review of
literature. Mycoses. 2021;Published online ahead of print. Available at:
27. Cohen J, Burbelo PD. Reinfection with SARS-CoV-2: implications for vaccines. Oxford Clin Infect Dis.
2020;Published online ahead of print. Available at: https://pubmed.ncbi.nlm.nih.gov/33338197.
28. Nonaka CKV, Franco MM, Graf T, et al. Genomic evidence of SARS-CoV-2 reinfection case with E484K
spike mutation, Brazil. Emerg Infect Dis. 2021;27(5). Available at:
29. Centers for Disease Control and Prevention. Interim guidance on duration of isolation and precautions for
adults with COVID-19. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-
isolation.html. Accessed August 31, 2021.
30. Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2
reinfection (ICR). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/php/invest-criteria.html.
Accessed August 31, 2021.
31. Kim AY, Gandhi RT. Reinfection with severe acute respiratory syndrome coronavirus 2: what goes around
may come back around. Clin Infect Dis. 2020. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665341.
32. BNO News. COVID-19 reinfection tracker. 2020. Available at:
https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker. Accessed August 31, 2021.
33. Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due
to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA.
34. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary
care. BMJ. 2020;370:m3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32784198.
35. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of Long-COVID: analysis of COVID cases
and their symptoms collected by the COVID symptoms study app. Nat Med. 2021;27(4):626-631. Available
at: https://pubmed.ncbi.nlm.nih.gov/33692530/.
36. 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:
37. Rawal G, Yadav S, Kumar R. Post-intensive care syndrome: an overview. J Transl Int Med. 2017;5(2):90-92.
38. 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
39. 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:
40. 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:

41. 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:
42. Logue JK, Franko NM, MucCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection.
JAMA Netw Open. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/33606031/.
43. 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:
44. Ludvigsson JF. Case report and systematic review suggest that children may experience similar long-term
effects to adults after clinical COVID-19. Acta Paediatr. 2021 Mar;110(3):914-921. Available at:
45. Buonsenso D, Munblit D, De Rose C, et al. Preliminary evidence on long COVID in children. Acta Paediatr.
2021;110(7):2208-2211. Available at: https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1.
46. 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:
47. Huang Y, Tan C, Wu J, et al. Impact of coronavirus disease 2019 on pulmonary function in early
convalescence phase. Respir Res. 2020;21(1):163. Available at:
48. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in
patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-
49. Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using
magnetic resonance imaging. JACC Cardiovasc Imaging. 2020;13(11):2330-2339. Available at:
50. 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:
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. Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from
COVID-19 relative to controls: an N = 84,285 online study. medRxiv. 2020;Preprint. Available at:
https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1.

Clinical Management 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, it is anticipated that therapies that
directly target SARS-CoV-2 would 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. Figure 1 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. Figure 2 provides guidance on the therapeutic management of hospitalized adult patients
according to their disease severity and oxygen requirements.



General Management of Nonhospitalized Patients With

Acute COVID-19
• 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.

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):475-481.
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.
25. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020.
Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_COVID_
pos_preg_patients_4-30-20_final.pdf.

Therapeutic Management of Nonhospitalized Adults With

COVID-19
Figure 1 outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for using
therapeutic interventions outside the hospital inpatient setting. These recommendations differ depending
on the patient’s disposition.

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 Figure 1

Two combination anti-SARS-CoV-2 monoclonal antibody (mAb) products (bamlanivimab plus
etesevimab and casirivimab plus imdevimab) and a single mAb (sotrovimab) have been shown to reduce
the risk of hospitalization and death in the outpatient setting in those with mild to moderate COVID-19
symptoms and certain risk factors for disease progression. As a result, these products have received
Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA) for the treatment
of COVID-19 in these individuals, as well as in those with other risk factors for progression that have
been identified in population-based studies. There are no comparative data to determine whether there are
differences in clinical efficacy or safety between these products.
The Panel recommends using one of the following anti-SARS-CoV-2 mAbs to treat outpatients with
mild to moderate COVID-19 who are at high risk of clinical progression, as defined by the EUA criteria
(treatments are listed in alphabetical order, and they may change based on circulating variants):
• Bamlanivimab plus etesevimab; or
• Casirivimab plus imdevimab; or
• Sotrovimab
The availability of bamlanivimab and etesevimab is restricted in areas with an elevated prevalence of
variants that have markedly reduced in vitro susceptibility to these agents (e.g., the Gamma and Beta
variants). Please see this statement from the Department of Health and Human Services for an update on
the distribution of bamlanivimab and etesevimab.
The Delta (B.1.617.2, non-AY.1/AY.2) variant is currently the predominant variant of concern (VOC)
in the United States. This VOC retains in vitro susceptibility to all the anti-SARS-CoV-2 mAbs that are
currently available through EUAs.3,4
Treatment should be started as soon as possible after the patient receives a positive result on a
SARS-CoV-2 antigen test or a nucleic acid amplification test (NAAT) and within 10 days of symptom
onset. When logistical or supply constraints limit the availability of anti-SARS-CoV-2 mAbs, the Panel
recommends prioritizing the treatment of patients who are at the highest risk of clinical progression (see
the Panel’s statement on prioritizing the use of anti-SARS-CoV-2 mAbs). For more details on the available
clinical trial data for these antibodies, see Anti-SARS-CoV-2 Monoclonal Antibodies and Table 3a.
The Centers for Disease Control and Prevention recommends deferring COVID-19 vaccination for at
least 90 days in those who have received anti-SARS-CoV-2 mAbs. This is a precautionary measure,
as the antibody treatment may interfere with vaccine-induced immune responses. In people who are
vaccinated and then develop COVID-19, prior receipt of a vaccine should not affect treatment decisions,
including the use of and timing of treatment with mAbs.5

Dexamethasone
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
(AIII). There is currently a lack of safety and efficacy data on the use of these agents, and systemic
glucocorticoids may cause harm in these patients. 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).
In the RECOVERY trial, dexamethasone was shown to reduce mortality in hospitalized patients with
COVID-19 who required supplemental oxygen. There was no observed benefit of dexamethasone in
hospitalized patients who did not receive oxygen support.6 Nonhospitalized patients who did not require
supplemental oxygen were not included in this trial; therefore, the safety and efficacy of corticosteroids
in this population have not been established. The Panel recommends against the use of dexamethasone
or other systemic glucocorticoids in this population, as there are no clinical trial data to support
their use (AIII). Moreover, 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.
Dexamethasone was stopped at the time of hospital discharge during the RECOVERY trial. For
hospitalized patients with COVID-19 who do not require supplemental oxygen after discharge, the Panel
recommends against the continuation of dexamethasone (AIIa).
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. The practice of discharging inpatients who still
require oxygen was likely uncommon during the RECOVERY trial; therefore, there is insufficient
evidence to recommend either for or against the continued use of dexamethasone after hospital discharge
in patients who require supplemental oxygen. Data that support the use of corticosteroids after discharge
are limited. The main concern is that discharged patients cannot be closely monitored for the toxicities that
are associated with corticosteroid use, which include increased blood glucose levels and neuropsychiatric
impairment. 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, and
these patients should be carefully monitored for adverse events. These individuals should receive oximetry
monitoring and close follow-up through telehealth, visiting nurse services, or in-person clinic visits.
In rare cases, patients with COVID-19 who require supplemental oxygen and hospital admission may
need to be discharged from the emergency department (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 orally 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
Remdesivir
Remdesivir is currently the only drug that is approved by the FDA for the treatment of COVID-19. It is
recommended for use in hospitalized patients who require supplemental oxygen. The clinical trials that
evaluated the safety and efficacy of remdesivir stopped this treatment at the time of discharge from the
hospital.7-9 The Panel recommends against the continuation of remdesivir in hospitalized patients with
COVID-19 who are stable enough for discharge and who do not require supplemental oxygen (AIIa).
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. There is insufficient evidence to recommend
either for or against the continued use of remdesivir after hospital discharge in patients who require
supplemental oxygen. Since remdesivir can only be administered by intravenous infusion, there may be
logistical issues with providing remdesivir to outpatients. If remdesivir is provided, it should only be
administered in health care settings that can provide a similar level of care to an inpatient hospital. These
individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse
services, or in-person clinic visits.
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). There is insufficient evidence to recommend either for or against the routine use of
remdesivir in this setting. If remdesivir is provided, it should only be administered in health care settings
that can provide a similar level of care to an inpatient hospital. These individuals should receive oximetry
Baricitinib
The pivotal safety and efficacy trials for baricitinib enrolled hospitalized patients with COVID-19,
and treatment was stopped at the time of hospital discharge.10,11 The Panel recommends against the
continuation of baricitinib in hospitalized patients with COVID-19 who are stable enough for discharge
and who do not require supplemental oxygen (AIIa).
There is insufficient evidence to recommend either for or against the continued use of baricitinib after
hospital discharge in patients who have been discharged from the inpatient setting but who still require
supplemental oxygen.
There are currently no data that assess the safety and efficacy of using baricitinib in patients who require
supplemental oxygen and hospital admission, but who have been discharged from the ED due to scarce
resources. Therefore, the Panel recommends against the use of baricitinib in these patients, except in a
clinical trial (AIII).
Other Agents That Have Been Studied or Are Under Investigation for Use in
Outpatients With COVID-19
• 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 and nitazoxanide
• Convalescent plasma
• Immunomodulators, such as colchicine and fluvoxamine
• Supplements, such as vitamin C, vitamin D, and zinc
• Anticoagulants and antiplatelet therapy should not be initiated in the outpatient setting 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 (AIII). 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-2.12 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.
Patients who use a continuous positive airway pressure (CPAP) device or a bilevel positive airway
pressure (BiPAP) device to manage obstructive sleep apnea may continue to use their machine. As with
nebulizers, patients should be advised to use the device only when they are isolated from others.
References
1. 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-
2. National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS
Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of
NICE guidelines. BMJ. 2020;369:m1461. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32312715.
bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download.
4. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA)
of REGEN-COV (casirivimab and imdevimab). 2021. Available at: https://www.fda.gov/media/145611/
download.
currently authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-
product/clinical-considerations.html. Accessed September 16, 2021.
6. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with
7. 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.
8. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919.
9. 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:

10. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N
11. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480861.
12. 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
Figure 2. Therapeutic Management of Hospitalized Adults With COVID-19 Based on

Disease Severity
Dosing regimens for the drugs recommended in this figure are listed in Table A below.

Table A. Dosing Regimens for the Drugs Recommended in Figure 2

Drug Name Dosing Regimen Comments
Remdesivir RDV 200 mg IV once, then RDV • If the patient progresses to more severe illness, complete the
100 mg IV once daily for 4 days course of RDV.
or until hospital discharge. • For a discussion on using RDV in patients with renal
insufficiency, see Remdesivir.
Dexamethasone DEX 6 mg IV or PO once daily for • If DEX is not available, an equivalent dose of another
up to 10 days or until hospital corticosteroid may be used.
discharge. • For more information, see Corticosteroids.
Baricitinib Baricitinib dose is dependent • eGFR ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once daily
on eGFR; duration of therapy is • eGFR 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO once daily
up to 14 days or until hospital
discharge. • eGFR 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO once daily
• eGFR <15 mL/min/1.73 m2: Baricitinib is not recommended.
Tofacitinib Tofacitinib 10 mg PO twice • Use as an alternative immunomodulatory drug if baricitinib is
daily for up to 14 days or until not available or not feasible to use (BIIa).
hospital discharge. • eGFR <60 mL/min/1.73 m2: Tofacitinib 5 mg PO twice daily
Tocilizumab Tocilizumab 8 mg/kg actual • In clinical trials, a third of the participants received a second
body weight (up to 800 mg) dose of tocilizumab 8 hours after the first dose if no clinical
administered as a single IV dose. improvement was observed.
Sarilumab Use the single-dose, prefilled • Use as an alternative immunomodulatory drug if tocilizumab is
syringe (not the prefilled pen) not available or not feasible to use (BIIa).
for SQ injection. Reconstitute • In the United States, the currently approved route of
sarilumab 400 mg in 100 cc administration for sarilumab is SQ injection. In the REMAP-CAP
0.9% NaCl and administer as an trial, the SQ formulation was used to prepare the IV infusion.
IV infusion over 1 hour.
Key: DEX = dexamethasone; eGFR = estimated glomerular filtration rate; IV = intravenous; PO = oral; RDV = remdesivir;
SQ = subcutaneous
Introduction
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. Subsequently, the disease appears to
be also 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, whereas immunosuppressive/anti-inflammatory
therapies are likely to be more beneficial after COVID-19 has progressed to stages characterized by
hypoxia.
Patients Who Do Not Require Supplemental Oxygen

Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of
dexamethasone (AIIa) or other corticosteroids (AIII) for the treatment of COVID-19. 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.
• There is insufficient evidence to recommend either for or against the routine use of remdesivir for
the treatment of COVID-19 in hospitalized patients who do not require supplemental oxygen, but
use may be appropriate in patients at high risk of disease progression.

Rationale for Recommending Against the Use of Dexamethasone or Other Corticosteroids

In the RECOVERY trial, a multicenter, open-label trial in the United Kingdom, hospitalized patients with
COVID-19 were randomized to receive dexamethasone plus standard of care or standard of care alone
(control arm).1 No survival benefit for dexamethasone was observed among the participants who did not
require supplemental oxygen at enrollment: 17.8% of participants in the dexamethasone arm and 14% in
the control arm died within 28 days of enrollment (rate ratio 1.19; 95% CI, 0.91–1.55). See Table 4a for
additional information. Based on these data, the Panel recommends against the use of dexamethasone
(AIIa) or other corticosteroids (AIII) for the treatment of COVID-19 in hospitalized patients who do not
require supplemental oxygen, unless the patient has another indication for corticosteroid therapy.
Rationale for Determining That There Is Insufficient Evidence to Recommend Either for or
Against the Use of Remdesivir
ACTT-1 was a multinational randomized controlled trial that compared intravenous (IV) remdesivir
to placebo in hospitalized patients with COVID-19. Remdesivir showed no significant benefit in
patients with mild to moderate disease, which was defined as oxygen saturation >94% on room air or
a respiratory rate <24 breaths/min without supplemental oxygen (rate ratio for recovery 1.29; 95% CI,
0.91–1.83); however, there were only 138 patients in this subgroup.2
In a manufacturer-sponsored, open-label randomized trial that included 596 patients with moderate
COVID-19, patients who received 5 days of remdesivir had higher odds of a better clinical status on
Day 11 (based on a 7-point ordinal scale) than those who received standard of care (OR 1.65; 95% CI,
1.09–2.48; P = 0.02).3
The Solidarity trial was a large, multinational, open-label randomized controlled trial that compared a
10-day course of remdesivir to standard of care. About 25% of hospitalized patients in both arms did not
require supplemental oxygen at study entry. The primary outcome of in-hospital mortality occurred in 11
of 661 patients (2%) in the remdesivir arm and 13 of 664 patients (2.1%) in the control arm (rate ratio
0.90; 99% CI, 0.31–2.58).4 Please see Table 2a for additional information.
Data supporting the clinical benefit of early treatment with remdesivir emerged from PINETREE, a
randomized placebo-controlled trial in nonhospitalized patients with COVID-19 at high risk of clinical
progression. Participants were randomized to receive 3 days of IV remdesivir or placebo as outpatients.
At treatment initiation, the median duration of symptoms was 5 days. By Day 28, there was a significant
decrease in hospitalization and/or death among the patients who received remdesivir: the primary
endpoint occurred in 0.7% of remdesivir recipients versus 5.3% of placebo recipients (HR 0.13; 95% CI,
0.03–0.59; P = 0.008).5
Because these trials produced conflicting results regarding the benefits of remdesivir, the Panel finds the
available evidence insufficient to recommend either for or against routine treatment with remdesivir for
all hospitalized patients with moderate COVID-19. However, the Panel recognizes that clinicians may
judge that remdesivir is appropriate for some hospitalized patients with moderate disease (e.g., those at
particularly high risk for clinical deterioration).
Patients Who Require Supplemental Oxygen

Patients who require supplemental oxygen, but not high-flow oxygen, noninvasive ventilation (NIV), or
mechanical ventilation are a heterogeneous group. Some of these patients will have mild disease that will
improve after a short period with or without treatment with remdesivir, dexamethasone, or both; others
will develop progressive disease despite treatment and require a more intensive level of care. There is no
consensus on which clinical or laboratory parameters allow for reliable risk-stratification to guide therapy
and/or identify which subsets of patients will experience progressive lung injury and hypoxemia.

Some studies have tried to define this group according to traditional risk factors for COVID-19
progression and/or by the presence of elevated inflammatory markers like C-reactive protein (CRP), but
evidence to support a specific identifying biomarker or clinical threshold is lacking.
Recommendations
The Panel recommends using 1 of the following options for hospitalized patients who require
supplemental oxygen:
• Remdesivir (e.g., for patients who require minimal supplemental oxygen) (BIIa)
• Dexamethasone plus remdesivir (BIIb)
• Dexamethasone (BI); for patients on dexamethasone who have rapidly increasing oxygen needs
and systemic inflammation, add a second immunomodulatory drug (e.g., tocilizumab or
baricitinib) (CIIa)
If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone,
or hydrocortisone can be used (BIII). See Corticosteroids for dosing recommendations.
Rationale for the Use of Remdesivir

In the ACTT-1 trial, remdesivir was associated with improved time to recovery in the 435 participants
who required oxygen supplementation but not high-flow oxygen, NIV, or mechanical ventilation (7
days for remdesivir vs. 9 days for placebo; recovery rate ratio 1.45; 95% CI, 1.18–1.79). Fewer patients
in the remdesivir arm than in the placebo arm progressed to requiring high-flow oxygen, mechanical
ventilation, or extracorporeal membrane oxygenation (ECMO) (17% vs. 24%). In a post hoc analysis of
deaths by Day 29, remdesivir appeared to confer a substantial survival benefit in this subgroup (HR for
death 0.30; 95% CI, 0.14–0.64).2
The Solidarity trial reported no difference in the rate of in-hospital deaths between patients who received
remdesivir and those who received standard of care (rate ratio for death in the overall study population
0.95; 95% CI, 0.81–1.11; rate ratio for death in patients who did not require mechanical ventilation at
entry 0.86; 99% CI, 0.67–1.11). There was no difference between patients who received remdesivir and
those who received standard of care in the percentage of those who progressed to mechanical ventilation
(11.9% vs. 11.5%) or in length of hospital stay.4 However, an open-label trial like Solidarity is less
well-suited to assess time to recovery than a placebo-controlled trial. In the Solidarity trial, because both
clinicians and patients knew that remdesivir was being administered, it is possible that hospital discharge
was delayed in order to complete the 10-day course of therapy.
DisCoVeRy was a multinational, open-label randomized controlled trial that compared up to 10 days
of remdesivir plus standard of care to standard of care alone in hospitalized patients with moderate or
severe COVID-19. There was no significant difference in the odds of improved clinical status by Day 15
between the patients in the remdesivir arm and the standard of care arm (OR 0.98; 95% CI, 0.77–1.25).
At Day 28, there were also no differences between the arms in either mortality (8% in remdesivir arm vs.
9% in standard of care arm) or clinical status. The DisCoVeRy trial shared with the Solidarity trial the
major limitation of open-label design. Additionally, 440 of the 832 participants in the DisCoVeRy trial
(219 in the remdesivir arm and 221 in the standard of care arm) were also Solidarity trial participants.6
Although the open-label Solidarity and DisCoVeRy trials demonstrated no mortality benefit for
remdesivir, in the large randomized placebo-controlled ACTT-1 trial, remdesivir significantly reduced
time to clinical recovery. In a post hoc analysis, this clinical benefit of remdesivir was most evident in
those who had symptoms for ≤10 days. The evidence from the ACTT-1 and PINETREE trials suggests
that remdesivir will have its greatest impact when administered early in the clinical course, which is also

the case for antiviral agents used to treat other viral infections.5 The Panel recommends remdesivir (without
dexamethasone) as a treatment option for certain patients with COVID-19 who require minimal supplemental
oxygen and are in the early course of the disease (BIIa). In these individuals, the hyperinflammatory state
where corticosteroids might be most beneficial may not yet be present or fully developed.
Although several trials studied a 10-day course of remdesivir,2,4 a 5-day course has been shown to be
comparable to 10 days of therapy in hospitalized patients with moderate-to-severe COVID-19.3,7 For more
information, please see Table 2a.
Rationale for the Use of Remdesivir Plus Dexamethasone

Data on the safety and efficacy of combination therapy consisting of remdesivir with corticosteroids
are primarily derived from observational studies, with some (but not all) suggesting a clinical benefit of
remdesivir plus dexamethasone.8-10 Remdesivir plus dexamethasone has not been directly compared to
dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19 may develop
a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The potent anti-
inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory effects. Thus,
the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent, such as
dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory response
that is a consequence of the infection.
Based on the theoretical combined benefit of antiviral and anti-inflammatory therapies, the Panel
recommends the combination of dexamethasone plus remdesivir as a treatment option for patients who
require supplemental oxygen (BIIb), despite important limitations of observational data.
Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among participants
who required supplemental oxygen at enrollment. Among these participants, fewer participants in the
dexamethasone arm than in the standard of care arm died within 28 days of enrollment (23.3% vs. 26.2%;
rate ratio 0.82; 95% CI, 0.72–0.94).1 However, the amount of supplemental oxygen that participants were
receiving and the proportions of participants who required oxygen through a high-flow device or NIV
were not reported. It is possible that the benefit of dexamethasone was greatest in those who required more
respiratory support. It should be noted that <0.1% of patients in the RECOVERY trial received concomitant
remdesivir. For more information, see Corticosteroids.
Some experts prefer not to use dexamethasone monotherapy in patients who require supplemental oxygen
because of the theoretical concern that corticosteroids might slow viral clearance when administered
without an antiviral drug. Corticosteroids have been associated with delayed viral clearance and/or worse
clinical outcomes in patients with other viral respiratory infections.11-13 Some studies have suggested that
corticosteroids slow SARS-CoV-2 clearance, but the results to date are inconclusive.14-18
Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain Patients

Who Require Rapidly Increasing Oxygen Supplementation
Several major randomized trials evaluating the use of interleukin (IL)-6 inhibitors or Janus Kinase
(JAK) inhibitors with or without corticosteroids in patients with COVID-19 have included patients who
required only low-flow supplemental oxygen. However, subgroup analyses in these trials have not clearly
defined which patients in this heterogeneous group are most likely to benefit from corticosteroids with
another immunomodulator. Direct comparison between trials is not possible because in some trials,
background therapies (e.g., corticosteroids) and inclusion criteria (e.g., the requirement for elevated
inflammatory markers) differed. Nonetheless, some trials suggest that adding a second immunomodulator to

dexamethasone provided benefits in patients requiring low-flow supplemental oxygen.19-21 For example,
the RECOVERY trial demonstrated a mortality benefit for adding tocilizumab to dexamethasone
compared to usual care alone (including dexamethasone) in a subgroup that included patients on low-flow
oxygen.19 Similarly, data on JAK inhibitors are also inconclusive; for example, the COV-BARRIER
trial did not find a statistically significant benefit of baricitinib versus placebo in patients on low-flow
oxygen,20 whereas the placebo-controlled STOP-COVID trial demonstrated a reduction in respiratory
failure or death in the subgroup of patients on low-flow oxygen who received tofacitinib.21
Given the uncertainty concerning which patients in this group would benefit from adding a second
immunomodulator, such as baricitinib or tocilizumab, to dexamethasone treatment, the Panel
recommends considering these therapies on a case-by-case basis for individuals with rapidly increasing
oxygen requirements and elevated markers of systemic inflammation (CIIa). 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. Treatment decisions should be
based on local guidance, drug availability, and patient comorbidities.
• Baricitinib or tocilizumab should only be given in combination with dexamethasone or another
corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before
deciding whether adding baricitinib or tocilizumab as a second immunomodulatory drug is
necessary.
• 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 or class of
drugs (i.e., JAK inhibitors, anti-IL-6 receptor mAbs) over the other. Treatment decisions should be
based on local guidance, drug availability, and patient comorbidities.
• If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used
instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
• The Panel recommends against the use of baricitinib in combination with tocilizumab for the
treatment of COVID-19, except in a clinical trial (AIII). Because both baricitinib and tocilizumab
are potent immunosuppressants, there is the potential for an additive risk of infection.
• Combination immunosuppressive therapy (e.g., dexamethasone with baricitinib or tocilizumab)
may increase the risk of opportunistic infections or reactivation of latent infections; however,
randomized trials to date have not demonstrated an increase in the frequency of infections.
• Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19
during treatment with tocilizumab and corticosteroids.22,23 Many clinicians would initiate empiric
treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without
serologic testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical,
or warm temperate areas).
Patients Who Require Oxygen Through a High-Flow Device or Noninvasive Ventilation

Recommendations
• The Panel recommends using 1 of the following options for hospitalized patients who require
oxygen through a high-flow device or NIV:
• Dexamethasone (AI)
• Dexamethasone plus remdesivir (BIII)
• For patients who have rapidly increasing oxygen needs and have increased markers of

inflammation, add either baricitinib (BIIa) or tocilizumab (BIIa) (drugs are listed alphabetically)
to 1 of the 2 options above.
• If dexamethasone is not available, an equivalent dose of another corticosteroid such as
prednisone, methylprednisolone, or hydrocortisone may be used (BIII). See Corticosteroids for
more information.
• Immunosuppressive therapy (e.g., dexamethasone with or without baricitinib or tocilizumab)
may increase the risk of opportunistic infections or reactivation of latent infections; however,
randomized trials to date have not demonstrated an increase in the frequency of infections.
treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without serologic
testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm
temperate areas).
Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among participants
who required supplemental oxygen without mechanical ventilation at enrollment: 23.3% of the
participants in the dexamethasone arm versus 26.2% in the standard of care arm died within 28 days of
enrollment (rate ratio 0.82; 95% CI, 0.72–0.94).1
Rationale for the Use of Remdesivir Plus Dexamethasone

As discussed above, data on the safety and efficacy of combination therapy of remdesivir with
corticosteroids are primarily derived from observational studies, with some, but not all suggesting clinical
benefit of remdesivir plus dexamethasone.8-10 Remdesivir plus dexamethasone has not been directly
compared to dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19
may develop a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The
potent anti-inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory
effects. Thus, the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent,
such as dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory
response that is a consequence of the infection. Based on the theoretical combined benefit of antiviral and
anti-inflammatory therapies, the Panel recommends the combination of dexamethasone plus remdesivir
as a treatment option for patients who require high-flow oxygen or NIV (BIIb), despite important
limitations of observational data.
Rationale for Not Recommending Remdesivir Monotherapy

In the ACTT-1 trial, there was no observed difference in time to recovery between the remdesivir and
placebo arms in the subgroup of 193 participants who required high-flow oxygen or NIV at enrollment
(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, but the trial was not powered to detect this difference.2 The Panel does not
recommend using remdesivir monotherapy in patients who require high-flow oxygen or NIV because
there is uncertainty regarding whether remdesivir alone confers a clinical benefit in this subgroup (AIIa).
Dexamethasone alone or remdesivir plus dexamethasone are better treatment options for COVID-19 in this
group of patients.
For patients who start remdesivir monotherapy and then progress to requiring oxygen through a
high-flow device or NIV, the Panel recommends initiating dexamethasone and continuing remdesivir
until the treatment course is completed. Clinical trials that evaluated the use of remdesivir categorized

patients based on their severity of illness at the start of treatment with remdesivir; therefore, patients
may benefit from remdesivir even if their clinical course progresses to a severity of illness for which the
benefits of remdesivir are less certain.
Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain

Hospitalized Patients
Several large clinical trials suggest that adding a second immunomodulatory drug, such as baricitinib or
tocilizumab, to dexamethasone provides clinical benefit in patients who require oxygen supplementation
through a high-flow device or NIV.
The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab
to date, have both reported a mortality benefit for tocilizumab among patients with rapid respiratory
decompensation who require oxygen delivery through a high-flow device or NIV.19,24 Most patients in
both studies received corticosteroids.
In the REMAP-CAP trial, patients admitted to an intensive care unit (ICU) with severe-to-critical
COVID-19 and rapid respiratory decompensation were randomized to receive open-label tocilizumab
or usual care. The use of tocilizumab reduced in-hospital mortality (28% in tocilizumab arm vs. 36%
in usual care arm) and, during 21 days of follow-up, increased the median number of days free of
respiratory and cardiovascular organ support (10 days in tocilizumab arm vs. 0 days in usual care arm;
OR 1.64; 95% CI, 1.25–2.14). Enrollment occurred within 24 hours of ICU admission and within a
median of 1.2 days of hospitalization (IQR 0.8–2.8 days), suggesting that the benefit of tocilizumab
occurs in patients experiencing rapid respiratory decompensation. The RECOVERY trial also suggested
a mortality benefit for tocilizumab plus dexamethasone in a subset of patients that included those who
required NIV or high-flow oxygen. In this study, a subset of participants with hypoxemia and CRP ≥75
mg/L were randomized to receive tocilizumab or usual care. Tocilizumab reduced all-cause mortality in
these patients; by Day 28, 29% of participants in the tocilizumab arm versus 33% in the usual care arm
had died (rate ratio 0.86; 95% CI, 0.77–0.96).
In the COV-BARRIER trial, 1,525 hospitalized patients with COVID-19 and ≥1 elevated inflammatory
biomarker were randomized 1:1 to receive oral baricitinib 4 mg or placebo in addition to the local
standard of care for up to 14 days (or until hospital discharge).20 Overall, there was no difference in the
occurrence of the primary endpoint of progression to high-flow oxygen, NIV, mechanical ventilation, or
death by Day 28 between the baricitinib arm (27.8% of patients) and the placebo arm (30.5% of patients;
OR 0.85; 95% CI, 0.67–1.08; P = 0.18). However, all-cause mortality by Day 28 was 8.1% in the
baricitinib arm and 13.1% in the placebo arm, resulting in a 38.2% reduction in mortality for baricitinib
(HR 0.57; 95% CI, 0.41–0.78; nominal P = 0.002). The difference in mortality was most pronounced
in the subgroup of 370 patients receiving high-flow oxygen or NIV at baseline (17.5% in the baricitinib
arm vs. 29.4% in the placebo arm; HR 0.52; 95% CI, 0.33–0.80; nominal P = 0.007). The occurrence
of adverse events, serious adverse events, serious infections, and venous thromboembolic events in the
arms was comparable.
The ACTT-2 trial demonstrated that baricitinib used in combination with remdesivir improved time to
recovery in hospitalized patients with COVID-19. The effect was most pronounced in patients who were
receiving high-flow oxygen or NIV. However, patients receiving corticosteroids were excluded from the
ACTT-2 trial, limiting the generalizability of these findings.
Given the clinical trial data (see Table 4e), the Panel recommends adding baricitinib or tocilizumab
as a second immunomodulatory treatment in combination with dexamethasone for patients who are
receiving oxygen supplementation through a high-flow device or NIV (BIIa).

• Baricitinib or tocilizumab should only be given in combination with dexamethasone or another
corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before
deciding whether adding baricitinib or tocilizumab is necessary.
• Studies that directly compare baricitinib to tocilizumab as treatments for COVID-19 are not
available. Therefore, there is insufficient evidence for the Panel to recommend 1 drug over the
other. Treatment decisions should be based on local guidance, drug availability, and patient
comorbidities.
• If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used
instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
• Although approximately a third of patients in the REMAP-CAP and RECOVERY trials received a
second dose of tocilizumab at the discretion of their treating physician, data on outcomes based on
receipt of 1 or 2 doses is not available. Therefore, there is insufficient evidence to determine which
patients, if any, would benefit from an additional dose of the drug.
Rationale for Recommending Against the Use of the Combination of Baricitinib and
Tocilizumab
The Panel recommends against the use of the combination of baricitinib and tocilizumab for the
treatment of COVID-19, except in a clinical trial (AIII), because there is insufficient evidence for the
use of this combination. Given that both baricitinib and tocilizumab are potent immunosuppressants,
there is the potential for an additive risk of infection.
Rationale for Recommending Sarilumab and Dexamethasone as an Alternative to

Tocilizumab and Dexamethasone in Certain Hospitalized Patients
In an updated report from the REMAP-CAP trial, the efficacy of tocilizumab and sarilumab
in improving survival and reducing the duration of organ support was similar. Compared to
noncontemporary control patients who received placebo plus dexamethasone, patients who received
sarilumab and dexamethasone demonstrated reduced mortality, shorter time to ICU discharge, and more
organ support-free days.25
In the REMAP-CAP trial, sarilumab in combination with dexamethasone (n = 483) was noninferior to
tocilizumab with dexamethasone (n = 943) with regards to the number of organ support-free days and
mortality with a probability of 99% and 98%, respectively.
Even though the REMAP-CAP trial supports that sarilumab and tocilizumab have similar efficacy in
the treatment of hospitalized patients with COVID-19, the Panel recommends sarilumab only when
tocilizumab is not available or is not feasible to use (BIIa). The rationales for this recommendation are:
• The evidence of efficacy for tocilizumab is more extensive than for sarilumab, and
• Currently, sarilumab is only approved as a subcutaneous (SQ) injection in the United States.
In the REMAP-CAP trial, a single dose of sarilumab 400 mg for SQ injection was reconstituted in 50 ml
or 100 ml of normal saline and administered as an IV infusion over 1 hour.
Rationale for Recommending the Use of Tofacitinib Plus Dexamethasone in Certain

In the STOP-COVID trial, a double-blind randomized placebo-controlled trial, use of tofacitinib was
associated with a decreased risk of respiratory failure and death (risk ratio 0.63; 95% CI, 0.41–0.97).

All-cause mortality within 28 days was 2.8% in the tofacitinib arm (n = 144) and 5.5% in the placebo arm
(n = 145) (HR 0.49; 95% CI, 0.15–1.63). Approximately 80% of participants in each arm also received
corticosteroids.21
The STOP-COVID trial supports that tofacitinib plus steroids is effective in improving outcomes in
hospitalized patients with COVID-19. Both baricitinib and tofacitinib belong to the same class of anti-
inflammatory drugs, the kinase inhibitors, and have overlapping mechanisms of action. The Panel
recommends tofacitinib as an alternative to baricitinib only when baricitinib is not available or not
feasible to use (BIIa) because the evidence of efficacy for tofacitinib is less extensive than for baricitinib.
Patients Who Require Mechanical Ventilation or Extracorporeal Membrane

Oxygenation
Recommendations
• The Panel recommends using dexamethasone for hospitalized patients with COVID-19 who
require mechanical ventilation or ECMO (AI).
• The Panel recommends using dexamethasone plus tocilizumab for patients with COVID-19 who
are within 24 hours of admission to the ICU (BIIa).
• If dexamethasone is not available, an equivalent dose of an alternative corticosteroid (e.g.,
prednisone, methylprednisolone, hydrocortisone) may be used (BIII).
• For patients who initially received remdesivir monotherapy and progressed to requiring mechanical
ventilation or ECMO, dexamethasone should be initiated and remdesivir should be continued until
the treatment course is completed.
• The Panel recommends against the initiation of remdesivir monotherapy (AIIa) in patients who
require mechanical ventilation or ECMO.
• Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at
an equivalent dose).
• Although some patients in the REMAP-CAP and RECOVERY trials received a second dose of
tocilizumab at the discretion of their treating physician, there is insufficient evidence to determine
which patients, if any, would benefit from an additional dose of the drug.
• The combination of dexamethasone and tocilizumab may increase the risk of opportunistic
infections or reactivation of latent infections. Prophylactic treatment for strongyloidiasis (e.g.,
with the antiparasitic drug ivermectin) should be considered for patients who are from areas where
Strongyloides is endemic.
Rationale for the Use of Dexamethasone Monotherapy

As COVID-19 progresses, a systemic inflammatory response may lead to multiple organ dysfunction
syndrome. The anti-inflammatory effects of corticosteroids mitigate the inflammatory response, and the
use of corticosteroids has been associated with improved outcomes in people with critical COVID-19.
Dexamethasone reduces mortality in critically ill patients with COVID-19 according to a meta-analysis that
aggregated 7 randomized trials and included data on 1,703 critically ill patients.26 The largest trial in the
meta-analysis was the RECOVERY trial, whose subgroup of mechanically ventilated patients was included.1
For details about the meta-analysis and the RECOVERY trial, see Corticosteroids and Table 4a. Because the
benefits of dexamethasone outweigh the potential harms, the Panel recommends using dexamethasone in
hospitalized patients with COVID-19 who require mechanical ventilation or ECMO (AI).

Considerations Related to the Use of Dexamethasone Plus Remdesivir Combination Therapy

Dexamethasone plus remdesivir combination therapy has not been evaluated in controlled studies;
therefore, there is insufficient information to make a recommendation either for or against the use of this
combination therapy. However, there is a theoretical reason to administer dexamethasone plus remdesivir
to patients who have recently been intubated. Antiviral therapy may prevent a steroid-related delay in viral
clearance. This delay has been reported in the setting of other viral infections.11,12
Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the studies to date
are not definitive. For example, an observational study in patients with nonsevere COVID-19 suggested
that viral clearance was delayed in those who received corticosteroids,27 whereas a more recent study in
patients with moderate to severe COVID-19 found no relationship between the use of corticosteroids and
the rate of viral clearance.18 Given the conflicting results from observational studies and the lack of clinical
trial data, some Panel members would coadminister dexamethasone and remdesivir in patients who have
recently been placed on mechanical ventilation (CIII) until more conclusive evidence becomes available,
based on their concerns about delayed viral clearance in patients who received corticosteroids. Other Panel
members would not coadminister dexamethasone and remdesivir due to uncertainties about the benefit of
using remdesivir in critically ill patients.
Rationale for Recommending the Use of Tocilizumab Plus Dexamethasone in Patients Within
24 Hours of Admission to the Intensive Care Unit
The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab
to date, both reported a mortality benefit for tocilizumab in patients who experienced rapid respiratory
decompensation and were recently admitted to the ICU, including those who required mechanical
ventilation.19,24 The REMAP-CAP trial enrolled patients within 24 hours of admission to the ICU. Previous
trials that enrolled patients later in the course of ICU care and/or who received oxygen support >24
hours after ICU admission have failed to show consistent clinical benefits for tocilizumab (see Table 4e).
Thus, it is unclear whether there is a clinical benefit for tocilizumab in patients who received mechanical
ventilation for >24 hours. Findings from the RECOVERY trial suggest a clinical benefit for tocilizumab
plus corticosteroids among patients with rapid clinical progression who received mechanical ventilation.
Please see the Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain
Hospitalized Patients section above for additional details on the clinical trial data and rationale for using
tocilizumab in this situation.
Rationale for Recommending Against the Use of Remdesivir Monotherapy

A clear benefit of remdesivir monotherapy has not been demonstrated in patients who require mechanical
ventilation or ECMO. In the ACTT-1 trial, remdesivir did not improve the recovery rate in this subgroup
of participants (recovery rate ratio 0.98; 95% CI, 0.70–1.36), and in a post hoc analysis of deaths by Day
29, remdesivir did not improve survival in this subgroup (HR 1.13; 95% CI, 0.67–1.89).2 In the Solidarity
trial, there was a trend toward increased mortality among patients who received mechanical ventilation and
were randomized to receive remdesivir rather than standard of care (rate ratio 1.27; 95% CI, 0.99–1.62).4
Taken together, these results do not demonstrate a clear benefit of remdesivir in critically ill patients.
For patients who start remdesivir monotherapy and then progress to requiring mechanical ventilation or
ECMO, the Panel recommends initiating dexamethasone and continuing remdesivir until the treatment
course is completed. Clinical trials that evaluated remdesivir categorized patients based on their severity of
illness at study enrollment; therefore, patients may benefit from receiving remdesivir even if their clinical
course progresses to a severity of illness for which the benefits of remdesivir are less certain.

Rationale for Recommending the Use of Sarilumab and Dexamethasone as an Alternative to

Tocilizumab and Dexamethasone in Certain Hospitalized Patients
Please refer to the Patients Who Require Oxygen Through a High-Flow Device or Noninvasive
Ventilation section above for the rationale regarding the use of sarilumab and dexamethasone as an
alternative to tocilizumab and dexamethasone in certain hospitalized patients.
Rationale for Determining That There is Insufficient Evidence to Recommend the Use of
Baricitinib in Addition to Standard of Care in Mechanically Ventilated Individuals
A cohort of critically ill patients was added to the COV-BARRIER trial after the completion of the
original study. The results for the cohort were not included in the primary results of the main trial.28 In this
addendum, 101 patients on mechanical ventilation or ECMO were randomized 1:1 to receive baricitinib
4 mg (n = 51) or placebo (n = 50) for up to 14 days in combination with standard of care. Baricitinib
significantly reduced 28-day all-cause mortality (39.2% in the baricitinib arm vs. 58.0% in the placebo
arm; HR 0.54; 95% CI, 0.31–0.96; P = 0.030). However, given the small sample size, the Panel considered
the evidence insufficient to issue a recommendation for patients on mechanical ventilation or ECMO.
References
COVID-19. N Engl J Med. 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J
3. 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:
4. 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:
5. Hill JA, Paredes R, Vaca C, et al. Remdesivir for the treatment of high-risk non-hospitalized individuals with
COVID-19: a randomized, double-blind, placebo-controlled trial. Presented at: IDWeek. 2021. Virtual.
6. 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. 2021;Published online ahead of print. Available at:
7. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl
8. Wong CKH, Lau KTK, Au ICH, et al. Optimal timing of remdesivir initiation in hospitalized COVID-19
patients administered with dexamethasone. Clin Infect Dis. 2021;Published online ahead of print. Available at:
9. Benfield T, Bodilsen J, Brieghel C, et al. Improved survival among hospitalized patients with COVID-19
treated with remdesivir and dexamethasone. A nationwide population-based cohort study. Clin Infect Dis.
10. Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a
comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect
Dis. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34596223.
11. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East
respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at:
12. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.


13. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment
of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at:
14. 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.
15. 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:
16. 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:
17. Liu J, Zhang S, Dong X, et al. Corticosteroid treatment in severe COVID-19 patients with acute respiratory
distress syndrome. J Clin Invest. 2020;130(12):6417-6428. Available at:
18. 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:
19. 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:
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: https://www.ncbi.nlm.nih.gov/pubmed/34480861.
21. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N
22. Lier AJ, Tuan JJ, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J
Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32830642.
23. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive therapy
for SARS-CoV-2 pneumonia. Infection. 2021;49(3):539-542. Available at:
24. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill
25. 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: https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.
26. 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:
27. Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized
with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020;9(4):823-836.
28. Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus standard of care for hospitalised adults with
COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: results of a
randomised, placebo-controlled trial. medRxiv. 2021;Preprint. Available at:

Care of Critically Ill Adult Patients With COVID-19

Infection Control
• For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19
Treatment Guidelines Panel (the Panel) recommends using an N95 respirator (or equivalent or higher-level respirator)
rather than surgical masks, in addition to other personal protective equipment (PPE) (i.e., gloves, gown, and eye
protection, such as a face shield or safety goggles) (AIII).
• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care unit patients with
COVID-19 and carrying out any necessary aerosol-generating procedures in a negative-pressure room, also known as
an airborne infection isolation room, when available (AIII).
• For health care workers who are providing usual care for nonventilated patients with COVID-19, the Panel
recommends using an N95 respirator (or equivalent or higher-level respirator) or a surgical mask in addition to other
PPE (i.e., gloves, gown, and eye protection, such as a face shield or safety goggles) (AIIa).
• For health care workers who are performing non-aerosol-generating procedures on patients with COVID-19 who are
on closed-circuit mechanical ventilation, the Panel recommends using an N95 respirator (or equivalent or higher-level
respirator) in addition to other PPE (i.e., gloves, gown, and eye protection, such as a face shield or safety goggles)
because ventilator circuits may become disrupted unexpectedly (BIII).
• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by health care providers
with extensive airway management experience, if possible (AIII).
• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa).
Hemodynamics
• For adults with COVID-19 and shock, 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 patients with
sepsis or septic shock (AI).
• When norepinephrine is available, the Panel recommends against using dopamine for 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 patients 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 patients who require vasopressors have an arterial catheter placed as soon as
practical, if the resources to do so are available (BIII).
• For adults with refractory septic shock who have completed a course of corticosteroids to treat their 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 high-flow nasal cannula (HFNC) oxygen over noninvasive ventilation (NIV) (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 using 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).
• 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).
Acute Kidney Injury and Renal Replacement Therapy
• For critically ill patients with COVID-19 who have acute kidney injury and who develop indications for renal
replacement therapy, the Panel recommends continuous renal replacement therapy (CRRT), if available (BIII).
• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged intermittent renal
replacement therapy rather than intermittent hemodialysis (BIII).
Pharmacologic Interventions
• In patients with COVID-19 and severe or critical illness, there is insufficient evidence for the Panel to recommend
either for or against the use of empiric broad-spectrum antimicrobial therapy in the absence of another indication.
• If antimicrobials are initiated, the Panel recommends reassessing the need for them daily to minimize the adverse
effects 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 for patients with COVID-19 and refractory hypoxemia.

Severe cases of COVID-19 may be associated with hypoxemic respiratory failure, acute respiratory
distress syndrome (ARDS), septic shock, cardiac dysfunction, elevation in multiple inflammatory
cytokines, thromboembolic disease, and/or exacerbation of underlying comorbidities. In addition to
pulmonary disease, patients with COVID-19 may also experience cardiac, hepatic, renal, and central
nervous system disease. Because patients with critical illness are likely to undergo aerosol-generating
procedures, they should be placed in airborne infection isolation rooms, when available.
Guidance on diagnostic testing for SARS-CoV-2 can be found in the Testing for SARS-CoV-2 Infection
section.
Most of the recommendations for the management of critically ill patients with COVID-19 are
extrapolated from experience with other causes of sepsis.1 Currently, there is limited information to
suggest that the critical care management of patients with COVID-19 should differ substantially from
the management of other critically ill patients; however, special precautions to prevent environmental
contamination by SARS-CoV-2 are warranted.
As with any patient in the intensive care unit (ICU), successful clinical management of a patient with
COVID-19 includes treating both the medical condition that initially resulted in ICU admission and
other comorbidities and nosocomial complications.
Comorbid Conditions
Certain attributes and comorbidities (e.g., older age, cardiovascular disease, diabetes, chronic obstructive
pulmonary disease, cancer, renal disease, obesity, sickle cell disease, receipt of a solid organ transplant)
are associated with an increased risk of severe illness from COVID-19.2
Bacterial Superinfection of COVID-19-Associated Pneumonia

Limited information exists about the frequency and microbiology of pulmonary coinfections and
superinfections in patients with COVID-19, such as hospital-acquired pneumonia (HAP) and ventilator-
associated pneumonia (VAP). Some studies from China emphasize the lack of bacterial coinfections in
patients with COVID-19, while other studies suggest that these patients experience frequent bacterial
complications.3-8 There is appropriate concern about performing pulmonary diagnostic procedures such
as bronchoscopy or other airway sampling procedures that require disruption of a closed airway circuit
in patients with COVID-19. Thus, while some clinicians do not routinely start empiric broad-spectrum
antimicrobial therapy for patients with severe COVID-19 disease, other experienced clinicians routinely
use such therapy. However, empiric broad-spectrum antimicrobial therapy is the standard of care for the
treatment of shock. Antibiotic stewardship is critical to avoid reflexive or continued courses of antibiotics.
Inflammatory Response Due to COVID-19

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,” although these are imprecise terms. However, these terms are misnomers because the
magnitude of cytokine elevation in patients with COVID-19 is modest compared to that in patients with
many other critical illnesses, such as sepsis and ARDS.9,10
Patients with COVID-19 and severe pulmonary involvement are well described to also manifest
extrapulmonary disease and to 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

In addition, there are case reports describing patients who had evidence of acute or recent SARS-CoV-2
infection (documented by a nucleic acid amplification test [NAAT] or antigen or antibody testing) with
minimal respiratory symptoms, but with laboratory markers of severe inflammation (e.g., elevated
C-reactive protein [CRP], ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) and various
other symptoms, including fever and shock; and signs of cardiovascular, gastrointestinal, dermatologic,
and neurologic disease. This constellation of signs and symptoms has been designated multisystem
inflammatory syndrome in adults (MIS-A).11 To date, most adults in whom MIS-A has been described
have survived. This syndrome is similar to a syndrome previously described in children (multisystem
inflammatory syndrome in children [MIS-C]).
MIS-A is defined by the following criteria:
1. A severe illness requiring hospitalization in an individual aged ≥21 years;
2. Current or past infection with SARS-CoV-2;
3. Severe dysfunction in one or more extrapulmonary organ systems;
4. Laboratory evidence of elevated inflammatory markers (e.g., CRP, ferritin, D-dimer, interleukin
[IL]-6);
5. Absence of severe respiratory illness; and
6. Absence of an alternative unifying diagnosis.11
Because there is no specific diagnostic test for MIS-A, diagnosis of this inflammatory syndrome is one
of exclusion after other causes (e.g., septic shock) 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-6 therapy.
COVID-19-Induced Cardiac Dysfunction, Including Myocarditis

A growing body of literature describes cardiac injury or dysfunction in approximately 20% of patients
who are hospitalized with COVID-19.4,6,12-15 COVID-19 may be associated with an array of cardiovascular
complications, including acute coronary syndrome, myocarditis, arrythmias, and thromboembolic disease.16
Thromboembolic Events and COVID-19

Critically ill patients with COVID-19 have been observed to have a prothrombotic state, which is
characterized by the elevation of certain biomarkers, and there is an apparent increase in the incidence of
venous thromboembolic disease in this population. In some studies, thromboemboli have been diagnosed
in patients who received chemical prophylaxis with heparinoids.17-19 Autopsy studies provide additional
evidence of both thromboembolic disease and microvascular thrombosis in patients with COVID-19.20
Some authors have called for routine surveillance of ICU patients for venous thromboembolism.21 See the
Antithrombotic Therapy in Patients with COVID-19 section 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 patients with severe COVID-19.4 In one case series of patients with critical disease, >15%
of the patients required continuous renal replacement therapy.6 See the Acute Kidney Injury and Renal

Replacement Therapy section for a more detailed discussion.
Several large epidemiologic studies suggest that rates of ICU admission are substantially lower for
children with COVID-19 than for adults with the disease. However, severe disease does occur in
children.22-27 The risk factors for severe COVID-19 in children have not yet been established. Data
from studies of adults with COVID-19 and extrapolation from data on other pediatric respiratory
viruses suggest that children who are severely immunocompromised and those with underlying
cardiopulmonary disease may be at higher risk for severe COVID-19.
MIS-C, the postinfectious complication of COVID-19 seen in some children, has been described.28,29
Certain symptoms of MIS-C often require ICU-level care, including blood pressure and inotropic
support. These symptoms include severe abdominal pain, multisystem inflammation, shock, cardiac
dysfunction, and, rarely, coronary artery aneurysm. A minority of children with MIS-C meet the criteria
for typical or atypical Kawasaki disease. For details on MIS-C clinical features and the treatments that
are being investigated, see the Special Considerations in Children section.
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 used off-label to treat COVID-19 and
concurrent drugs should be considered.
Sedation Management in Patients With COVID-19

International guidelines provide recommendations on the prevention, detection, and treatment of pain,
sedation, and delirium.30,31 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-19.32,33
The Society of Critical Care Medicine’s (SCCM’s) 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.34
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.35 Despite the known benefits of the A-F Bundle, its impact has not been directly
assessed in patients with COVID-19; however, the 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 the PADIS Guidelines.
This puts patients at additional risk for ICU and post-ICU complications.
Post-Intensive Care Syndrome

Patients with COVID-19 are reported to experience prolonged delirium and/or encephalopathy. Risk
factors that are associated with delirium include the use of mechanical ventilation; the use of restraints;
the use of benzodiazepine, opioid, and vasopressor infusions; and the use of antipsychotics.36,37
Neurological complications are associated with older age and underlying conditions, such as hypertension
and diabetes mellitus.38 Autopsy studies have reported both macrovascular and microvascular thrombosis,
with evidence of hypoxic ischemia.39 Adequate management requires careful attention to best sedation
practices and vigilance in stroke detection.
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.40 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.41-43 Cognitive dysfunction affects 30% to 80% of
patients discharged from the ICU.44-46 About 50% of ICU survivors do not return to work within 1 year
after discharge.47 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 one study, a third of family members who had
main decision-making roles experienced mental health problems, such as depression, anxiety, and PTSD.48
Early reports suggest that some patients with COVID-19 who have been treated in the ICU express
manifestations of PICS.49 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.
Other Intensive Care Unit-Related Complications

Patients who are critically ill with COVID-19 are at risk for nosocomial infections and other
complications of critical illness care, such as VAP, HAP, catheter-related bloodstream infections, and
venous thromboembolism. When treating patients with COVID-19, clinicians also need to minimize the
risk of conventional ICU complications to optimize the likelihood of a successful ICU outcome.
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 at 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 the 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 2020.1 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.
References
1. 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). Crit Care Med. 20200;48(6):e440-e469.
2. Centers for Disease Control and Prevention. Evidence used to update the list of underlying medical conditions
that increase a person’s risk of severe illness from COVID-19. 2020. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/need-extra-precautions/evidence-table.html. Accessed December 8, 2020.
3. 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.
4. 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: https://www.ncbi.nlm.nih.gov/
pubmed/32191259.
5. 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:
6. 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. Available at:
7. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019:
retrospective study. BMJ. 2020;368:m1091. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32217556.
8. Du Y, Tu L, Zhu P, et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective
observational study. Am J Respir Crit Care Med. 2020;201(11):1372-1379. Available at:
9. Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid
systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med.
10. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med.
11. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults associated
with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR Morb Mortal
Wkly Rep. 2020;69(40):1450-1456. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33031361.

12. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with
COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-810. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32211816.
13. 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.
14. 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:
15. 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:
16. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic
mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17(9):543-558. Available at:
17. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated
severe COVID-19 patients. J Thromb Haemost. 2020;18(7):1743-1746. Available at:
18. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection:
a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. Available at:
19. Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU
patients with COVID-19. Thromb Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32291094.
20. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse
alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting
vascular dysfunction. Histopathology. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32364264.
21. Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: an urgent
call for ultrasound screening. Intensive Care Med. 2020. Available at:
22. 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. Available at:
23. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6).
24. Centers for Disease Control and Prevention. Coronavirus disease 2019 in children—United States, February
12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm. Accessed
January 5, 2021.
25. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically
ill children and adolescents with coronavirus disease 2019 (COVID-19) at a tertiary care medical center in
New York City. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
26. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492092.
27. DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in children and young adults in the Washington,
DC metropolitan region. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405091.
28. 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. Available at:

29. 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. Available at:
30. 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:
31. 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.
32. 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:
33. 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: https://www.ncbi.nlm.nih.gov/pubmed/18191684.
34. Society of Critical Care Medicine. ICU Liberation Bundle (A-F). Available at:
https://www.sccm.org/ICULiberation/ABCDEF-Bundles. Accessed January 5, 2021.
35. 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.
36. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med.
37. 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:
38. 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: https://www.ncbi.nlm.nih.gov/
pubmed/32275288.
39. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of COVID-19. N Engl J Med.
40. Society of Critical Care Medicine. Post-intensive care syndrome. 2013. Available at:
https://www.sccm.org/MyICUCare/THRIVE/Post-intensive-Care-Syndrome. Accessed September 22, 2020.
41. 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:
42. 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: https://www.ncbi.nlm.nih.gov/
pubmed/12472328.
43. 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:
44. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl
45. 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:
46. 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.


47. 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.
48. 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:
49. 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.

Infection Control
Health care workers should follow the infection control policies and procedures issued by their health
care institutions.
Recommendation
• For health care workers who are performing aerosol-generating procedures on patients with
COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using an N95
respirator (or equivalent or higher-level respirator) rather than surgical masks, in addition to other
personal protective equipment (PPE) (i.e., gloves, gown, and eye protection such as a face shield
or safety goggles) (AIII).
• Aerosol-generating procedures include endotracheal intubation and extubation, sputum
induction, bronchoscopy, mini-bronchoalveolar lavage, open suctioning of airways, manual
ventilation, unintentional or intentional ventilator disconnections, noninvasive positive pressure
ventilation (NIPPV) (e.g., bilevel positive airway pressure [BiPAP], continuous positive airway
pressure [CPAP]), cardiopulmonary resuscitation, and, potentially, nebulizer administration and
high-flow oxygen delivery. Caution regarding aerosol generation is appropriate in situations
such as tracheostomy and proning, where ventilator disconnections are likely to occur.
Rationale
During the severe acute respiratory syndrome (SARS) epidemic, aerosol-generating procedures
increased the risk of infection among health care workers.1,2 N95 respirators block 95% to 99% of
aerosol particles; however, medical staff must be fit-tested for the type used.3 Surgical masks block large
particles, droplets, and sprays, but are less effective in blocking small particles (<5 μm) and aerosols.4
Recommendation
• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care
unit patients with COVID-19 and carrying out any necessary aerosol-generating procedures
in a negative-pressure room, also known as an airborne infection isolation room (AIIR), when
available (AIII).
• The Panel recognizes that aerosol-generating procedures are necessary to perform in some
patients, and that such procedures can be carried out with a high degree of safety if infection
control guidelines are followed.
Rationale
AIIRs lower the risk of cross-contamination among rooms and lower the risk of infection for staff and
patients outside the room when aerosol-generating procedures are performed. AIIRs were effective
in preventing virus spread during the SARS epidemic.2 If an AIIR is not available, a high-efficiency
particulate air (HEPA) filter should be used, especially for patients on high-flow nasal cannula or
noninvasive ventilation. HEPA filters reduce virus transmission in simulations.5
Recommendations
• For health care workers who are providing usual care for nonventilated patients with COVID-19,
the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) or a
surgical mask, in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield

or safety goggles) (AIIa).

• For health care workers who are performing non-aerosol-generating procedures on patients with
COVID-19 who are on closed-circuit mechanical ventilation, the Panel recommends using an N95
respirator (or equivalent or higher-level respirator) in addition to other PPE (i.e., gloves, gown,
and eye protection such as a face shield or safety goggles) because ventilator circuits may become
disrupted unexpectedly (BIII).
Rationale
There is evidence from studies of viral diseases, including SARS, that both surgical masks and N95
respirators reduce the risk of transmission.6 Moreover, surgical masks are probably not inferior to N95
respirators for preventing the transmission of respiratory viral infections; a recent systematic review and
meta-analysis of randomized controlled trials that compared the protective effects of medical masks and
N95 respirators demonstrated that the use of medical masks did not increase the incidence of laboratory-
confirmed viral respiratory infections (including coronavirus infections) or clinical respiratory illness.7
Recommendations
• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by
health care providers with extensive airway management experience, if possible (AIII).
• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa).
Rationale
Practices that maximize the chances of first-pass success and minimize aerosolization should be used
when intubating patients with suspected or confirmed COVID-19.8,9 Thus, the Panel recommends that
the health care worker with the most experience and skill in airway management be the first to attempt
intubation. The close facial proximity of direct laryngoscopy can expose health care providers to higher
concentrations of viral aerosols. It is also important to avoid having unnecessary staff in the room during
intubation procedures.
References
1. Yam LY, Chen RC, Zhong NS. SARS: ventilatory and intensive care. Respirology. 2003;8 Suppl:S31-35.
2. Twu SJ, Chen TJ, Chen CJ, et al. Control measures for severe acute respiratory syndrome (SARS) in Taiwan.
Emerg Infect Dis. 2003;9(6):718-720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12781013.
3. Centers for Disease Control and Prevention. The National Personal Protective Technology Laboratory
(NPPTL): respirator trusted-source information. 2020. Available at: https://www.cdc.gov/niosh/npptl/topics/
respirators/disp_part/respsource1quest2.html. Accessed September 23, 2020.
4. Milton DK, Fabian MP, Cowling BJ, Grantham ML, McDevitt JJ. Influenza virus aerosols in human exhaled
breath: particle size, culturability, and effect of surgical masks. PLoS Pathog. 2013;9(3):e1003205. Available
5. Qian H, Li Y, Sun H, Nielsen PV, Huang X, Zheng X. Particle removal efficiency of the portable HEPA air
cleaner in a simulated hospital ward. Building Simulation. 2010;3:215-224. Available at:
https://link.springer.com/article/10.1007/s12273-010-0005-4.
6. Offeddu V, Yung CF, Low MSF, Tam CC. Effectiveness of masks and respirators against respiratory infections
in halthcare workers: a systematic review and meta-analysis. Clin Infect Dis. 2017;65(11):1934-1942.
7. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95 respirators for preventing

COVID-19 in healthcare workers: a systematic review and meta-analysis of randomized trials. Influenza Other
Respir Viruses. 2020;14(4):365-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32246890.
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.
2012;7(4):e35797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22563403.
9. Lewis SR, Butler AR, Parker J, Cook TM, Schofield-Robinson OJ, Smith AF. Videolaryngoscopy versus direct
laryngoscopy for adult patients requiring tracheal intubation: a Cochrane Systematic Review. Br J Anaesth.

Hemodynamics
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

The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations in this section were
informed by the recommendations from the Surviving Sepsis Campaign Guidelines for managing adult
sepsis, pediatric sepsis, and COVID-19.
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
strategy (median SpO2 of 96%) was associated with an increased risk of in-hospital mortality when
compared to a more conservative SpO2 strategy (relative risk 1.21; 95% CI, 1.03–1.43).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 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 positive pressure ventilation 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 HFNC oxygen over NIV (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; 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 NIV arm (mean of 19 days; P =
0.02). In addition, 90-day mortality was lower in the HFNC oxygen arm than in either the conventional
oxygen therapy arm (HR 2.01; 95% CI, 1.01–3.99) or the NIV arm (HR 2.50; 95% CI, 1.31–4.78).3 In the
subgroup of more 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 for the HFNC
oxygen arm than for the conventional oxygen therapy or NIV arms (HR 2.07 and 2.57, respectively).
The trial’s findings were corroborated by a meta-analysis of 8 trials with 1,084 participants that was
conducted to assess the effectiveness of oxygenation strategies prior to intubation. 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
NIV is an aerosol-generating procedure, and it may increase the risk of nosocomial transmission
of SARS-CoV-2.5,6 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 patients 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 using 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.7
• Some patients do not tolerate awake prone positioning. Failure rates as high as 63% have been
reported in the literature.8
• Awake proning 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 proning 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 or delirium,
hemodynamic instability, an inability to independently change position, recent abdominal surgery,
or recent nausea or vomiting.

Rationale
Awake proning, 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,9,10 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 similarly reported that awake
prone positioning improves oxygenation,11-14 and some series have also reported low intubation rates
after proning.11,13
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; the intention-to-treat
analysis included 1,121 patients. Two hundred twenty-three of 564 patients (40%) who underwent
awake prone positioning met the primary composite outcome 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 at 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 occurred more
frequently in patients who experienced 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.15
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.9,10
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

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 Acute Respiratory Distress Syndrome
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).16
Although there is no clear standard as to what constitutes a high level of PEEP, a conventional threshold
is >10 cm H2O.17 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.18,19 Other studies 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.20-23 These seemingly contradictory observations suggest that COVID-19 patients
with ARDS are a heterogeneous population, and assessment 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.9 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).24
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 Acute

Respiratory Distress Syndrome
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
(NMBA) 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 NMBA or a continuous infusion of NMBA 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 Acute Respiratory Distress
Syndrome
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 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).
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 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.25 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). A subgroup analysis
found that traditional recruitment maneuvers significantly reduced hospital mortality (risk ratio 0.85;
95% CI, 0.75–0.97), whereas incremental PEEP titration recruitment maneuvers increased mortality
(risk ratio 1.06; 95% CI, 0.97–1.17).26
Although there are no published studies of inhaled nitric oxide in patients with COVID-19, a Cochrane
review of 13 trials that evaluated inhaled nitric oxide use in patients with ARDS found no mortality
benefit.27 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, Liu D, Liang BM, Liang ZA. 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. 2018;36(2):226-233. Available at:
5. 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.
6. 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:
7. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19.
2020.Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_
COVID_pos_preg_patients_4-30-20_final.pdf.
8. 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.

9. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N
10. 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.
11. 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:
12. 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:
13. 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.
14. 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-
15. 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. 2021;
Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34425070.
16. 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.
17. 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). Crit Care Med. 2020;48(6):e440-e469.
18. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330.
19. Tsolaki V, Siempos I, Magira E, Kokkoris S, Zakynthinos GE, Zakynthinos S. PEEP levels in COVID-19
pneumonia. Crit Care. 2020;24(1):303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32505186.
20. 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: https://www.ncbi.nlm.nih.gov/pubmed/32227758.
21. 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.
22. 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:
23. 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:
24. 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:
25. 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.

26. 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.
27. 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:

Acute Kidney Injury and Renal Replacement Therapy

Recommendations
• For critically ill adults with COVID-19 who have acute kidney injury (AKI) and who develop
indications for renal replacement therapy (RRT), the COVID-19 Treatment Guidelines Panel (the
Panel) recommends continuous renal replacement therapy (CRRT), if available (BIII).
• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged
intermittent renal replacement therapy (PIRRT) rather than intermittent hemodialysis (IHD)
(BIII).
Rationale
AKI that requires RRT occurs in approximately 22% of patients with COVID-19 who are admitted to the
intensive care unit.1 Evidence pertaining to RRT in patients with COVID-19 is scarce. Until additional
evidence is available, the Panel suggests using the same indications for RRT in patients with COVID-19
as those used for other critically ill patients.2
RRT modalities have not been compared in COVID-19 patients; the Panel’s recommendations are
motivated by the desire to minimize the risk of viral transmission to health care workers. The Panel
considers CRRT to be the preferred RRT modality. CRRT is preferable to PIRRT because medication
dosing for CRRT is more easily optimized and CRRT does not require nursing staff to enter the patient’s
room to begin and end dialysis sessions. CRRT and PIRRT are both preferable to IHD because neither
requires a dedicated hemodialysis nurse.3 Peritoneal dialysis has also been used during surge situations
in patients with COVID-19.
In situations where there may be insufficient CRRT machines or equipment to meet demand, the Panel
advocates performing PIRRT instead of CRRT, and then using the machine for another patient after
appropriate cleaning.
References
1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among
5,700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020. Available at:
2. American Society of Nephrology. Recommendations on the care of hospitalized patients with COVID-19 and
kidney failure requiring renal replacement therapy. 2020. Available at: https://www.asn-online.org/g/blast/
files/AKI_COVID-19_Recommendations_Document_03.21.2020.pdf. Accessed November 20, 2020.
3. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): considerations for
providing hemodialysis to patients with suspected or confirmed COVID-19 in acute care settings. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/dialysis/dialysis-in-acute-care.html. Accessed
November 19, 2020.

Pharmacologic Interventions
Therapeutic Management of Adults with COVID-19

See Therapeutic Management of Hospitalized Adults with COVID-19 for the COVID-19 Treatment
Guidelines Panel’s (the Panel) recommendations on when to use the following drugs alone or in
combination: baricitinib, dexamethasone, remdesivir, and tocilizumab.
Immune-Based Therapy
See the Immunomodulators sections for additional recommendations regarding the use of
immunomodulators not listed above.
Adjunctive Therapy
Recommendations regarding adjunctive therapy in the critical care setting, including antithrombotic
therapy and vitamin C, can be found in Antithrombotic Therapy in Patients With COVID-19 and in the
Supplements sections.
Empiric Broad-Spectrum Antimicrobial Therapy

Recommendations
• In patients with severe or critical COVID-19, there is insufficient evidence for the Panel to
recommend either for or against empiric broad-spectrum antimicrobial therapy in the absence of
another indication.
• If antimicrobials are initiated, the Panel recommends that their use should be reassessed daily to
minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
Rationale
At this time, there are no reliable estimates of the incidence or prevalence of copathogens with
SARS-CoV-2.
Some experts routinely administer broad-spectrum antibiotics as empiric therapy for bacterial
pneumonia to all patients with COVID-19 and moderate or severe hypoxemia. Other experts administer
antibiotics only for 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.
Gram stain, culture, or other testing of respiratory specimens is often not available due to concerns about
aerosolization of SARS-CoV-2 during diagnostic procedures or when processing specimens.
There are no clinical trials that have evaluated the use of empiric antimicrobial agents in patients with
COVID-19 or other severe coronavirus infections.

Extracorporeal Membrane Oxygenation

Recommendation
• There is insufficient evidence 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 A recent case series of 83 COVID-19 patients in Paris reported a 60-day mortality of 31%
for patients on ECMO.8 This mortality was similar to the mortality observed in a 2018 study of non-
COVID-19 patients with ARDS who were treated with ECMO during the ECMO to Rescue Lung Injury
in Severe ARDS (EOLIA) trial; that study reported a mortality of 35% at Day 60.3
The Extracorporeal Life Support Organization (ELSO) Registry provides the largest multicenter
outcome dataset of patients with confirmed COVID-19 who received ECMO support and whose data
were voluntarily submitted. A recent cohort study evaluated ELSO Registry data for 1,035 COVID-19
patients who initiated EMCO between January 16 and May 1, 2020, at 213 hospitals in 36 countries.
This study reported an estimated cumulative in-hospital mortality of 37.4% in these patients 90 days
after they initiated ECMO (95% CI; 34.4% to 40.4%).9 Without a controlled trial that evaluates 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.
Ideally, 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. The following resources provide
more information on the use of ECMO in patients with COVID-19:
• The ELSO ECMO in COVID-19 website
• A list of clinical trials that are evaluating ECMO in patients with COVID-19 on 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 EM, 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;Published online ahead of print. Available at:
8. 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. 2020.
9. 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.

Antiviral Drugs That Are Approved or Under Evaluation for

the Treatment of COVID-19
Remdesivir is the only drug that is approved by the Food and Drug Administration for the treatment of COVID-19. In
this section, the COVID-19 Treatment Guidelines Panel (the Panel) provides recommendations for using antiviral drugs to
treat COVID-19 based on the available data. For more information on these antiviral agents, see Table 2f.
Remdesivir
• See Therapeutic Management of Hospitalized Adults with COVID-19 for recommendations on using remdesivir for the
Ivermectin
• There is insufficient evidence for the Panel to recommend either for or against the use of ivermectin for the treatment
of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to
provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.
Interferons
• 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).
Nitazoxanide
• The Panel recommends against the use of nitazoxanide for the treatment of COVID-19, except in a clinical trial
(BIIa).
Hydroxychloroquine or Chloroquine and/or Azithromycin
• The Panel recommends against the use of chloroquine or hydroxychloroquine and/or azithromycin for the treatment
of COVID-19 in hospitalized patients (AI) and in nonhospitalized patients (AIIa).
Lopinavir/Ritonavir and Other HIV Protease Inhibitors
• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of
COVID-19 in hospitalized patients (AI) and in nonhospitalized patients (AIII).
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 inhibit viral entry (via the
angiotensin-converting enzyme 2 [ACE2] receptor and transmembrane serine protease 2 [TMPRSS2]),
viral membrane fusion and endocytosis, or the activity of the SARS-CoV-2 3-chymotrypsin-like protease
(3CLpro) and the RNA-dependent RNA polymerase.1 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.2 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
1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for Coronavirus Disease
2019 (COVID-19): a review. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32282022.
2. 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:

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
Intravenous remdesivir is approved by the Food and Drug Administration (FDA) for the treatment of
COVID-19 in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). It is
also available through an FDA Emergency Use Authorization (EUA) for the treatment of COVID-19
in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.
Remdesivir should be administered in a hospital or a health care setting that can provide a similar level
of care to an inpatient hospital.
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 2a for more information.
Data on the safety and efficacy of using remdesivir in combination with corticosteroids are
primarily derived from observational studies, with some (but not all) of these studies suggesting
that remdesivir plus dexamethasone provides a clinical benefit for patients with COVID-19.3-5
Remdesivir plus dexamethasone has not been directly compared to dexamethasone alone in a large
randomized trial. However, there are theoretical reasons that combination therapy may be beneficial
for some patients with severe COVID-19. Remdesivir has also been studied in combination with
other immunomodulators, including baricitinib6 and tocilizumab.7 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.
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.
Liver function tests and prothrombin time tests should be performed for all patients before they receive
remdesivir, and these tests should be repeated during treatment as clinically indicated. 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 an increase in ALT level and signs or symptoms of liver
inflammation are observed.8
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.8 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 estimated glomerular filtration
rate (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 Renal function should be monitored before and
during remdesivir treatment as clinically indicated.8
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 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 1 (MATE1).8
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). Remdesivir is not expected to have any significant interactions with oseltamivir or baloxavir,
according to information provided by Gilead Sciences (written communications, August and September
2020).
See Table 2f for more information.
Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.
Pregnant patients were excluded from the clinical trials that evaluated the safety and efficacy of
remdesivir for the treatment of COVID-19, but preliminary reports of remdesivir use in pregnant
patients from small studies and case reports are reassuring.13 Among 86 pregnant and postpartum
hospitalized patients with severe COVID-19 who received compassionate use remdesivir, the therapy
was well tolerated, with a low rate of serious adverse effects.14
Remdesivir is available through an FDA EUA for the treatment of COVID-19 in hospitalized pediatric
patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg. There are insufficient data
on the safety and efficacy of using remdesivir to treat COVID-19 in hospitalized pediatric patients aged
<12 years or weighing <40 kg because these populations have not been evaluated in the clinical trials
for remdesivir. The limited data from the compassionate use program and small case series suggest
that remdesivir was well tolerated in children who met the EUA criteria, but the data on young infants
and neonates are extremely limited.15-19 A clinical trial is currently evaluating the pharmacokinetics of
remdesivir in children (ClinicalTrials.gov Identifier NCT04431453).

Clinical Trials
Several clinical trials that are evaluating the use of remdesivir for the treatment of COVID-19 are
currently underway or in development. Please see ClinicalTrials.gov for the latest information.
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:
3. Wong CKH, Lau KTK, Au ICH, et al. Optimal timing of remdesivir initiation in hospitalized COVID-19
patients administered with dexamethasone. Clin Infect Dis. 2021;Published online ahead of print. Available at:
4. Benfield T, Bodilsen J, Brieghel C, et al. Improved survival among hospitalized patients with COVID-19
treated with remdesivir and dexamethasone. A nationwide population-based cohort study. Clin Infect Dis.
2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34111274.
5. Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a
comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect
Dis. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34596223.
7. 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:
8. Remdesivir (veklury) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.
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. 2020;Published online ahead of print. 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). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33229428.
13. Jorgensen SCJ, Davis MR, Lapinsky SE. A review of remdesivir for COVID-19 in pregnancy and lactation. J
Antimicrob Chemother. 2021;Published online ahead of print. Available at:
14. Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with
severe COVID-19. Clin Infect Dis. 2020;Published online ahead of print. Available at:
15. Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe

COVID-19. Pediatrics. 2021;147(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33883243.

16. 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:
17. Saikia B, Tang J, Robinson S, et al. Neonates with SARS-CoV-2 infection and pulmonary disease safely
treated with remdesivir. Pediatr Infect Dis J. 2021;40(5):e194-e196. Available at:
18. Hammad M, Shalaby L, Sidhom I, et al. Management and outcome of coronavirus disease 2019 (COVID-19)
in pediatric cancer patients: a single centre experience from a developing country. Clin Lymphoma Myeloma
Leuk. 2021;21(11):e853-e864. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34420893.
19. Weclawek-Tompol J, Zakrzewska Z, Gryniewicz-Kwiatkowska O, et al. COVID-19 in pediatric cancer
patients is associated with treatment interruptions but not with short-term mortality: a Polish national study. J
Hematol Oncol. 2021;14(1):163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34635137.

Table 2a. 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 the randomized controlled trials that have had the greatest impact on the Panel’s recommendations.
Methods Results Limitations and Interpretation

ACTT-1: Multinational, Placebo-Controlled, Double-Blind RCT of Remdesivir in Hospitalized Patients With COVID-191
Key Inclusion Criteria: Participant Characteristics: Key Limitations:
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 58.9 years • Wide range of disease severity among
• ≥1 of the following criteria: • 53.3% White, 21.3% Black, 12.7% Asian, 23.5% Hispanic/ patients, and study was not powered to
Latinx detect differences within subgroups
• Pulmonary infiltrates
• 26.2% with 1 and 55.2% with ≥2 coexisting conditions • Powered to detect differences in clinical
• SpO2 ≤94% on room air improvement, not mortality
• Need for supplemental oxygen, high-flow oxygen, • 13.0% not on oxygen; 41.0% on supplemental oxygen;
18.2% on high-flow oxygen or NIV; 26.8% on MV or ECMO • No data on longer-term morbidity
NIV, MV, or ECMO
• Median time from symptom onset to randomization was 9 Interpretation:
Key Exclusion Criteria:
days (IQR 6–12 days) • In patients with severe COVID-19, RDV
• ALT or AST >5 times ULN reduced time to clinical recovery.
• 21.6% in RDV arm and 24.4% in placebo arm received
• eGFR <30 mL/min corticosteroids during the study • The benefit was most apparent in
• Pregnancy or breastfeeding Primary Outcomes: hospitalized patients who were receiving
Interventions: supplemental oxygen.
• RDV reduced time to recovery compared to placebo (10 days
• RDV 200 mg IV on Day 1, then RDV 100 mg daily vs. 15 days; rate ratio for recovery 1.29; 95% CI, 1.12–1.49; • There was no observed benefit in those
for up to 9 more days (n = 541) P < 0.001). on high-flow oxygen, NIV, MV, or ECMO,
but study was not powered to detect
• Placebo for up to 10 days (n = 521) • Benefit of RDV was greatest in patients randomized during differences within subgroups.
first 10 days after symptom onset and those who required
Primary Endpoint:
supplemental oxygenation at enrollment.
• Time to clinical recovery
• No difference in time to recovery for patients on high-flow
Key Secondary Endpoints: oxygen, NIV, MV, or ECMO at enrollment.
• Clinical status at Day 15, as measured by an OS Secondary Outcomes:
• Mortality by Day 29 • Patients in RDV arm were more likely to show clinical
• Occurrence of SAEs improvement at Day 15 (OR 1.5; 95% CI, 1.2–1.9; P < 0.001).
• No difference between arms in mortality by Day 29.
• Proportion of patients with SAEs was similar between arms
(25% vs. 32%).


DisCoVeRy: Open-Label, Adaptive RCT of Remdesivir in Hospitalized Patients With Moderate or Severe COVID-19 in Europe2
• 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 during the study enrolled in the Solidarity trial
high-flow oxygen devices, NIV, or MV • Median days from symptom onset to randomization was 9 Interpretation:
Key Exclusion Criteria: days in both arms • There was no clinical benefit of RDV
• ALT or AST >5 times ULN • 61% with moderate disease and 39% with severe disease in hospitalized patients who were
• Severe chronic kidney disease Primary Outcomes: symptomatic for >7 days and who
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 status
• SOC (n = 428) between arms.
Primary Endpoint: Secondary Outcomes:
• Clinical status at Day 15, as measured by an OS • No difference in mortality between arms (8% in RDV arm
Key Secondary Endpoints: vs. 9% in SOC arm).
• Mortality at Day 29 • No difference in the proportion of patients with SAEs
between arms (33% in RDV arm vs. 31% in SOC arm; P =
• Occurrence of SAEs 0.48).
WHO Solidarity Trial: Multinational, Open-Label, Adaptive RCT of Repurposed Drugs in Hospitalized Patients With COVID-193
• Aged ≥18 years • 47% aged 50–69 years; 18% aged ≥70 years • Open-label design limits ability to
• Not known to have received any study drug • 67% on supplemental oxygen and 9% on MV at entry assess time to recovery as RDV
• Not expected to be transferred elsewhere within 72 hours may have been continued even if
• Rates of comorbidities were similar between arms patient improved
Interventions: • 48% in both arms received corticosteroids during the • No data on time from symptom
• RDV 200 mg IV on Day 0, then RDV 100 mg daily on Days study onset to enrollment
1–9 (n = 2,743) Primary Outcome: • No assessment of outcomes post
• Local SOC (n = 2,708) • In-hospital mortality: 11.0% in RDV arm vs. 11.2% in SOC hospital discharge
Primary Endpoint: arm (rate ratio 0.95; 95% CI, 0.81–1.11) Interpretation:
• In-hospital mortality Secondary Outcome: • RDV did not decrease in-hospital
Key Secondary Endpoint: • Initiation of MV: 10.8% in RDV arm vs. 10.5% in SOC arm mortality or the need for MV
compared to SOC.
• Initiation of MV


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-194
• Laboratory-confirmed SARS-CoV-2 infection • Demographic and baseline disease characteristics similar • Open-label design may have
• Pulmonary infiltrates across arms affected decisions on concomitant
• Ranges for participant characteristics across the 3 arms: medications (e.g., more patients in
• SpO2 >94% on room air the SOC arm received AZM, HCQ
• Median age 56–58 years or CQ, and LPV/RTV) and time of
• Men: 60% to 63% hospital discharge
• ALT or AST >5 times ULN
• 81% to 87% required no supplemental oxygen; 12% to • No data on time to return to activity
• CrCl <50 mL/min
18% required low-flow oxygen; 1% required high-flow for discharged patients
Interventions: oxygen or NIV
Interpretation:
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 9 • Concomitant medication use in the 10-day RDV, 5-day
days (n = 193) RDV, and SOC arms: • Hospitalized patients with moderate
COVID-19 who received 5 days of
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 4 • Steroids: 15%, 17%, 19% RDV had better clinical status at Day
days (n = 191) • Tocilizumab: 1%, 1%, 5% 11 than those who received SOC.
• Local SOC (n = 200) • HCQ/CQ: 11%, 8%, 45% • There was no difference in the
Primary Endpoint: • LPV/RTV: 6%, 5%, 22% clinical status at Day 11 between
patients who received 10 days of
• Clinical status at Day 11, as measured by an OS • AZM: 21%, 18%, 31% RDV and those who received SOC.
• Median length of therapy was 6 days in 10-day RDV arm
and 5 days in 5-day RDV arm
Primary Outcomes:
• 5-day RDV arm had significantly better clinical status at
Day 11 than SOC arm (OR 1.65; 95% CI, 1.09–2.48; P =
0.02).
• No difference in clinical status at Day 11 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
Moderate COVID-195
• Laboratory-confirmed COVID-19 • Median age 61 years in 5-day arm vs. 62 years in 10-day • Open-label trial
• Pulmonary infiltrates and SpO2 ≤94% on room air or arm • Baseline imbalances in clinical
receipt of supplemental oxygen • 60% were men in 5-day arm vs. 68% in 10-day arm status of patients in 5-day and 10-
• Oxygen requirements at baseline for the 5-day and 10-day day arms
arms: Interpretation:
• Need for MV or ECMO
• None: 17%, 11% • In hospitalized patients with severe
• Multiorgan failure
• Low-flow supplemental oxygen: 56%, 54% COVID-19 who were not receiving
• ALT or AST >5 times ULN MV or ECMO, using RDV for 5 or 10
• High-flow oxygen or NIV: 24%, 30%
• Estimated CrCl <50 mL/min days had similar clinical benefits.
• MV or ECMO: 2%, 5%
Interventions:
• Patients in 10-day arm had worse baseline clinical status
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 4 than those in 5-day arm (P = 0.02)
days (n = 200)
Primary Outcome:
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 9
days (n = 197) • After adjusting for baseline clinical status, Day 14
distribution in clinical status was similar between arms (P
Primary Endpoint: = 0.14).
• Clinical status at Day 14, as measured by an OS
Secondary Outcomes:
Key Secondary Endpoints: • Time to clinical improvement was similar between arms
• Time to clinical improvement (10 days in 5-day arm vs. 11 days in 10-day arm).
• Time to recovery • Median duration of hospitalization for patients who were
discharged on or before Day 14 was similar between arms
(7 days in 5-day arm vs. 8 days in 10-day arm).
Key: ALT = alanine transaminase; AST = aspartate aminotransferase; AZM = azithromycin; CQ = chloroquine; CrCl = creatinine clearance; ECMO = extracorporeal
membrane oxygenation; eGFR = estimated glomerular filtration rate; HCQ = hydroxychloroquine; IV = intravenous; 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; SAE = serious adverse event; SOC = standard of care; SpO2 = oxygen saturation; ULN = upper limit of normal
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. 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. 2021; Published online ahead of print.
3. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J
4. 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.
5. 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.

Chloroquine or Hydroxychloroquine and/or Azithromycin

Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analogue of

chloroquine, was developed in 1946. Hydroxychloroquine is used to treat autoimmune diseases, such as
systemic lupus erythematosus and rheumatoid arthritis, in addition to malaria.
Both chloroquine and hydroxychloroquine increase the endosomal pH, which inhibits fusion between
SARS-CoV-2 and the host cell membrane.1 Chloroquine inhibits glycosylation of the cellular
angiotensin-converting enzyme 2 (ACE2) receptor, which may interfere with the binding of SARS-CoV
to the cell receptor.2 In vitro studies have suggested that both chloroquine and hydroxychloroquine may
block the transport of SARS-CoV-2 from early endosomes to endolysosomes, possibly preventing the
release of the viral genome.3 Both chloroquine and hydroxychloroquine also have immunomodulatory
effects, which have been hypothesized to be another potential mechanism of action for the treatment of
COVID-19. Azithromycin has antiviral and anti-inflammatory properties. When used in combination
with hydroxychloroquine, it has been shown to have a synergistic effect on SARS-CoV-2 in vitro and
in molecular modeling studies.4,5 However, despite demonstrating antiviral activity in some in vitro
systems, neither hydroxychloroquine plus azithromycin nor hydroxychloroquine alone reduced upper or
lower respiratory tract viral loads or demonstrated clinical efficacy in a rhesus macaque model.6
The safety and efficacy of chloroquine or hydroxychloroquine with or without azithromycin and
azithromycin alone have been evaluated in randomized clinical trials, observational studies, and/or
single-arm studies. Please see Table 2b for more information.
Recommendation
chloroquine or hydroxychloroquine and/or azithromycin for the treatment of COVID-19 in
hospitalized patients (AI) and in nonhospitalized patients (AIIa).
Rationale
In a large randomized controlled platform trial of hospitalized patients in the United Kingdom
(RECOVERY), hydroxychloroquine did not decrease 28-day mortality when compared to the usual
standard of care. Patients who were randomized to receive hydroxychloroquine had a longer median
hospital stay than those who received the standard of care. In addition, among patients who were not on
invasive mechanical ventilation at the time of randomization, those who received hydroxychloroquine
were more likely to subsequently require intubation or die during hospitalization than those who
received the standard of care.7
The results from several additional large randomized controlled trials have been published; these trials
have failed to show a benefit for hydroxychloroquine with or without azithromycin or azithromycin
alone in hospitalized adults with COVID-19. In the Solidarity trial, an international randomized
controlled platform trial that enrolled hospitalized patients with COVID-19, the hydroxychloroquine
arm was halted for futility. There was no difference in in-hospital mortality between patients in the
hydroxychloroquine arm and those in the control arm.8 Similarly, PETAL, a randomized, placebo-
controlled, blinded study, was stopped early for futility. In this study, there was no difference in the
median scores on the COVID Outcomes Scale between patients who received hydroxychloroquine and
those who received placebo.9 Data from two additional randomized studies of hospitalized patients

with COVID-19 did not support using hydroxychloroquine plus azithromycin over hydroxychloroquine
alone.10,11 In RECOVERY, azithromycin alone (without hydroxychloroquine) did not improve survival or
other clinical outcomes when compared to the usual standard of care.12
In addition to these randomized trials, data from large retrospective observational studies do not
consistently show evidence of a benefit for hydroxychloroquine with or without azithromycin in
hospitalized patients with COVID-19.13-15 Please see Table 2b or the archived versions of the Guidelines
for more information.
Given the lack of a benefit seen in the randomized clinical trials, the Panel recommends against using
hydroxychloroquine or chloroquine and/or azithromycin to treat COVID-19 in hospitalized patients (AI).
Nonhospitalized Patients
Several randomized trials have not shown a clinical benefit for hydroxychloroquine in nonhospitalized
patients with early, asymptomatic, or mild COVID-19.16,17 In an open-label trial, Mitja et al.
randomized 307 nonhospitalized people who were recently confirmed to have COVID-19 to receive
hydroxychloroquine or no antiviral treatment. Patients in the hydroxychloroquine arm received
hydroxychloroquine 800 mg on Day 1 followed by 400 mg daily for an additional 6 days. The
authors reported no difference in the mean reduction in SARS-CoV-2 RNA at Day 3 or the time to
clinical improvement between the two arms (see Table 2b for more information). In another trial,
treating patients who had asymptomatic or mild COVID-19 with hydroxychloroquine with or without
azithromycin did not result in greater rates of virologic clearance (as measured by a negative polymerase
chain reaction [PCR] result on Day 6).18
An open-label, prospective, randomized trial compared oral azithromycin 500 mg once daily for 3
days plus standard of care to standard of care alone in nonhospitalized, high-risk, older adults who had
laboratory-confirmed or suspected COVID-19. No differences were observed between the arms in the
primary endpoints of time to first self-reported recovery and hospitalization or death due to COVID-19.
These findings remained consistent in an analysis that was restricted to participants with positive
SARS-CoV-2 PCR results. The study was ultimately halted due to futility.19 Similarly, in a preliminary
report from ATOMIC-2, adding oral azithromycin 500 mg once daily to standard of care for 14 days did
not reduce the risk of hospitalization or death among 292 participants with mild to moderate COVID-19.20
While ongoing clinical trials are still evaluating the use of chloroquine, hydroxychloroquine, and
azithromycin in outpatients, the existing data suggest that it is unlikely that clinical benefits will be
identified for these agents. The Panel recommends against the use of chloroquine or hydroxychloroquine
and/or azithromycin for the treatment of COVID-19 in nonhospitalized patients (AIIa).
Adverse Effects
Chloroquine and hydroxychloroquine have similar toxicity profiles, although hydroxychloroquine is
better tolerated and has a lower incidence of toxicity than chloroquine. Cardiac adverse events that
have been reported in people who received hydroxychloroquine include QTc prolongation, Torsades de
Pointes, ventricular arrythmia, and cardiac deaths.21
The use of azithromycin has also been associated with QTc prolongation,22 and using it in combination
with hydroxychloroquine has been associated with a higher incidence of QTc prolongation and cardiac
adverse events in patients with COVID-19.23,24
Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 2D6, and these drugs

are also P-glycoprotein inhibitors. Chloroquine and hydroxychloroquine may decrease the antiviral
activity of remdesivir; coadministration of these drugs is not recommended.25
Drug Availability
Hydroxychloroquine, chloroquine, and azithromycin are not approved by the Food and Drug
Administration (FDA) for the treatment of COVID-19. Furthermore, the FDA Emergency Use
Authorization for hydroxychloroquine and chloroquine was revoked in June 2020.
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. 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.
3. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting
SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at:
4. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in
combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal. Int J
Antimicrob Agents. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32405156/.
5. Andreani J, Bideau ML, Duflot I, et al. In vitro testing of combined hydroxychloroquine and azithromycin on
SARS-CoV-2 shows synergistic effect. Microb Pathog. 2020. Available at:
https://pubmed.ncbi.nlm.nih.gov/32344177/.
6. Maisonnasse P, Guedj J, Contreras V, et al. Hydroxychloroquine use against SARS-CoV-2 infection in
non-human primates. Nature. 2020;585(7826):584-587. Available at:
7. Recovery Collaborative Group, Horby P, Mafham M, et al. Effect of hydroxychloroquine in hospitalized
WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511. Available at:
9. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in
hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(21):2165-2176. Available
10. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus
standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil
(COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-967. Available at:
11. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-
moderate COVID-19. N Engl J Med. 2020;383(21):2041-2052. Available at:
12. Recovery Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY):
a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10274):605-612. Available at:
13. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin
with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020. Available at:

14. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with
15. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination
in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. Available at:
16. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early
COVID-19: a randomized trial. Ann Intern Med. 2020;173(8):623-631. Available at:
17. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild
COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020;Published online ahead of print. Available at:
18. Omrani AS, Pathan SA, Thomas SA, et al. Randomized double-blinded placebo-controlled trial
of hydroxychloroquine with or without azithromycin for virologic cure of non-severe COVID-19.
EClinicalMedicine. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/33251500/.
19. PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19
in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled,
open-label, adaptive platform trial. The Lancet. 2021;397(10279):1063-1074. Available at:
20. Hinks TS, Lucy C, Knight R, et al. A randomised clinical trial of azithromycin versus standard care in
ambulatory COVID-19—the ATOMIC2 trial. MedRxiv. 2021;Preprint. Available at:
21. Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine
and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation.
22. Azithromycin (Zithromax) [package insert]. Food and Drug Administration. 2013. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf.
23. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of
hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive
for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):1036-1041. Available at:
24. Chorin E, Wadhwani L, Magnani S, et al. QT interval prolongation and torsade de pointes in patients with
COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425-1433. Available
25. Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential
drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/
medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-
interaction-may-reduce.

Table 2b. Chloroquine or Hydroxychloroquine and/or Azithromycin: Selected

Clinical Data
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 CQ, HCQ, and/or AZM.
The Panel has reviewed other clinical studies of HCQ with or without AZM, CQ, and AZM for the treatment of COVID-19.1-19 These studies
have limitations that make them less definitive and informative than the studies discussed here. The Panel’s summaries and interpretations of
some of those studies are available in the archived versions of the COVID-19 Treatment Guidelines.
Study Design Methods Results Limitations and Interpretation
Solidarity Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1920

Open-label randomized Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled platform trial • Aged ≥18 years • ITT analysis: HCQ (n = 947) and HCQ control (n = 906) • Not blinded
with multiple arms;
in 1 arm, hospitalized • Received a diagnosis of COVID-19 • Enrollment occurred between March 22 and October 4, 2020. • Disease severity varied widely
patients received HCQ among patients.
Key Exclusion Criteria: Participant Characteristics:
(n = 11,330) • Already receiving study drug • 35% of patients enrolled in each arm were aged <50 years; Interpretation:
• Expected to be transferred 21% of patients were aged ≥70 years. • HCQ does not decrease in-
elsewhere within 72 hours • 21% to 23% of patients had diabetes mellitus, 20% to 21% hospital mortality in hospitalized
had heart disease, and 6.5% to 7% had chronic lung disease. patients with COVID-19 when
Interventions: compared to SOC.
• At entry, 36% to 38% of patients were not on supplemental
• HCQ plus local SOC. Patients • HCQ does not decrease the need
oxygen, 53% to 55% were receiving supplemental oxygen
received a loading dose of HCQ for mechanical ventilation when
only, and 9% were receiving IMV.
800 mg PO at entry, then HCQ compared to SOC.
800 mg PO 6 hours later followed • SOC included corticosteroids for 23% of patients in HCQ arm
and 22% of patients in SOC only arm. • There was no evidence of harm in
by a daily dose of HCQ 400
the HCQ arm.
mg PO twice daily for 10 days, Outcomes:
starting 12 hours after the entry
dose. • No significant difference in in-hospital mortality; 104 patients
(10.2%) in HCQ arm and 84 patients (8.9%) in SOC arm died
• Local SOC alone by Day 28 (rate ratio 1.19; 95% CI, 0.89–1.59; P = 0.23).

Solidarity Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1920, continued

Primary Endpoint: •S ubgroup analyses based on age or respiratory support at entry
• In-hospital mortality (i.e., death reported no significant difference in mortality between the arms.
during the original hospitalization; • N o difference between the arms in the secondary outcome
follow-up ended at discharge of initiation of ventilation, and no difference in the composite
from the hospital) outcome of in-hospital mortality or initiation of ventilation
• T he number of deaths due to any cardiac cause during the 14
days after enrollment (the dosing period) was lower in these 2
arms than in the other study arms (the RDV, LPV/RTV, and IFN
arms and their respective control arms).
PETAL Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1921
Randomized, placebo- Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled, blinded trial • Laboratory-confirmed SARS- • E nrollment occurred between April 2 and June 19, 2020. • It is unclear how the primary
in hospitalized adults CoV-2 infection outcome of this study (a median
(n = 479) •H CQ (n = 242) and placebo (n = 237)
• Symptoms of respiratory illness COVID Outcomes Scale score)
•P lanned sample size was 510 participants, but study enrollment translates to clinical practice.
for <10 days was halted early due to futility.
Key Exclusion Criteria: Interpretation:
Participant Characteristics:
• More than 1 dose of HCQ or CQ • HCQ does not improve patient
•M edian age was 58 and 57 years in HCQ and placebo arms, scores on the COVID Outcomes
during the previous 10 days respectively; 33% of patients were aged ≥65 years and 24% of Scale in hospitalized patients with
• Prolonged QTc interval (>500 ms) patients were Black/African American. laboratory-confirmed SARS-
Interventions: • 3 3% to 36% of patients had diabetes mellitus, 6% to 12% had CoV-2 infection when compared
heart disease, and 7% to 9% had chronic lung disease. to placebo.
• HCQ 400 mg PO twice daily for
2 doses, then HCQ 200 mg PO • A t randomization, 5.4% of patients in HCQ arm and 8% in • HCQ did not improve survival or
twice daily for 8 doses placebo arm were receiving IMV or ECMO. In both arms, 11% time to discharge in these patients
to 12% of patients were receiving noninvasive ventilation or when compared to placebo.
• Matching placebo
HFNC oxygen, 46% to 48% were receiving low-flow oxygen,
Primary Endpoint: and 35% were receiving no respiratory support.
• Clinical status 14 days after • Among the patients who received concomitant medications,
randomization, as measured by a 22% received RDV, 19% received AZM, and 18% received
7-point ordinal scale (the COVID corticosteroids. There was no difference in concomitant
Outcomes Scale) medication use between the arms.

PETAL Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1921, continued

Outcomes:
• Median COVID Outcomes Scale score was 6 in HCQ arm
(IQR 4–7) and 6 in placebo arm (IQR 4–7; aOR 1.02; 95% CI,
0.73–1.42).
• No difference between the arms in the secondary outcome of
all-cause, all-location death at Day 14 and Day 28
• No difference between the arms in the number of any of the
following systematically collected safety events: cardiac arrest
treated with CPR, symptomatic hypoglycemia, ventricular
arrhythmia, or seizure
• Among patients who had QTc assessed, 5.9% in HCQ arm and
3.3% in placebo arm had a recorded QTc interval >500 ms
during the first 5 days of dosing.
RECOVERY Trial22
Open-label, randomized Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled platform trial • Clinically suspected or • HCQ (n = 1,561) and SOC (n = 3,155) • Not blinded
with multiple arms; laboratory-confirmed SARS-
in 1 arm, hospitalized • Study enrollment ended early after investigators and trial- • Information on occurrence of new
CoV-2 infection steering committee concluded that the data showed no benefit major cardiac arrythmia was not
patients received HCQ
(n = 11,197) Key Exclusion Criteria: for HCQ. collected throughout the trial.
• Patients with prolonged QTc Participant Characteristics: Interpretation:
intervals were excluded from • Mean age was 65 years in both arms; 41% of patients were • HCQ does not decrease 28-day all-
HCQ arm. aged ≥70 years. cause mortality when compared
Interventions: • 90% of patients had laboratory-confirmed SARS-CoV-2 to the usual SOC in hospitalized
infection. patients with clinically suspected
• HCQ 800 mg at entry and at 6
or laboratory-confirmed SARS-
hours, then HCQ 400 mg every • 57% of patients had ≥1 major comorbidity: 27% had diabetes CoV-2 infection.
12 hours for 9 days or until mellitus, 26% had heart disease, and 22% had chronic lung
discharge disease. • Patients who received HCQ
had a longer median length of
• Usual SOC • At randomization, 17% of patients were receiving IMV or hospital stay, and those who
Primary Endpoint: ECMO, 60% were receiving oxygen only (with or without were not on IMV at the time of
noninvasive ventilation), and 24% were receiving neither. randomization were more likely
• All-cause mortality at Day 28
after randomization • Use of AZM or another macrolide during the follow-up period to require intubation or die during
was similar in both arms, as was use of dexamethasone. hospitalization if they received
HCQ.

RECOVERY Trial22, continued

Outcomes:
• No significant difference in 28-day mortality between
the 2 arms; 421 patients (26.8%) in HCQ arm and 790
patients (27.0%) in SOC arm had died by Day 28 (rate
ratio 1.09; 95% CI, 0.97–1.23; P = 0.15).
• A similar 28-day mortality for HCQ patients was
reported during the post hoc exploratory analysis that
was restricted to the 4,266 participants (90.5%) who
had a positive SARS-CoV-2 test result.
• Patients in HCQ arm were less likely to survive
hospitalization and had a longer median time to
discharge than patients in SOC arm.
• Patients who received HCQ and who were not on
IMV at baseline had an increased risk of requiring
intubation and an increased risk of death.
• At the beginning of the study, the researchers did not
record whether a patient developed a major cardiac
arrhythmia after study enrollment; however, these
data were later collected for 735 patients (47.1%) in
HCQ arm and 1,421 patients (45.0%) in SOC arm.
• No differences between the arms in the frequency of
supraventricular tachycardia, ventricular tachycardia
or fibrillation, or instances of AV block that required
intervention; 1 case of Torsades de Pointes was
reported in HCQ arm.
Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1923
Open-label, 3-arm RCT Key Inclusion Criteria: Number of Participants: Key Limitations:
in hospitalized adults • Aged ≥18 years • mITT analysis included patients with laboratory- • Not blinded
(n = 667) confirmed SARS-CoV-2 infection (n = 504).
• Clinically suspected or • F ollow-up period was restricted to 15 days.
laboratory-confirmed SARS- Participant Characteristics: Interpretation:
CoV-2 infection
• Mean age was 50 years. • Neither HCQ alone nor HCQ plus AZM
• Mild or moderate COVID-19
• 58% of patients were men. improved clinical outcomes at Day 15 after
• Duration of symptoms ≤14 days randomization among hospitalized patients

Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1923, continued
Key Exclusion Criteria: • At baseline, 58.2% of patients were Ordinal Level 3; with mild or moderate COVID-19.
• Need for >4 L of supplemental 41.8% were Ordinal Level 4.
oxygen or ≥40% FiO2 by face mask • Median time from symptom onset to randomization was
• History of ventricular tachycardia 7 days.
• QT interval ≥480 ms • 23.3% to 23.9% of patients received oseltamivir.
Interventions: Outcomes:
• HCQ 400 mg twice daily for 7 days • No significant difference in the odds of worse clinical
plus SOC status at Day 15 between patients in HCQ arm (OR 1.21;
95% CI, 0.69–2.11; P = 1.00) and patients in HCQ plus
• HCQ 400 mg twice daily plus AZM AZM arm (OR 0.99; 95% CI, 0.57–1.73; P = 1.00)
500 mg daily for 7 days plus SOC
• No significant differences in secondary outcomes of the
• SOC alone 3 arms, including progression to mechanical ventilation
Primary Endpoint: during the first 15 days and mean number of days “alive
• Clinical status at Day 15, as and free of respiratory support”
measured by a 7-point ordinal • A greater proportion of patients in HCQ plus AZM arm
scale among the patients with (39.3%) and HCQ arm (33.7%) experienced AEs than
confirmed SARS-CoV-2 infection those in SOC arm (22.6%).
Ordinal Scale Definitions: • QT prolongation was more common in patients who
received HCQ plus AZM or HCQ alone than in patients
1. Not hospitalized, no limitations
who received SOC alone, but fewer patients in SOC
2. Not hospitalized, with limitations arm had serial electrocardiographic studies performed
3. Hospitalized, not on oxygen during the follow-up period.
4. Hospitalized, on oxygen
5. Hospitalized, oxygen administered
by HFNC or noninvasive
ventilation
6. Hospitalized, on mechanical
ventilation
7. Death

Hydroxychloroquine in Nonhospitalized Adults With Early COVID-1924

Randomized, placebo- Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled trial in • Symptoms that were compatible • Contributed to primary endpoint data: HCQ (n = 212) and • This study enrolled a highly
nonhospitalized adults with COVID-19 and lasted ≤4 placebo (n = 211) heterogeneous population.
(n = 491) days
Participant Characteristics: • Only 227 of 423 participants (53.7%)
• Either laboratory-confirmed were confirmed PCR-positive for
• 241 patients were exposed to people with COVID-19
SARS-CoV-2 infection or high- SARS-CoV-2.
through their position as health care workers (57%), 106
risk exposure within the previous
were exposed through household contacts (25%), and 76 • Changing the primary endpoint
14 days without a new power calculation
had other types of exposure (18%).
Key Exclusion Criteria: makes it difficult to assess whether
• Median age was 40 years.
the study is powered to detect
• Aged <18 years • 56% of patients were women. differences in outcomes between the
• Hospitalized • Only 3% of patients were Black. study arms.
• Receipt of certain medications • Very few patients had comorbidities: 11% had • This study used surveys for
Interventions: hypertension, 4% had diabetes, and 68% had no chronic screening, symptom assessment,
medical conditions. and adherence reporting.
• HCQ 800 mg once, then HCQ 600
mg in 6–8 hours, then HCQ 600 • 56% of patients were enrolled on Day 1 of symptom • Visual analogue scales are not
mg once daily for 4 days onset. commonly used, and their ability
• Placebo • 341 participants (81%) had either a positive PCR result or to assess acute viral respiratory
a high-risk exposure to a PCR-positive contact. infections in clinical trials has not
Primary Endpoints: been validated.
Outcomes:
• Planned primary endpoint was Interpretation:
ordinal outcome by Day 14 in • Compared to the placebo recipients, HCQ recipients
had a nonsignificant 12% difference in improvement in • The study has some limitations,
4 categories: not hospitalized,
symptoms between baseline and Day 14 (-2.60 vs. -2.33 and it did not find evidence that
hospitalized, ICU stay, or death.
points; P = 0.117). early administration of HCQ reduced
• Because event rates were lower symptom severity in patients with
than expected, a new primary • Ongoing symptoms were reported by 24% of those in mild COVID-19.
endpoint was defined: change in HCQ arm and 30% of those in the placebo arm at Day 14
overall symptom severity over 14 (P = 0.21).
days, measured by a 10-point, • No difference in the incidence of hospitalization between
self-reported, visual analogue the arms (4 patients in the HCQ arm vs. 10 patients
scale in placebo arm); 2 of 10 placebo participants were
hospitalized for reasons that were unrelated to COVID-19
• A higher percentage of patients in HCQ arm experienced
AEs than patients in placebo arm (43% vs. 22%; P <
0.001).

Hydroxychloroquine in Nonhospitalized Adults With Mild COVID-1925

Open-label RCT in Key Inclusion Criteria: Number of Participants: Key Limitations:
nonhospitalized adults • Laboratory-confirmed SARS- • ITT analysis: HCQ (n = 136) and control (n = 157) • Open-label, non-placebo-
(n = 353) CoV-2 infection controlled trial
• 60 patients were excluded from the ITT analysis due to
• <5 days of mild COVID-19 negative baseline RT-PCR, missing RT-PCR at follow-up • Study design allowed for the
symptoms visits, or consent withdrawal. possibility of dropouts in control
arm and over-reporting of AEs in
Key Exclusion Criteria: Participant Characteristics:
HCQ arm.
• Moderate to severe COVID-19 • Mean age was 41.6 years.
• The intervention changed during
• Severe liver or renal disease • 67% of patients were woman. the study; the authors initially
• History of cardiac arrhythmia • Majority of patients were health care workers (87%). planned to include HCQ plus DRV/
• QT prolongation • 53% of patients reported chronic health conditions. COBI.
• Median time from symptom onset to enrollment was 3 days • The majority of the participants
Interventions:
(IQR 2–4 days). were relatively young health care
• HCQ 800 mg on Day 1, then HCQ workers.
400 mg once daily for 6 days • Most common COVID-19 symptoms were fever, cough, and
sudden olfactory loss. Interpretation:
• No antiviral treatment (control
arm) Outcomes: • Early administration of HCQ to
patients with mild COVID-19
Primary Endpoint: • No significant difference in viral load reduction between did not result in improvement in
control arm and HCQ arm at Day 3 virologic clearance, a lower risk of
• Reduction in SARS-CoV-2 viral
load, assessed using NP swabs • (-1.41 vs. -1.41 log10 copies/mL; difference of 0.01; 95% CI, disease progression, or a reduced
on Days 3 and 7 -0.28 to 0.29), or at Day 7 (-3.37 vs. -3.44 log10 copies/mL; time to symptom improvement.
difference of -0.07; 95% CI, -0.44 to 0.29).
Secondary Endpoints:
• No difference in the risk of hospitalization between control
• Disease progression up to Day 28 arm and HCQ arm (7.1% vs. 5.9%; risk ratio 0.75; 95% CI,
• Time to complete resolution of 0.32–1.77)
symptoms • No difference in the median time from randomization to the
resolution of COVID-19 symptoms between the 2 arms (12.0
days in control arm vs. 10.0 days in HCQ arm; P = 0.38)
• A higher percentage of participants in the HCQ arm than in
the control arm experienced AEs during the 28-day follow-up
period (72% vs. 9%). Most common AEs were GI disorders
and “nervous system disorders.”
• SAEs were reported in 12 patients in control arm and 8
patients in HCQ arm. SAEs that occurred among patients in
HCQ arm were not deemed to be related to the drug.

Observational Study on Hydroxychloroquine With or Without Azithromycin26

Retrospective, Key Inclusion Criteria: Number of Participants: Key Limitations:
multicenter, • Laboratory-confirmed SARS- • HCQ plus AZM (n = 735), HCQ alone (n = 271), AZM • This study has the inherent
observational study in CoV-2 infection alone (n = 211), and neither drug (n = 221) limitations of an observational study,
a random sample of including residual confounding from
hospitalized adults with Interventions: Participant Characteristics:
confounding variables that were
COVID-19 from the New • HCQ plus AZM • Patients in the treatment arms had more severe disease unrecognized and/or unavailable for
York Department of at baseline than those who received neither drug. analysis.
• HCQ alone
Health (n = 1,438) Outcomes:
• AZM alone Interpretation:
• Neither drug • In adjusted analyses, patients who received 1 of the • Despite the limitations discussed
3 treatment regimens did not show a decreased in- above, these findings suggest that
Primary Endpoint: hospital mortality rate when compared with those who although HCQ and AZM are not
• In-hospital mortality received neither drug. associated with an increased risk of
Secondary Endpoint: • Patients who received HCQ plus AZM had a greater risk in-hospital death, the combination of
of cardiac arrest than patients who received neither drug HCQ and AZM may be associated with
• Cardiac arrest and arrhythmia or
(OR 2.13; 95% CI, 1.12–4.05). an increased risk of cardiac arrest.
QT prolongation on an ECG
Observational Study of Hydroxychloroquine Versus No Hydroxychloroquine in New York City27
Observational study in Key Inclusion Criteria: Number of Participants: Key Limitations:
hospitalized adults with • Laboratory-confirmed SARS- • Received HCQ (n = 811) and did not receive HCQ (n = • This study has the inherent
COVID-19 at a large CoV-2 infection 565) limitations of an observational study,
medical center (n = including residual confounding from
1,376) Key Exclusion Criteria: Participant Characteristics:
confounding variables that were
• Intubation, death, or transfer to • HCQ recipients were more severely ill at baseline than unrecognized and/or unavailable for
another facility within 24 hours those who did not receive HCQ. analysis.
of arriving at the emergency
Outcomes: Interpretation:
department
• Using propensity scores to adjust for major predictors • The use of HCQ for treatment of
Interventions: of respiratory failure and inverse probability weighting, COVID-19 was not associated
• HCQ 600 mg twice daily on Day the study demonstrated that HCQ use was not with harm or benefit in a large
1, then HCQ 400 mg once daily associated with intubation or death (HR 1.04; 95% CI, observational study.
for 4 days 0.82–1.32).
• No HCQ • No association between concomitant use of AZM and
the composite endpoint of intubation or death (HR 1.03;
Primary Endpoint:
95% CI, 0.81–1.31)
• Time from study baseline (24
hours after patients arrived at the
ED) to intubation or death

Key: AE = adverse event; AV = atrioventricular; AZM = azithromycin; CPR = cardiopulmonary resuscitation; CQ = chloroquine; DRV/COBI = darunavir/cobicistat; ECG
= electrocardiogram; ECMO = extracorporeal membrane oxygenation; ED = emergency department, FiO2 = fraction of inspired oxygen; GI = gastrointestinal; HCQ =
hydroxychloroquine; HFNC = high-flow nasal cannula; ICU = intensive care unit; IFN = interferon; IMV = invasive mechanical ventilation; ITT = intention-to-treat; LPV/
RTV = lopinavir/ritonavir; mITT = modified intention-to-treat; NP = nasopharyngeal; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain
reaction; PO = orally; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse event;
SOC = standard of care
References
1. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med.
2. Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19
patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020:101663. Available at:
3. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized
clinical trial. Int J Antimicrob Agents. 2020:105949. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32205204.
4. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020;12(4):322-325. Available at:
5. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med (N Y).
2020;1(1):114-127.e3. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32838355.
6. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and
azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384. Available at:
7. Satlin MJ, Goyal P, Magleby R, et al. Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019
disease. PLoS One. 2020;15(7):e0236778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32701969.
8. Mikami T, Miyashita H, Yamada T, et al. Risk factors for mortality in patients with COVID-19 in New York City. J Gen Intern Med. 2021;36(1):17-26.
9. Catteau L, Dauby N, Montourcy M, et al. Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide
observational study of 8075 participants. Int J Antimicrob Agents. 2020:106144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32853673.
10. COVID-19 RISK and Treatments (CORIST) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced
mortality: findings from the observational multicentre Italian CORIST study. Eur J Intern Med. 2020;82:38-47. Available at:
11. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients
admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-967. Available at:
12. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised

controlled trial. BMJ. 2020;369:m1849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409561.

13. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. Available
14. Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen:
observational comparative study using routine care data. BMJ. 2020;369:m1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409486.
15. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
Int J Infect Dis. 2020;97:396-403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623082.
16. Recovery Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label,
platform trial. Lancet. 2021;397(10274):605-612. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33545096.
17. Omrani AS, Pathan SA, Thomas SA, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin
for virologic cure of non-severe COVID-19. EClinicalMedicine. 2020;29:100645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33251500.
18. Principle Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical
course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;397(10279):1063-1074. Available at:
19. Hinks TSC, Cureton L, Knight R, et al. A randomised clinical trial of azithromycin versus standard care in ambulatory COVID-19–the ATOMIC2 trial.
medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.21.21255807v1.
21. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a
randomized clinical trial. JAMA. 2020;324(21):2165-2176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33165621.
22. Recovery Collaborative Group, Horby P, Mafham M, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med.
23. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med.
24. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med.
25. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial.
Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674126.
26. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with
COVID-19 in New York state. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.
27. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020;382(25):2411-

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 2c).
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. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
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:
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:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103132Orig1s5199lbl.pdf.
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 pharmacovigilance database on interferon beta-1b exposure. Ther Adv Neurol Disord.
2020;13:1756286420910310. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32201504.
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.

Table 2c. 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)
Key Secondary Endpoints:
• 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 Outcome: • 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:
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

Ivermectin
Last Updated: February 11, 2021
Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat
several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 It is also being
evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on
treated humans and livestock.2 For these indications, ivermectin has been widely used and is generally
well tolerated.1,3 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 the host importin alpha/beta-1
nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to
enhance infection by suppressing the host’s antiviral response.4,5 In addition, ivermectin docking may
interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
spike protein to the human cell membrane.6 Ivermectin is thought to be a host-directed agent, which may
be the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV,
and yellow fever.4,7-9 Despite this in vitro activity, no clinical trials have reported a clinical benefit for
ivermectin in patients with these viruses. Some studies of ivermectin have also reported potential anti-
inflammatory properties, which have been postulated to be beneficial in people with COVID-19.10-12
Some observational cohorts and clinical trials have evaluated the use of ivermectin for the prevention
and treatment of COVID-19. Data from some of these studies can be found in Table 2d.
Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to
recommend either for or against the use of ivermectin for the treatment of COVID-19. Results
from adequately powered, well-designed, and well-conducted clinical trials are needed to provide
more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.
Rationale
Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell cultures.13 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.14,15 Even though ivermectin appears to accumulate in
the lung tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 µM,
the half-maximal inhibitory concentration (IC50) against SARS-CoV-2 in vitro.16-19 Subcutaneous
administration of ivermectin 400 µg/kg had no effect on SARS-CoV-2 viral loads in hamsters. 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.20
Since the last revision of this section of the Guidelines, 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. Some clinical
studies showed no benefits or worsening of disease after ivermectin use,21-24 whereas others reported
shorter time to resolution of disease manifestations that were attributed to COVID-19,25-27 greater
reduction in inflammatory marker levels,26 shorter time to viral clearance,21 or lower mortality rates in
patients who received ivermectin than in patients who received comparator drugs or placebo.21,27

However, most of these studies had incomplete information and significant methodological limitations,
which make it difficult to exclude common causes of bias. These limitations include:
• The sample size of most of the trials was small.
• Various doses and schedules of ivermectin were used.
• Some of the randomized controlled trials were open-label studies in which neither the participants
nor the investigators were blinded to the treatment arms.
• Patients received various concomitant medications (e.g., doxycycline, hydroxychloroquine,
azithromycin, zinc, corticosteroids) in addition to ivermectin or the comparator drug. This
confounded the assessment of the efficacy or safety of ivermectin.
• The severity of COVID-19 in the study participants was not always well described.
• The study outcome measures were not always clearly defined.
Table 2d includes summaries of key studies. Because most of these studies have significant limitations,
the Panel cannot draw definitive conclusions on the clinical efficacy of ivermectin for the treatment
of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are
needed to provide further guidance on the role of ivermectin in the treatment of COVID-19.
Monitoring, Adverse Effects, and Drug-Drug Interactions

• Ivermectin is generally well tolerated. Adverse effects may include dizziness, pruritis, nausea, or
diarrhea.
• 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.28
• Ivermectin is a minor cytochrome P 3A4 substrate and a p-glycoprotein substrate.
• Ivermectin is generally given on an empty stomach with water; however, administering ivermectin
with food increases its bioavailability.
• The FDA issued a warning in April 2020 that ivermectin intended for use in animals should not
be used to treat COVID-19 in humans.
• Please see Table 2d for additional information.
In animal studies, ivermectin was shown to be teratogenic when given in doses that were maternotoxic.
These results raise concerns about administering ivermectin to people who are in the early stages of
pregnancy (prior to 10 weeks gestation).29 A 2020 systematic review and meta-analysis reviewed the
incidence of poor maternal and fetal outcomes after ivermectin was used for its antiparasitic properties
during pregnancy. However, the study was unable to establish a causal relationship between ivermectin
use and poor maternal or fetal outcomes due to the quality of evidence. There are numerous reports of
inadvertent ivermectin use in early pregnancy without apparent adverse effects.30-32 Therefore, there is
insufficient evidence to establish the safety of using ivermectin in pregnant people, especially those in
the later stages of pregnancy.
One study reported that the ivermectin concentrations secreted in breastmilk after a single oral dose were
relatively low. No studies have evaluated the ivermectin concentrations in breastmilk in patients who
received multiple doses.

Ivermectin is used in children weighing >15 kg for the treatment of helminthic infections, pediculosis,
and scabies. The safety of using ivermectin in children weighing <15 kg has not been well established.
Ivermectin is generally well tolerated in children, with a side effect profile similar to the one seen in
adults. Currently, there are no available pediatric data from clinical trials to inform the use of ivermectin
for the treatment or prevention of COVID-19 in children.
Clinical Trials
Several clinical trials that are evaluating the use of ivermectin for the treatment of COVID-19 are
References
1. Omura S, Crump A. Ivermectin: panacea for resource-poor communities? Trends Parasitol. 2014;30(9):445-
2. Fritz ML, Siegert PY, Walker ED, Bayoh MN, Vulule JR, Miller JR. Toxicity of bloodmeals from ivermectin-
treated cattle to Anopheles gambiae s.l. Ann Trop Med Parasitol. 2009;103(6):539-547. Available at:
3. 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
4. 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. Available at:
5. Arévalo AP, Pagotto R, Pórfido J, et al. Ivermectin reduces coronavirus infection in vivo: a mouse
experimental model. bioRxiv. 2020;Preprint. Available at:
6. 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.
7. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein
5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013;99(3):301-306.
8. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin
alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J.
9. Barrows NJ, Campos RK, Powell ST, et al. A screen of FDA-approved drugs for inhibitors of Zika virus
infection. Cell Host Microbe. 2016;20(2):259-270. Available at:
10. 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:
11. 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.
12. 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.
13. 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:

14. 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:
15. 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:
16. 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.
17. 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.
18. 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. Biotechnology & Biotechnological
Equipment. 2020;34(1):469-474. Available at:
https://www.tandfonline.com/doi/full/10.1080/13102818.2020.1775118.
19. Jermain B, Hanafin PO, Cao Y, Lifschitz A, Lanusse C, Rao GG. 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:
20. de Melo GD, Lazarini F, Larrous F, et al. Anti-COVID-19 efficacy of ivermectin in the golden hamster.
bioRxiv. 2020;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2020.11.21.392639v1.
21. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may
reduce the duration of illness. Int J Infect Dis. 2020;103:214-216. Available at:
22. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in
SARS-COV-2/COVID-19 Patients. Int J of Sci. 2020;9:31-35. Available at:
https://www.ijsciences.com/pub/article/2378.
23. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Guo D, He S. A randomized trial of ivermectin-
doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Research Square.
2020;Preprint. Available at:
https://assets.researchsquare.com/files/rs-38896/v1/3ee350c3-9d3f-4253-85f9-1f17f3af9551.pdf.
24. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of
hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target
trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv. 2020;Preprint.
Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.
25. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized
clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv.
2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.
26. Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19
patients: a randomized multi-center clinical trial. Research Square. 2020;Preprint. Available at:
https://www.researchsquare.com/article/rs-109670/v1.
27. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with
COVID-19. Arch Bronconeumol. 2020;56(12):828-830. Available at:

28. 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:
29. Ivermectin [package insert]. DailyMed. 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/fda/
fdaDrugXsl.cfm?setid=847a1dd7-d65b-4a0e-a67d-d90392059dac&type=display.
30. Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent
ivermectin treatment during community-based distribution. Lancet. 1990;336(8729):1486-1489. Available at:
31. Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent
ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg. 1993;87(3):318. Available at:
32. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and
albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health. 2003;8(12):1093-

Table 2d. Ivermectin: Selected Clinical Data

The Panel has 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 discussed below. The studies summarized below are the randomized controlled trials that
have had the greatest impact on the Panel’s recommendations.
IVERCOR-COVID19: Double-Blind, Placebo-Controlled RCT of Ivermectin to Prevent Hospitalizations in Patients With COVID-19 in Argentina27
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 • Study enrolled a fairly young population
screening • 47% were women with few comorbidities that predict
disease progression
Key Exclusion Criteria: • 24% with HTN; 10% with DM; 58% with ≥1 comorbidity
• Oxygen supplementation or hospitalization • Median time from symptom onset was 4 days Interpretation:
• Concomitant use of CQ or HCQ • In patients who had recently acquired
Primary Outcome: SARS-CoV-2 infection, there was no
Interventions: • COVID-19-related hospitalizations: 5.6% in IVM arm vs. evidence of a clinical benefit for IVM.
• Weight-based doses of IVM given at enrollment and 24 8.3% in placebo arm (OR 0.65; 95% CI, 0.32–1.31; P =
hours later for a maximum total dose of 48 mg (n = 250) 0.23)
• Placebo (n = 251) Secondary Outcomes:
Primary Endpoint: • Need for MV: 2% in IVM arm vs. 1% in placebo arm (P
= 0.7)
• Hospitalization for any reason
• All-cause deaths: 2% in IVM arm vs. 1% in placebo arm
Key Secondary Endpoints: (P = 0.7)
• Need for MV • AEs: 18% in IVM arm vs. 21% in placebo arm (P = 0.6)
• All-cause mortality

Double-Blind, Placebo-Controlled RCT of Ivermectin for Treatment of Mild COVID-19 in Columbia28

• Positive SARS-CoV-2 PCR or antigen test result • Median age 37 years; 4% in IVM arm and 8% in placebo • Primary endpoint changed from
• Symptoms for ≤7 days arm aged ≥65 years proportion of patients with clinical
• 39% in IVM arm and 45% in placebo arm were men deterioration to time to symptom
• Mild disease resolution during the trial due to low
• 79% had no known comorbidities event rates
• Median of 5 days from symptom onset to randomization • Study enrolled younger, healthier
• Asymptomatic disease
• Severe pneumonia Primary Outcomes: patients; this population does not
• Hepatic dysfunction • Median time to symptom resolution: 10 days in IVM arm typically develop severe COVID-19
vs. 12 days in placebo arm (HR 1.07; P = 0.53) Interpretation:
Interventions:
• Symptoms resolved by Day 21: 82% in IVM arm vs. • A 5-day course of IVM 300 μg/kg per day
• IVM 300 μg/kg per day for 5 days (n = 200) 79% in placebo arm did not improve the time to resolution
• Placebo (n = 198) Secondary Outcomes: of symptoms in patients with mild
COVID-19.
Primary Endpoint: • No difference between arms in proportion of patients
• Time to resolution of symptoms within 21 days who had clinical deterioration or who required escalation
in care.
• Proportion of patients with clinical deterioration Safety Outcomes:
• Proportion of patients who required escalation in care • Discontinued treatment due to an AE: 8% in IVM arm vs.
3% in placebo arm
• No SAEs were considered to be related to study
interventions.

Open-Label RCT of Ivermectin Plus Doxycycline Versus Hydroxychloroquine Plus Azithromycin for Asymptomatic Patients and Patients With Mild to Moderate
COVID-19 in Bangladesh29
• Aged 16–80 years • Mean age 34 years; 78% were men • Small sample size
• PCR-confirmed SARS-CoV-2 infection • 78% were symptomatic at baseline • Open-label study
• SpO2 ≥95% Primary Outcomes: • No SOC alone group
• Normal or near-normal CXR • Mean time to negative PCR result: 9 days in both • Study enrolled young patients who were
• No unstable comorbidities arms not at high risk for disease progression
Interventions: • In patients who were symptomatic at baseline, mean Interpretation:

time to negative PCR result: 9 days in IVM/DOX arm • There was no difference in the time to
• Single dose of IVM 200 μg/kg plus DOX 100 mg twice daily vs. 10 days in HCQ/AZM arm (P = 0.07)
for 10 days (n = 60) a negative SARS-CoV-2 PCR result or
• Mean time to symptom recovery: 6 days in IVM/DOX symptom recovery between patients who
• HCQ 400 mg on Day 1, then HCQ 200 mg twice daily for 9 arm vs. 7 days in HCQ/AZM arm (P = 0.07) received IVM plus DOX and those who
days plus AZM 500 mg once daily for 5 days (n = 56) received HCQ plus AZM.
• Patients who received IVM/DOX had fewer AEs than
Primary Endpoints: those who received HCQ/AZM (32% vs. 46%).
• Time to negative PCR result
• Time to resolution of symptoms
Double-Blind, Placebo-Controlled RCT of Ivermectin for Treatment of Mild to Moderate COVID-19 in India30
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 53 years; 28% were women • The primary endpoint of the study was
• Hospitalized with mild or moderate COVID-19 • 35% with HTN; 36% with DM a negative SARS-CoV-2 RT-PCR result
on Day 6. However, the study reported
Interventions: • 79% with mild COVID-19 no RT-PCR result or an inconclusive
• IVM 12 mg for 2 days (n = 55) • Mean of 6.9 days from symptom onset RT-PCR result for 42% of patients in the
• Placebo (n = 57) • 100% received HCQ, steroids, and antibiotics; 21% IVM arm and 23% in the placebo arm.
received RDV; 6% received tocilizumab • 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
Key Secondary Endpoints: vs. 32% in placebo arm (rate ratio 0.8; P = 0.348) Interpretation:
• Symptom resolution by Day 6 • There was no significant virologic or
Secondary Outcomes:
• Discharge by Day 10 clinical benefit of IVM for patients with
• Symptom resolution by Day 6: 84% in IVM arm vs. mild to moderate COVID-19.
• Need for ICU admission or MV 90% in placebo arm (rate ratio 0.9; P = 0.36)
• Mortality

Double-Blind, Placebo-Controlled RCT of Ivermectin for Treatment of Mild to Moderate COVID-19 in India30, continued
• Discharge by Day 10: 80% in IVM arm vs. 74% in placebo arm
(RR 1.1; P = 0.43)
• No difference between arms in proportion of patients who were
admitted to ICU or who required MV.
• Inpatient deaths: 0 in IVM arm (0%) vs. 4 in placebo arm (7%)
RIVET-COV : Double-Blind, Placebo-Controlled RCT of Ivermectin in Patients With Mild to Moderate COVID-19 in India31
• Positive SARS-CoV-2 PCR or antigen test result • Mean age 35 years; 89% were men • Small sample size
• Nonsevere COVID-19 • 60% to 68% had mild COVID-19 (including asymptomatic Interpretation:
patients); 33% to 40% had moderate COVID-19
Key Exclusion Criteria: • There was no difference in the rate
• Median duration of symptoms was similar between arms (4–5 of negative PCR results on Day 5 or
• CrCl <30 mL/min
days). clinical outcomes between patients
• Transaminases >5 times ULN who received IVM and those who
• 10% received concurrent antivirals (RDV, favipiravir, or HCQ);
• MI, heart failure, QTc interval prolongation no difference between arms. received placebo.
• Severe comorbidity Primary Outcomes:
Interventions: • Proportion with negative PCR result on Day 5: 48% in IVM 24
• Single dose of IVM 24 mg (n = 51) mg arm vs. 35% in IVM 12 mg arm vs. 31% in placebo arm (P
• Single dose of IVM 12 mg (n = 49) = 0.30)
• Placebo (n = 52) • VL at enrollment did not impact conversion to negative RT-
PCR on Day 5.
Primary Endpoints:
• No significant difference between arms in VL decline by Day 5.
• Reduction of SARS-CoV-2 VL at Day 5
Secondary Outcomes:
• Negative PCR result at Day 5
• No difference between arms in time to symptom resolution or
Key Secondary Endpoints: number of hospital-free days at Day 28.
• Time to symptom resolution • Proportion with clinical worsening similar across arms: 8% in
• Clinical status at Day 14 IVM 24 mg arm vs. 5% in IVM 12 mg arm vs. 11% in placebo
arm (P = 0.65)
• Number of hospital-free days at Day 28
• No difference between arms in frequency of AEs.
• No SAEs reported.

Double-Blind RCT of Ivermectin, Chloroquine, or Hydroxychloroquine in Hospitalized Adults With Severe COVID-19 in Brazil32
• Hospitalized with laboratory-confirmed SARS-CoV-2 • Mean age 53 years; 58% were men • Small sample size
infection • Most common comorbidities: HTN (43%); DM (28%); BMI >30 • No placebo control
• ≥1 of the following severity criteria: (38%) • No clearly defined primary endpoint
• Dyspnea • 76% had respiratory failure on admission
Interpretation:
• Tachypnea (>30 breaths/min) Outcomes: • Compared to CQ or HCQ, IVM did not
• SpO2 <93% • No difference between IVM, CQ, and HCQ arms in: reduce the proportion of hospitalized
• PaO2/FiO2 <300 mm Hg • Proportion requiring supplemental oxygen: 88% vs. 89% vs. patients with severe COVID-19 who
• Involvement of >50% of lungs on CXR or CT 90% required supplemental oxygen, ICU
admission, or MV or the proportion of
Key Exclusion Criterion: • ICU admission: 28% vs. 22% vs. 21% patients who died.
• Cardiac arrhythmia • Need for MV: 24% vs. 21% vs. 21%
• Mortality: 23% vs. 21% vs. 22%
Interventions:
• Mean number of days of supplemental oxygen: 8 days for
• IVM 14 mg once daily for 3 days (n = 53)
each arm
• CQ 450 mg twice daily on Day 0, then once daily for
• No difference in proportion of patients with AEs between the
4 days (n = 61)
arms.
• HCQ 400 mg twice daily on Day 0, then once daily for
• Baseline characteristics that were significantly associated with
4 days (n = 54)
mortality:
Endpoints: • Aged >60 years (HR 2.4)
• Need for supplemental oxygen, MV, or ICU admission • DM (HR 1.9)
• Mortality • BMI >33 (HR 2.0)
• SpO2 <90% (HR 5.8)

Double-Blind RCT of Ivermectin as Adjunctive Therapy in Hospitalized Patients With Mild to Severe COVID-19 in Iran33
Key Inclusion Criterion: Participant Characteristics: Key Limitations:
• Symptoms suggestive of COVID-19 pneumonia, with • Median age 53–61 years across arms; 50% were men • Since IVM was given as a single dose
compatible chest CT scan or positive SARS-CoV-2 • Disease severity stratification (based on CT findings): negative or multiple doses and no placebo was
PCR result (1%), mild (14%), moderate (73%), severe (12%) given to patients in these arms, the
study was not truly blinded
Key Exclusion Criterion: • Median SpO2 at baseline was 88% to 91% across arms
• Large proportion of patients did not
• Severe immunosuppression, malignancy, or chronic • Proportion of patients in each arm with a positive SARS-CoV-2 have laboratory-confirmed SARS-
kidney disease PCR result varied, with a range of 47% to 97% CoV-2 infection, and there was
Interventions: Primary Outcomes: an imbalance across arms in the
• HCQ 200 mg twice daily as SOC plus 1 of the • Median duration of hypoxemia was shorter in IVM arms than proportion of patients with laboratory-
following: in placebo arm (P = 0.025). confirmed SARS-CoV-2 infection
• SOC alone (n = 30) • Median duration of hospitalization was shorter in IVM arms • Concerns have been raised about
than in placebo arm (P = 0.006). whether the study was conducted as
• Placebo (n = 30)
reported34
• Single dose of IVM 200 μg/kg (n = 30) • No difference between the arms in number of days of
tachypnea or number of days to return to normal temperature. • Post hoc grouping of randomized
• IVM 200 μg/kg on Days 1, 3, and 5 (n = 30) arms raises risk of false positive
• Mortality was higher in SOC and placebo arms (18%) than in findings
• Single dose of IVM 400 μg/kg (n = 30)
IVM arms (3%; P < 0.001).
• IVM 400 μg/kg on Day 1, then IVM 200 μg/kg on Interpretation:
Days 3 and 5 (n = 30) • The unclear treatment arm
Primary Endpoints: assignments and the lack of
accounting for disease severity at
• Clinical recovery
baseline make it difficult to draw
• All-cause mortality conclusions about the efficacy of
using IVM to treat mild COVID-19.
Key: AE = adverse event; AZM = azithromycin; BMI = body mass index; CQ = chloroquine; CrCl = creatinine clearance; CT = computed tomography; CXR = chest
X-ray; DM = diabetes mellitus; DOX = doxycycline; HCQ = hydroxychloroquine; HTN = hypertension; ICU = intensive care unit; IVM = ivermectin; MI = myocardial
infarction; 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; PCR = polymerase chain reaction; 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

References
1. Spoorthi V, Sasank S. Utility of ivermectin and doxycycline combination for the treatment of SARSCoV-2. International Archives of Integrated
Medicine. 2020;7(10):117-182. Available at: https://iaimjournal.com/wp-content/uploads/2020/10/iaim_2020_0710_23.pdf.
2. Camprubi D, Almuedo-Riera A, Marti-Soler H, et al. Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients. PLoS One.
3. Bhattacharya R, Ray I, Mukherjee R, Chowdhury S, Kulasreshtha MK, Ghosh R. Observational study on clinical features, treatment and outcome
of COVID-19 in a tertiary care centre in India—a restrospective case series. International Journal of Scientific Research. 2020;9(10). Available at:
https://www.worldwidejournals.com/international-journal-of-scientific-research-(IJSR)/article/observational-study-on-clinical-features-treatment-and-
outcome-of-covid-19-in-a-tertiary-care-centre-in-india-andndash-a-retrospective-case-series/MzI0NTg=/?is=1&b1=141&k=36.
4. Morgenstern J, Redondo JN, León A, et al. The use of compassionate ivermectin in the management of symptomatic outpatients and hospitalized
patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican
Republic, from May 1 to August 10, 2020. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.29.20222505v1.
5. Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in
outpatient settings significantly reduced symptoms compared to known outcomes in untreated patients. medRxiv. 2020;Preprint. Available at:
6. Carvallo H, Roberto H, Eugenia FM. Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID
19. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.09.10.20191619v1.
7. Bukhari KHS, Asghar A, Perveen N, et al. Efficacy of ivermectin in COVID-19 patients with mild to moderate disease. medRxiv. 2021;Preprint.
8. Elalfy H, Besheer T, El-Mesery A, et al. Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study)
on the clearance of mild COVID-19. J Med Virol. 2021;93(5):3176-3183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33590901.
9. Chahla RE, Ruiz LM, Mena T, et al. Cluster randomised trials—ivermectin repurposing for COVID-19 treatment of outpatients with mild disease in
primary health care centers. Research Square. 2021;Preprint. Available at: https://www.researchsquare.com/article/rs-495945/v1.
10. Tanioka H, Tanioka S, Kaga K. Why COVID-19 is not so spread in Africa: how does ivermectin affect it? medRxiv. 2021;Preprint. Available at:
11. Roy S, Samajdar SS, Tripathi SK, Mukherjee S, Bhattacharjee K. Outcome of different therapeutic interventions in mild COVID-19 patients in a single
OPD clinic of West Bengal: a retrospective study. medRxiv. 2021;Preprint. Available at:
12. Pott-Junior H, Bastos Paoliello MM, Miguel AQC, et al. Use of ivermectin in the treatment of COVID-19: a pilot trial. Toxicol Rep. 2021;8:505-510.
13. Merino J, Borja VH, Lopez O, et al. Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based
on a public intervention in Mexico City. SocArXiv Papers. 2021;Preprint. Available at: https://osf.io/preprints/socarxiv/r93g4/.
14. Shahbaznejad L, Davoudi A, Eslami G, et al. Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled
clinical yrial. Clin Ther. 2021;43(6):1007-1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34052007.

15. Roman YM, Burela PA, Pasupuleti V, Piscoya A, Vidal JE, Hernandez AV. Ivermectin for the treatment of COVID-19: a systematic review and meta-
analysis of randomized controlled trials. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.05.21.21257595v2.full.
16. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect
Dis. 2020;103:214-216. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278625.
17. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response
in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine. 2021;32:100720.
18. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in SARS-COV-2/COVID-19 patients. Int J of Sci.
2020;9:31-35. Available at: https://www.ijsciences.com/pub/article/2378.
19. Gonzalez JLB, Gámez MG, Enciso EAM, et al. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A
randomized controlled trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.18.21252037v1.
20. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using ivermectin with
doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020;Preprint. Available at:
https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.
21. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch Bronconeumol.
22. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial.
EClinicalMedicine. 2021;37:100959. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34189446.
23. Okumus N, Demirturk N, Cetinkaya RA, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19
patients. BMC Infect Dis. 2021;21(1):411. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33947344.
24. Podder CS, Chowdhury N, Sina MI, Haque W. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label,
randomised controlled study. IMC Journal of Medical Science. 2021. Available at: https://doi.org/10.3329/imcjms.v14i2.52826.
25. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin
among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru.
26. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with
coronavirus disease 2019: the ivermectin in COVID nineteen study. Chest. 2021;159(1):85-92. Available at:
27. 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. 2021;21(1):635. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34215210.
28. 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: https://www.ncbi.nlm.nih.gov/pubmed/33662102.
29. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Dan G, He S. A comparative study on ivermectin-doxycycline and hydroxychloroquine-
azithromycin therapy on COVID-19 patients. EJMO. 2021;5(1):63-70. Available at: https://ejmo.org/pdf/A%20Comparative%20Study%20on%20

IvermectinDoxycycline%20and%20HydroxychloroquineAzithromycin%20Therapy%20on%20COVID19%20Patients-16263.pdf.
30. Ravikirti, Roy R, Pattadar C, et al. Evaluation of ivermectin as a potential treatment for mild to moderate COVID-19: a double-blind randomized
placebo controlled trial in Eastern India. J Pharm Pharm Sci. 2021;24:343-350. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34265236.
31. Mohan A, Tiwari P, Suri TM, et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-
controlled trial. J Infect Chemother. 2021;27(12):1743-1749. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34483029.
32. Galan LEB, Santos NMD, Asato MS, et al. Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with
severe manifestations of SARS-CoV-2 infection. Pathog Glob Health. 2021;115(4):235-242. Available at:
33. Niaee MS, Namdar P, Allami A, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical
trial. Asian Pac J Trop Med. 2021;14:266-273. Available at: https://www.apjtm.org/text.asp?2021/14/6/266/318304.
34. Lawrence JM, Meyerowitz-Katz G, Heathers JAJ, Brown NJL, Sheldrick KA. The lesson of ivermectin: meta-analyses based on summary data alone
are inherently unreliable. Nat Med. 2021;27(11):1853-1854. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34552263.

Lopinavir/Ritonavir and Other HIV Protease Inhibitors

The replication of SARS-CoV-2 depends on the cleavage of polyproteins into an RNA-dependent

RNA polymerase and a helicase.1 Two proteases are responsible for this cleavage: 3-chymotrypsin-like
protease (3CLpro) and papain-like protease (PLpro).
Lopinavir/ritonavir and darunavir/cobicistat have been studied in patients with COVID-19. The clinical
trials discussed below have not demonstrated a clinical benefit for protease inhibitors in patients with
COVID-19.
Recommendations
lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in
hospitalized patients (AI).
• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease
inhibitors for the treatment of COVID-19 in nonhospitalized patients (AIII).
Rationale
The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug
concentrations that can inhibit the SARS-CoV-2 proteases.2,3 In addition, lopinavir/ritonavir did not
show efficacy in two large randomized controlled trials in hospitalized patients with COVID-19.4,5
There is currently a lack of data on the use of lopinavir/ritonavir in nonhospitalized patients with
COVID-19. However, the pharmacodynamic concerns and the lack of evidence for a clinical benefit
among hospitalized patients with COVID-19 undermine confidence that lopinavir/ritonavir has a clinical
benefit at any stage of SARS-CoV-2 infection.
Adverse Events
The adverse events for lopinavir/ritonavir include:
• Nausea, vomiting, diarrhea (common)
• QTc prolongation
• Hepatotoxicity
Lopinavir/ritonavir is a potent inhibitor of cytochrome P450 3A. Coadministering lopinavir/ritonavir
with medications that are metabolized by this enzyme may increase the concentrations of those
medications, resulting in concentration-related toxicities. Please refer to the Guidelines for the Use of
Antiretroviral Agents in Adults and Adolescents with HIV for a list of potential drug interactions.
Summary of Clinical Data for COVID-19

• The plasma drug concentrations achieved using typical doses of lopinavir/ritonavir are far below
the levels that may be needed to inhibit SARS-CoV-2 replication.3
• Lopinavir/ritonavir did not demonstrate a clinical benefit in hospitalized patients with COVID-19
during a large randomized trial in the United Kingdom.4

• In a large international randomized trial, lopinavir/ritonavir did not reduce the mortality rate
among hospitalized patients with COVID-19.5
• A moderately sized randomized trial (n = 199) failed to find a virologic or clinical benefit of
lopinavir/ritonavir over standard of care.6
• Results from a small randomized controlled trial showed that darunavir/cobicistat was not
effective for the treatment of COVID-19.7
• There are no data from clinical trials that support using other HIV protease inhibitors to treat
COVID-19.
• Please see Clinical Data for COVID-19 below for more information.
Clinical Data for COVID-19

The information presented in this section 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 lopinavir/ritonavir.
Lopinavir/Ritonavir in Hospitalized Patients With COVID-19: The RECOVERY Trial

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an ongoing, open-label,
randomized controlled trial with multiple arms, including a control arm; in one arm, participants
received lopinavir/ritonavir. The trial was conducted across 176 hospitals in the United Kingdom and
enrolled hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection.4
Patients were randomized into several parallel treatment arms; this included randomization in a 2:1
ratio to receive either the usual standard of care only or the usual standard of care plus lopinavir 400
mg/ritonavir 100 mg orally every 12 hours for 10 days or until hospital discharge. Patients who had
severe hepatic insufficiency or who were receiving medications that had potentially serious or life-
threatening interactions with lopinavir/ritonavir were excluded from randomization into either of these
arms. Mechanically ventilated patients were also underrepresented in this study because it was difficult
to administer the oral tablet formulation of lopinavir/ritonavir to patients who were on mechanical
ventilation. The primary outcome was all-cause mortality at Day 28 after randomization.
The lopinavir/ritonavir arm was discontinued on June 29, 2020, after the independent data monitoring
committee concluded that the data showed no clinical benefit for lopinavir/ritonavir.
Patient Characteristics
• Of the 7,825 participants who were eligible to receive lopinavir/ritonavir, 1,616 were randomized
to receive lopinavir/ritonavir and 3,424 were randomized to receive standard of care only. The
remaining participants were randomized to other treatment arms in the study.
• In both the lopinavir/ritonavir arm and the standard of care arm, the mean age was 66 years; 44%
of patients were aged ≥70 years.
• Test results for SARS-CoV-2 infection were positive for 88% of patients. The remaining 12% had
a negative test result.
• Comorbidities were common; 57% of patients had at least one major comorbidity. Of those
patients, 28% had diabetes mellitus, 26% had heart disease, and 24% had chronic lung disease.
• At randomization, 4% of patients were receiving invasive mechanical ventilation, 70% were
receiving oxygen only (with or without noninvasive ventilation), and 26% were receiving neither.
• The percentages of patients who received azithromycin or another macrolide during the follow-up

period were similar in both arms (23% in the lopinavir/ritonavir arm vs. 25% in the standard of
care arm). In addition, 10% of patients in both arms received dexamethasone.
Results
• There was no significant difference in the primary outcome of 28-day mortality between the two
arms; 374 patients (23%) in the lopinavir/ritonavir arm and 767 patients (22%) in the standard of
care arm had died by Day 28 (rate ratio 1.03; 95% CI, 0.91–1.17; P = 0.60).
• A similar 28-day mortality was reported for patients who received lopinavir/ritonavir in an
analysis that was restricted to the 4,423 participants who had positive SARS-CoV-2 test results
(rate ratio 1.05; 95% CI, 0.92–1.19; P = 0.49).
• Patients in the lopinavir/ritonavir arm and patients in the standard of care arm had similar median
times to discharge (11 days in both arms) and similar probabilities of being discharged alive within
28 days (69% vs. 70%).
• Among participants who were not on invasive mechanical ventilation at baseline, patients who
received lopinavir/ritonavir and those who received standard of care only had similar risks of
progression to intubation or death.
• Results were consistent across subgroups defined by age, sex, ethnicity, or respiratory support at
baseline.
Limitations
• The study was not blinded.
• No laboratory or virologic data were collected.
Interpretation
Lopinavir/ritonavir did not decrease 28-day all-cause mortality when compared to the usual standard of
care in hospitalized persons with clinically suspected or laboratory-confirmed SARS-CoV-2 infection.
Participants who received lopinavir/ritonavir and those who received standard of care only had similar
median lengths of hospital stay. Among the patients who were not on invasive mechanical ventilation at
the time of randomization, those who received lopinavir/ritonavir were as likely to require intubation or
die during hospitalization as those who received standard of care.
Lopinavir/Ritonavir in Hospitalized Patients with COVID-19: The Solidarity Trial

The Solidarity trial was an open-label, randomized controlled trial that enrolled hospitalized patients
with COVID-19 in 405 hospitals across 30 countries. The study included multiple arms; in one arm,
participants received lopinavir/ritonavir. The control group for this arm included people who were
randomized at the same site and time who could have received lopinavir/ritonavir but received standard of
care instead. Lopinavir 400 mg/ritonavir 100 mg was administered orally twice daily for 14 days or until
hospital discharge. Only the oral tablet formulation of lopinavir/ritonavir was available, which precluded
administration to those on mechanical ventilation. The primary outcome was in-hospital mortality.5
After the results of the RECOVERY trial prompted a review of the Solidarity data, the lopinavir/
ritonavir arm ended enrollment on July 4, 2020. At that time, 1,411 patients had been randomized to
receive lopinavir/ritonavir, and 1,380 patients received standard of care.
Patient Characteristics
• In both the lopinavir/ritonavir arm and the standard of care arm, 20% of the participants were aged
≥70 years and 37% were aged <50 years.
• Comorbidities were common. Diabetes mellitus was present in 24% of patients, heart disease in
21%, and chronic lung disease in 7%.

• At randomization, 8% of patients were receiving invasive mechanical ventilation or extracorporeal

membrane oxygenation, 53% were receiving oxygen only (with or without noninvasive
ventilation), and 39% were receiving neither.
• Similar percentages of patients received corticosteroids in the lopinavir/ritonavir arm and the
standard of care arm (23% vs. 24%). Other nonstudy treatments were administered less often, and
the use of these treatments was balanced between arms.
Results
• There was no significant difference in in-hospital mortality between the two arms; 148 patients
(9.7%) in the lopinavir/ritonavir arm and 146 patients (10.3%) in the standard of care arm had died
by Day 28 (rate ratio 1.00; 95% CI, 0.79–1.25; P = 0.97).
• Progression to mechanical ventilation among those who were not ventilated at randomization
occurred in 126 patients in the lopinavir/ritonavir arm and 121 patients in the standard of care arm.
• In-hospital mortality results appeared to be consistent across subgroups.
Limitations
• The study was not blinded.
• Those who were on mechanical ventilation were unable to receive lopinavir/ritonavir.
• The study includes no data on time to recovery.
Interpretation
Among hospitalized patients, lopinavir/ritonavir did not decrease in-hospital mortality or the number of
patients who progressed to mechanical ventilation compared to standard of care.
Lopinavir/Ritonavir Pharmacokinetics in Patients With COVID-19

In a case series, eight patients with COVID-19 were treated with lopinavir 400 mg/ritonavir 100
mg orally twice daily and had plasma trough levels of lopinavir drawn and assayed by liquid
chromatography-tandem mass spectrometry.3
Results
• The median plasma lopinavir concentration was 13.6 μg/mL.
• After correcting for protein binding, trough levels would need to be approximately 60-fold
to 120-fold higher to achieve the in vitro half-maximal effective concentration (EC50) for
SARS-CoV-2.
Limitations
• Only the trough levels of lopinavir were quantified.
• The concentration of lopinavir required to effectively inhibit SARS-CoV-2 replication in vivo is
currently unknown.
Interpretation
The plasma drug concentrations that were achieved using typical doses of lopinavir/ritonavir are far
below the levels that may be needed to inhibit SARS-CoV-2 replication.
Other Reviewed Studies

The Panel has reviewed other clinical studies that evaluated the use of protease inhibitors for the
treatment of COVID-19.6,8,9 These studies have limitations that make them less definitive and

informative than larger randomized clinical trials. The Panel’s summaries and interpretations of some of
these studies are available in the archived versions of the Guidelines.
References
1. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - drug discovery and therapeutic options. Nat
Rev Drug Discov. 2016;15(5):327-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26868298.
2. Marzolini C, Stader F, Stoeckle M, et al. Effect of systemic inflammatory response to SARS-CoV-2 on
lopinavir and hydroxychloroquine plasma concentrations. Antimicrob Agents Chemother. 2020;64(9).
3. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in
patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020. Available at:
4. Group RC. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised,
controlled, open-label, platform trial. Lancet. 2020. Available at:
WHO Solidarity Trial results. N Engl J Med. 2020. Available at:
6. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N
7. 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.
8. 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. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
9. Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/
moderate COVID-19: an exploratory randomized controlled trial. Med. 2020:[In Press]. Available at:
https://www.sciencedirect.com/science/article/pii/S2666634020300015.

Nitazoxanide
Nitazoxanide is a broad-spectrum thiazolide antiparasitic agent that is approved by the Food and
Drug Administration (FDA) for the treatment of Cryptosporidium parvum and Giardia duodenalis
infections in children aged ≥1 year and adults. Nitazoxanide is rapidly metabolized to its active
metabolite, tizoxanide, and has in vitro antiviral activity against a range of viruses, including influenza
viruses, hepatitis B and C viruses, norovirus, rotavirus, Ebola virus, Middle East respiratory syndrome
coronavirus (MERS-CoV), and SARS-CoV-2.1-3 The mechanism of antiviral activity is not fully
characterized. Nitazoxanide inhibits host enzymes, which impairs the posttranslational processing of
viral proteins. It also has inhibitory effects on proinflammatory cytokines. With the exception of a Phase
2b/3 trial for uncomplicated influenza, the evidence for clinical activity of nitazoxanide against other
viruses is limited or of low quality.4
Recommendation
nitazoxanide for the treatment of COVID-19, except in a clinical trial (BIIa).
Rationale
Two randomized controlled trials that were conducted in Brazil and the United States did not find a
significant clinical benefit for nitazoxanide treatment in nonhospitalized adults with COVID-19 when
treatment was initiated within 2 to 5 days after illness onset.5,6 One of these trials, which has not yet
been published, reported that fewer patients in the nitazoxanide arm progressed to severe COVID-19
than in the placebo arm. However, the study was underpowered to detect a difference, and this finding
was not statistically significant.6 Additional small, unpublished studies were reviewed; however, due
to their limitations, they did not provide support for the use of nitazoxanide.7,8 Nitazoxanide was well
tolerated in these trials. The Panel concluded that results from adequately powered, well-designed, and
well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role
of nitazoxanide in the treatment of COVID-19.
Please see Table 2e for more information.

• Nitazoxanide is generally well tolerated. The most commonly reported side effects include
abdominal pain, diarrhea, headache, nausea, vomiting, urine discoloration, and, rarely, ocular
discoloration.
• Nitazoxanide is a highly plasma protein-bound drug (>99.9%). Drug-drug interactions may occur
when nitazoxanide is administered concurrently with other highly plasma protein-bound drugs due
to competition for binding sites. If nitazoxanide is coadministered with other highly protein-bound
drugs with narrow therapeutic indices, monitor the patient for adverse drug reactions.
• Please see Table 2f for more information.
According to the animal study data included in the product label, nitazoxanide does not appear to affect
fertility, nor does it cause fetal toxicity.9 There are no data on using nitazoxanide to treat COVID-19 in
pregnant women.

Nitazoxanide is approved by the FDA for use in children aged ≥1 year old to treat Cryptosporidium
parvum and Giardia duodenalis infections. Dosing for the nitazoxanide suspension or tablets is available
for children that provides exposure that is similar to the approved adult dose of oral nitazoxanide 500
mg twice daily. There are no data on using nitazoxanide to treat COVID-19 in children.
Clinical Trials
Several clinical trials that are evaluating the use of nitazoxanide for the treatment of COVID-19 are
References
1. Jasenosky LD, Cadena C, Mire CE, et al. The FDA-approved oral drug nitazoxanide amplifies host antiviral
responses and inhibits ebola virus. iScience. 2019;19:1279-1290. Available at:
2. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014;110:94-103.
3. Cao J, Forrest JC,Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential
anti-coronavirus drugs. Antiviral Res. 2015;114:1-10. Available at:
4. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute
uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis.
5. Rocco PRM, Silvia PL, Cruz FF, et al. Early use of nitazoxanide in mild COVID-19 disease: randomised,
placebo-controlled trial. Eur Respir J. 2021;Published online ahead of print. Available at:
6. Rossignol J, Bardin MC, Oaks JB,et al. Early treatment with nitazoxanide prevents worsening of mild and
moderate COVID-19 and subsequent hospitalization. medRxiv. 2021;Preprint. Available at:
7. Blum VF, Cimerman S, Hunter JR,et al. Nitazoxanide in vitro efficacy against SARS CoV-2 and in vivo
superiority to placebo to treat moderate COVID-19—a Phase 2 randomized double-blind clinical trial.
Preprints with the Lancet. 2021. Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3763773.
8. Silva M, Espejo A, Pereyra ML, et al. Efficacy of nitazoxanide in reducing the viral load in COVID-19
patients: randomized, placebo-controlled, single-blinded, parallel-group, pilot study. MedRxiv. 2021;Preprint.
Available at: https://www.medrxiv.org/content/10.1101/2021.03.03.21252509v1.full.pdf.
9. Nitazoxanide (Alinia) [package insert]. Lupin Pharma. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021497s001,021498s004lbl.pdf.

Table 2e. Nitazoxanide: Selected Clinical Data

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 NTZ for the
treatment of COVID-19. The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing
recommendations for NTZ.1,2

Early Treatment of Mild COVID-19 with Nitazoxanide3
Randomized, Key Inclusion Criteria: Number of Participants: Key Limitations:
double-blind, • Clinical signs and symptoms of • NTZ (n = 194) and placebo (n = 198) • In general, the patients in this study
placebo- COVID-19 for ≤3 days (fever, dry were young and relatively healthy.
controlled trial in Participant Characteristics:
cough, and/or fatigue) • At baseline, the median VL was 0.43
nonhospitalized • Median age of patients was 37 years.
adults with mild Key Exclusion Criteria: log10 c/mL lower in the NTZ arm
• Percentage of patients aged 18–39 years: 58% than in the placebo arm; however,
COVID-19 in Brazil • Negative SARS-CoV-2 RT-PCR result
(n = 475) • Percentage of patients aged 40–59 years: 36% this difference was not statistically
from an NP swab
• Percentage of patients aged 60–77 years: 6% significant (trend toward a significant
• Renal, heart, respiratory, liver, or difference; P = 0.065). Although the
autoimmune diseases • 53% of patients were women. difference in absolute VLs between
• Participant had a history of cancer in • 69% of patients were White. the arms at Day 5 was reported as
the past 5 years • 31% of patients had a BMI ≥30. statistically significant, without the
information on the change in VL in
Interventions: • 85% of patients had no reported comorbidities. each arm, it is difficult to interpret
• NTZ 500 mg 3 times daily for 5 days • Median time from symptom onset to first dose of study the significance of the findings.
using the oral liquid formulation drug was 5 days (IQR 4–5 days). • Some participants who received
• Color-matched placebo 3 times daily • Baseline median SARS-CoV-2 VL was 7.06 log10 c/mL the study drug were excluded from
for 5 days (IQR 5.77–8.13) in NTZ arm and 7.49 log10 c/mL (IQR the analysis population due to
6.15–8.32) in placebo arm (P = 0.065). discontinued intervention (21 in
Primary Endpoint:
Primary Outcome: NTZ arm vs. 18 in placebo arm);
• Complete resolution of dry cough, AEs (6 in NTZ arm vs. 1 in placebo
fever, and/or fatigue after receiving • There was no difference in time to complete resolution of arm); hospitalization (5 in NTZ arm
treatment for 5 days symptoms between NTZ and placebo arms (P = 0.277) vs. 5 in placebo arm); and protocol
Key Secondary Endpoints: Secondary Outcomes: deviations (7 in NTZ arm vs. 7 in
• Reduction in SARS-CoV-2 VL placebo arm). This complicates the
• After 5 days, median SARS-CoV-2 VL was lower in NTZ
interpretation of the study results,
• Incidence of hospital admission after arm (3.63 log10 c/mL [IQR 0–5.03]) than in placebo arm because an ITT analysis was not
completing therapy (4.13 log10 c/mL [IQR 2.88–5.31]; P = 0.006).
included.


Early Treatment of Mild COVID-19 with Nitazoxanide3, continued
• 29.9% of patients in NTZ arm and 18.2% of patients in placebo Interpretation:
arm had a negative SARS-CoV-2 RT-PCR result at the fifth • NTZ did not improve time
treatment visit (P = 0.009). to resolution of symptoms
• In the ITT study population, 5 patients on NTZ and 5 on placebo compared to placebo.
were hospitalized due to clinical deterioration; 2 who received • Median VL was lower at Day
NTZ required ICU admission vs. 0 who received placebo. These 5 in the NTZ arm than in the
individuals were excluded from the analysis population because placebo arm, but this may
they did not complete the 5-day treatment course before clinical reflect differences in baseline
progression occurred. VLs.
Other Outcomes: • NTZ was well tolerated.
• Mild to moderate AEs occurred in about 30% of participants in
each arm who completed 5 days of therapy.
Early Treatment of Mild to Moderate COVID-19 with an Investigational Formulation of Nitazoxanide4
Randomized, Key Inclusion Criteria: Number of Participants: Key Limitations:
double-blind, • Aged ≥12 years • mITT analysis: NTZ (n = 184) and placebo (n = 195) • Information is limited in this
placebo- preliminary report.
controlled trial in • Enrollment ≤72 hours of symptom Participant Characteristics:
nonhospitalized onset • Because the number of
• Median age of patients was 40 years.
patients with • Mild to moderate COVID-19 high-risk participants
• 43.5% of patients were men. who progressed to severe
COVID-19 in the • ≥2 respiratory symptom domains
United States and • 87.6% of patients were White. COVID-19 in this study was
with a score ≥2 on FLU-PRO small, the results for this
Puerto Rico (n = questionnaire at screening, and no • Median BMI was 28.9.
1,092) subgroup are fragile. Larger
improvement in overall symptom •M edian time from symptom onset to randomization was 45.9 hours. studies are needed.
This is a preliminary, severity compared to previous day • 64.8% of patients had mild disease.
unpublished Interpretation:
Key Exclusion Criteria: • 35.2% of patients had moderate disease.
report that has not • NTZ did not demonstrate
• Signs or symptoms of severe • 62.8% of patients were at risk for severe illness. significant clinical or virologic
been peer reviewed.
COVID-19 benefits when compared to
Primary Outcome:
• Previous COVID-19 or any placebo.
symptom suggestive of COVID-19 • NTZ was not associated with a reduction in median time to
sustained response compared to placebo (13.3 days in NTZ arm • NTZ was well tolerated.
• Recent acute upper respiratory vs. 12.4 days in placebo arm; P = 0.88)
tract infection
Secondary Outcomes:
• Severe immunodeficiency
• Progression to severe disease occurred in 1 of 184 patients
• Severe heart, lung, neurological, or
(0.5%) in NTZ arm and 7 of 195 patients (3.6%) in placebo arm (P
other systemic diseases
= 0.07).

Early Treatment of Mild to Moderate COVID-19 with an Investigational Formulation of Nitazoxanide4, continued
Interventions: • Among a subgroup of patients who had a high risk for severe
• 2 investigational NTZ 300 mg illness according to CDC criteria, 1 of 112 patients (0.9%)
extended-release tablets (for a in NTZ arm and 7 of 126 patients (5.6%) in placebo arm
total dose of 600 mg) PO with food progressed to severe disease (P = 0.07).
twice daily for 5 days • 1 of 184 patients (0.5%) in NTZ arm and 5 of 195 (2.6%) in
• Matching placebo for 5 days placebo arm were hospitalized (P = 0.18).
• All subjects received a vitamin B • There was no significant difference in viral endpoints between
complex supplement twice daily arms at Days 4 and 10.
to mask potential NTZ-associated Other Outcomes:
chromaturia.
• The safety analysis included 935 participants (472 in NTZ arm
Primary Endpoint: and 463 in placebo arm).
• Time from first dose to sustained • 2 patients in NTZ arm and 3 patients in placebo arm stopped
response the study drug due to AEs.
Secondary Endpoint:
• Rate of progression to severe
COVID-19
Key: AE = adverse event; BMI = body mass index; CDC = Centers for Disease Control and Prevention; FLU-PRO = Influenza Patient Reported Outcomes; ICU =
intensive care unit; ITT = intention-to-treat; mITT = modified intention-to-treat; NP = nasopharyngeal; NTZ = nitazoxanide; the Panel = the COVID-19 Treatment
Guidelines Panel; PO = orally; RT-PCR = reverse transcription polymerase chain reaction; VL = viral load
References
1. Blum VF, Cimerman S, Hunter JR, et al. Nitazoxanide superiority to placebo to treat moderate COVID-19–a pilot prove of concept randomized
double-blind clinical trial. EClinicalMedicine. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/34222847/.
2. Silva M, Espejo A, Pereyra ML, et al. Efficacy of nitazoxanide in reducing the viral load in COVID-19 patients. Randomized, placebo-controlled,
single-blinded, parallel group, pilot study. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.03.21252509v1.
3. Rocco PRM, Silva PL, Cruz FF, et al. Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial. Eur Respir J. 2021.
4. Rossignol J, Bardin MC, Oaks JB, et al. Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent
hospitalization. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.19.21255441v1.

Table 2f. Characteristics of Antiviral Agents

• RDV is the only antiviral drug that is approved by the FDA for the treatment of COVID-19. Some 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 approves of their use.
• Information on CQ, HCQ, and LPV/RTV are available in the archived versions of the Guidelines. The Panel recommends against using
these agents to treat COVID-19.
• 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 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 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 individual drug sections or Therapeutic
Management of Hospitalized Adults With COVID-19.
Dosing Regimens
The doses listed here are for approved Drug-Drug Interaction Comments and Links to
Adverse Events Monitoring Parameters
indications or from reported experiences Potential Clinical Trials
or clinical trials.
Remdesivir
Approved by the FDA for the treatment of COVID-19 in individuals aged ≥12 years and weighing ≥40 kg.
Please see Therapeutic Management of • Nausea • Infusion reactions • Clinical drug-drug • RDV should be
Hospitalized Adults With COVID-19 for • ALT and AST elevations • Renal function and hepatic interaction studies of administered in a hospital
the Panel’s recommendations on when to function as clinically RDV have not been or a health care setting
use RDV. • Hypersensitivity conducted. that can provide a
indicated
• Increases in prothrombin time • In vitro, RDV is a minor similar level of care to an
For Hospitalized Adults and Children • FDA does not recommend
• D
rug vehicle is SBECD, which inpatient hospital.
(Aged ≥12 Years and Weighing ≥40 kg): RDV when eGFR is <30 mL/ substrate of CYP3A4,
has been associated with min. See the Remdesivir and a substrate of • A list of clinical trials is
• RDV 200 mg IV on Day 1, then RDV renal and liver toxicity. SBECD section for information on OATP1B1, and P-gp and available: Remdesivir
100 mg IV once daily on Days 2–5. accumulation may occur in using RDV in people with an inhibitor of CYP3A4,
Administer RDV IV infusion over patients with moderate or renal insufficiency. OATP1B1, OATP1B3,
30–120 minutes. severe renal impairment. and MATE1.1

Dosing Regimens
The doses listed here are for approved Drug-Drug Interaction Comments and Links to
Adverse Events Monitoring Parameters
indications or from reported experiences Potential Clinical Trials
or clinical trials.
Remdesivir, continued
Dose Recommended in FDA EUA For • Each 100 mg vial of RDV • No significant
Hospitalized Children Weighing 3.5 kg lyophilized powder contains interaction is expected
to <40 kg: 3 g of SBECD, and each between RDV and
• RDV 5 mg/kg IV on Day 1, then RDV 100 mg/20 mL vial of RDV oseltamivir or baloxavir
2.5 mg/kg IV once daily on Days 2–5. solution contains 6 g of (Gilead Sciences,
Administer RDV IV infusion over SBECD. personal and written
30–120 minutes. • Clinicians may consider communications,
preferentially using August and September
the lyophilized powder 2020).
formulation (which contains
less SBECD) in patients with
renal impairment.
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 that are associated • Respiratory symptoms • Low potential for drug- • T he nebulized formulation
Dose for COVID-19 in Clinical Trials: with inhaled therapy (e.g., after inhalation drug interactions of IFN alfa has been the
throat irritation, cough, formulation most commonly
• Nebulized IFN alfa-2b 5 million bronchospasm) used in clinical trials for
international units twice daily; the the treatment of COVID-19.
optimal duration of treatment is unclear. • Systemic effects of IFN are IFN alfa is usually included
expected to be minimal.
as part of a combination
regimen.
•A list of clinical trials is
available: Interferon Alfa
Availability:
•N
ebulized IFN alfa-2b is not
approved by the FDA for use
in the United States.

Dosing Regimens
The doses listed here are for approved Monitoring Drug-Drug Interaction Comments and Links to
Adverse Events
indications or from reported experiences Parameters Potential Clinical Trials
or clinical trials.
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 SQ or IV every other • Leukopenia, neutropenia, • Liver enzymes •U se with caution with Availability
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: •A
vonex, Plegridy, Rebif
• Injection site reactions times ULN.
• IFN beta-1b 8 million international units Brand Names of IFN Beta-1b
• Headache Products:
SQ every other day for up to 7 days
total • Hypertonia •B
etaseron, Extavia
• Pain
• Rash
• Worsening depression
• Induction of autoimmunity
Interferon Lambda
PEG-IFN Lambda-1a • Liver function abnormalities • CBC with • Low potential for drug- •A
Dose for COVID-19 in Clinical Trials: • Injection site reactions differential drug interactions available: Interferon Lambda
• Single dose of PEG-IFN lambda-1a 180 • Liver enzymes •U se with caution with Availability:
µg SQ • Monitor for other hepatotoxic
•P
EG-IFN lambda-1a is not
potential AEs. agents.
approved by the FDA for use
in the United States.
Ivermectin
Dose for COVID-19 in Clinical Trials: • Dizziness • Monitor for • Minor CYP3A4 •G
enerally given on an
• IVM 0.2–0.6 mg/kg PO given as a single • P ruritis potential AEs. substrate empty stomach with water;
dose or as a once-daily dose for up to • P-gp substrate however, administering
•G I effects (e.g., nausea, diarrhea) IVM with food increases its
5 days
• Neurological AEs have been reported bioavailability.2
when IVM has been used to treat

Dosing Regimens
The doses listed here are for Monitoring Comments and Links to
Adverse Events Drug-Drug Interaction Potential
approved indications or from Parameters Clinical Trials
reported experiences or clinical trials.
Ivermectin, continued
p arasitic diseases, but it is not clear •A
whether these AEs were caused by available: Ivermectin
IVM or the underlying conditions.
Nitazoxanide
For Adults: • Abdominal pain • Monitor for • Drug-drug interactions may •N TZ should be taken
• Doses studied for COVID-19 range • Diarrhea potential AEs. occur if NTZ is administered with food.
from NTZ 500 mg PO 3 times daily • Headache concurrently with other highly • T he oral suspension is
to 4 times daily. plasma protein-bound drugs due not bioequivalent to the
• Nausea to competition for binding sites.3 tablet formulation.
• Higher doses are being studied.
• Vomiting • If NTZ is coadministered with •A list of clinical trials is
• Doses used for antiprotozoal other highly protein-bound drugs
indications range from NTZ 500 • U
rine discoloration available: Nitazoxanide
with narrow therapeutic indices,
mg–1 g PO twice daily. • Ocular discoloration (rare)
monitor the patient for AEs.
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; CBC = complete blood count; CHF = congestive heart failure; CQ =
chloroquine; CYP = cytochrome P450; eGFR = estimated glomerular filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI
= gastrointestinal; HCQ = hydroxychloroquine; IFN = interferon; IV = intravenous; IVM = ivermectin; LPV/RTV = lopinavir/ritonavir; MATE = multidrug and toxin
extrusion protein; NTZ = nitazoxanide; OATP = organic anion transporting polypeptide; the Panel = the COVID-19 Treatment Guidelines Panel; PEG-IFN = pegylated
interferon; P-gp = P-glycoprotein; PO = orally; RDV = remdesivir; SBECD = sulfobutylether-beta-cyclodextrin; SQ = subcutaneous; ULN = upper limit of normal
References
1. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2020/214787Orig1s000lbl.pdf.
2. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2009/050742s024s025lbl.pdf.
3. Nitazoxanide (Alinia) [package insert]. Food and Drug Administration. 2017. Available at: https://www.alinia.com/wp-content/uploads/2017/08/
prescribing-information.pdf.

Anti-SARS-CoV-2 Antibody Products

Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using 1 of the following anti-SARS-CoV-2
monoclonal antibody (mAb) products (listed alphabetically) to treat nonhospitalized patients with mild to moderate
COVID-19 who are at high risk of clinical progression, as defined by criteria in the Food and Drug Administration (FDA)
Emergency Use Authorizations (EUAs) for the products:
• Bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an intravenous (IV) infusion; or
• Casirivimab 600 mg plus imdevimab 600 mg administered as an IV infusion or as subcutaneous (SQ) injections; or
• Sotrovimab 500 mg administered as an IV infusion.
• When using casirivimab plus imdevimab, the Panel recommends:
• Casirivimab 600 mg plus imdevimab 600 mg administered as an IV infusion (AIIa).
• If an IV infusion is not feasible or would cause a delay in treatment, casirivimab 600 mg plus imdevimab 600 mg
can be administered as 4 SQ injections (2.5 mL per injection) (BIII).
• 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 risk for progression to severe COVID-19 and/or hospitalization (see Anti-SARS-CoV-2
Monoclonal Antibodies). The ratings for the Panel’s recommendations for using anti-SARS-CoV-2 mAbs as treatment
are based on the FDA EUA criteria for:
• High-risk conditions represented in clinical trials (AIIa); and
• Other medical conditions and factors with limited representation in clinical trials (BIII) except for
immunocompromising conditions or receipt of immunosuppressive therapy, for which the rating is AIII.
• When using anti-SARS-CoV-2 mAbs, treatment should be started as soon as possible after the patient receives a positive
result on a SARS-CoV-2 antigen test or nucleic acid amplification test (NAAT) and within 10 days of symptom onset.
• The use of 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 EUA criteria for outpatient treatment.
• Anti-SARS-CoV-2 mAbs are not currently authorized for use in patients who are hospitalized with severe COVID-19;
however, they may be available through expanded access programs for patients who either have not developed an
antibody response or are not expected to mount an effective immune response to SARS-CoV-2 infection.
Anti-SARS-CoV-2 Monoclonal Antibodies as Post-Exposure Prophylaxis for SARS-CoV-2 Infection
• The Panel recommends using 1 of the following anti-SARS-CoV-2 mAb combinations as post-exposure prophylaxis
(PEP) for people who are at high risk of progressing to severe COVID-19 if infected with SARS-CoV-2 AND who have
the vaccination status AND exposure history outlined in the Prevention of SARS-CoV-2 Infection section:
• Bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an IV infusion; or
• Casirivimab 600 mg plus imdevimab 600 mg administered as SQ injections (AI) or as an IV infusion (BIII).
COVID-19 Convalescent Plasma
• The Panel recommends against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in
hospitalized patients without impaired humoral immunity (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of COVID-19 convalescent
plasma for the treatment of COVID-19 in:
• Hospitalized or nonhospitalized patients with impaired humoral immunity.
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
a clinical benefit in treating SARS-CoV-2 infection (as discussed below). Some anti-SARS-CoV-2 mAbs
have been found to be effective in preventing SARS-CoV-2 infection in household contacts of infected
patients2 and during SARS-CoV-2 outbreaks in skilled nursing and assisted living facilities.3
Anti-SARS-CoV-2 Monoclonal Antibodies That Have Received Emergency Use

Authorizations From the Food and Drug Administration
Currently, 3 anti-SARS-CoV-2 mAb products have received Emergency Use Authorizations (EUAs)
from the Food and Drug Administration (FDA) 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 and/or hospitalization. The issuance of an EUA does not constitute FDA
approval. These products are:
• Bamlanivimab plus etesevimab: These are neutralizing mAbs that bind to different, but
overlapping, epitopes in the spike protein RBD of SARS-CoV-2.
• The distribution of bamlanivimab plus etesevimab was paused in the United States because
both the Gamma (P.1) and Beta (B.1.351) variants have reduced susceptibility to bamlanivimab
and etesevimab.4 However, distribution of the agents has been reinstated in states with low rates
of these and other variants that have reduced susceptibility to bamlanivimab and etesevimab.
Please refer to the FDA webpage Bamlanivimab and Etesevimab Authorized States, Territories,
and U.S. Jurisdictions for the latest information on bamlanivimab plus etesevimab distribution.
• Bamlanivimab plus etesevimab is authorized for adults and children of all ages, including
infants and neonates. Please see Special Considerations in Children for therapeutic
recommendations for children.
• Casirivimab plus imdevimab: These are recombinant human mAbs that bind to nonoverlapping
epitopes of the spike protein RBD of SARS-CoV-2.
• Sotrovimab: This mAb was originally identified in 2003 from a SARS-CoV survivor. It targets an
epitope in the RBD of the spike protein that is conserved between SARS-CoV and SARS-CoV-2.
The FDA has expanded the EUAs for bamlanivimab plus etesevimab and casirivimab plus imdevimab
to authorize their use as post-exposure prophylaxis (PEP) for certain individuals who are at high risk of
acquiring SARS-CoV-2 infection and, if infected, are at high risk of progressing to serious illness. See
Prevention of SARS-CoV-2 Infection and the FDA EUA fact sheets for bamlanivimab plus etesevimab
and casirivimab plus imdevimab for more information.
Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19

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. For recommendations and discussion regarding the use
of mAb products as PEP, see Prevention of SARS-CoV-2 Infection.

Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using 1 of the following anti-
SARS-CoV-2 mAb products (listed alphabetically) to treat nonhospitalized patients with mild to
moderate COVID-19 who are at high risk of clinical progression (see the EUA criteria for use of
the products and the related discussion below):
• Bamlanivimab 700 mg plus etesevimab 1,400 mg (or weight-based dosing for pediatric
patients weighing <40 kg)5 administered as an intravenous (IV) infusion in regions where the
combined frequency of potentially resistant SARS-CoV-2 variants is low (see the FDA webpage
Bamlanivimab and Etesevimab Authorized States, Territories, and U.S. Jurisdictions; or
• Casirivimab 600 mg plus imdevimab 600 mg administered as an IV infusion or as
subcutaneous (SQ) injections; or
• Sotrovimab 500 mg administered as an IV infusion.
• When using casirivimab plus imdevimab, the Panel recommends:
• Casirivimab 600 mg plus imdevimab 600 mg administered as an IV infusion (AIIa).
• If an IV infusion is not feasible or would cause a delay in treatment, casirivimab 600 mg plus
imdevimab 600 mg can be administered as 4 SQ injections (2.5 mL per injection) (BIII).
• When using anti-SARS-CoV-2 mAbs, treatment should be started as soon as possible after the
patient receives a positive result on a SARS-CoV-2 antigen test or nucleic acid amplification test
(NAAT) and within 10 days of symptom onset.
• The use of 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
EUA criteria for outpatient treatment.
• Anti-SARS-CoV-2 mAbs are not currently authorized for use in patients who are hospitalized with
severe COVID-19; however, they may be available through expanded access programs for patients
who either have not developed an antibody response to SARS-CoV-2 infection or are not expected
to mount an effective immune response to infection.
• For guidance on prioritizing the use of anti-SARS-CoV-2 mAbs for the treatment or prevention of
SARS-CoV-2 infection when logistical or supply constraints limit their availability, see the Panel’s
statement on patient prioritization for outpatient therapies.
Rationale
In randomized placebo-controlled trials in nonhospitalized patients who had 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 3a).5-7 It is worth noting that these
studies were conducted before the widespread circulation of variants of concern (VOC). The potential
impact of these variants and their susceptibility to different anti-SARS-CoV-2 mAbs is discussed below.
Bamlanivimab Plus Etesevimab
This anti-SARS-CoV-2 mAb combination has demonstrated a clinical benefit in people with mild to
moderate COVID-19 who are at high risk for progression to severe disease and/or hospitalization (see
Table 3a).8 The distribution of bamlanivimab plus etesevimab was paused in the United States because
both the Gamma (P.1) and Beta (B.1.351) variants have reduced susceptibility to bamlanivimab and
etesevimab.4 However, distribution of the product has been reinstated across the United States because
the combined frequency of the Gamma and Beta variants is <5%. Casirivimab plus imdevimab and
sotrovimab are expected to remain active against the Gamma and Beta variants.

The FDA provides a list of states, territories, and U.S. jurisdictions in which bamlanivimab plus
etesevimab is currently authorized. The Centers for Disease Control and Prevention (CDC) COVID-19
Data Tracker website has the latest information on variant frequencies by region in the United States.
Casirivimab Plus Imdevimab
On June 3, 2021, the FDA updated the EUA for casirivimab plus imdevimab to reduce the authorized
dosage for a single IV infusion from casirivimab 1,200 mg plus imdevimab 1,200 mg to casirivimab
600 mg plus imdevimab 600 mg.6 The update also authorized SQ injection of these lower doses of
casirivimab and imdevimab if an IV infusion is not feasible or would delay treatment. SQ administration
requires 4 injections (2.5 mL per injection) at 4 different sites (see the FDA EUA for details).
The recommendation for using the lower dose of casirivimab 600 mg plus imdevimab 600 mg IV is
based on the Phase 3 results from the R10933-10987-COV-2067 study (ClinicalTrials.gov Identifier
NCT04425629). This double-blind randomized placebo-controlled trial in outpatients with mild
to moderate COVID-19 evaluated different doses of casirivimab plus imdevimab. The modified
full analysis set included participants aged ≥18 years who had a positive SARS-CoV-2 polymerase
chain reaction result at randomization and who had 1 or more risk factors for progression to severe
COVID-19. The results demonstrated a 2.2% absolute reduction and a 70% relative reduction in
hospitalization or death with receipt of casirivimab 600 mg plus imdevimab 600 mg. These results
are comparable to the those observed for IV infusions of casirivimab 1,200 mg plus imdevimab 1,200
mg, which demonstrated a 3.3% absolute reduction and a 71% relative reduction in hospitalization or
death among patients who received this higher dose of casirivimab plus imdevimab.9 See Table 3a for
additional details from the trial.
The recommendation for using SQ injections to administer casirivimab plus imdevimab is based on safety
data from the Phase 1 R10933-10987-HV-2093 study (ClinicalTrials.gov Identifier NCT04519437). This
double-blind randomized placebo-controlled trial compared casirivimab plus imdevimab administered
by SQ injection to placebo in healthy volunteers who did not have SARS-CoV-2 infection. Injection
site reactions were observed in 12% of the 729 casirivimab plus imdevimab recipients and in 4% of the
240 placebo recipients. According to the FDA EUA, in a separate trial that evaluated casirivimab plus
imdevimab in symptomatic participants, there were similar reductions in viral load in the participants
in the IV and SQ arms of the trial.6 However, because the safety and efficacy data for casirivimab plus
imdevimab administered by SQ injection are limited, this route of administration should only be used
when IV infusion is not feasible or would lead to a delay in treatment (BIII).
Sotrovimab
The data that support the EUA for sotrovimab are from the Phase 3 COMET-ICE trial (ClinicalTrials.
gov Identifier NCT04545060). The COMET-ICE trial included outpatients with mild to moderate
COVID-19 who were at high risk for progression to severe disease and/or hospitalization. A total of
583 participants were randomized to receive sotrovimab 500 mg IV (n = 291) or placebo (n = 292). 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 3 of 291 participants (1%) in the sotrovimab
arm and 21 of 292 participants (7%) in the placebo arm (P = 0.002), resulting in a 6% absolute reduction
and an 85% relative reduction in hospitalizations or death associated with sotrovimab.7,10
Criteria for Using Anti-SARS-CoV-2 Monoclonal Antibodies Under the 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.5,6 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 agents in patients with the following
conditions: sickle cell disease, neurodevelopmental disorders, medical-related technological dependence,
asthma, cardiovascular disease, hypertension, and chronic lung disease.
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 and/or
hospitalization. The ratings for the recommendations for the use of anti-SARS-CoV-2 mAbs as treatment
are based on the FDA EUA criteria for the following conditions and other factors.
Medical Conditions or Other Factors That Were Represented in Patients in Clinical Trials That
Evaluated Anti-SARS-CoV-2 Monoclonal Antibodies
• 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)
Other Conditions or Factors That Had Limited Representation in Patients in Clinical Trials but Are
Considered Risk Factors for Progression to Severe COVID-19 by the Centers for Disease Control
and Prevention
• An immunocompromising condition or immunosuppressive treatment (AIII). Many experts
strongly recommend therapy for patients with these conditions, despite their limited representation
in clinical trials.
• Being overweight (BMI 25–30) as the sole risk factor (BIII)
• Chronic kidney disease (BIII)
• Pregnancy (BIII)
• Sickle cell disease (BIII)
• Neurodevelopmental disorders (e.g., cerebral palsy) or other conditions that confer medical
complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies) (BIII)
• Medical-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure
ventilation that is not related to COVID-19) (BIII)
• Infants aged <1 year (for bamlanivimab plus etesevimab only) (CIII)
It is important to note that the likelihood of developing severe COVID-19 increases when a person
has multiple high-risk conditions or comorbidities.11-14 Medical conditions or other factors (e.g., race
or ethnicity) not listed in the 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 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.7
Some of the Panel’s recommendations for using anti-SARS-CoV-2 mAbs according to the updated EUA
criteria are based on preliminary results from the clinical trials that have evaluated these products. The
details on the study designs, methods, and follow-up periods for these trials are currently limited. When

peer-reviewed data from the Phase 3 trials become publicly available, the Panel will review the results
and update the recommendations for using anti-SARS-CoV-2 mAbs if necessary.
Using Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for

COVID-19
The FDA EUAs do not authorize the use of anti-SARS-CoV-2 mAbs for the following patients:
• Those hospitalized for COVID-19; or
• Those who require oxygen therapy 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 because of COVID-19.
The FDA EUAs do permit the use of these agents 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.15-17
Anti-SARS-CoV-2 mAbs have been evaluated in hospitalized patients with severe COVID-19. A
substudy of the ACTIV-3 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.18,19
There are now data that support the use of casirivimab 4,000 mg plus imdevimab 4,000 mg in
hospitalized patients with COVID-19 who are seronegative for the anti-spike protein antibody. In the
RECOVERY study, hospitalized patients with COVID-19 were randomized to receive standard of
care with casirivimab 4,000 mg plus imdevimab 4,000 mg IV or standard of care alone. There was no
difference in 28-day all-cause mortality between the casirivimab plus imdevimab arm and the standard
of care arm; 944 of 4,839 patients (20%) in the casirivimab plus imdevimab arm died versus 1,026
of 4,946 patients (21%) in the standard of care arm (rate ratio 0.94; 95% CI, 0.86–1.03; P = 0.17).
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. 451 of 1,520 standard of care recipients
[30%]; rate ratio 0.80; 95% CI, 0.70–0.91; P = 0.001).20 This higher dose of casirivimab plus imdevimab
is not available through the current EUA, and currently, casirivimab plus imdevimab 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.
SARS-CoV-2 Variants and Their 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 a number of the authorized anti-SARS-CoV-2 mAbs.21 The clinical relevance of reduced
in vitro susceptibility of select variants to anti-SARS-CoV-2 mAbs is under investigation.
Some of the key SARS-CoV-2 variants that have been identified are:
• Alpha (B.1.1.7): This variant retains in vitro susceptibility to all the anti-SARS-CoV-2 mAbs that

are currently available through EUAs.5,6

• Beta (B.1.351): This variant includes the E484K and K417N mutations, which results in markedly
reduced in vitro susceptibility to bamlanivimab and etesevimab.5 In vitro studies also suggest
that the Beta (B.1.351) variant has markedly reduced susceptibility to casirivimab, although
the combination of casirivimab and imdevimab appears to retain activity against the variant.
Sotrovimab also appears to retain activity against the variant.6,7
• Gamma (P.1): This variant includes the E484K and K417T mutations, which results in markedly
reduced in vitro susceptibility to bamlanivimab and etesevimab.5,22,23 The Gamma (P.1) variant
also has reduced susceptibility to casirivimab; however, the combination of casirivimab plus
imdevimab appears to retain activity against the variant. Sotrovimab also appears to retain activity
against the Gamma (P.1) variant.6,7
• Delta (B.1.617.2, non-AY.1/AY.2): This is the predominant VOC circulating in the United States.
This VOC retains in vitro susceptibility to all the anti-SARS-CoV-2 mAbs that are currently
available through FDA EUAs.5,6
• Omicron (B.1.1.529): Ongoing studies are evaluating the susceptibility of this VOC to the anti-
SARS-CoV-2 mAbs. This variant, which includes numerous mutations in the spike protein, is
predicted to have markedly reduced susceptibility to some anti-SARS-CoV-2 mAb products,
including bamlanivimab plus etesevimab and casirivimab plus imdevimab. Sotrovimab appears to
retain activity against this variant.24
Table A. SARS-CoV-2 Variants and Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies
BAM Plus ETE CAS Plus IMD SOT
CDC Anti- Anti- Anti-
WHO Pango Notable
Variant In Vitro cipated In Vitro cipated In Vitro cipated
Label Lineage Mutations
Class Susceptibilitya clinical Susceptibilitya clinical Susceptibilitya clinical
activity activity activity
Alpha B.1.1.7 VBM N501Y No change Active No change Active No change Active
Beta B.1.351 VBM K417N, Marked Unlikely No changeb Active No change Active
E484K, reduction to be
N501Y active
Gamma P.1 VBM K417T, Marked Unlikely No changeb 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
non-AY.1/ T478K
AY.2
Omicron B.1.1.529 VOC K417N, Anticipated Unlikely Anticipated Unlikely Anticipated no Active
N440K, marked to be marked to be change24
G446S, reduction active reduction active
E484A,
Q493R,
N501Y
a
Based on the fold reduction in susceptibility reported in the FDA EUAs.5-7
b
Marked change for CAS and no change for IMD. The combination of CAS plus IMD appears to retain activity against the
variant.
Key: BAM = bamlanivimab; CAS = casirivimab; CDC = Centers for Disease Control and Prevention; ETE = etesevimab;
EUA = Emergency Use Authorization; FDA = Food and Drug Administration; IMD = imdevimab; SOT = sotrovimab; VBM =
variant being monitored; VOC = variant of concern; WHO = World Health Organization

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 in defining the utility of specific mAbs in the future.
Clinical Trials
See Table 3a for information on the clinical trials that are evaluating the safety and efficacy of anti-
SARS-CoV-2 mAbs in patients with COVID-19.
COVID-19 Vaccination
For people who have received anti-SARS-CoV-2 mAbs for treatment, CDC recommends that
COVID-19 vaccination be deferred until at least 90 days after therapy. For people who have received
anti-SARS-CoV-2 mAbs for PEP, vaccination should be deferred until at least 30 days after PEP. These
deferrals are precautionary because of the theoretic possibility that anti-SARS-CoV-2 mAb treatment
may interfere with vaccine-induced immune responses.25
For people who develop COVID-19 after vaccination, if there are no logistical or supply constraints
limiting the availability of the authorized anti-SARS-CoV-2 mAbs, prior vaccination should not affect
decisions regarding the use and timing of anti-SARS-CoV-2 mAb treatment.25 For guidance on the use
of anti-SARS-CoV-2 mAbs when there are logistical or supply constraints, see the Panel’s statement on
patient prioritization for outpatient therapies.
Monitoring
The authorized anti-SARS-CoV-2 mAbs should be administered by IV infusion or SQ injections 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 infusion or SQ injections and for at least 1 hour after the
infusion or injections are 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, dizziness, and pruritis have also been
reported.6,7,16 Injection site reactions, including ecchymosis and erythema, were reported in clinical trial
participants who received casirivimab plus imdevimab by SQ administration.6
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 3c).
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 in the setting of 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 and/or prevention of COVID-19.
Please see Special Considerations in Children for therapeutic recommendations for children.
Drug Availability
Bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab are available through
FDA EUAs. The availability of bamlanivimab plus etesevimab was previously restricted in areas
with an elevated combined frequency of variants that have markedly reduced in vitro susceptibility
to these agents (e.g., the Gamma and Beta variants). The FDA provides updated information on the
distribution of bamlanivimab plus etesevimab in the United States. Efforts should be made to ensure that
communities most affected by COVID-19 have equitable access to these mAbs.
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. O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent
3. Cohen MS, Nirula A, Mulligan MJ, et al. Effect of bamlanivimab vs placebo on incidence of COVID-19
among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial. JAMA.
4. Public Health Emergency. Pause in the distribution of bamlanivimab/etesevimab. 2021. Available at:
https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/
bamlanivimab-etesevimab-distribution-pause.aspx. Accessed October 14, 2021.
bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download.
REGEN-COV (casirivimab and imdevimab). 2021. Available at:
sotrovimab. 2021. Available at: https://www.fda.gov/media/149534/download.
8. 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:
9. Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV antibody combination and outcomes in
outpatients with COVID-19. N Engl J Med. 2021; Published online ahead of print. Available at:
10. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early treatment for COVID-19 with SARS-CoV-2 neutralizing
antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950. Available at:
11. 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 U.S. coronavirus disease 2019 (COVID-19)-associated
hospitalization surveillance network (COVID-NET). Clin Infect Dis. 2021;72(9):e206-e214. Available at:

12. 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.
13. 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. 2021; Published
online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34043784.
14. Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk factors associated with in-hospital mortality in a US
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
15. Food and Drug Administration. Frequently asked questions on the emergency use authorization of casirivimab
+ imdevimab. 2020. Available at: https://www.fda.gov/media/143894/download. Accessed January 20, 2021.
16. Food and Drug Administration. Frequently asked questions on the emergency use authorization for
bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145808/download. Accessed
February 17, 2021.
17. Food and Drug Administration. Frequently asked questions on the emergency use authorization of sotrovimab.
18. 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.
19. 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:
20. RECOVERY Collaborative Group, Horby PW, Mafham M, et al. Casirivimab and imdevimab in patients
admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.06.15.21258542v1.full.
21. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.
html. Accessed April 5, 2021.
22. Wang P, Liu L, Iketani S, et al. Increased resistance of SARS-CoV-2 variants B.I.315 and B.I.I.7 to antibody
neutralization. bioRxiv. 2021;Preprint. Available at:
23. Wang P, Wang M, Yu J, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization.
bioRxiv. 2021;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.03.01.433466v1.
24. Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831
and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. 2021;Preprint.
Available at: https://www.biorxiv.org/content/10.1101/2021.03.09.434607v9.
covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed November 17, 2021.

Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data

This table describes only clinical trials that have evaluated anti-SARS-CoV-2 mAbs for the treatment of COVID-19. Please refer to the
Prevention of SARS-CoV-2 Infection section for a discussion of clinical trials that have evaluated anti-SARS-CoV-2 mAbs for PEP of
SARS-CoV-2 infection.
Methods Results Interpretation

BLAZE-1: Double-Blind, Phase 3 RCT of Bamlanivimab 700 mg Plus Etesevimab 1,400 mg in Nonhospitalized Patients With Mild to Moderate COVID-191
Key Inclusion Criteria: Participant Characteristics: Interpretation:
• Aged ≥12 years • Median age 56 years; 30% ≥65 years; 53% women • Compared to placebo, BAM plus ETE
• At high risk for severe COVID-19 or hospitalization • 87% White, 27% Hispanic/Latinx, 8% Black/African American was associated with 5% absolute
reduction and 87% relative reduction
Interventions: • Mean duration of symptoms was 4 days. in COVID-19-related hospitalizations
• Within 3 days of a positive SARS-CoV-2 test result, • 76% had mild COVID-19 and 24% had moderate COVID-19. or all-cause deaths.
single infusion of: Primary Outcomes:
• BAM 700 mg plus ETE 1,400 mg (n = 511) • COVID-19-related hospitalizations or all-cause deaths by Day
• Placebo (n = 258) 29: 4 (0.8%) in BAM plus ETE arm vs. 15 (5.8%) in placebo
arm (Δ [95% CI] = -5.0 [-8.0, -2.1]; P <0.001).
Primary Endpoint:
• All-cause deaths by Day 29: 0 in BAM plus ETE arm vs. 4
• COVID-19-related hospitalization (defined as ≥24 hours
(1.6%) in placebo arm.
of acute care) or death from any cause by Day 29
BLAZE-1: Double-Blind, Phase 3 RCT of Bamlanivimab 2,800 mg Plus Etesevimab 2,800 mg in Nonhospitalized Patients With Mild to Moderate COVID-192
• Aged ≥12 years • Mean age 53.8 years; 31% ≥65 years; 52% women; 48% • Compared to placebo, BAM plus ETE
• At high risk for severe COVID-19 or hospitalization men was associated with 4.8% absolute
• 87% White, 29% Hispanic/Latinx, 8% Black/African American reduction and 70% relative reduction
Key Exclusion Criteria: in COVID-19-related hospitalizations
• Median days from symptom onset to infusion was 4 days. or all-cause deaths.
• SpO2 ≤93% on room air; or
• 77% had mild COVID-19.
• Respiratory rate ≥30 breaths/min; or
• Heart rate ≥125 bpm Primary Outcomes:
• COVID-19-related hospitalizations or all-cause deaths by Day
Interventions:
29: 11 (2.1%) in BAM plus ETE arm vs. 36 (7.0%) in placebo
• Within 3 days of testing SARS-CoV-2 positive, single arm; relative risk difference: 70% (P < 0.001).
infusion of:
• All-cause deaths by Day 29: 0 in BAM plus ETE arm vs. 10
• BAM 2,800 mg plus ETE 2,800 mg (n = 518) (1.9%) in placebo arm.


BLAZE-1: Double-Blind, Phase 3 RCT of Bamlanivimab 2,800 mg Plus Etesevimab 2,800 mg in Nonhospitalized Patients With Mild to Moderate COVID-192,
continued
Primary Endpoint: Secondary Outcome:
• COVID-19-related hospitalization or death from any • Percentage of patients with SARS-CoV-2 VL >5.27 log10
cause by Day 29 copies/mL at Day 7: 9.8% in BAM plus ETE arm vs. 29.5%
in placebo arm (P < 0.001).
Secondary Endpoint:
• SARS-CoV-2 VL >5.27 log10 copies/mL at Day 7
Double-Blind, Phase 3 RCT of Casirivimab Plus Imdevimab in Nonhospitalized Patients With Mild to Moderate COVID-193
• Aged ≥18 years • Median age 50 years; 35% Hispanic/Latinx, 5% Black/ • Compared to placebo, CAS 600 mg plus
• Laboratory-confirmed SARS-CoV-2 infection African American IMD 600 mg was associated with 2.2%
• Median duration of symptoms prior to enrollment was 3 absolute reduction and 70% relative
• Symptom onset within 7 days of randomization risk reduction in COVID-19-related
days.
• For patients included in the modified full analysis hospitalizations or all-cause deaths.
only: Primary Outcomes:
• Compared to placebo, CAS 1,200 mg
• ≥1 risk factor for severe COVID-19 • COVID-19-related hospitalizations or all-cause deaths plus IMD 1,200 mg was associated
• Positive SARS-CoV-2 RT-PCR at baseline through Day 29: with 3.3% absolute reduction and 71%
• 7 (1.0%) in CAS 600 mg plus IMD 600 mg arm vs. 24 relative risk reduction in COVID-19-related
Interventions: (3.2%) in placebo arm (P = 0.002). hospitalizations or all-cause deaths.
• 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. 3
• ≥1 COVID-19-related hospitalization or death from (0.2%) in placebo arm.
any cause through Day 29

COMET-ICE: Double-Blind, Phase 3 RCT of Sotrovimab in Nonhospitalized Patients With Mild to Moderate COVID-19, Interim Analysis4
• Aged ≥18 years with ≥1 comorbidity or aged ≥55 • Median age 53 years; 22% ≥65 years • Compared to placebo, SOT was associated
years • 63% Hispanic/Latinx, 7% Black/African American with 6% absolute reduction and 85%
• Laboratory-confirmed COVID-19 relative risk reduction in all-cause
Primary Outcome: hospitalizations or deaths.
• Symptom onset ≤5 days before enrollment
• Hospitalizations or all-cause deaths by Day 29: 3 (1%) in
Key Exclusion Criteria: SOT arm vs. 21 (7%) in placebo arm (P = 0.002).
• Hospitalized or requiring supplemental oxygen
• Severely immunocompromised
Interventions:
• SOT 500 mg IV (n = 291)
Primary Endpoint:
• Hospitalization or death from any cause by Day 29
Key: BAM = bamlanivimab; CAS = casirivimab; ETE = etesevimab; IMD = imdevimab; IV = intravenous; mAbs = anti-SARS-CoV-2 monoclonal antibodies; PEP = post-
exposure prophylaxis; RCT = randomized controlled trial; RT-PCR = reverse transcription polymerase chain reaction; SOT = sotrovimab; SpO2 = oxygen saturation; VL
= viral load
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. Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus etesevimab in mild or moderate COVID-19. N Engl J Med. 2021;385(15):1382-1392.
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. Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med.

Convalescent Plasma
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 convalescent plasma for the treatment of hospitalized
patients with COVID-19. On February 4, 2021, the FDA revised the convalescent plasma EUA to limit
the authorization to high-titer COVID-19 convalescent plasma and only for the treatment of hospitalized
patients with COVID-19 early in their disease course or hospitalized patients who have impaired
humoral immunity.2 Use of convalescent plasma should be limited to those products that contain high
levels of anti-SARS-CoV-2 antibodies (i.e., high-titer products). Products that are not labeled “high
titer” should not be used.
Recommendations
COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients without
impaired humoral immunity (AI).
COVID-19 convalescent plasma for the treatment of COVID-19 in:
• Nonhospitalized or hospitalized patients with impaired humoral immunity.
Rationale
For Hospitalized Patients Without Impaired Humoral Immunity
Clinical data on the use of convalescent plasma for the treatment of COVID-19, including data from
several randomized trials and the U.S. Expanded Access Program (EAP) for Convalescent Plasma, are
summarized in Table 3b.
The EUA for convalescent plasma for the treatment of hospitalized patients with COVID-19 was issued
on the basis of retrospective, indirect evaluations of efficacy generated from the convalescent plasma
EAP, which allowed for its use regardless of titer. Several retrospective analyses of the EAP data
indicated that patients who received high-titer plasma had a lower relative risk of death than patients
who received low-titer plasma.3,4 The Panel reviewed the EAP analyses and determined that the data
were not sufficient to establish the efficacy or safety of COVID-19 convalescent plasma due to potential
confounding, the lack of randomization, and the lack of an untreated control group.
Data from the initial randomized clinical trials evaluating convalescent plasma, which were all
underpowered, did not demonstrate the product’s efficacy for the treatment of hospitalized patients with
COVID-19.5-12
Subsequently, results from the 3 largest randomized clinical trials evaluating convalescent plasma
in hospitalized patients—RECOVERY,13 CONCOR-1,14 and REMAP-CAP15—found no evidence
of benefit from high-titer convalescent plasma in hospitalized patients with COVID-19. All 3 were
open-label trials that were stopped early due to futility.
In the RECOVERY trial, patients were randomized to receive convalescent plasma (n = 5,795) or usual
care (n = 5,763). The trial demonstrated no significant difference in the primary endpoint of 28-day

mortality between the convalescent plasma arm and the usual care arm (24% in each arm; risk ratio
1.00; 95% CI, 0.93–1.07). Additionally, there were no differences between the arms in the secondary
endpoints of time to hospital discharge and receipt of mechanical ventilation or death.
In the CONCOR-1 trial, patients were randomized to receive convalescent plasma or standard of care.
The primary endpoint of intubation or death by Day 30 occurred in 199 of 614 patients (32%) in the
convalescent plasma arm and 86 of 307 patients (28%) in the standard of care arm (relative risk 1.16;
95% CI, 0.94–1.43). There were no differences between the arms in secondary endpoints, including time
to intubation or death, mortality, or intensive care unit and hospital length of stay. Serious adverse events
occurred in 33% of the patients in the convalescent plasma arm and 26% of those in the standard of care
arm, including 35 transfusion-related complications reported in the convalescent plasma arm.
The REMAP-CAP trial evaluated convalescent plasma in hospitalized patients. Although noncritically
ill patients participated in the study, the reported outcomes are only for those who were critically ill
at enrollment (1,084 patients in the convalescent plasma arm and 916 patients in the control arm).
There was no difference in the primary endpoint of organ support-free days up to Day 21 between the
arms (median of 0 days in the convalescent plasma arm [IQR -1 to 16 days] vs. 3 days in the control
arm [IQR -1 to 16 days]). There were also no differences between the arms in secondary endpoints,
including in-hospital mortality (401 of 1,075 patients [37.3%] in the convalescent plasma arm died
vs. 347 of 904 patients [38.4%] in the control arm). The study showed a potential for harm (90.3%
posterior probability) in 126 patients who were randomized to convalescent plasma after >7 days of
hospitalization.
Although these trials 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. Based on the collective results from these studies, the Panel recommends
against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized
patients who do not have impaired humoral immunity (AI).
For Nonhospitalized Patients Without Impaired Humoral Immunity

Current data are insufficient to establish the safety or efficacy of convalescent plasma in nonhospitalized
patients with COVID-19. Convalescent plasma is not authorized for nonhospitalized patients with
COVID-19 under the EUA.
Data from a double-blind, placebo-controlled, randomized trial of high-titer convalescent plasma in
older, nonhospitalized adults with <72 hours of mild COVID-19 symptoms demonstrated benefit in
reduced progression of respiratory disease.4 However, the trial included relatively few participants (80
participants in each arm).
The C3PO study was a single-blind randomized trial that evaluated high-titer convalescent plasma
for the treatment of nonhospitalized patients with ≤7 days of mild or moderate COVID-19 symptoms
and at least 1 risk factor for severe COVID-19.16 Trial participants (n = 511) were randomized to
receive convalescent plasma or a placebo transfusion. The trial was halted after a second interim
analysis indicated a priori futility criteria were reached. There was no difference in the occurrence
of the composite primary endpoint of disease progression (i.e., hospital admission, death without
hospitalization, or urgent or emergency care within 15 days after randomization) between the patients
in the convalescent plasma arm and the placebo arm (30% vs. 32%; risk difference 1.9%; 95% CI, -6.0
to 9.8). There were no differences between the arms in any secondary endpoints, including the worst
severity of illness based on an 8-point ordinal scale and hospital-free days after randomization. Five
patients in the convalescent plasma arm and 1 patient in the placebo arm died. Infusion-related reactions,

which occurred more often in the convalescent plasma arm, included 3 serious reactions.
Results from additional, adequately powered, well-designed, and well-conducted randomized clinical
trials are needed to provide more specific, evidence-based guidance on the role of COVID-19
convalescent plasma in the treatment of nonhospitalized patients with COVID-19.
The FDA has issued EUAs for several anti-SARS-CoV-2 monoclonal antibody products for the
treatment of nonhospitalized patients with mild to moderate COVID-19 who are at high risk of
progression to severe disease (see Anti-SARS-CoV-2 Monoclonal Antibodies). The Panel recommends
using these products for the population specified in the EUAs.
For Hospitalized or Nonhospitalized Patients With Impaired Humoral Immunity

People who are immunocompromised are more likely to become severely ill from COVID-19,
experience prolonged SARS-CoV-2 infection and shedding, and require hospitalization for breakthrough
SARS-CoV-2 infection despite COVID-19 vaccination.17,18 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 reduced antibody responses to SARS-CoV-2 infection and
vaccination.19-21 An analysis from the RECOVERY trial suggests that SARS-CoV-2 seronegative patients
are more likely to benefit from convalescent plasma than seropositive patients.22 Therefore, convalescent
plasma may be effective in SARS-CoV-2 seronegative patients even though no benefit was observed in
the overall population of patients enrolled in the RECOVERY trial.
The REMAP-CAP investigators performed a prespecified subgroup analysis of 126 patients with
immunodeficiencies who were critically ill.15 Immunodeficiency was defined as recent chemotherapy or
radiation, high-dose or long-term steroid use, or presence of immunocompromising diseases. Although
not statistically significant, results of this analysis suggest that, compared to placebo, convalescent
plasma offers a potential benefit of improved survival and/or more organ support-free days in this
subgroup of immunocompromised patients (OR 1.51; 95% CI, 0.80–2.92).
Severely immunocompromised individuals may experience prolonged SARS-CoV-2 infection with
persistent viral replication over several months, as described in the case report of a patient with
lymphoma who had received chimeric antigen receptor T cell therapy and who subsequently recovered
following repeat transfusions of high-dose convalescent plasma.23 Data from case reports, case series,
and a retrospective case-control study also suggest a potential benefit of convalescent plasma 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.24-37
Although there is physiologic rationale for the value of convalescent plasma in immunocompromised
people and some reports suggesting benefit, there are no definitive data to support the use of
convalescent plasma in this patient population. Therefore, there is insufficient evidence for the Panel
to recommend either for or against the use of COVID-19 convalescent plasma for the treatment
of COVID-19 in hospitalized or nonhospitalized patients who have impaired humoral immunity.
Adequately powered, well-designed, and well-conducted randomized clinical trials are needed to
provide more specific, evidence-based guidance on the role of convalescent plasma in the treatment of
patients with COVID-19 who have impaired humoral immunity.
Clinical Data to Date

Table 3b includes a summary of key studies of convalescent plasma for the treatment of COVID-19.

The safety and efficacy of using COVID-19 convalescent plasma 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.38 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.39,40 If otherwise indicated, pregnancy is not a reason to withhold
convalescent plasma.
The safety and efficacy of COVID-19 convalescent plasma have not been systematically evaluated in
pediatric patients. Published literature on its use in children is limited to case reports and case series,
as well as a systematic review of these reports. A few clinical trials of COVID-19 convalescent plasma
in children are ongoing. The use of convalescent plasma may be considered on a case-by-case basis
for hospitalized children with impaired immunity who meet the EUA criteria for its use. Convalescent
plasma is not authorized by the FDA for use in nonhospitalized patients with COVID-19.
Several anti-SARS-CoV-2 monoclonal antibody products have received EUAs for treatment of
nonhospitalized patients aged ≥12 years with mild to moderate COVID-19 who are at high risk of
progression to severe disease. Use of these products may be considered on a case-by-case basis for
children who meet the EUA criteria (see Anti-SARS-CoV-2 Monoclonal Antibodies).
Adverse Effects
Available data suggest that serious adverse reactions following the administration of COVID-19
convalescent plasma 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.2,41,42
Additional risks of COVID-19 convalescent plasma 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 the use of convalescent plasma with nonfunctional anti-
SARS-CoV-2 antibodies may be harmful.14 Subgroup analysis in the REMAP-CAP trial showed
potential harm in convalescent plasma transfused >7 days into hospitalization.15
When considering convalescent plasma for patients with a history of severe allergic or anaphylactic
transfusion reactions, consultation with a transfusion medicine specialist is advised.
Clinical Trials
Randomized clinical trials evaluating convalescent plasma for the treatment of COVID-19 are underway.
Please see ClinicalTrials.gov for the latest information.
References
1. Wang X, Guo X, Xin Q, et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and
convalescent patients. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32497196.
2. Food and Drug Administration. EUA of COVID-19 convalescent plasma for the treatment of COVID-19 in
hospitalized patients: fact sheet for health care providers. 2020. Available at:

3. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from
4. 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. 2021;384(7):610-618. Available at:
5. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19
severe pneumonia. N Engl J Med. 2021;384(7):619-629. Available at:
6. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate COVID-19
in adults in India: open label Phase II multicentre randomised controlled trial (PLACID Trial). BMJ.
2020;371:m3939. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33093056.
7. Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients
with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-470.
8. Gharbharan A, Jordans CCE, Geurtsvankessel C, et al. Convalescent plasma for COVID-19: a randomized
clinical trial. medRxiv. 2020;Preprint. Available at:
9. Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, et al. Convalescent plasma for COVID-19: a
multicenter, randomized clinical trial. medRxiv. 2020;Preprint. Available at:
10. AlQahtani M, Abdulrahman A, Almadani A, et al. Randomized controlled trial of convalescent plasma therapy
against standard therapy in patients with severe COVID-19 disease. Sci Rep. 2021;11(1):9927. Available at:
11. Ray Y, Ranjan Paul SR, Bandopadhyay P, et al. Clinical and immunological benefits of convalescent plasma
therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv.
2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.25.20237883v1.
12. O’Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized double-blind controlled trial of convalescent
plasma in adults with severe COVID-19. J Clin Invest. 2021;131(13). Available at:
13. 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.
14. Begin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an
open-label, randomized controlled trial. Nat Med. 2021;Published online ahead of print. Available at:
15. 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.
16. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with
COVID-19. N Engl J Med. 2021;Published online ahead of print. Available at:
17. Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical
characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect.
18. Tenforde MW, Patel MM, Ginde AA, et al. Effectiveness of SARS-CoV-2 mRNA vaccines for preventing

COVID-19 hospitalizations in the United States. Clin Infect Dis. 2021. Available at:
19. Hallett AM, Greenberg RS, Boyarsky BJ, et al. SARS-CoV-2 messenger RNA vaccine antibody response and
reactogenicity in heart and lung transplant recipients. J Heart Lung Transplant. 2021;Published online ahead
20. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2
vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021;21(8):2719-
21. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with
chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. Available at:
22. Hamilton FW, Lee T, Arnold DT, Lilford R, Hemming K. Is convalescent plasma futile in COVID-19? A
Bayesian re-analysis of the RECOVERY randomized controlled trial. Int J Infect Dis. 2021;109:114-117.
23. Nussenblatt V, Roder AE, Das S, et al. Year-long COVID-19 infection reveals within-host evolution of
SARS-CoV-2 in a patient with B cell depletion. medRxiv. 2021;Preprint. Available at:
24. Ferrari S, Caprioli C, Weber A, Rambaldi A, Lussana F. Convalescent hyperimmune plasma for chemo-
immunotherapy induced immunodeficiency in COVID-19 patients with hematological malignancies. Leuk
Lymphoma. 2021;62(6):1490-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33461387.
25. Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted
COVID-19. Blood. 2020;136(20):2290-2295. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32959052.
26. Rahman F, Liu STH, Taimur S, et al. Treatment with convalescent plasma in solid organ transplant
recipients with COVID-19: Experience at large transplant center in New York City. Clin Transplant.
27. Mira E, Yarce OA, Ortega C, et al. Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia
patient after infusion of COVID-19 convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(8):2793-2795.
28. 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:
29. Quinti I, Lougaris V, Milito C, et al. A possible role for B cells in COVID-19? Lesson from patients with
agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-213 e214. Available at:
30. Jin H, Reed JC, Liu STH, et al. Three patients with X-linked agammaglobulinemia hospitalized for COVID-19
improved with convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(10):3594-3596 e3593. Available
31. Betrains A, Godinas L, Woei AJF, et al. Convalescent plasma treatment of persistent severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral
immunity and lack of neutralising antibodies. Br J Haematol. 2021;192(6):1100-1105. Available at:
32. Balashov D, Trakhtman P, Livshits A, et al. SARS-CoV-2 convalescent plasma therapy in pediatric patient
after hematopoietic stem cell transplantation. Transfus Apher Sci. 2021;60(1):102983. Available at:
33. 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. Available at:

34. Senefeld JW, Klassen SA, Ford SK, et al. Therapeutic use of convalescent plasma in COVID-19 patients with
immunodeficiency. medRxiv. 2020;Preprint. Available at:
35. Clark E, Guilpain P, Filip IL, et al. Convalescent plasma for persisting COVID-19 following therapeutic
lymphocyte depletion: a report of rapid recovery. Br J Haematol. 2020;190(3):e154-e156. Available at:
36. Van Damme KFA, Tavernier S, Van Roy N, et al. Case report: convalescent plasma, a targeted therapy for
patients with CVID and severe COVID-19. Front Immunol. 2020;11:596761. Available at:
37. Tremblay D, Seah C, Schneider T, et al. Convalescent plasma for the treatment of severe COVID-19 infection
in cancer patients. Cancer Med. 2020;9(22):8571-8578. Available at:
38. Franchini M, Prefumo F, Grisolia G, et al. Convalescent plasma for pregnant women with COVID-19: a
systematic literature review. Viruses. 2021;13(7). Available at:
39. Revello MG, Lazzarotto T, Guerra B, et al. A randomized trial of hyperimmune globulin to prevent congenital
cytomegalovirus. N Engl J Med. 2014;370(14):1316-1326. Available at:
40. Hughes BL, Clifton RG, Rouse DJ, et al. A trial of hyperimmune globulin to prevent congenital
cytomegalovirus infection. N Engl J Med. 2021;385(5):436-444. Available at:
41. Nguyen FT, van den Akker T, Lally K, et al. Transfusion reactions associated with COVID-19 convalescent
plasma therapy for SARS-CoV-2. Transfusion. 2021;61(1):78-93. Available at:
42. The RECOVERY Collaborative Group, Horby PW, Estcourt L, et al. Convalescent plasma in patients admitted
to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv.

Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data

COVID-19 CP. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
Note: The current EUA for COVID-19 CP is limited to the use of high-titer CP. Refer to the revised EUA Letter of Authorization for a list of
anti-SARS-CoV-2 antibody tests that can be used to qualify COVID-19 CP as high titer.

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


CONCOR-1: Multinational, Open-Label RCT of Convalescent Plasma for Hospitalized Patients With COVID-19 in Canada, the United States, and Brazil2
• Hospitalized patients receiving 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 after 78% of
planned enrollment after
Key Exclusion Criteria: Primary Outcome:
meeting prespecified futility
• Imminent or current intubation • Intubation or death occurred in 32% of patients in CP criteria for early termination
Interventions: arm and 28% in SOC arm (relative risk 1.16; 95% CI,
0.94–1.43, P = 0.18). Interpretation:
• 1–2 units CP (approximately 500 mL) from 1–2 donors (n = 625) • There was no benefit of
• SOC (n = 313) Secondary Outcomes:
CP in oxygen-dependent,
• By Day 30, no difference between the CP and SOC arms hospitalized COVID-19 patients
Primary Endpoint: in: within 12 days of symptom
• Intubation or death at Day 30 • Time to intubation or death onset.
Key Secondary Endpoints: •A ll-cause mortality (23% in CP arm vs. 21% in SOC arm)
• Time to intubation or death by Day 30 • ICU LOS (mean 4.3 days in CP arm vs. 3.7 days in SOC
• Mortality at Day 30 and Day 90 arm)
• ICU LOS by Day 30 • Need for renal dialysis (1.6% in CP arm vs. 2.0% in SOC
• Need for renal dialysis by Day 30 arm)
• SAE by Day 30 • More SAEs reported in CP arm (33% vs. 26% in SOC arm)
RECOVERY Trial: Open-Label RCT of High-Titer Convalescent Plasma in Hospitalized Patients in the United Kingdom3
• Hospitalized patients with clinically suspected or laboratory- • Mean age 63.5 years; 64% men • Open-label study
confirmed SARS-CoV-2 infection • 5% on MV Interpretation:
Key Exclusion Criteria: • 92% received corticosteroids • There was no benefit of CP
• CP contraindicated Primary Outcomes: in hospitalized patients with
COVID-19.
Interventions: • No difference between the arms in:
• 2 units high-titer CP (IgG SARS-CoV-2 spike protein ratio ≥6.0), • Mortality (24% in each arm).
first unit ASAP after randomization, second unit ≥12 hours later • Mortality in patients without detectable SARS-CoV-2
the next day (n = 5,795) antibodies (32% in CP arm and 34% in SOC arm).
• Usual care (n = 5,763)
Secondary Outcomes:
Primary Endpoint: • No difference between the arms in:
• All-cause mortality at Day 28


RECOVERY Trial: Open-Label RCT of High-Titer Convalescent Plasma in Hospitalized Patients in the United Kingdom3, continued
Key Secondary Endpoints: • Proportion of patients discharged (66% in CP arm and
• Time to hospital discharge by Day 28 67% in SOC arm).
• Among patients not receiving MV, receipt of MV or death by Day • Proportion of patients who progressed to MV or death
28 (28% in CP arm and 29% in SOC arm).
PLACID Trial: Open-Label RCT of Convalescent Plasma in Hospitalized Adults With Severe COVID-19 in India4
• Hospitalized patients with moderate, laboratory-confirmed • Median age 52 years; 76% men • Open-label study
SARS-CoV-2 infection • Higher prevalence of DM in CP arm (48%) than SOC arm • SARS-CoV-2 antibody testing
• PaO2/FiO2 200–300 mm Hg or respiratory rate >24 breaths/min (38%) not used to select CP; many
with SpO2 ≤93% on room air participants may have received
Primary Outcomes:
low-titer CP
Key Exclusion Criteria: • No difference in proportion of patients who progressed
• Critical illness to severe disease or death between CP arm (19%) and Interpretation:
SOC arm (18%) (risk ratio 1.04; 95% CI, 0.71–1.54). • CP use did not reduce
Interventions:
• Among patients without detectable SARS-CoV-2 progression to severe disease
• 2 doses of 200 mL of CP transfused 24 hours apart (n = 235) or death in hospitalized patients
neutralizing antibody titers at baseline (n = 70), no
• SOC (n = 229) difference in proportion of patients who progressed to with moderate COVID-19.
Primary Endpoint: severe disease or death in CP arm and SOC arm (30%
vs. 25%; risk ratio 1.2; 95% CI, 0.6–2.6).
• Progression to severe disease (defined as PaO2/FiO2 <100 mm
Hg) or death within 28 days
PlasmAr Study: Double-Blind RCT of Convalescent Plasma in Hospitalized Adults in Argentina5
• PCR-confirmed, severe COVID-19 • Median age 62 years; 68% men • Small sample size
Key Exclusion Criteria: • 65% with coexisting condition Interpretation:
• Critical illness Primary Outcome: • There was no benefit of CP in
• No significant difference between the arms in clinical hospitalized patients with severe
Interventions:
status at 30 days (OR 0.83; 95% CI, 0.52–1.35; P = COVID-19.
• 1 unit CP with SARS-CoV-2 viral spike-RBD IgG titer ≥1:800 (n =
0.46).
228)
• 30-day mortality 11% in both arms.
Primary Endpoint:
• Clinical status at 30 days (ordinal score)


Multicenter, Double-Blind RCT of Convalescent Plasma in Hospitalized Adults With Severe COVID-19 in the United States and Brazil6
• Severe COVID-19 pneumonia • Median age 61 years; 66% men • Small sample size
• SpO2 ≤94% on room air or requirement of supplemental oxygen, • 57% required supplemental oxygen at baseline: 25% • Control arm intervention was
MV, or ECMO high-flow oxygen or NIV and 13% MV or ECMO blood plasma without SARS-
• 81% received corticosteroids CoV-2 antibodies, therefore not
possible to identify potential
• >5 days on MV or ECMO Primary Outcome: harm due to plasma infusion
• Severe multiorgan failure • No difference in Day 28 clinical status between the arms Interpretation:
(OR 1.5; 95% CI, 0.83–2.68; P = 0.18).
Interventions: • Although the difference in
• Single dose of CP with SARS-CoV-2 spike-RBD IgG titer ≥1:400 Secondary Outcomes: clinical status on Day 28
(n = 150) • In-hospital mortality lower in CP arm than control arm between the arms was not
• Non-SARS-CoV-2 plasma (control) (n = 73) (13% vs. 25%; OR 0.44; 95% CI, 0.22–0.91; P = 0.034). statistically significant, lower
The difference was no longer significant after adjustment 28-day mortality in the CP arm
Primary Endpoint: for age, sex, and duration of symptoms. suggests potential benefit of
• Clinical status on Day 28 (ordinal score) • No difference between CP arm and control arm in CP in hospitalized patients with
median time to: severe COVID-19.
• In-hospital and 28-day mortality • Clinical improvement (5 vs. 7 days).
• Time to clinical improvement • Discontinuation of supplemental oxygen (6 vs. 7 days).
• Time to discontinuation of supplemental oxygen • Hospital discharge (9 vs. 8 days).
• Time to hospital discharge
Double-Blind RCT of Early High-Titer Convalescent Plasma Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina7
• Nonhospitalized • Mean age 77 years; 38% men • Small sample size
• Aged ≥75 years or aged 65–74 years with ≥1 coexisting • Most with comorbidities • Early termination because
condition COVID-19 cases decreased
Primary Outcome:
• Mild COVID-19 with symptoms for <72 hours Interpretation:
• 16% of patients in CP arm and 31% in placebo arm
Key Exclusion Criteria: experienced severe respiratory disease by Day 15 • This trial demonstrated a benefit
• Severe respiratory disease (relative risk 0.52; 95% CI, 0.29–0.94; P = 0.03). of CP in older adult outpatients
with <72 hours of mild
Interventions: COVID-19 symptoms.
• 250 mL of CP with IgG against SARS-CoV-2 spike protein
>1:1,000 (n = 80)


Double-Blind RCT of Early High-Titer Convalescent Plasma Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina7, continued
Primary Endpoint:
• Severe respiratory disease, defined as respiratory rate ≥30
breaths/min and/or SpO2 <93% on room air by Day 15
C3PO: Multicenter, Single-Blind RCT of High-Titer Convalescent Plasma in the United States8
• ED patient with ≤7 days of symptoms • Median age 54 years; 46% men • Imbalance of patients requiring
• PCR-confirmed SARS-CoV-2 infection • More patients with immunosuppression in CP arm (33 hospital admission during
[13%]) than in placebo arm (17 [7%]) the index visit included in the
• Aged ≥50 years or aged ≥18 years with ≥1 risk factor for disease primary analysis
progression • More patients with ≥3 risk factors in CP arm (141
[55%]) than in placebo arm (123 [48%]) • Slightly more patients with
Key Exclusion Criteria: multiple risk factors, including
• Need for supplemental oxygen Primary Outcomes: immunosuppression, in CP arm
• There was no difference between the arms in the number Interpretation:
Interventions:
of patients with disease progression: 77 (30%) in CP
• 250 mL high-titer CP (median titer 1:641) (n = 257) arm vs. 81 (32%) in placebo arm (risk difference 1.9%; • In outpatients with COVID-19 at
• Placebo (n = 254) 95% CrI, -6.0% to 9.8%). high risk of severe disease, use
of high-titer CP within 1 week of
Primary Endpoint: • 25 patients (19 in CP arm and 6 in placebo arm) symptom onset did not prevent
required hospitalization during the index visit. In a disease progression.
• Disease progression, defined as hospital admission, death,
post hoc analysis that excluded these patients, disease
or seeking emergency or urgent care within 15 days of
progression occurred in 24% of patients in CP arm vs.
randomization
30% in placebo arm (risk difference 5.8% [-1.9% to
Key Secondary Endpoints: 13.6%]).
• Severity of illness (ordinal score) Secondary Outcomes:
• All-cause mortality within 30 days • 5 patients (1.9%) in CP arm and 1 patient (0.4%) in
• Hospital-free days over 30 days placebo arm died.
• No difference in scores for illness severity or mean
number of hospital-free days between the CP and
placebo arms.


Retrospective Evaluation of Convalescent Plasma Antibody Levels and the Risk of Death From COVID-19 in the United States9
• 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 CP were available for Hispanic/Latinx Interpretation:
retrospective analysis of antibody titer • 61% in ICU; 33% on MV • The study data are not sufficient
Intervention: • 51% received corticosteroids and 31% received RDV to establish the efficacy or
safety of COVID-19 CP.
• High-titer CP (n = 515), medium-titer CP (n = 2,006), or low-titer Primary Outcomes:
CP (n = 561), characterized retrospectively • Mortality at 30 days after transfusion was 22% in high-
Primary Endpoint: titer CP arm, 27% in medium-titer CP arm, and 30% in
low-titer CP arm.
• Mortality at 30 days after CP transfusion
• Patients in high-titer CP arm had a lower risk of death
than those in low-titer CP arm (relative risk 0.75; 95%
CI, 0.61–0.93).
• Mortality was lower among patients who were not
receiving MV before CP transfusion (relative risk 0.66;
95% CI, 0.48–0.91).
• Among the patients who were on MV before the CP
transfusion, there was no difference in mortality between
the high-titer and low-titer arms (relative risk 1.02; 95%
CI, 0.78–1.32).
Key: ASAP = as soon as possible; CP = convalescent plasma; DM = diabetes; ECMO = extracorporeal membrane oxygenation; EUA = Emergency Use Authorization;
HFNC = high-flow nasal cannula; ICU = intensive care unit; Ig = immunoglobulin; IL = interleukin; LOS = length of stay; MV = mechanical ventilation; NIV =
noninvasive ventilation; 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; RBD = receptor binding domain; RCT = randomized controlled trial; RDV = remdesivir; SAE = serious adverse event; SOC =
standard of care; SpO2 = oxygen saturation
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. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate COVID-19 in adults in India: open label Phase II
multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33093056.
5. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med.
6. O’Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe
COVID-19. J Clin Invest. 2021;131(13). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33974559.
7. 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.
8. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with COVID-19. N Engl J Med.
9. 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 3c. 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 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

Dosing Regimens Adverse Events Monitoring Parameters
Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment or PEP of COVID-19 under FDA EUA.
Dose Recommended in EUA for • Nausea • Only for administration • Drug-drug interactions Availability:
Treatment and PEP of COVID-19 • Dizziness in health care settings are unlikely between •U
nder the FDA EUA, BAM plus
in Adults and Pediatric Patients by qualified health care BAM plus ETE and ETE is available as treatment for
Weighing ≥40 kg: • Pruritis providers who have medications that are high-risk outpatients with mild to
• BAM 700 mg plus ETE 1,400 mg • H
ypersensitivity, including immediate access to renally excreted or that moderate COVID-19 and as PEP
as a single IV infusion anaphylaxis and infusion- emergency medical are CYP substrates, for certain high-risk patients.1 See
related reactions services and medications inhibitors, or inducers. Anti-SARS-CoV-2 Monoclonal
Doses Recommended in EUA for • These AEs were observed to treat severe infusion Antibodies and Prevention of
Treatment and PEP of COVID-19 in in multiple trials in which reactions. SARS-CoV-2 Infection for a list of
Neonates, Infants, Children, and participants received either • Monitor patient during high-risk conditions and criteria
Adolescents Weighing <40 kg: the authorized doses of BAM the IV infusion and for ≥1 for use of BAM plus ETE.
• 1 –12 kg: BAM 12 mg/kg plus ETE and ETE or higher doses of hour after the infusion is •A
list of clinical trials is available:
24 mg/kg as a single IV infusion each drug. completed. Bamlanivimab Plus Etesevimab


Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies), continued
• > 12 kg to 20 kg: BAM 175 mg
plus 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
Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment or PEP of COVID-19 under FDA EUA.
Dose Recommended in EUA for • Hypersensitivity, including • Only for administration • Drug-drug interactions Availability:
Treatment and PEP of COVID-19 in anaphylaxis and infusion- in health care settings are unlikely between •U
nder the FDA EUA, CAS plus
Adults and Pediatric Patients Aged related reactions by qualified health care CAS plus IMD and IMD is available as treatment
≥12 Years and Weighing ≥40 kg: • These AEs were observed providers who have medications that are for high-risk outpatients with
• CAS 600 mg plus IMD 600 mg as in multiple trials in which immediate access to renally excreted or that mild to moderate COVID-19
a single IV infusion over 1 hour. participants received CAS emergency medical are CYP substrates, and as PEP for certain high-risk
600 mg plus IMD 600 mg or services and medications inhibitors, or inducers. individuals.2 See Anti-SARS-
• IV infusion is the preferred route to treat severe infusion
of administration. However, higher doses of each drug. CoV-2 Monoclonal Antibodies
reactions. and Prevention of SARS-CoV-2
when IV infusion is not feasible • Injection site reactions,
or would delay treatment, CAS including ecchymosis and • Monitor patient during Infection for a list of high-risk
600 mg plus IMD 600 mg can be erythema, in clinical trial the IV infusion or SQ conditions and criteria for use of
administered as 4 SQ injections participants who received CAS injections and for ≥1 CAS plus IMD.
(2.5 mL per injection) at 4 plus IMD administered by SQ hour after the infusion or •A
different sites. See the FDA EUA injections. injections are completed. Casirivimab Plus Imdevimab
for detailed information.
Dose Recommended in 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
SQ injections or IV infusion every
4 weeks for duration of ongoing
exposure.


Potential Trials
Sotrovimab (Anti-SARS-CoV-2 Monoclonal Antibody)
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in EUA for • Rash • Only for administration • Drug-drug interactions Availability:
Treatment of COVID-19 in Adults • Diarrhea in health care settings are unlikely between •U
nder the FDA EUA, SOT is
and Pediatric Patients Aged ≥12 by qualified health care SOT and medications available for the treatment of
Years and Weighing ≥40 kg: • Hypersensitivity, including providers who have that are renally excreted high-risk outpatients with mild
anaphylaxis and infusion- immediate access to or that are CYP
• SOT 500 mg administered by IV related reactions to moderate COVID-19.3 See
infusion over 30 minutes emergency medical services substrates, inhibitors, Anti-SARS-CoV-2 Monoclonal
and medications to treat or inducers. Antibodies for a list of high-risk
severe infusion reactions. conditions.
• Monitor patient during •A
the IV infusion and for ≥1 Sotrovimab
hour after the infusion is
completed.
COVID-19 Convalescent Plasma
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in EUA for • TRALI • Before administering CP • Drug products should • T he decision to use COVID-19 CP
Treatment of COVID-19: • TACO to patients with a history not be added to the for the treatment of COVID-19 in
• Per the EUA, consider starting of severe allergic or IV infusion line for the patients aged <18 years should
• Allergic reactions anaphylactic transfusion blood product be based on an individualized
clinical dosing with 1 high-titer
COVID-19 CP unit (about 200 • Anaphylactic reactions reactions, the Panel assessment of risk and benefit.5
mL), with administration of • Febrile nonhemolytic recommends consulting • In patients with impaired cardiac
additional CP units based on the reactions a transfusion medicine function and heart failure, it
prescribing provider’s medical specialist who is associated may be necessary to reduce
• Hemolytic reactions
judgment and the patient’s clinical with the hospital blood the CP volume or decrease the
• Hypothermia bank.
response. transfusion rate.
• Metabolic complications • Monitor for transfusion-
Availability:
• Transfusion-transmitted related reactions.
infections4 •U
nder the FDA EUA, high-
• Monitor patient’s vital signs
titer COVID-19 CP is available
• Thrombotic events at baseline and during and
for hospitalized patients with
• Theoretical risk of antibody- after transfusion.
COVID-19.6 See Convalescent
mediated enhancement of Plasma.
infection and suppressed •A
long-term immunity COVID-19 Convalescent Plasma


Potential Trials
SARS-CoV-2-Specific Immunoglobulin
Dose in Clinical Trials for • TRALI • Monitor for transfusion- • Drug products should •A
Treatment of COVID-19: • TACO related reactions. not be added to the SARS-CoV-2 Immunoglobulin
• Dose varies by clinical trial • Monitor patient’s vital signs IV infusion line for the
• Allergic reactions blood product.
at baseline and during and
• Antibody-mediated after transfusion.
enhancement of infection
• RBC alloimmunization
• Transfusion-transmitted
infections4
Key: Key: AE = adverse event; BAM = bamlanivimab; CAS = casirivimab; CP = convalescent plasma; CYP = cytochrome P450; ETE = etesevimab; EUA = Emergency
Use Authorization; FDA = Food and Drug Administration; IMD = imdevimab; IV = intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PEP = post-
exposure prophylaxis; RBC = red blood cell; SOT = sotrovimab; SQ = subcutaneous; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related
acute lung injury
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021.
Available at: https://www.fda.gov/media/145802/download.
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of REGEN-COV (casirivimab and
imdevimab). 2021. Available at: https://www.fda.gov/media/145611/download.
3. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of sotrovimab. 2021. Available at:
4. 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
5. Food and Drug Administration. EUA of COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients: fact sheet for health
care providers. 2020. Available at: https://www.fda.gov/media/141478/download.
6. Food and Drug Administration. Convalescent plasma letter of authorization. 2020. Available at: https://www.fda.gov/media/141477/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 (AII).
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.

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)


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
For Nonhospitalized Patients With COVID-19
COLCORONA, a large randomized placebo-controlled 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 (NP) swab, a slight reduction in
hospitalizations was observed among those who received colchicine.
PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus
usual care, was stopped for futility when no significant difference in time to first self-reported recovery
from COVID-19 between the colchicine and usual care recipients was found.5
The PRINCIPLE trial showed no benefit of 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 in 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).
For Hospitalized Patients With COVID-19

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).

Colchicine in Nonhospitalized Patients With COVID-19
The COLCORONA Trial
The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in

outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged
≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications:
body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart
failure or coronary disease, fever ≥38.4°C within the last 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 colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days
or placebo. 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.4
Results
• The study enrolled 4,488 participants.
• The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of
2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
• There were no statistically significant differences in the secondary outcomes between the arms.
• In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by
PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less
likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo
arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup
of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a
secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of
patients; OR 0.75; 95% CI, 0.57–0.99).
• More participants in the colchicine arm experienced gastrointestinal adverse events, including
diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P <
0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the
placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P = 0.01).
Limitations
• Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target
enrollment, which may have limited the study’s power to detect differences for the primary outcome.
• There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
• Some patient-reported clinical outcomes were potentially misclassified.
The PRINCIPLE Trial
PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic,
nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities
or shortness of breath, and who had symptoms for ≤14 days. 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 that they completed online
daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The
investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit
in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster
recovery in the colchicine arm.
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 SARS-CoV-2 positive test results (156
in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
• The trial was stopped early because the criterion for futility was met; 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 of self-reported time to recovery and hospitalizations or death due to COVID-19 among
concurrent controls also showed no significant differences between the colchicine and usual care
arms.
• There were no statistically significant differences in the secondary outcomes between the colchicine
and usual care arms in both the primary analysis population and in subgroups, including subgroups
based on symptom duration, baseline disease severity, age, or comorbidities.
• The occurrence of adverse events was similar in the colchicine and usual care arms.
Limitations
• The design of the study was open-label treatment.
• The sample size of the colchicine arm was small.
Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial
In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine
(1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until
discharge) or usual care.6
Results
• The study enrolled 11,340 participants.
• At randomization, 10,603 patients (94%) were receiving corticosteroids.
• The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants
(21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio
1.01; 95% CI, 0.93–1.10; P = 0.77).
• There were no statistically significant differences between the arms for the secondary outcomes of
median time to being discharged 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 one case of rhabdomyolysis.
Limitations
• The trial’s open-label design may have introduced bias for assessing some of the secondary
endpoints.
The GRECCO-19 Trial
GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized
with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with
colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until
hospital discharge or for up to 3 weeks) or standard of care alone.7

Results
• Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50
patients) reached the primary clinical endpoint of deterioration in clinical status 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 group were significantly more likely to experience diarrhea (occurred
in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).
Limitations
• The overall sample size and the number of clinical events reported were small.
• The study design was open-label treatment assignment.
The results of several small randomized trials and retrospective cohort studies that have evaluated various
doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-
reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown
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
have reported higher discharge rates or fewer deaths among patients who received colchicine than among
those who received comparator drugs or placebo. However, the findings of these studies are difficult to
interpret due to significant design or methodological limitations, including small sample sizes, open-label
designs, and differences in the clinical and demographic characteristics of participants and permitted use
of various cotreatments (e.g., remdesivir, corticosteroids) 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. Use of colchicine should be avoided in patients with
severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should
be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs
that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase
the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The
risk of myopathy may be increased with the 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.12,13 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.12,14
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. 2021 May;80(5):550-557. Available at:
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. PRINCIPLE Trial Collaborative Group, Dorward J, Yu L, et al. Colchicine for COVID-19 in adults in
the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. medRxiv. 2021;Preprint.
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;Published
7. 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:
8. 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). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
9. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
10. 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). Available
11. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial.
Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
12. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at:
13. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at:
https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-
management-of-clinically-significant-drug. Accessed November 2, 2021.
14. 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:

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
presumably by mitigating the COVID-19-induced systemic inflammatory response that can lead to lung
injury and multisystem organ dysfunction. There is no observed benefit of systemic corticosteroids
in hospitalized patients with COVID-19 who do not require supplemental oxygen.2 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 Patients 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.
For Hospitalized Patients 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.
• There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
Systemic Corticosteroids in Patients With COVID-19

Nonhospitalized Patients
There are no data to support the use of systemic corticosteroids in nonhospitalized patients with
COVID-19. Therefore, the safety and efficacy of systemic corticosteroids in this population have
not been established. Generally, systemic corticosteroids are associated with adverse events (e.g.,
hyperglycemia, neuropsychiatric symptoms, secondary infections), which may be difficult to detect
and monitor in an outpatient setting (see General Management of Nonhospitalized Patients With Acute
COVID-19 for further information). 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).
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 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.2 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.2 For additional information
on the RECOVERY trial, see Table 4a.
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 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, ICU-free days over 28 days, or duration of mechanical ventilation at 28 days.3
See Table 4a for additional information.
Systemic corticosteroids used in combination with other agents, including other immunomodulators such
as tocilizumab (see Interleukin-6 Inhibitors)4,5 or baricitinib (see Kinase Inhibitors),6 have demonstrated
clinical benefit in subsets of hospitalized patients with COVID-19, especially those with early critical
illness and/or 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 evaluating corticosteroid use for COVID-19.
Systemic Corticosteroids Other Than Dexamethasone

Systemic corticosteroids other than dexamethasone, including hydrocortisone7,8 and
methylprednisolone,9,10 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, if true, suggested a beneficial effect). Therefore, evidence to support the use of hydrocortisone
or methylprednisolone for the treatment of COVID-19 is not as strong as 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 (oral or IV)11 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 previously studied in patients

with ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on
sodium balance and fluid volume.12
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-213 and downregulate expression of the receptors used
for cell entry.14,15 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
There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
Rationale
Inhaled budesonide was studied in 2 open-label randomized controlled trials in outpatients with mild
symptoms of COVID-19.16,17 The small STOIC trial suggested that initiation of inhaled budesonide in
adult outpatients with mild COVID-19 may reduce the need for urgent care or emergency department
assessment or hospitalization.16 PRINCIPLE, a larger, open-label trial in nonhospitalized patients with
COVID-19 at high risk of disease progression, found that use of inhaled budesonide did not affect the
rate of hospitalization or death but did reduce the time to self-reported recovery.18 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.19 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 7.20
The above-described studies of inhaled corticosteroid therapy for outpatients with mild COVID-19
have identified inconsistent effects of the therapy on subsequent hospitalization, and similar placebo-
controlled trials have not demonstrated that this therapy results in improvements in symptom resolution.
The placebo-controlled studies did not enroll enough patients at high risk of disease progression, and
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).21-25

antiparasitic treatment (e.g., with ivermectin) with or without serologic testing in patients from
areas where Stronglyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).28
• Using systemic corticosteroids with other immunosuppressants, such as tocilizumab or baricitinib,
could theoretically increase the risk of secondary infections. However, this adverse effect has not
been reported in clinical trials to date.
• 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 review a patient’s medication regimen 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 of 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.29,30
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 dexamethasone or other corticosteroids for COVID-19 treatment
have not been sufficiently evaluated in pediatric patients and caution is warranted when extrapolating
recommendations for adults to patients aged <18 years. 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 perceived
to outweigh the risks. The dexamethasone dosing regimen for pediatric patients is dexamethasone
0.15 mg/kg/dose (maximum dose 6 mg) once daily for up to 10 days. There is insufficient evidence
to recommend for or against the use of inhaled corticosteroids for pediatric patients with COVID-19.
Corticosteroids are second to IV immunoglobulin as the most used therapy for the treatment of
multisystem inflammatory syndrome in children (MIS-C).31,32 See Special Considerations in Children for
more information on the management of MIS-C.
Clinical Trials
Several clinical trials evaluating 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:
3. 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
4. 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.
adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled
Phase 3 trial. Lancet Respir Med. 2021; Published online ahead of print. Available at:
7. 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.
8. 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.
9. 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.
10. 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.
11. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically
administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98. Available at:
12. 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:
13. 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:
14. 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.
15. 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:

16. 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
17. PRINCIPLE Collaborative Group, Yu L, Bafadhel M, et al. Inhaled budesonide for COVID-19 in people at
higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. medRxiv.
18. 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:
19. 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.
20. 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:
21. 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:
22. 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. 2021:1-8. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33716414.
23. 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:
24. 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.
25. 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
26. Lier AJ, Tuan JJ, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am
J Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32830642.
29. 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:
30. 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:
31. 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.


32. 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: https://www.ncbi.nlm.nih.gov/pubmed/34133855.

Table 4a. 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 included participants aged 18 years or older.
RECOVERY: Open-Label RCT of Dexamethasone in Hospitalized Patients With COVID-19 in the United Kingdom1
Key Inclusion Criterion: Participant Characteristics: Key Limitations:
• Hospitalized with suspected or laboratory- • Mean age 66 years; 64% men • Open-label study
confirmed SARS-CoV-2 infection • 56% had ≥1 comorbidity; 24% with diabetes • Published data did not include results for key
Key Exclusion Criterion: • 89% with laboratory-confirmed SARS-CoV-2 infection secondary endpoints (e.g., cause-specific
mortality, need for renal replacement), AEs, and
• Physician determination that risks of • Median duration of DEX therapy: 7 days key subgroups (e.g., patients with comorbidities)
participation too great based on patient’s • At randomization: 16% received MV or ECMO, 60%
medical history or an indication for • Participants who required supplemental oxygen
required supplemental oxygen but not MV, 24% required (but not MV) had variable severity. It is unclear
corticosteroid therapy outside of the study no supplemental oxygen whether all patients in this group benefited from
Interventions: • Received RDV: <1% in each arm DEX or whether benefit is restricted to those
• DEX 6 mg IV or PO once daily plus SOC for • Received tocilizumab or sarilumab: 2% in DEX arm vs. 3% requiring higher levels of supplemental oxygen
up to 10 days or until discharge (n = 2,104) in SOC arm • Patients >80 years were preferentially assigned to
• SOC alone (n = 4,321) Primary Outcome: supplemental oxygen therapy (and not MV)
Primary Endpoint: • Mortality at 28 days • High mortality of this patient population may limit
generalizability of results to populations with a
• All-cause mortality at 28 days • All participants: 23% in DEX arm vs. 26% in SOC arm lower baseline mortality
(age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P <
0.001). Interpretation:
• Participants who required MV or ECMO at • In hospitalized patients with severe COVID-19
randomization: 29% in DEX arm vs. 41% in SOC arm who required supplemental oxygen, DEX reduced
(rate ratio 0.64; 95% CI, 0.51–0.81). mortality at 28 days, with greatest benefit in those
with MV at randomization.
• Participants who required supplemental oxygen but not
MV at randomization: 23% in DEX arm vs. 26% in SOC • No survival benefit of DEX in patients who did not
arm (rate ratio 0.82; 95% CI, 0.72–0.94). require supplemental oxygen at baseline.
• Participants who did not require supplemental oxygen
at randomization: 18% in DEX arm vs. 14% in SOC arm
(rate ratio 1.19, 95% CI, 0.91–1.55).

CoDEX: Open-Label RCT of Dexamethasone in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19 in Brazil2
• Confirmed or suspected COVID-19 • Mean age: 60 years in DEX arm vs. 63 years in SOC arm • Open-label study
• Received MV within 48 hours of meeting • Women: 40% in DEX arm vs. 35% in SOC arm • Underpowered; enrollment stopped after release
criteria for moderate to severe ARDS (PaO2/ • Obesity: 31% in DEX arm vs. 24% in SOC arm; DM: 38% of data from the RECOVERY trial
FiO2 ≤200 mm Hg) in DEX arm vs. 47% in SOC arm • Patients discharged before 28 days were not
Key Exclusion Criteria: • Vasopressor use: 66% in DEX arm vs. 68% in SOC arm; followed for rehospitalization or mortality
• Immunosuppressive drugs in past 21 days mean PaO2/FiO2: 131 mm Hg in DEX arm vs. 133 mm Hg • High mortality in this study may limit
in SOC arm generalizability to populations with a lower
• Expected death within 24 hours
• Median duration of DEX therapy: 10 days baseline mortality
Interventions: • More than one-third of those randomized to SOC
• None received RDV or tocilizumab
• DEX 20 mg IV daily for 5 days, then DEX 10 also received corticosteroids
mg IV daily for 5 days or until ICU discharge • 35% in SOC arm received corticosteroids for indications
such as bronchospasm or septic shock Interpretation:
(n = 151)
Primary Outcome: • Compared with SOC alone, DEX increased the
• SOC alone (n = 148)
number of days alive and free of MV over 28 days
Primary Endpoint: • Mean number of days alive and free from MV by Day 28: 7 in patients with COVID-19 and moderate to severe
days in DEX arm vs. 4 days in SOC arm (P = 0.04). ARDS.
• Days alive and free from MV by Day 28
Secondary Outcomes:
• No differences in arms for Day 28 all-cause mortality
• All-cause mortality at Day 28 (56.3% vs. 61.5%), ICU-free days, and duration of MV, or
• ICU-free days by Day 28 for Day 15 score on 6-point ordinal scale.
• Duration of MV by Day 28 • Mean SOFA score at 7 days: 6.1 in DEX arm vs. 7.5 in SOC
• Score on 6-point ordinal scale at Day 15 arm (P = 0.004).
• SOFA score at 7 days 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; P = 0.01).

COVID STEROID 2: Multinational Blinded RCT of Dexamethasone 12 mg Versus 6 mg in Adults With COVID-19 and Severe Hypoxemia3
• Confirmed SARS-CoV-2 infection • Median age 65 years; 31% women • The randomized intervention was <10 days in
• Requiring oxygen ≥10 L/min, NIV, CPAP, or • DM: 27% in 12 mg arm vs. 34% in 6 mg arm some patients because the trial allowed up to 5
MV days of DEX before enrollment
• Median onset of symptoms to hospitalization: 7 days
Key Exclusion Criteria: • ICU care: 78% in 12 mg arm vs. 81% in 6 mg arm Interpretation:
• Treated with DEX >6 mg (or equivalent) • Oxygen requirements: 54% on oxygen via nasal cannula or • Among patients with COVID-19 and severe
face mask (median flow rate 23 L/min); 25% via NIV; 21% hypoxemia, DEX 12 mg once daily did not result
• Treated with corticosteroid ≥5 days in more days alive without life support at 28 days
via MV
• Invasive fungal infection than DEX 6 mg once daily.
• 63% received RDV; 12% received IL-6 inhibitors or JAK
• Active TB
inhibitors
Interventions: • Median duration of DEX treatment: 7 days in both arms
• DEX 12 mg IV once daily for up to 10 days (n
Primary Outcome:
= 503)
• Median days alive without life support: 22 days in 12 mg
• DEX 6 mg IV once daily for up to 10 days (n
arm vs. 20 days in 6 mg arm (adjusted mean difference
= 497)
1.3 days; 95% CI, 0.0–2.6; P = 0.07).
Primary Endpoint:
Secondary Outcomes:
• Days alive without life support (MV,
• At 90 days:
circulatory support, or kidney replacement
therapy) at 28 days • Median days alive without life support: 84 days in 12 mg
arm vs. 80 days in 6 mg arm.
• Median days alive and out of hospital: 62 days in 12 mg
• Days alive without life support at 90 days arm vs. 48 days in 6 mg arm.
• Days alive and out of hospital at 90 days • Mortality: 32% in 12 mg arm vs. 38% in 6 mg arm
• Mortality at 90 days (adjusted relative risk 0.87; 99% CI, 0.70–1.07).
• Mortality at 28 days • Mortality at 28 days: 27% in 12 mg arm vs. 32% in 6 mg
• SAEs at 28 days arm (adjusted relative risk 0.86; 99% CI, 0.68–1.08).
• 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).

CAPE COVID: Double-Blind RCT of Hydrocortisone Among Critically Ill Patients With COVID-19 in France4
• Confirmed SARS-CoV-2 infection or • Mean age 62 years; 70% men; median BMI 28 • Underpowered; enrollment stopped after release
radiographically suspected COVID-19 with • 96% with confirmed SARS-CoV-2 infection of data from the RECOVERY trial
≥1 of the following: • Limited information about comorbidities
• Median symptom duration: 9–10 days
• MV with PEEP ≥5 cm H2O
• Required MV: 81% at baseline Interpretation:
• PaO2/FiO2 <300 mm Hg and FiO2 ≥50% on
• Received vasopressors: 24% in hydrocortisone arm vs. • Hydrocortisone did not reduce treatment failure
HFNC
18% in placebo arm at Day 21 in patients with COVID-19 and acute
• PaO2/FiO2 <300 mm Hg on reservoir mask respiratory failure, although early termination
oxygen • Received RDV and tocilizumab: <3%
limited power to detect difference between study
• Pulmonary severity index >130 • Median duration of treatment with study drug: 11 days in arms.
hydrocortisone arm vs. 13 days in placebo arm (P = 0.25)
Primary Outcome:
• Septic shock
• Treatment failure by Day 21: 42% in hydrocortisone arm
• Do-not-intubate orders vs. 51% in placebo arm (P = 0.29).
Interventions:
Secondary Outcomes:
• Continuous infusion of hydrocortisone
• No difference in need for intubation or prone positioning
200 mg/day for 7 days, then 100 mg/day
(too few patients received ECMO or inhaled nitric oxide for
for 4 days, then 50 mg/day for 3 days; if
comparisons).
improvement by Day 4, then 200 mg/day for
4 days, then 100 mg/day for 2 days, then 50 • Among patients who did not require MV at baseline, 50%
mg/day for 2 days (n = 76) in hydrocortisone arm vs. 75% in placebo arm required
subsequent MV.
• No difference in proportion with nosocomial infection by
Primary Endpoint: Day 28
• Treatment failure (death or dependency on • Clinical status on Day 21: no difference in arms, but 15%
MV or high-flow oxygen) by Day 21 deaths in hydrocortisone arm vs. 27% deaths in placebo
Key Secondary Endpoints: arm (P = 0.06).
• Need for MV, prone positioning, ECMO, • Discharged from ICU by Day 21: 57% in hydrocortisone
inhaled nitric oxide arm vs. 44% in placebo arm; 23% in both arms still
required MV.
• Nosocomial infection by Day 28
• Clinical status on Day 21

REMAP-CAP: Randomized, Open-Label, Adaptive Trial of Hydrocortisone in Patients With Severe COVID-195
• Presumed or confirmed SARS-CoV-2 infection • Mean age 60 years; 71% men • Open-label study
• ICU admission for respiratory support • Mean BMI 29.7–30.9 • Early termination following release of
Key Exclusion Criteria: • 50% to 64% required MV RECOVERY trial results
• Presumed imminent death Primary Outcomes: Interpretation:
• Systemic corticosteroid use • No difference in organ support–free days at Day 21 • Hydrocortisone did not increase support-free
• >36 hours since ICU admission (median 0 days in each group). days in either the fixed-dose or the shock-
dependent group, although early termination
Interventions: • Median adjusted ORs for primary outcome for limited power to detect differences between
hydrocortisone arms compared to no hydrocortisone arm: study arms.
• Hydrocortisone 50 mg IV 4 times daily for 7
days (n = 137) • OR 1.43 (95% CrI, 0.91–2.27) with 93% Bayesian
probability of superiority for fixed-dose hydrocortisone
• Septic shock-based hydrocortisone 50 mg IV 4 arm.
times daily for duration of shock (n = 146)
• OR 1.22 (95% CrI, 0.76–1.94) with 80% Bayesian
• No hydrocortisone (n = 101) probability of superiority for septic shock-based
Primary Endpoint: hydrocortisone arm.
• Days free of respiratory and cardiovascular Key Secondary Outcome:
support up to Day 21 • No differences in mortality: 30% in fixed-dose
Key Secondary Endpoint: hydrocortisone arm, 36% in septic shock-based
• In-hospital mortality hydrocortisone arm, 33% in no hydrocortisone arm.
Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China6
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 56 years; 48% men • Small sample size
• Chest CT-confirmed pneumonia • Median 8 days from symptom onset to randomization • Terminated early because of decreasing
• Hospitalized on general ward • At randomization, 71% received oxygen via nasal cannula incidence of COVID-19 pneumonia at study
sites
Key Exclusion Criteria: Primary Outcome:
Interpretation:
• Severe immunosuppression • Clinical deterioration at 14 days: 5% in each arm (OR 1.0;
95% CI, 0.134–7.442; P = 1.00). • The incidence of clinical deterioration did not
• Corticosteroid use for other diseases differ between the methylprednisolone and
Interventions: Secondary Outcomes: control arms.
• Methylprednisolone 1 mg/kg/day IV for 7 days • No difference (all P > 0.05) between methylprednisolone
(n = 43) arm and saline arm for:
• Saline (n = 43) • Clinical cure at 14 days: 51% vs. 58%

Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China6, continued
Primary Endpoint: • Time to clinical cure: 14 days vs. 12 days
• Clinical deterioration at 14 days • ICU admission: 5% each
Key Secondary Endpoints: • In-hospital mortality: 0% vs. 2%
• Clinical cure at 14 days • Days hospitalized: 17 days vs. 13 days
• Time to clinical cure
• ICU admission
• In-hospital mortality
• Days hospitalized
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; IV = intravenous; JAK = Janus kinase; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment
Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; 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. COVID Steroid 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:
4. 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.
5. 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:
6. 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:

Table 4b. 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
Interventions:
• Usual care plus budesonide 800 mcg inhaled twice daily until symptom
resolution (n = 73)

STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults with Early COVID-192, continued
• Usual care (n = 73) Primary Outcomes: Interpretation:
Primary Endpoint: • Median duration of budesonide use: 7 days. • In adult outpatients with mild COVID-19,
• Percentage of patients with COVID-19-related inhaled budesonide may reduce the need
• COVID-19-related urgent care visit, including ED visit or
urgent care visit or hospitalization: 1% in for urgent care or ED assessment and/or
hospitalization
budesonide arm vs.14% in usual care arm (relative hospitalization.
risk reduction 91%).
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.

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
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 4c. 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.
• Proportion of patients who were adherent to study drugs, drug due to issues of tolerability. • The use of fluvoxamine did not impact
defined as receiving >80% of possible doses • Mortality (ITT): 2% in fluvoxamine arm vs. 3% in the incidence of COVID-19-related
placebo arm (OR 0.68; 95% CI, 0.36–1.27) hospitalizations.

TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil1, continued
• Mortality in both the primary ITT population and a PP • Mortality (PP): <1% in fluvoxamine • It is difficult to define the clinical relevance of the >6-hour
population that included patients who took >80% of the arm vs. 2% in placebo arm (OR 0.09; emergency setting observation endpoint and apply it to
study medication doses 95% CI, 0.01–0.47) practice settings in different countries.
• 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%
Key Secondary Endpoint:
• 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
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a myelopoietic growth factor and

proinflammatory cytokine that plays a central role in a broad range of immune-mediated diseases.
GM-CSF, 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
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
patients with COVID-19.
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. Preliminary data from a double-blind, placebo-
controlled randomized 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. 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.11-13 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 invasive mechanical ventilation.
Each of these GM-CSF inhibitors remains under investigation.

Lenzilumab, mavrilimumab, and otilimab have been evaluated in clinical trials in hospitalized adults
with SARS-CoV-2 pneumonia.11-13 Clinical data are not yet available for gimsilumab or namilumab. The
Panel’s recommendations are based on the results of the available clinical studies. Clinical data on the
use of anti-GM-CSF monoclonal antibodies for the treatment of COVID-19 are summarized in Table 4d.
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.14
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.
6. Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+
monocytes in severe pulmonary syndrome patients of a new coronavirus. biorxiv. 2020. 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, Wang B, White B, Magrini F. 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. Patel J, Beishuizen A, Ruiz XB, et al. A randomized trial of otilimab in severe COVID-19 pneumonia
(OSCAR). medRxiv. 2021;Preprint. Available at:

12. 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;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33972949.
13. 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:
14. 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 4d. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors:

Selected Clinical Data
GM-CSF inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
Otilimab in Severe COVID-19 Pneumonia (OSCAR Trial)1

Phase 2, double-blind RCT Key Inclusion Criteria: Number of Participants: Key Limitations:
in patients with severe • Hospitalized adults with confirmed • mITT analysis (n = 793): otilimab (n = 395) and placebo • Changes in SOC occurred
COVID-19 pulmonary disease SARS-CoV-2 pneumonia (n = 398) during the study period and
in 17 countries, including the may have affected outcomes.
United States (n = 806) • New onset of oxygenation • Participants were enrolled from May 28–November 15,
impairment requiring high-flow 2020, across 108 study sites. • A preplanned subgroup
This is a preliminary report oxygen (≥15 L/min), noninvasive analysis suggested a benefit
that has not yet been peer Participant Characteristics:
ventilation, or IMV ≤48 hours of otilimab in participants
reviewed. before dosing • Mean age was 59 years. aged ≥70 years, but subgroup
• CRP or ferritin >ULN • 77% received high-flow oxygen or noninvasive ventilation. analyses were not adjusted for
• 22% were on IMV. multiple comparisons.
• 52% were in the ICU but not on IMV. Interpretation:
• Death considered likely within 48
hours • 83% received corticosteroids; 34% received RDV • In this large study, no
differences in outcomes
• Multiple organ failure • Participants were stratified by clinical status (ordinal scale
were observed between the
• SOFA score >10 if in the ICU 5 or 6) and age (<60 years, 60–69 years, and ≥70 years).
otilimab or placebo recipients
• ECMO Primary Outcome: with severe COVID-19
• 277 of 389 participants (71%) in the otilimab arm vs. 262 pneumonia, except for those
• Dialysis
of 393 participants (67%) in the placebo arm were alive in a subgroup of participants
• High-dose noradrenaline (>0.15 aged ≥70 years.
and free of respiratory failure at Day 28 (model-adjusted
ug/kg/min) or equivalent
absolute difference of 5.3%; 95% CI, -0.8 to 11.4; P =
• More than 1 vasopressor 0.09)
Interventions Key Secondary Outcomes:
1:1 Randomization: • No difference in all-cause mortality at Day 60 between the
• Otilimab 90 mg IV as a single otilimab arm and the placebo arm (23% vs. 24%; model-
infusion adjusted difference -2.4%; 95% CI, -8.0 to 3.3; P = 0.41)
• Placebo

Otilimab in Severe COVID-19 Pneumonia (OSCAR Trial)1, continued

Primary Endpoint: • No difference between the arms for other secondary
• Proportion of participants alive and endpoints
free of respiratory failure at Day 28 • In a preplanned analysis, a benefit of otilimab was
observed among those aged ≥70 years (n = 180):
• 65.1% of otilimab recipients vs. 45.9% of placebo
• All-cause mortality at Day 60 and
recipients met the primary endpoint (model-adjusted
time to all-cause mortality
difference 19.1%; 95% CI, 5.2–33.1; P = 0.009)
• Time to recovery
• Mortality at Day 60 was lower in otilimab arm than in
• Admission to ICU placebo arm (27% vs. 41%; model-adjusted difference
• Time to ICU discharge of 14.4%; 95% CI, 0.9–27.9; P = 0.04).
Lenzilumab in Hospitalized Patients With COVID-19 Pneumonia (LIVE-AIR Trial)2
Phase 3, double-blind RCT Key Inclusion Criteria: Number of Participants: Key Limitations:
in hospitalized patients with • Hospitalized adults with confirmed • mITT (n = 479): lenzilumab (n = 236) and placebo (n = • The study was not powered to
severe COVID-19 pneumonia SARS-CoV-2 pneumonia 243) detect a survival benefit.
in the United States and
Brazil (n = 520 across 29 • SpO2 ≤94% on room air or Participant Characteristics: • There were differences in
study sites) requiring low-flow supplemental access to supportive care
• Mean age was 60.5 years.
oxygen, high-flow oxygen support, across the study sites.
This is a preliminary report or NIPPV • 64.7% were men.
that has not yet been peer Interpretation:
Key Exclusion Criteria: • 43.2% were White.
reviewed. • In this large, unpublished,
• Requiring IMV • 55.1% had a BMI ≥30. placebo-controlled study,
• Pregnancy • 40.5% received high-flow oxygen support or NIPPV at lenzilumab improved
baseline. ventilator-free survival
• Confirmed bacterial pneumonia or in participants who were
active/uncontrolled fungal or viral • 93.7% received corticosteroids; 72.4% received RDV;
69.1% received both corticosteroids and RDV. hypoxic but not mechanically
infection ventilated.
• Not expected to survive the 48 Primary Outcome:
hours following randomization • Lenzilumab improved ventilator-free survival through Day
• Use of IL-1 inhibitors, IL-6 28:
inhibitors, kinase inhibitors, • mITT participants: HR 1.54; 95% CI, 1.02–2.31; P =
or SARS-CoV-2 neutralizing 0.041
monoclonal antibodies within prior • ITT participants: HR 1.90; 95% CI, 1.02–3.52; P = 0.043
8 weeks

Lenzilumab in Hospitalized Patients With COVID-19 Pneumonia (LIVE-AIR Trial)2, continued

Interventions • Kaplan-Meier estimate for proportion of participants who
1:1 Randomization: had required IMV or died through Day 28:
• Lenzilumab 600 mg IV every 8 • mITT lenzilumab arm: 15.6% (95% CI, 11.5–21.0);
hours for 3 doses placebo arm: 22.1% (95% CI, 17.4–27.9)
• Placebo • ITT lenzilumab arm: 18.9% (95% CI, 14.5–24.3);
placebo arm: 23.6% (95% CI, 18.8–29.3)
Primary Endpoint:
• Primary outcome sensitivity mITT analyses showed
• Ventilator-free survival through lenzilumab improved the likelihood of ventilator-free
Day 28 (composite endpoint of survival in participants:
time to death and time to IMV)
• Aged <85 years with CRP <150 mg/L (n = 336): HR 2.96;
Key Secondary Endpoints: 95% CI, 1.63–5.37; P = 0.0003
• Survival • Receiving corticosteroids plus RDV (n = 331): HR 1.92;
• Proportion of IMV, ECMO, or death 95% CI, 1.20–3.07; P = 0.0067
• Time to recovery • Hospitalized ≤2 days prior to randomization (n = 297):
HR 1.88; 95% CI, 1.13–3.12; P = 0.015
Key Secondary Outcomes:
• No difference in proportion of participants who died: 9.6%
in lenzilumab arm vs. 13.9% in placebo arm (HR 1.38;
95% CI, 0.81–2.37; P = 0.239)
• No difference between the arms in the incidence of IMV,
ECMO, or death: HR 0.67; 95% CI, 0.41–1.10; P = 0.111
• No difference between the arms in time to recovery: HR
1.09; 95% CI, 0.88–1.35; P = 0.43)
Mavrilimumab in Patients With Severe COVID-19 Pneumonia and Systemic Hyperinflammation (MASH-COVID Trial)3
Multicenter, double-blind Key Inclusion Criteria: Number of Participants: Key Limitations:
RCT in hospitalized patients • Hospitalization with SARS-CoV-2 • Mavrilimumab (n = 21) and placebo (n = 19) • The small sample size
with COVID-19 pneumonia in pneumonia resulted in low power to
the United States (n = 40) • Study enrollment was from May 28–September 15, 2020.
• Hypoxemia (SpO2 <92% or identify a clinically meaningful
Participant Characteristics: treatment effect.
requirement for supplemental
oxygen) • 65% were men. • The study was stopped early
• CRP >5 mg/dL • 40% were African American. due to slow enrollment.

Mavrilimumab in Patients With Severe COVID-19 Pneumonia and Systemic Hyperinflammation (MASH-COVID Trial)3, continued
Multicenter, double-blind Key Exclusion Criteria: • 50% required nasal high-flow oxygen or noninvasive Interpretation:
RCT in hospitalized patients • Mechanical ventilation ventilation. • In this small study, no
with COVID-19 pneumonia in • Corticosteroids use: 67% in the mavrilimumab arm, 63% differences in outcomes
the United States (n = 40) • ANC <1,500/mm3
in the placebo arm were observed between the
• Uncontrolled bacterial infection mavrilimumab and placebo
• RDV use: 76% in the mavrilimumab arm, 74% in the
Interventions placebo arm arms among participants
1:1 Randomization: who were not mechanically
Primary Outcome: ventilated.
• Mavrilimumab 6 mg/kg as a single • No significant difference in primary outcome: 12 of 21
IV infusion participants (57%) in the mavrilimumab arm vs. 9 of 19
• Placebo participants (47%) in the placebo arm (OR 1.48; 95% CI,
Primary Endpoint: 0.43–5.16; P = 0.76)
• Proportion of participants alive and Key Secondary Outcomes:
off supplemental oxygen at Day 14 • No difference in survival: 1 participant in the
Key Secondary Endpoints: mavrilimumab arm vs. 3 in the placebo arm had died by
Day 28 (HR 3.72; 95% CI, 0.39–35.79; P = 0.22)
• Survival at Day 28
• No difference in respiratory failure free survival at Day 28:
• Respiratory failure-free survival at 20 participants (95%) in the mavrilimumab arm vs. 15
Day 28 (79%) in the placebo arm (OR 5.33; 95% CI, 0.54–52.7;
P = 0.43)
Key: ANC = absolute neutrophil count; BMI = body mass index; CRP = C-reactive protein; ECMO = extracorporeal membrane oxygenation; GM-CSF = granulocyte
macrophage-colony stimulating factor; ICU = intensive care unit; IL = interleukin; IMV = invasive mechanical ventilation; ITT = intention-to-treat; IV = intravenous;
mITT = modified intention-to-treat; NIPPV = noninvasive positive pressure ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; 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. Patel J, Beishuizen A, Ruiz XB, et al. A randomized trial of otilimab in severe COVID-19 pneumonia (OSCAR). medRxiv. 2021;Preprint. Available at:
2. 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;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33972949.
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

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.

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:
16. 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.
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).
18. 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:
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:

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
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
4e.
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
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 4e).
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 4e.

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 it is being studied in a clinical trial of
hospitalized patients with COVID-19. In the REMAP-CAP trial, a single SQ dose of sarilumab 400 mg
was reconstituted in 100 cc 0.9% NaCl and given as an IV infusion over 1 hour.10
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:
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:
7. Lier AJ, Tuan JJ, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am
J Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32830642.


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
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:
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. A randomized placebo-controlled trial of sarilumab in
hospitalized patients with COVID-19. medRxiv. 2021;Preprint. 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 4e. Interleukin-6 Inhibitors: Selected Clinical Data

Last Updated December 16, 2021
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.
RECOVERY Trial: Open-Label RCT of Tocilizumab and Usual Care in Hospitalized Patients With COVID-191
• SpO2 <92% on room air or receipt of • Mean age 63.6 years; 67% men; 76% White • Arbitrary enrollment cut off at CRP ≥75 mg/L
supplemental oxygen • 95% had PCR-confirmed SARS-CoV-2 • Difficult to define exact subset of patients in RECOVERY
• CRP ≥75 mg/L infection cohort who were subsequently selected for secondary
• At baseline: randomization/tocilizumab trial
• Non-SARS-CoV-2 infection • 45% on conventional oxygen Interpretation:
• 41% on HFNC oxygen or NIV • Among hospitalized COVID-19 patients with hypoxemia
Interventions:
• 14% on MV and elevated CRP, tocilizumab was associated with
• Single weight-based dose of tocilizumab reduced all-cause mortality and shorter time to discharge.
(maximum 800 mg) and possible second dose (n • 82% on corticosteroids
= 2,022) Primary Outcomes:
• Usual care (n = 2,094) • Day 28 mortality was lower in tocilizumab arm
Primary Endpoint: than in usual care arm (31% vs. 35%; rate ratio
• 28-day all-cause mortality 0.85; 95% CI, 0.76–0.94; P = 0.003).
• Among those who required MV at baseline,
Day 28 mortality was similar between arms
• Time to discharge alive within 28 days (49% in tocilizumab arm vs. 51% in usual care
• Among those not on MV at enrollment, receipt of arm; risk ratio 0.93; 95% CI, 0.74–1.18).
MV or death within 28 days Secondary Outcomes:
• Proportion of patients discharged alive within
28 days was greater in tocilizumab arm than
usual care arm (57% vs. 50%; rate ratio 1.22;
95% CI, 1.12–1.33; P < 0.0001).
• Proportion of patients not on MV at baseline
who died or required MV within 28 days was
lower in tocilizumab arm than usual care
arm (35% vs. 42%; 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 Patients With COVID-192,3
• ICU admission • Mean age 60 years; 69% men; 75% White • Enrollment in tocilizumab and sarilumab arms was
• Suspected or laboratory-confirmed COVID-19 • 86% had PCR-confirmed SARS-CoV-2 infection partially nonconcurrent with SOC arm; while the
comparisons to SOC arm were adjusted for time period,
• Receipt of MV, NIV, or cardiovascular support • Median time from ICU admission until there is a possibility of bias
enrollment was 14 hours
Key Exclusion Criteria: Interpretation:
• At baseline:
• >24 hours since ICU admission • Among patients with respiratory failure who were within
• 67% on HFNC oxygen or NIV
• Presumption of imminent death 24 hours of ICU admission, the tocilizumab and sarilumab
• 33% on MV arms had higher rates of in-hospital survival and shorter
• Immunosuppression
• 67% on corticosteroids in SOC arm, 82% in durations of organ support than the SOC arm.
• ALT >5 times ULN
tocilizumab arm, and 89% in sarilumab arm • The treatment effect appeared to be strongest in the
Interventions: highest CRP tercile.
Primary Outcomes
• Single dose of tocilizumab 8 mg/kg IV and • Tocilizumab and sarilumab were similarly effective, with a
Tocilizumab Versus SOC:
possible second dose in 12–24 hours, plus SOC 99% probability of noninferiority of sarilumab.
(n = 952) • Median number of organ support-free days was
7 in tocilizumab arm and 0 in SOC arm.
• Single dose of sarilumab 400 mg IV plus SOC (n
= 485) • Median adjusted OR for ordinal scale was 1.46
(95% CrI, 1.13–1.87).
• SOC (n = 406)
• In highest CRP tercile, aOR was 1.87 (95% CrI,
Randomization: 1.35–2.59).
• Adaptative randomization. Patients were • Outcomes were consistent across subgroups
randomized to receive SOC only, SOC plus according to oxygen requirement at baseline.
tocilizumab, or SOC plus sarilumab based on
provider preference, availability, or adaptive Sarilumab Versus SOC:
probability. SOC arm was closed in November • Median number of organ support-free days was
2020 (n = 366 for tocilizumab, n = 48 for 9 in sarilumab arm and 0 in SOC arm.
sarilumab, n = 412 for SOC). • Median adjusted OR for ordinal scale was 1.50
• After November 2020, patients were randomized (95% CrI, 1.13–2.00).
mostly to receive tocilizumab, sarilumab, or • In highest CRP tercile, aOR was 1.85 (95% CrI,
anakinra until April 10, 2021. 1.24–2.69).
Primary Endpoint: • Outcomes were consistent across subgroups
• Composite ordinal endpoint of in-hospital according to oxygen requirements at study
mortality and organ support-free days to Day 21 entry.

REMAP-CAP: Open-Label, Adaptive-Platform RCT of Tocilizumab and Sarilumab in Patients With COVID-192,3, continued
Key Secondary Endpoint: Secondary Outcomes
• In-hospital survival Tocilizumab Versus SOC:
• In-hospital survival was 66% in tocilizumab arm and
63% in SOC arm (aOR 1.42; 95% CrI, 1.05–1.93).
Sarilumab Versus SOC:
• In-hospital survival was 67% in sarilumab arm and
63% in SOC arm (aOR 1.51; 95% CrI, 1.06–2.20).
COVACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-194
• PCR-confirmed SARS-CoV-2 infection • Mean age 61 years; 70% men; 58% White • Modest power to detect differences in Day 28
• Hypoxemia • 30% on HFNC oxygen or NIV clinical status
• Bilateral chest infiltrates • 14% on MV • More patients in placebo arm than tocilizumab
arm received corticosteroids
Key Exclusion Criteria: • 25% with multiorgan failure
• Few patients on MV
• Death imminent • 36% in tocilizumab arm and 55% in placebo arm
received corticosteroids at entry or during follow-up Interpretation:
• Active infection other than SARS-CoV-2
Primary Outcome: • There was no difference between arms in Day 28
Interventions: clinical status or survival.
• No significant difference between arms in clinical
• Single dose of tocilizumab 8 mg/kg and possible • The median times for recovery and ICU LOS were
status at Day 28.
second dose, plus SOC (n = 294) shorter in the tocilizumab arm than in the placebo
• Placebo plus SOC (n = 144) Secondary Outcomes: arm.
• Shorter median time to discharge in tocilizumab arm
Primary Endpoint:
than placebo arm (20 vs. 28 days; HR 1.35; 95% CI,
• Day 28 clinical status (ordinal score) 1.02–1.79).
Key Secondary Endpoints: • Shorter median ICU LOS in tocilizumab arm than
• Time to discharge placebo arm (9.8 vs. 15.5 days).
• ICU LOS • No difference in Day 28 mortality between arms
(19.7% in tocilizumab arm vs. 19.4% placebo arm).
• Day 28 mortality

EMPACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-195

• PCR-confirmed SARS-CoV-2 infection • Mean age 56 years; 59% men; 56% Hispanic/Latinx, 15% • Moderate sample size
• COVID-19 pneumonia Black/African American, 13% American Indian/Alaska Native
Interpretation:
• 84% with elevated CRP
Key Exclusion Criteria: • Among patients with COVID-19 pneumonia,
• Concomitant medications: tocilizumab lowered rates of MV, ECMO, or
• NIV or MV
• 80% on corticosteroids and 53% on RDV in tocilizumab death by Day 28 but provided no benefit for
Interventions: arm 28-day all-cause mortality.
• Single dose of tocilizumab 8 mg/kg plus SOC, • 88% on corticosteroids and 59% on RDV in placebo arm
possible second dose (n = 249)
Primary Outcome:
• Placebo plus SOC (n = 128)
• Proportion of patients who required MV or ECMO or died
Primary Endpoint: by Day 28 was 12% in tocilizumab arm and 19% in placebo
• MV, ECMO, or death by Day 28 arm (HR 0.56; 95% CI, 0.33–0.97; P = 0.04).
Key Secondary Endpoints: Secondary Outcomes:
• Time to hospital discharge or readiness for • Median time to hospital discharge or readiness for discharge
discharge (ordinal score) was 6.0 days in tocilizumab arm and 7.5 days in placebo
• All-cause mortality by Day 28 arm (HR 1.16; 95% CI, 0.91–1.48).
• All-cause mortality by Day 28 was not statistically different
between arms (10.4% in tocilizumab arm vs. 8.6% in
placebo arm).
BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-196
• Laboratory-confirmed SARS-CoV-2 infection • Median age 60 years; 58% men; 45% Hispanic/Latinx • Wide confidence intervals due to small sample
• ≥2 of the following conditions: • 50% with BMI ≥30; 49% with HTN; 31% with DM size and low event rates
• Fever >38°C • 80% receiving oxygen ≤6 L/min; 4% receiving high-flow • Few patients received RDV or corticosteroids
• Pulmonary infiltrates oxygen; 16% receiving no supplemental oxygen Interpretation:
• Need for oxygen • Concomitant medications: • There was no benefit of tocilizumab in
• ≥1 of the following laboratory criteria: • 11% on corticosteroids and 33% on RDV in tocilizumab preventing MV or death, reducing the risk of
arm clinical worsening, or reducing the time to
• CRP ≥50 mg/L discontinuation of oxygen. This could be due
• 6% on glucocorticoids and 29% on RDV in placebo arm
• D-dimer >1,000 ng/mL to the low rate of concomitant corticosteroid
• LDH ≥250 U/L Primary Outcome: use among the study participants.
• Ferritin >500 ng/mL • No difference between arms in rate of Day 28 MV or death
(10.6% in tocilizumab arm vs. 12.5% in placebo arm; HR
0.83; 95% CI, 0.38–1.81; P = 0.64).

BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-196, continued
Key Exclusion Criteria: Secondary Outcomes:
• Requiring supplemental oxygen at rate >10 L/min • No difference between arms in proportion of patients
• Recent use of biologic agents or small molecule who had worsening of disease by Day 28 (19% in
immunosuppressive therapy that investigators believe tocilizumab arm vs. 17% in placebo arm; HR 1.11;
place the patient at a higher risk for infection 95% CI, 0.59–2.10).
• Median number of days to discontinuation of oxygen
Interventions:
was 5.0 in tocilizumab arm and 4.9 in placebo arm (P
• Tocilizumab 8 mg/kg plus usual care (n = 161) = 0.69).
• Placebo plus usual care (n = 81)
Primary Endpoint:
• 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 Patients With Severe or Critical COVID-197
• Severe or critical laboratory-confirmed COVID-19 • Median age 59 years; 63% men; 77% White; 36% • Only 20% of patients received
• COVID-19 pneumonia Hispanic/Latinx corticosteroids
• 39% on HFNC oxygen, MV, or NIV • Moderate sample size and a small placebo
• 42% with BMI ≥30; 43% with HTN; 26% with type 2 arm
• Low probability of surviving or remaining at study site
DM Interpretation:
• Dysfunction of ≥2 organ systems and need for ECMO or
• 20% received systemic corticosteroids before • There was no benefit of sarilumab in
renal replacement therapy
receiving intervention hospitalized adults with COVID-19 in time
Interventions: to clinical improvement or mortality. This
Primary Outcome:
• Sarilumab 400 mg IV (n = 173) could be due to the low rate of concomitant
• No difference in median time to clinical improvement corticosteroid use among the study
• Sarilumab 200 mg IV (n = 159) among the sarilumab arms (10 days for each) and participants.
• Placebo (n = 84) placebo arm (12 days).
Primary Endpoint: Secondary Outcome:
• Time to clinical improvement of ≥2 points on a 7-point • No difference among the arms in survival rate at Day
scale 29 (92% in placebo arm vs. 90% in sarilumab 200 mg
arm vs. 92% in sarilumab 400 mg arm).

Double-Blind, RCT of Sarilumab in Hospitalized Patients With Severe or Critical COVID-197, continued
Key Secondary Endpoint:
• Survival at Day 29
REMDACTA: Double-Blind RCT of Tocilizumab and Remdesivir in Hospitalized Patients With Severe COVID‑19 Pneumonia8
• PCR-confirmed SARS-CoV-2 infection • Mean age 59 years; 40% in tocilizumab arm and 34% • During the trial, primary outcome changed
• Hospitalized with pneumonia confirmed by CXR or CT in placebo arm aged ≥65 years from clinical status on Day 28 to time to
and requiring supplemental oxygen >6 L/min • 63% men; 67% White discharge or “ready for discharge” to Day
28
Key Exclusion Criteria: • Respiratory support:
• Imbalances in patient characteristics at
• eGFR <30 mL/min • 78% in tocilizumab arm and 83% in placebo arm on baseline between arms
NIV or high-flow oxygen
• ALT or AST >5 times ULN • Possible underrepresentation of patients
• 15% in tocilizumab arm and 11% in placebo arm with rapidly progressive disease
• Infection other than SARS-CoV-2
required MV or ECMO
• Treatment with antivirals, CP, CQ, HCQ, JAK inhibitors Interpretation:
• Corticosteroid use:
Interventions: • 83% in tocilizumab arm and 86% in placebo arm at • Compared with placebo plus RDV,
• Up to 10 days RDV plus: baseline tocilizumab plus RDV did not shorten the
time to discharge or “ready for discharge”
• Tocilizumab 8 mg/kg IV, with second dose within 8–24 • 88% in each arm during the trial in patients with severe COVID-19
hours if indicated (n = 434) pneumonia.
Primary Outcome:
• Placebo (n = 215) • There was no difference in mortality
• No difference between arms in time to discharge or
Primary Endpoint: “ready for discharge” through Day 28 (14 days in each between the arms.
• Time to discharge or “ready for discharge” through Day arm; HR 0.97; 95% CI, 0.78–1.19; P = 0.74).
28 Secondary Outcomes:
Key Secondary Endpoints: • There was no difference between the arms in key
• Time to MV or death through Day 28 secondary outcomes:
• Day 14 clinical status (ordinal score) • Proportion of patients in each arm who required MV
or died by Day 28 was 29%; time to death was non-
• Time to death through Day 28
evaluable (HR 0.98; 95% CI, 0.72–1.34; P = 0.90).
• Mean ordinal score for clinical status at Day 14 was
2.8 in tocilizumab arm and 2.9 in placebo arm (P =
0.72).
• 18% of patients in tocilizumab arm and 20% in
placebo arm died by Day 28; time to death was non-
evaluable (HR 0.95; 95% CI, 0.65–1.39; P = 0.79).

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
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.
4. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med.
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.
6. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med.
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:
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 interfere with phosphorylation of signal transducer and activator of
transcription (STAT) proteins1,2 that are involved in vital cellular functions, including signaling, growth,
and survival. These kinase inhibitors are proposed 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
Immunosuppression induced by JAK inhibitors could potentially reduce the inflammation and associated
immunopathologies observed in patients with COVID-19. 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
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 baricitinib and tofacitinib
for certain hospitalized patients who require oxygen supplementation.
• 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
The Panel’s recommendations are based on data from the ACTT-2,5 COV-BARRIER,6 and
STOP-COVID7 clinical trials. The ACTT-2 trial demonstrated that baricitinib improved time to recovery
when given in combination with remdesivir to hospitalized patients with COVID-19 who require
supplemental oxygen but not mechanical ventilation. However, a key limitation of the ACTT-2 trial is
that corticosteroids were not used as the standard of care; thus, it was not possible to evaluate the effect
of baricitinib when given in addition to corticosteroids.
The COV-BARRIER trial enrolled patients with COVID-19 pneumonia and at least 1 elevated
inflammatory marker at enrollment who were not on mechanical ventilation. This trial reported an
additional survival benefit of baricitinib when added to the standard of care of corticosteroids (with
or without remdesivir). If baricitinib is not available, tofacitinib may be an alternative because it has
demonstrated clinical benefit in the STOP-COVID trial.
The clinical trial data on the use of baricitinib and tofacitinib in patients with COVID-19 is summarized
below, and all related treatment recommendations are reviewed in Therapeutic Management of

Most of the data on adverse effects of JAK inhibitors were reported based on chronic use of the agents
for the treatment of autoimmune diseases. Adverse effects include infections (typically respiratory
and urinary tract infections) and the reactivation of herpes viruses; myelosuppression; transaminase
elevations; and, rarely, gastrointestinal perforation. The Food and Drug Administration (FDA) review
of a large, randomized, safety clinical trial comparing tofacitinib to antitumor necrosis factor inhibitors
in people with rheumatoid arthritis found that tofacitinib was associated with additional serious adverse

events, including heart attack or stroke, cancer, blood clots, and death.8 The FDA is therefore requiring
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 are limited. The data to date have not revealed significant safety signals, including
thrombosis; however, these trials may be underpowered for detecting rare adverse events.5-7
A complete blood count with differential, liver function tests, and kidney function tests should be
obtained in all patients before baricitinib is administered and during treatment as clinically indicated.
Screening for viral hepatitis and tuberculosis should be considered. Considering its immunosuppressive
effects, all patients receiving baricitinib should also be monitored for new infections.
Tofacitinib is a cytochrome P 450 (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.
The ACTT-2 and COV-BARRIER trials evaluated oral baricitinib 4 mg once daily, which is twice the
standard baricitinib dose (2 mg once daily) for FDA-approved indications.5,6 In patients with severe
hepatic impairment, baricitinib should only be used if the potential benefit outweighs the potential risk.9
Baricitinib has not been evaluated in clinical studies for FDA-approved indications in patients with an
estimated glomerular filtration rate (eGFR) ≤30 mL/min. When baricitinib is used for the treatment of
COVID-19 in adults with renal insufficiency, the Panel recommends reducing the dose of baricitinib
from 4 mg to 2 mg daily for adults with an eGFR ≥30 to <60 mL/min and to 1 mg daily for those with
an eGFR of 15 to <30 mL/min. Baricitinib is not recommended for patients with an eGFR <15 mL/
min.9 There are limited clinical data on the use of baricitinib in combination with strong organic anion
transporter 3 inhibitors, and, in general, coadministration is not advised.10,11
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, and therefore fetal risk cannot be ruled out.12 Decisions
regarding the administration of JAK inhibitors must include shared decision-making between the
pregnant individual and their health care provider, considering potential maternal benefit and fetal
risks. Factors that may weigh into the decision-making process 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.13-15
An FDA Emergency Use Authorization (EUA) has been issued for the use of baricitinib in hospitalized
adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, mechanical
ventilation, or extracorporeal membrane oxygenation (ECMO).9 The safety and efficacy of baricitinib
have not been evaluated in pediatric patients with COVID-19. As noted above, tofacitinib was shown to
decrease the risk of respiratory failure and death in adults with COVID-19 in the STOP-COVID trial.7
Tofacitinib is FDA approved for a pediatric indication; however, the safety and efficacy of tofacitinib
have not been evaluated in pediatric patients with COVID-19. Thus, there is insufficient evidence
to recommend either for or against the use of baricitinib in combination with corticosteroids and/or
remdesivir for the treatment of COVID-19 in hospitalized children.
Baricitinib
Baricitinib is an oral JAK inhibitor that is selective for JAK1 and JAK2 and is FDA approved for the

treatment of rheumatoid arthritis.10 Baricitinib can modulate downstream inflammatory responses

via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-induced STAT3
phosphorylation.16 Baricitinib has postulated antiviral effects by blocking SARS-CoV-2 from entering
and infecting lung cells.17 Baricitinib reduced inflammation and lung pathology in macaques infected
with SARS-CoV-2, but an antiviral effect was not confirmed.18
In the ACTT-2 trial, 1,033 patients hospitalized with COVID-19 were randomized 1:1 to receive
baricitinib 4 mg daily for 14 days (or until hospital discharge) or placebo, both given in combination
with remdesivir. The primary endpoint was time to recovery as measured on an 8-category ordinal scale.
Recovery time was shorter in the baricitinib arm (7 days) than in the placebo arm (8 days) (rate ratio
for recovery 1.16; 95% CI, 1.01–1.32; P = 0.03). Mortality by 28 days was lower in the baricitinib arm
than in the placebo arm, but the difference was not statistically significant. A key limitation of the study
is that corticosteroids were not used as background standard care for patients with severe or critical
COVID-19 pneumonia.5
In the COV-BARRIER trial, 1,525 hospitalized patients with COVID-19 pneumonia and an elevation in
1 or more inflammatory markers were randomized 1:1 to receive baricitinib 4 mg orally or placebo for
up to 14 days (or until hospital discharge). Patients on mechanical ventilation were excluded from study
enrollment. Overall, 79% of patients received corticosteroids and 19% received remdesivir. The primary
endpoint was the proportion of patients who progressed to high-flow oxygen, noninvasive ventilation,
mechanical ventilation, or death by Day 28. Progression to the primary endpoint occurred among
27.8% of patients in the baricitinib arm versus 30.5% in the placebo arm (OR 0.85; 95% CI, 0.67–1.08;
P = 0.18). All-cause mortality within 28 days, which was a key secondary endpoint, was 8.1% in the
baricitinib arm and 13.1% in the placebo arm, resulting in a 38.2% reduction in mortality associated with
baricitinib (HR 0.57; 95% CI, 0.41–0.78). The mortality difference was most pronounced in the subgroup
of patients receiving high-flow oxygen or noninvasive ventilation at baseline (17.5% for baricitinib
recipients vs. 29.4% for placebo recipients; HR 0.52; 95% CI, 0.33–0.80). However, subgroup analyses
did not identify a statistically significant benefit of baricitinib versus placebo among patients receiving
low-flow oxygen at baseline. The occurrence of adverse events, serious adverse events, serious infections,
and venous thromboembolic events was comparable in the baricitinib and placebo arms.6
The COV-BARRIER trial added a critically ill cohort to the original study. In this cohort, participants on
mechanical ventilation or ECMO at baseline (n = 101) were randomly assigned to baricitinib 4 mg (n =
51) or placebo (n = 50) for up to 14 days in combination with the standard of care. At baseline, 86% of
participants were receiving corticosteroids and 2% were receiving remdesivir. Baricitinib significantly
reduced the prespecified endpoint of 28-day all-cause mortality when compared with placebo (39.2%
vs. 58.0%; HR 0.54; 95% CI, 0.31–0.96; P = 0.03). Significant reductions were also reported with
baricitinib versus placebo in 60-day mortality (45% vs. 62%; P = 0.027) and hospital days (23.7 vs. 26.1
days; P = 0.05). The implications of these findings are limited due to the very small sample size of this
addendum trial population.19
The collective data from these studies have informed the Panel’s recommendations on the use of
baricitinib in hospitalized patients with COVID-19. The specific recommendations and additional
information on the rationale can be found in 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.

Drug Availability
Baricitinib is approved by the FDA for the treatment of rheumatoid arthritis. On November 19, 2020,
the FDA issued an initial EUA for the use of baricitinib in combination with remdesivir for the treatment
of COVID-19 in certain hospitalized children and adults who require supplemental oxygen, mechanical
ventilation, or ECMO. The EUA was revised on July 28, 2021, to remove the requirement that
baricitinib be used only in combination with remdesivir for the treatment of COVID-19.9
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.20 Tofacitinib is also FDA approved for the treatment of psoriatic arthritis, juvenile
idiopathic arthritis, and ulcerative colitis.21
The double-blind STOP-COVID trial randomized 289 hospitalized patients with COVID-19 in Brazil
to receive tofacitinib 10 mg or placebo orally twice daily for up to 14 days (or until hospital discharge).
Patients who were on mechanical ventilation or who had an immunocompromising condition were
excluded from the trial. The background standard of care included corticosteroids (79.2% of patients
were receiving corticosteroids at randomization and overall, 89.3% received corticosteroids during the
study) but not remdesivir. The primary outcome of death or respiratory failure through Day 28 occurred
in 18.1% of patients in the tofacitinib arm and 29.0% in the placebo arm (risk ratio 0.63; 95% CI,
0.41–0.97). All-cause mortality within 28 days was 2.8% in the tofacitinib arm and 5.5% in the placebo
arm (risk ratio 0.49; 95% CI, 0.15–1.63). Serious adverse events occurred in 14.2% of the patients in the
tofacitinib arm and 12.0% in the placebo arm. Limitations of the trial include the small sample size.7
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.22 Like baricitinib, it can modulate
downstream inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent
inhibition of IL-6-induced STAT3 phosphorylation.16 Ruxolitinib also has postulated antiviral effects by
blocking SARS-CoV-2 from entering and infecting lung cells.17
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 as 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.23 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.
Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor and cytokine
receptor pathways.
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 Evaluation of the data to discern any clinical benefit is limited by the study’s small
sample size and lack of a control group.
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 were receiving the drug for a condition other than COVID-19.28 Evaluation of the
data for any clinical benefit is limited by the series’ small sample size and lack of a control group.
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 of 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. Use of BTK inhibitors
for the treatment of COVID-19 in pediatric patients is not recommended, except in a clinical trial.
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.
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: https://pubmed.ncbi.nlm.nih.gov/34480861/.
7. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N
8. 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 December 2, 2021.
9. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of
baricitinib. 2021. Available at: https://www.fda.gov/media/143823/download.
10. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at:

11. Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter-mediated drug-drug interactions for
baricitinib. Clin Transl Sci. 2017;10(6):509-519. Available at:
13. 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:
14. 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:
15. 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.
16. 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.
17. 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.
18. 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. 2020. Available at:
19. Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus standard of care for hospitalised adults with
COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: results of a
randomised, placebo-controlled trial. medRxiv. 2021;Preprint. Available at:
20. 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.
21. Tofacitinib (Xeljanz) [package insert]. Food and Drug Administration. 2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203214s024,208246s010lbl.pdf.
22. Ruxolitinib (JAKAFI) [package insert]. 2020. Available at:
https://www.jakafi.com/pdf/prescribing-information.pdf.
23. 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. Available at:
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:
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 December 2, 2021.

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 4f. 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, 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 the Panel’s recommendations on using the drugs listed in this table, please refer to the drug-specific sections of the Guidelines and
to Therapeutic Management of Nonhospitalized Adults With COVID-19, and Therapeutic Management of Hospitalized Adults With
COVID-19.
Dosing Regimen
The doses listed are for approved Monitoring Comments and Links to Clinical
Drug Name indications or from clinical trials Adverse Events Drug-Drug Interaction Potential
Parameters Trials
or clinical experience in patients
with COVID-19.
Colchicine
Colchicine Dose for COVID-19 in • Diarrhea • CBC • P-gp and CYP3A4 substrate •U se of colchicine should be
COLCORONA Trial: • Nausea • Renal • T he risk of myopathy may be avoided in patients with severe
• Colchicine 0.5 mg twice daily • Vomiting function increased with the concomitant use of renal insufficiency, and those
for 3 days and then once certain HMG-CoA reductase inhibitors with moderate renal insufficiency
• C
ramping • Hepatic who receive the drug should be
daily for 27 days1
function (e.g., atorvastatin, lovastatin,
• Abdominal pain simvastatin) due to potential monitored for AEs.
• Bloating competitive interactions mediated by • A list of clinical trials is available:
P-gp and CYP3A4 pathways. Colchicine
• Loss of appetite
• F atal colchicine toxicity has been Availability:
• Neuromyotoxicity
reported in individuals with renal
(rare) 2
• In the COLCORONA trial, 0.5
or hepatic impairment who used
• Blood dyscrasias mg colchicine tablets were used
colchicine in conjunction with
(rare) for dosing; in the United States,
P-gp inhibitors or strong CYP3A4
colchicine is available as 0.6 mg
inhibitors.
tablets.

Dosing Regimen
The doses listed are for approved Drug-Drug Interaction Comments and Links to
Drug Name indications or from clinical trials Adverse Events Monitoring Parameters
Potential Clinical Trials
with COVID-19.
Corticosteroids (Inhaled)
Budesonide Dose for COVID-19 in Clinical • Secondary infections • Signs of AEs involving •C
YP3A4 substrate •A
list of clinical trials
(Inhaled) Trials: • Oral thrush the oral mucosa or throat •D
o not use with strong is available: Inhaled
• Budesonide 800 mcg oral including thrush CYP3A4 inhibitors. Budesonide
• Systemic AEs (less
inhalation twice daily until common) • S
igns of systemic
symptom resolution or for up corticosteroid effects (e.g.,
to 14 days3,4 adrenal suppression)
Ciclesonide Dose for COVID-19 in Clinical • Secondary infections • Signs of AEs involving •C YP3A4 substrate • A list of clinical trials is
(Inhaled) Trials: •O
ral thrush the oral mucosa or throat • E ffect of strong CYP3A4 available: Ciclesonide
• Ciclesonide 160 mcg: 2 MDI • Systemic AEs (less including thrush inhibitors on ciclesonide
inhalations twice daily for 30 common) • Signs of systemic exposure is not expected
days5 corticosteroid effects (e.g., to be as significant as
adrenal suppression) that on budesonide.
Corticosteroid (Systemic)
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Dexamethasone Dose for COVID-19: • Hyperglycemia • Blood glucose •M oderate CYP3A4 • If DEX is not available, an
(Systemic) • DEX 6 mg IV or PO once • Secondary infections • BP inducer alternative corticosteroid
daily for up to 10 days or •C YP3A4 substrate (e.g., prednisone,
• Reactivation of latent • Signs and symptoms of methylprednisolone,
until hospital discharge, infections (e.g., HBV, new infection • Although
whichever comes first 6 hydrocortisone) can be
HSV, strongyloidiasis, • Cases of disseminated coadministration of used.
TB) strongyloidiasis have been RDV and DEX has not
been formally studied, • The approximate total
• Psychiatric reported in patients with daily dose equivalencies
disturbances COVID-19 during treatment a clinically significant for these glucocorticoids
with corticosteroids PK interaction is not
• Avascular necrosis predicted (Gilead, written to DEX 6 mg (PO or IV)
and tocilizumab. are:
• Adrenal insufficiency Prophylactic treatment for communication, August
• Increased BP strongyloidiasis (e.g., with 2020). • Prednisone 40 mg
• Peripheral edema IVM) should be considered • Methylprednisolone 32
for persons from areas mg
• Myopathy
where Strongyloides is • Hydrocortisone 160 mg
(particularly if used
endemic.7
with neuromuscular • A list of clinical trials is
blocking agents) available: Dexamethasone

Dosing Regimen
with COVID-19.
Fluvoxamine
Fluvoxamine Dose for COVID-19 in Clinical • Nausea • Hepatic function •C YP2D6 substrate • F luvoxamine may enhance
Trials: • Diarrhea • Drug interactions • F luvoxamine inhibits anticoagulant effects
• Various dosing regimens several CYP isoenzymes of antiplatelets and
• Dyspepsia • Monitor for withdrawal anticoagulants; consider
used, including: symptoms when tapering (CYP1A2, CYP2C9,
• Asthenia CYP3A4, CYP2C19, additional monitoring
• Fluvoxamine 50 mg twice dose when these drugs are
daily • I
nsomnia CYP2D6)
used concomitantly with
• Fluvoxamine 100 mg twice • Somnolence •C oadministration of fluvoxamine.
daily • Sweating tizanidine, thioridazine,
alosetron, or pimozide • T he use of MAOIs
• Fluvoxamine 100 mg 3 • Suicidal ideation concomitantly with
with fluvoxamine is
times daily (rare) fluvoxamine or within
contraindicated.
14 days of treatment
with fluvoxamine is
contraindicated.
•A list of clinical trials is
available: Fluvoxamine

Dosing Regimen
with COVID-19.
Anakinra FDA-Approved Dose for • Neutropenia • CBC with differential •U se with TNF- • Anakinra for IV
Rheumatoid Arthritis: (particularly when • Liver enzymes blocking agents is not administration is not an
• Anakinra 100 mg SQ once used concomitantly recommended due approved formulation in
with other agents • Renal function; reduce to increased risk of the United States.8
daily dose if CrCl <30 mL/min.
that can cause infection. • A list of clinical trials is
Dose for COVID-19 in Clinical neutropenia)
• Avoid concomitant available: Anakinra
Trials:
• Anaphylaxis and administration of live
• Dose and duration vary by angioedema vaccines.
study.
• Headache
• Has also been used as IV
• Nausea
infusion.
• Diarrhea
• Sinusitis
• Arthralgia
• Flu-like symptoms
• Abdominal pain
• Injection site
reactions
• Liver enzyme
elevations

Dosing Regimen
with COVID-19.
Interleukin-1 Inhibitors, continued
Canakinumab FDA-Approved Dose for • HSR • HSR •B inding of canakinumab • Canakinumab for IV
Systemic Juvenile Idiopathic • Neutropenia • CBC with differential to IL-1 may increase administration is not an
Arthritis: formation of CYP approved formulation in
• Nasopharyngitis • Liver enzymes enzymes and alter the United States.9
• Canakinumab 4 mg/kg
(maximum 300 mg) SQ • Diarrhea metabolism of drugs that • A list of clinical trials is
every 4 weeks9 • Respiratory tract are CYP substrates. available: Canakinumab
infections •U se with TNF-
Dose for COVID-19 in Clinical
• Bronchitis blocking agents is not
Trials:
recommended due to
• Dose and duration vary by • Gastroenteritis
potential increased risk
study. • Pharyngitis of infection.
CAN-COVID Trial: • Musculoskeletal pain • Avoid concomitant
• Single weight-based dose of • Vertigo administration of live
canakinumab in 250 mL of • Abdominal pain vaccines.
5% dextrose by IV infusion
• Injection site
over 2 hours:10
reactions
• 40 to <60 kg: 450 mg
• Liver enzyme
• 60–80 kg: 600 mg elevations
• >80 kg: 750 mg

Dosing Regimen
The doses listed are for approved Drug-Drug Interaction Comments and Links to Clinical
Drug Name indications or from clinical trials or Adverse Events Monitoring Parameters
Potential Trials
clinical experience in patients with
COVID-19.
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Sarilumab11 Dose for COVID-19 in Clinical • Neutropenia, • HSR • E levated IL-6 may • Treatment with sarilumab
Trials: thrombocytopenia • Infusion reactions downregulate CYP may mask signs of acute
• Single dose of sarilumab 400 • GI perforation enzymes; thus, use of inflammation or infection by
• Neutrophils sarilumab may lead to suppressing fever and CRP
mg IV 12
• HSR • Platelets increased metabolism levels.
• The only FDA-approved route • Increased liver of drugs that are CYP
of administration for sarilumab • L
iver enzymes • A list of clinical trials is
enzymes substrates. available: Sarilumab
is SQ. In the REMAP-CAP trial,
an SQ formulation of sarilumab • H
BV reactivation • T he effects of
Availability:
400 mg (in a prefilled syringe) • I
nfusion-related sarilumab on CYP
reaction enzymes may persist • Sarilumab for IV administration
was reconstituted in 100 mL
for weeks after the is not an approved formulation
0.9% NaCl and given as an IV
drug is stopped. in the United States.
infusion over 1 hour.
• In the REMAP-CAP trial, SQ
• Sarilumab infusion should
formulations of sarilumab
be used within 4 hours of
were reconstituted for IV
preparation; it can be stored
administration.13
at room temperature until
administered.13
Tocilizumab 14
EUA Dose for COVID-19 • Infusion-related • HSR • E levated IL-6 may • Tocilizumab use should
For Hospitalized Patients Aged ≥2 reaction • Infusion reactions downregulate CYP be avoided in patients
Years Based on Body Weight: • HSR enzymes; use of who are significantly
• Neutrophils tocilizumab may immunocompromised. The
• <30 kg: Tocilizumab 12 mg/kg • GI perforation • Platelets lead to increased safety of using tocilizumab
administered by IV infusion over • Hepatotoxicity metabolism of plus a corticosteroid in
1 hour • Liver enzymes
• Treatment-related • Cases of disseminated drugs that are CYP immunocompromised patients
• ≥30 kg: Tocilizumab 8 mg/ changes on substrates. is unknown.
kg (maximum dose 800 mg) strongyloidiasis have
laboratory tests been reported in • T he effects of • The SQ formulation of
administered by IV infusion over for neutrophils, tocilizumab on CYP tocilizumab is not intended for
1 hour patients with COVID-19
platelets, lipids, during treatment enzymes may persist IV administration.
and liver enzymes with tocilizumab and for weeks after the • A list of clinical trials is
• HBV reactivation corticosteroids. drug is stopped. available: Tocilizumab

Dosing Regimen
Potential Trials
COVID-19.
Interleukin-6 Inhibitors, continued
Anti-Interleukin-6 Receptor Monoclonal Antibodies, continued
Tocilizumab14, • Per the EUA, if clinical signs • Secondary rophylactic treatment
P Availability:
continued or symptoms worsen or do infections for strongyloidiasis • IV tocilizumab, which has been
not improve following the first (e.g., with IVM) should approved for non-COVID-19
infusion, 1 additional dose of be considered for indications, is available
tocilizumab may be administered persons from areas commercially and through an
at least 8 hours after the first where Strongyloides is FDA EUA for the treatment of
dose. endemic.7 COVID-19 in hospitalized adults
and pediatric patients aged
≥2 years who are receiving
systemic corticosteroids
and require supplemental
oxygen, NIV, MV, or ECMO.
The EUA does not authorize
the use of tocilizumab for
SQ administration for the
treatment of COVID-19.15
Anti-Interleukin-6 Monoclonal Antibody
Siltuximab FDA-Approved Dose for • Infusion-related • Neutrophils • E levated IL-6 may • Treatment with siltuximab
Multicentric Castleman Disease: reaction • HSR downregulate CYP may mask signs of acute
• Siltuximab 11 mg/kg • HSR enzymes; use of inflammation or infection by
• Infusion reactions siltuximab may lead to suppressing fever and CRP
administered over 1 hour by IV • GI perforation
infusion every 3 weeks16 increased metabolism levels.
• Neutropenia of drugs that are CYP • A list of clinical trials is
Dose for COVID-19: • HTN substrates. available: Siltuximab
• Dose and duration unknown • Dizziness • T he effects of
siltuximab on CYP
• Rash
enzymes may persist
• Pruritus for weeks after therapy
• Hyperuricemia is stopped.

Dosing Regimen
Potential Trials
COVID-19.
Kinase Inhibitors
Janus Kinase Inhibitors
Baricitinib and Tofacitinib: Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Ruxolitinib: Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Baricitinib17 EUA Dose for COVID-1918 • Lymphoma • CBC with differential •D ose modification • Baricitinib for the treatment of
For Adults and Children Aged ≥9 and other • Renal function is recommended COVID-19 is available through
Years Based on eGFR: malignancies when administering an FDA EUA. See the EUA for
• Liver enzymes concurrently with a dosing guidance for patients
• ≥60 mL/min/1.73 m2: Baricitinib 4 • Thrombosis • New infections strong OAT3 inhibitor. with:
mg PO once daily • GI perforation
• Avoid concomitant • ALC <200 cells/µL
• 30 to <60 mL/min/1.73 m2: • Treatment- administration of live
Baricitinib 2 mg PO once daily related changes • ANC <500 cells/µL
vaccines.
• 15 to <30 mL/min/1.73 m2: in lymphocytes, • If increases in ALT or AST
Baricitinib 1 mg PO once daily neutrophils, Hgb, are observed and DILI is
liver enzymes suspected, interrupt baricitinib
• eGFR <15 mL/min/1.73 m2: Not treatment until the diagnosis of
recommended • HSV reactivation
DILI is excluded.
• Herpes zoster
For Children Aged 2 to <9 Years • A list of clinical trials is
Based on eGFR: • Serious cardiac- available: Baricitinib
related events
• ≥60 mL/min/1.73 m2: Baricitinib 2 Availability:
(e.g., MI, stroke)
mg PO once daily
• Baricitinib, which has been
• 30 to <60 mL/min/1.73 m2: approved for non-COVID-19
Baricitinib 1 mg PO once daily indications, is available
• <30 mL/min/1.73 m2: Not commercially and through
recommended an EUA for the treatment of
Duration of Therapy: hospitalized patients with
COVID-19 aged ≥2 years.18
• For up to 14 days or until hospital
discharge

Dosing Regimen
COVID-19.
Kinase Inhibitors, continued
Janus Kinase Inhibitors, continued
Ruxolitinib Dose for FDA-Approved • Thrombocytopenia • CBC with differential •D ose modification • Dose modification may
Indications: • Anemia • Liver enzymes required when be required in patients
• Ruxolitinib 5 mg–20 mg PO twice administered with with hepatic impairment,
• Neutropenia • New infections strong CYP3A4 moderate or severe
daily
• Liver enzyme elevations inhibitor. renal impairment, or
Dose for COVID-19 in Clinical thrombocytopenia.
Trials: • Risk of infection • Avoid use with
• Dizziness fluconazole doses • A list of clinical trials is
• Ruxolitinib 5 mg–20 mg PO twice >200 mg. available: Ruxolitinib
daily for 14 days19 • Headache
• Diarrhea
• CPK elevation
• Herpes zoster
Tofacitinib Dose for COVID-19 in Clinical • Thrombotic events • CBC with differential •D ose modifications • Avoid use in patients with
Trial: (e.g., PE, DVT, arterial • Liver enzymes required when ALC <500 cells/mm3, ANC
• Tofacitinib 10 mg PO twice daily thrombosis) administered with <1,000 cells/mm3, or Hgb
• New infections strong CYP3A4 <9 grams/dL.
for up to 14 days or until hospital • Anemia
discharge20 inhibitors or when • Dose modification may be
• Risk of infection used with a moderate required in patients with
• GI perforation CYP3A4 inhibitor that moderate or severe renal
• Diarrhea is coadministered with impairment or moderate
a strong CYP2C19 hepatic impairment.
• Headache
inhibitor.
• Herpes zoster • A list of clinical trials is
• Coadministration available: Tofacitinib
• Lipid elevations with strong CYP3A4
• Liver enzyme elevations inducers is not
• Lymphoma and other recommended.
malignancies • Avoid concomitant
• Serious cardiac-related administration of live
events (e.g., MI, stroke) vaccines.

Dosing Regimen
COVID-19.
Non-SARS-CoV-2 Specific Immunoglobulin
Primarily used for the treatment of multi-system inflammatory syndrome in children (MIS-C). Currently under investigation in clinical trials.
Non-SARS- • Dose varies based on indication • Allergic reactions, including • Transfusion-related • IVIG may interfere • A list of clinical trials is
CoV-2 Specific and formulation. anaphylaxis reactions with immune available: Intravenous
Immunoglobulin • Renal failure • Vital signs at baseline response to certain Immunoglobulin
and during and after vaccines.
• Thrombotic events
infusion
• Aseptic meningitis
syndrome • Renal function;
discontinue treatment
• Hemolysis if function deteriorates.
• TRALI
• Transmission of infectious
pathogens
• AEs may vary by
formulation.
• AEs may be increased with
high dose, 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; Hgb = hemoglobin; HSR =
hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IL = interleukin; IV = intravenous; IVIG = intravenous immunoglobulin; IVM = ivermectin;
MAOI = monoamine oxidase inhibitor; MDI = metered dose inhaler; MI= myocardial infarction; MV = mechanical ventilation; NaCl = sodium chloride; NIV =
noninvasive ventilation; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; PE = pulmonary embolism; P-gp= P-glycoprotein; PK
= pharmacokinetic; PO = orally; RDV = remdesivir; SQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung injury
References
1. 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:

2. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at:
3. 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.
4. 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 Sep 4;398(10303):843-855. Available at:
5. 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;Published online ahead of print. Available at:
6. 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 February 9, 2021.
7. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA.
8. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at:
9. Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at:
10. 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. 2021;326(3):230-239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34283183.
11. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at:
12. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial of KEVZARA® (sarilumab) in hospitalized COVID-19 patients [press
release]. 2020.
13. 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:
14. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2019. Available at:
15. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for actemra (tocilizumab). 2021. Available at:
16. Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at:

17. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at:
18. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2021. Available at:
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
20. 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.

Antithrombotic Therapy in Patients with COVID-19

Laboratory Testing
• In nonhospitalized patients with COVID-19, there are currently no data to support the measurement of coagulation
markers (e.g., D-dimers, prothrombin time, platelet count, fibrinogen) (AIII).
• In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured, although
there is currently insufficient evidence to recommend either for or against using this data to guide management
decisions.
Chronic Anticoagulant and Antiplatelet Therapy
• Patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions should continue these
medications if they receive a diagnosis of COVID-19 (AIII).
Venous Thromboembolism Prophylaxis and Screening
• For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the
prevention of venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the
therapy or is participating in a clinical trial (AIII).
• Hospitalized nonpregnant adults with COVID-19 should receive prophylactic dose anticoagulation (AIII) (see the
recommendations for pregnant individuals below). Anticoagulant or antiplatelet therapy should not be used to prevent
arterial thrombosis outside of the usual standard of care for patients without COVID-19 (AIII).
• There is currently insufficient evidence to recommend either for or against the use of thrombolytics or higher than the
prophylactic dose of anticoagulation for VTE prophylaxis in hospitalized COVID-19 patients outside of a clinical trial.
• Hospitalized patients with COVID-19 should not routinely be discharged from the hospital while on VTE prophylaxis
(AIII). Continuing anticoagulation with a Food and Drug Administration-approved regimen for extended VTE
prophylaxis after hospital discharge can be considered for patients who are at low risk for bleeding and high risk for
VTE, as per the protocols for patients without COVID-19 (see details on defining at-risk patients below) (BI).
• There is currently insufficient evidence to recommend either for or against routine deep vein thrombosis screening in
COVID-19 patients without signs or symptoms of VTE, regardless of the status of their coagulation markers.
• For hospitalized COVID-19 patients who experience rapid deterioration of pulmonary, cardiac, or neurological
function, or of sudden, localized loss of peripheral perfusion, the possibility of thromboembolic disease should be
evaluated (AIII).
Hospitalized Children With COVID-19
• For hospitalized children with COVID-19, indications for VTE prophylaxis should be the same as those for children
without COVID-19 (BIII).
Treatment
• When diagnostic imaging is not possible, patients with COVID-19 who experience an incident thromboembolic
event or who are highly suspected to have thromboembolic disease should be managed with therapeutic doses of
anticoagulant therapy (AIII).
• Patients with COVID-19 who require extracorporeal membrane oxygenation or continuous renal replacement therapy
or who have thrombosis of catheters or extracorporeal filters should be treated with antithrombotic therapy as per the
standard institutional protocols for those without COVID-19 (AIII).
Special Considerations During Pregnancy and Lactation
• If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this therapy should be
continued (AIII).
• For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is recommended unless
contraindicated (see below) (BIII).

• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for pregnant patients
(AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be
individualized, considering concomitant VTE risk factors.
• Anticoagulation therapy use 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 that require
anticoagulation in pregnancy (AIII).
• Unfractionated heparin, low molecular weight heparin, 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
with or without COVID-19 who require VTE prophylaxis or treatment (AIII). In contrast, use of direct-acting oral
anticoagulants during pregnancy is not routinely recommended due to lack of safety data (AIII).
Association Between COVID-19 and Thromboembolism

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the
resulting syndrome, COVID-19, have been associated with inflammation and a prothrombotic state, with
increases in fibrin, fibrin degradation products, fibrinogen, and D-dimers.1,2 In some studies, elevations
in these markers have been associated with worse clinical outcomes.3,4
A number of studies have reported varying incidences of venous thromboembolism (VTE) in patients
with COVID-19. A meta-analysis of studies in hospitalized patients with COVID-19 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 COVID-19 pandemic, the incidence of VTE
in non-COVID-19 hospitalized patients 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 non-COVID-19 patients who received prophylactic dose 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 VTE guidelines for non-COVID-19 patients 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.13 Although the incidence of thromboembolic
events, especially pulmonary emboli, can be high among hospitalized patients with COVID-19, there
are no published data demonstrating the clinical utility of routine surveillance for deep vein thrombosis
using lower extremity ultrasound in this population.
A meta-analysis performed by an American Society of Hematology guidelines panel compared the
odds of bleeding and thrombotic outcomes in patients with COVID-19 treated with prophylactic dose
anticoagulation versus in those treated with intermediate or therapeutic dose anticoagulation.14 Overall,
the odds of VTE and mortality were not different between the patients treated with prophylactic
dose anticoagulation and those treated with higher doses of anticoagulation. In critically ill patients,
intermediate or therapeutic dose anticoagulation was associated with a lower odds of pulmonary
embolism (OR 0.09; 95% CI, 0.02–0.57) but a higher odds of major bleeding (OR 3.84; 95% CI, 1.44–
10.21). In studies in patients with COVID-19, incidences of symptomatic VTE between 0% to 0.6%
at 30 to 42 days after hospital discharge have been reported.15-17 Epidemiologic studies that control for
clinical characteristics, underlying comorbidities, prophylactic anticoagulation, and COVID-19-related
therapies are needed.
There are limited prospective data demonstrating the safety and efficacy of using therapeutic doses
of anticoagulants to prevent VTE in patients with COVID-19. A retrospective analysis of 2,773

hospitalized COVID-19 patients from a single center in the United States reported in-hospital mortality
in 22.5% of patients who received therapeutic anticoagulation and 22.8% of patients who did not
receive anticoagulation. The study further reported that in a subset of 395 mechanically ventilated
patients, 29.1% of the patients who received anticoagulation and 62.7% of those who did not receive
anticoagulation died. The study had important limitations: it lacked details on patient characteristics,
indications for anticoagulant initiation, and descriptions of other therapies that the patients received
that may have influenced mortality. In addition, the authors did not discuss the potential impact of
survival bias on the study results. For these reasons, the data are not sufficient to influence standard
of care, and this study further emphasizes the need for prospective trials to define the risks and
potential benefits of therapeutic anticoagulation in patients with COVID-19.18 Three international
trials (Antithrombotic Therapy to Ameliorate Complications of COVID-19 [ATTACC], Therapeutic
Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 [ACTIV-4], and the
Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia
[REMAP-CAP]) compared the effectiveness of therapeutic dose anticoagulation and prophylactic
dose anticoagulation in reducing the need for organ support over 21 days in moderately ill or critically
ill adults hospitalized for COVID-19. The need for organ support was defined as requiring high-flow
nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or extracorporeal
membrane oxygenation (ECMO). The trials paused enrollment of patients requiring intensive care unit
(ICU)-level care after an interim pooled analysis demonstrated futility of therapeutic anticoagulation
in improving organ support, and a concern for safety. The results of the interim analysis are available
on the ATTACC website. Unblinded data and additional study outcomes, including the occurrence of
thrombosis, are expected to be reported soon.19
A small, single-center randomized trial (n = 20) compared therapeutic and prophylactic anticoagulation
in mechanically ventilated patients with D-dimers >1,000 µg/L (as measured by the VIDAS D-dimer
Exclusion II assay). Only the patients treated with therapeutic anticoagulation showed improvement
in the ratio of arterial oxygen partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2).
The number of ventilator-free days was higher in the therapeutic anticoagulation arm than in the
prophylactic anticoagulation arm (15 days [IQR 6–16] vs. 0 days [IQR 0–11]; P = 0.028). There was
no difference between the arms in in-hospital or 28-day mortality. Two patients treated with therapeutic
anticoagulation had minor bleeding, and two patients in each arm experienced thrombosis.20 Additional
evidence from large, multicenter trials is needed, and the trial results are expected soon.
Several randomized controlled trials have been developed to evaluate the risks and benefits of
anticoagulation in patients with COVID-19 (visit ClinicalTrials.gov for the current list of trials).
Guidelines about coagulopathy and prevention and management of VTE in patients with COVID-19
have been released by multiple organizations, including the Anticoagulation Forum,21 the American
College of Chest Physicians,22 the American Society of Hematology,23 the International Society of
Thrombosis and Haemostasis (ISTH),24 the Italian Society on Thrombosis and Haemostasis,25 and the
Royal College of Physicians.26 In addition, a paper that outlines issues related to thrombotic disease with
implications for prevention and therapy has been endorsed by the ISTH, the North American Thrombosis
Forum, the European Society of Vascular Medicine, and the International Union of Angiology.27
All of the guidelines referenced above agree that hospitalized patients with COVID-19 should receive
prophylactic dose anticoagulation for VTE. Some guidelines note that intermediate dose anticoagulation
can be considered for critically ill patients.21,23,26,28 Given the variation in VTE incidence and the
unknown risk of bleeding in critically ill patients with COVID-19, the COVID-19 Treatment Guidelines
Panel and guideline panels of the American Society of Hematology and the American College of Chest
Physician recommend treating all hospitalized patients with COVID-19, including critically ill patients,
with prophylactic dose anticoagulation.22,29 Results from clinical trials that assess the safety and efficacy

of different anticoagulant doses will provide further information on the best prophylactic strategies for
patients with COVID-19.
Monitoring Coagulation Markers in Patients With COVID-19

In nonhospitalized patients with COVID-19, markers of coagulopathy, such as D-dimer level,
prothrombin time, fibrinogen level, and platelet count, should not routinely be obtained (AIII). Although
abnormalities in these coagulation markers have been associated with worse outcomes, prospective data
demonstrating that the markers can be used to predict the risk of VTE in those who are asymptomatic or
who have mild SARS-CoV-2 infection is lacking.
In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly
measured; however, there is currently insufficient evidence to recommend either for or against using
such data to guide management decisions.
Managing Antithrombotic Therapy in Patients With COVID-19

Selection of Anticoagulant or Antiplatelet Drugs for Patients With COVID-19
Whenever anticoagulant or antiplatelet therapy is used, potential drug-drug interactions with other
concomitant drugs must be considered (AIII). The University of Liverpool has collated a list of drug
interactions. In hospitalized, critically ill patients, low molecular weight heparin or unfractionated
heparin is preferred over oral anticoagulants because the two types of heparin have shorter half-lives,
can be administered intravenously or subcutaneously, and have fewer drug-drug interactions (AIII).
Chronic Anticoagulant or Antiplatelet Therapy

COVID-19 outpatients receiving warfarin who are in isolation and thus unable to have international
normalized ratio monitoring may be candidates for switching to direct oral anticoagulant therapy.
Patients receiving warfarin who have a mechanical heart valve, ventricular assist device, valvular atrial
fibrillation, or antiphospholipid antibody syndrome or who are lactating should continue treatment with
warfarin (AIII). Hospitalized patients with COVID-19 who are taking anticoagulant or antiplatelet
therapy for underlying medical conditions should continue this treatment unless significant bleeding
develops, or other contraindications are present (AIII).
Patients with COVID-19 Who Are Managed as Outpatients

For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be
initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the
therapy or is participating in a clinical trial (AIII).
Hospitalized Patients With COVID-19

For hospitalized patients with COVID-19, prophylactic dose anticoagulation should be prescribed unless
contraindicated (e.g., a patient has active hemorrhage or severe thrombocytopenia) (AIII). Although
data supporting this recommendation are limited, a retrospective study showed reduced mortality in
patients who received prophylactic anticoagulation, particularly if the patient had a sepsis-induced
coagulopathy score ≥4.4 For those without COVID-19, anticoagulant or antiplatelet therapy should not
be used to prevent arterial thrombosis outside of the standard of care (AIII). Anticoagulation is routinely
used to prevent arterial thromboembolism in patients with heart arrhythmias. Although there are reports
of strokes and myocardial infarction in patients with COVID-19, the incidence of these events is
unknown.

When imaging is not possible, patients with COVID-19 who experience an incident thromboembolic
event or who are highly suspected to have thromboembolic disease should be managed with therapeutic
doses of anticoagulant therapy as per the standard of care for patients without COVID-19 (AIII).
There is currently insufficient evidence to recommend either for or against the use of thrombolytic
agents or higher than the prophylactic dose of anticoagulation for VTE prophylaxis for hospitalized
patients with COVID-19 outside of a clinical trial. Three international trials (ACTIV-4, REMAP-CAP,
and ATTACC) compared the effectiveness of therapeutic dose anticoagulation and prophylactic dose
anticoagulation in reducing the need for organ support over 21 days in moderately ill or critically ill
adults hospitalized for COVID-19. The need for organ support was defined as requiring high-flow nasal
oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO. The trials
paused enrollment of patients requiring ICU-level care at enrollment after an interim pooled analysis
demonstrated futility of therapeutic anticoagulation in reducing the need for organ support and a concern
for safety. The results of the interim analysis are available on the ATTACC website. Unblinded data and
additional study outcomes, including the occurrence of thrombosis, are expected to be reported soon.19
Although there is evidence that multi-organ failure is more likely in patients with sepsis who develop
coagulopathy,30 there is no convincing evidence to show that any specific antithrombotic treatment
will influence outcomes in those with or without COVID-19. Participation in randomized trials is
encouraged.
Patients with COVID-19 who require ECMO or continuous renal replacement therapy or who have
thrombosis of catheters or extracorporeal filters should be treated as per the standard institutional
protocols for those without COVID-19 (AIII).
Hospitalized Children With COVID-19

A recent meta-analysis of publications on COVID-19 in children did not discuss VTE.31 Indications for
VTE prophylaxis in hospitalized children with COVID-19 should be the same as those for hospitalized
children without COVID-19 (BIII).
Patients With COVID-19 Who Are Discharged from the Hospital

VTE prophylaxis after hospital discharge is not recommended for patients with COVID-19 (AIII). For
certain 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.32,33 Inclusion criteria for the trials that studied post-discharge VTE prophylaxis
included:
• Modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE)
VTE risk score ≥4; or
• Modified IMPROVE VTE risk score ≥2 and D-dimer level >2 times the upper limit of normal.32
Any decision to use post-discharge VTE prophylaxis for patients with COVID-19 should include
consideration of the individual patient’s risk factors for VTE, including reduced mobility, 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.34 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.35-37 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 women hospitalized with COVID-19, particularly for those who have severe
disease.38 If there are no contraindications to use, the Society of Maternal Fetal Medicine recommends
prophylactic heparin or low molecular weight heparin in critically ill or mechanically ventilated
pregnant patients.39 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.40,41 If delivery is threatened, or if there are other risks for bleeding, the risk of bleeding may
outweigh the potential benefit of VTE prophylaxis in pregnancy.
There are no data on the use of scoring systems to predict VTE risk in pregnant individuals.
Additionally, during pregnancy, the D-dimer level may not be a reliable predictor of VTE because there
is a physiologic increase of D-dimer levels throughout gestation.42-44
In general, the preferred anticoagulants during pregnancy are heparin compounds. Because of its
reliability and ease of administration, low-molecular weight heparin is recommended, rather than
unfractionated heparin, for the prevention and treatment of VTE in pregnancy.41
Direct-acting anticoagulants are not routinely used during pregnancy due to the lack of safety data
in pregnant individuals.40 The use of warfarin to prevent or treat VTE should be avoided in pregnant
individuals, regardless of their COVID-19 status, and especially during the first trimester due to the
concern for teratogenicity.
Specific recommendations for pregnant or lactating individuals with COVID-19 include:
• If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this
therapy should be continued (AIII).
• For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is
recommended unless contraindicated (BIII).
• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for
pregnant patients (AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum
patient should be individualized, considering concomitant VTE risk factors.
• Anticoagulation therapy use 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 that require anticoagulation in pregnancy (AIII).
• Unfractionated heparin, low molecular weight heparin, 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 women with or without COVID-19 who require VTE prophylaxis or treatment
(AIII). In contrast, use of direct-acting oral anticoagulants during pregnancy is not routinely
recommended due to lack of safety data (AIII).40
References
1. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
Clin Chem Lab Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32172226.
2. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers,
and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol. 2020.

4. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality
in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.
5. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a
systematic review and meta-analysis. Res Pract Thromb Haemost. 2020. Available at:
6. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of
venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ.
7. Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the
prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874-879.
8. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of
venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin
Study Group. N Engl J Med. 1999;341(11):793-800. Available at:
9. Fraisse F, Holzapfel L, Couland JM, et al. Nadroparin in the prevention of deep vein thrombosis in acute
decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of
France. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1109-1114. Available at:
10. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand
Intensive Care Society Clinical Trials Group, et al. Dalteparin versus unfractionated heparin in critically ill
patients. N Engl J Med. 2011;364(14):1305-1314. Available at:
11. Shorr AF, Williams MD. Venous thromboembolism in critically ill patients. Observations from a randomized
trial in sepsis. Thromb Haemost. 2009;101(1):139-144. Available at:
12. Kaplan D, Casper TC, Elliott CG, et al. VTE incidence and risk factors in patients with severe sepsis and
septic shock. Chest. 2015;148(5):1224-1230. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26111103.
13. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and
prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice
guidelines. Chest. 2012;141(2 Suppl):e195S-e226S. Available at:
14. American Society of Hematology. Should DOACs, LMWH, UFH, Fondaparinux, Argatroban, or Bivalirudin
at intermediate-intensity or therapeutic-intensity vs. prophylactic intensity be used for patients with
COVID-19 related critical illness who do not have suspected or confirmed VTE? 2020. Available at:
https://guidelines.ash.gradepro.org/profile/3CQ7J0SWt58. Accessed December 7, 2020.
15. Roberts LN, Whyte MB, Georgiou L, et al. Postdischarge venous thromboembolism following hospital
admission with COVID-19. Blood. 2020;136(11):1347-1350. Available at:
16. Engelen MM, Vanassche T, Balthazar T, et al. Incidence of venous thromboembolism in patients discharged
after COVID-19 Hostpialization [abstract]. Res Pract Thromb Haemost. 2020;4 (Suppl 1). Available at:
https://abstracts.isth.org/abstract/incidence-of-venous-thromboembolism-in-patients-discharged-after-covid-
19-hospitalisation/.
17. Patell R, Bogue T, Koshy A, et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19.
Blood. 2020;136(11):1342-1346. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32766883.

18. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in-hospital survival
among hospitalized patients with COVID-19. Journal of the American College of Cardiology. 2020;In press.
Available at: https://www.sciencedirect.com/science/article/pii/S0735109720352189?via%3Dihub.
19. NIH ACTIV Trial of blood thinners pauses enrollment of critically ill COVID-19 patients [press release].
2020. Available at: https://www.nih.gov/news-events/news-releases/nih-activ-trial-blood-thinners-pauses-
enrollment-critically-ill-covid-19-patients. Accessed February 8, 2021.
20. Lemos ACB, do Espirito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for
severe COVID-19: a randomized Phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359-366.
21. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19
pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-
22. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with
coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163. Available
23. American Society of Hematology. ASH guidelines on use of anticoagulation in patients with COVID-19.
2020. Available at: https://www.hematology.org/education/clinicians/guidelines-and-quality-care/
clinical-practice-guidelines/venous-thromboembolism-guidelines/ash-guidelines-on-use-of-anticoagulation-in-
patients-with-covid-19. Accessed November 13, 2020.
24. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in
COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. Available at:
25. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on
Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-169. Available at:
26. Royal College of Physicians. Clinical guide for the prevention, detection and management of thromboembolic
disease in patients with COVID-19. 2020. Available at: https://icmanaesthesiacovid-19.org/clinical-guide-
prevention-detection-and-management-of-vte-in-patients-with-covid-19. Accessed November 13, 2020.
27. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease:
Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020. Available at:
28. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical
guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with
COVID-19. J Thromb Haemost. 2020;18(8):1859-1865. Available at:
29. American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. 2020.
Available at: https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. Accessed February 8,
2021.
30. Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC)
following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open.
31. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than
adults. Acta Paediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32202343.
32. Spyropoulos AC, Lipardi C, Xu J, et al. Modified IMPROVE VTE risk score and elevated D-dimer identify
a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH
Open. 2020;4(1):e59-e65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32190813.
33. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill

medical patients. N Engl J Med. 2016;375(6):534-544. Available at:

34. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Trends in the incidence of
venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med.
35. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. Coronavirus disease 2019 infection among asymptomatic
and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York
City hospitals. Am J Obstet Gynecol MFM. 2020;2(2):100118. Available at:
36. Knight M, Bunch K, Vousden N, et al. Characteristics and outcomes of pregnant women admitted to hospital
with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107.
37. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized
pregnant women with laboratory-confirmed COVID-19 - COVID-NET, 13 states, March 1–August 22, 2020.
gyns-obstetrics. Accessed February 8, 2021.
39. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19.
2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_
COVID_pos_preg_patients_4-30-20_final.pdf. Accessed February 8, 2021.
40. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for
management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv.
41. ACOG practice bulletin no. 196 summary: thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):243-
42. Wang M, Lu S, Li S, Shen F. Reference intervals of D-dimer during the pregnancy and puerperium period on
the STA-R evolution coagulation analyzer. Clin Chim Acta. 2013;425:176-180. Available at:
43. Reger B, Peterfalvi A, Litter I, et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant
women. Thromb Res. 2013;131(4):e183-187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23481480.
44. Hu W, Wang Y, Li J, et al. The predictive value of D-dimer test for venous thromboembolism during
puerperium: a prospective cohort study. Clin Appl Thromb Hemost. 2020;26:1076029620901786. 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
randomized clinical trial. JAMA. 2019;322(13):1261-1270. Available at:
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 L, Blood Institute PCTN, 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 at:
9. Institue 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
print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33247380.
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
Respir Med. 2021;9(3):275-284. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33422263.
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
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.

COVID-19 and Special Populations

Key Considerations
There is current guidance from the Centers for Disease Control and Prevention (CDC), the American College of
Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM) on the management of
pregnant patients with COVID-19.1-4 This section of the COVID-19 Treatment Guidelines complements that guidance.
Below are key considerations regarding the management of COVID-19 in pregnancy.
• Pregnant women should be counseled about the potential for severe disease from SARS-CoV-2 infection and the
recommended measures to take to protect themselves and their families from infection.
• If hospitalization for COVID-19 is indicated in a pregnant woman, care should be provided in a facility that can
conduct maternal and fetal monitoring, when appropriate.
• Management of COVID-19 in the pregnant patient should include:
• Fetal and uterine contraction monitoring, when appropriate, based on gestational age
• Individualized delivery planning
• A multispecialty, team-based approach that may include consultation with obstetric, maternal-fetal medicine,
infectious disease, pulmonary and critical care, and pediatric specialists, as appropriate
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that potentially effective treatment for COVID-19
should not be withheld from pregnant women because of theoretical concerns related to the safety of therapeutic
agents in pregnancy (AIII).
• Decisions regarding the use of drugs approved for other indications or investigational drugs for the treatment of
COVID-19 in pregnant patients must be made with shared decision-making between the patient and the clinical
team, considering the safety of the medication for the pregnant woman and the fetus and the severity of maternal
disease. For detailed guidance on the use of COVID-19 therapeutic agents in pregnancy, please refer to the pregnancy
considerations subsection of each individual section of the Guidelines.

To date, most of the data generated about the epidemiology, clinical course, prevention, and treatment of
COVID-19 have come from studies of nonpregnant adults. More information is urgently needed
regarding COVID-19 in other patient populations, such as in children, pregnant individuals, and other
populations as outlined in the following sections of the Guidelines.
Although children with COVID-19 may have less severe disease overall than adults with COVID-19,
the recently described multisystem inflammatory syndrome in children (MIS-C) requires further study.
Data are also emerging on the clinical course of COVID-19 in pregnant patients, pregnancy outcomes in
the setting of COVID-19, and vertical transmission of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). There are special considerations for transplant recipients, patients with cancer, persons
with HIV, and patients with other immunocompromising conditions, as some of these patients may be at
increased risk of serious complications as a result of COVID-19.
The following sections review the available data on COVID-19 in some of these populations and discuss
the specific considerations that clinicians should take into account for the prevention and treatment of
SARS-CoV-2 infections in these populations.

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
• 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.

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-CoV2
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
• 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
1. 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,
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
Mortal Wkly Rep. 2020;69(44):1635-1640. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33151917.
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

Wkly Rep. 2020;69(25):769-775. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32584795.

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.
2021;175(2):157-167. Available at: https://pubmed.ncbi.nlm.nih.gov/33044493/.
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:

Special Considerations in Children

• SARS-CoV-2 infection is generally milder in children than in adults, and a substantial proportion of children with the
disease have asymptomatic infection.
• Most children with SARS-CoV-2 infection will not require any specific therapy.
• Children who have a history of medical complexity (e.g., due to neurologic impairment, developmental
delays, or genetic syndromes including trisomy 21), obesity, chronic cardiopulmonary disease, or who are
immunocompromised, as well as nonwhite children and older teenagers may be at increased risk for severe disease.
• There are limited data on the pathogenesis and clinical spectrum of COVID-19 disease in children. There are no
pediatric data from placebo-controlled randomized clinical trials and limited data from observational studies to inform
the development of pediatric-specific recommendations for the treatment of COVID-19.
Specific Therapy for Children
• In the absence of adequate data on the treatment of children with acute COVID-19, recommendations are based on
outcome and safety data for adult patients and the child’s risk of disease progression.
• Most children with mild or moderate disease can be managed with supportive care alone (AIII).
• Remdesivir is recommended for:
• Hospitalized children aged ≥12 years with COVID-19 who have risk factors for severe disease and have an
emergent or increasing need for supplemental oxygen (BIII).
• Hospitalized children aged ≥16 years with COVID-19 who have an emergent or increasing need for supplemental
oxygen regardless of whether they have risks factors for severe disease (BIII).
• In consultation with a pediatric infectious disease specialist, remdesivir can be considered for hospitalized children of
all ages with COVID-19 who have an emergent or increasing need for supplemental oxygen (CIII).
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using dexamethasone for hospitalized
children with COVID-19 who require high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or
extracorporeal membrane oxygenation (BIII).
• There is insufficient evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2
monoclonal antibody products for children with COVID-19 who are not hospitalized but who have risk factors for
severe disease. Based on adult studies, bamlanivimab plus etesevimab or casirivimab plus imdevimab may be
considered on a case-by-case basis for nonhospitalized children who meet Emergency Use Authorization (EUA)
criteria for high-risk of severe disease, especially those who meet more than one criterion or are aged ≥16 years. The
Panel recommends consulting a pediatric infectious disease specialist in such cases.
• The Panel recommends against the use of convalescent plasma for hospitalized children with COVID-19 who
do not require mechanical ventilation, except in a clinical trial (AIII). The Panel recommends against the use of
convalescent plasma for pediatric patients with COVID-19 who are mechanically ventilated (AIII). In consultation
with a pediatric infectious disease specialist, high-titer convalescent plasma may be considered on a case-by-case
basis for hospitalized children who meet the EUA criteria for its use.
• There is insufficient evidence for the Panel to recommend either for or against the use of baricitinib in combination
with remdesivir for the treatment of COVID-19 in hospitalized children in whom corticosteroids cannot be used.
• There is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab in hospitalized
children with COVID-19 or multisystem inflammatory syndrome in children (MIS-C). The Panel recommends against
the use of sarilumab for hospitalized children with COVID-19 or MIS-C, except in a clinical trial (AIII).
• MIS-C is a serious delayed complication of SARS-CoV-2 infection that may develop in a minority of children and
young adults.
• Consultation with a multidisciplinary team is recommended when considering and managing immunomodulating
therapy for children with MIS-C (AIII). Intravenous immunoglobulin and/or corticosteroids are generally used as
first-line therapy, although interleukin-1 antagonists have been used for refractory cases. The optimal choice and
combination of immunomodulating therapies have not been definitively established.


Epidemiology
Data from the Centers for Disease Control and Prevention (CDC) demonstrate a lower incidence
of SARS-CoV-2 infection and severe disease in children than in adults.1 However, without more
systematic testing for children, including for children with mild symptoms as part of contact tracing,
or seroprevalence studies, the true burden of pediatric SARS-CoV-2 infection remains unclear. Data
on the pathogenesis and disease severity of SARS-CoV-2 infection in children are increasing but are
still limited compared to the data in adults. Several large epidemiologic studies suggest that severe
manifestations of acute disease are substantially less common in children than in adults. Although
only a small percentage of children with COVID-19 will require medical attention, intensive care unit
(ICU)-admission rates for hospitalized children are comparable to those for hospitalized adults with
COVID-19.2-10
Clinical Manifestations
The signs and symptoms of SARS-CoV-2 infection in children may be similar to those in adults,
but most children may be asymptomatic or only have a few symptoms. The most common signs and
symptoms of COVID-19 in hospitalized children are fever, nausea/vomiting, cough, shortness of
breath, and upper respiratory symptoms.9,11 Of note, signs and symptoms of COVID-19 may overlap
significantly with those of other viral infections, including influenza and other respiratory and enteric
viral infections. Although the true incidence of asymptomatic SARS-CoV-2 infection is unknown,
asymptomatic infection was reported in up to 45% of children who underwent surveillance testing at the
time of hospitalization for a non-COVID-19 indication.12
SARS-CoV-2 has been associated with a potentially severe inflammatory syndrome in children and
young adults (multisystem inflammatory syndrome in children [MIS-C]), which is discussed below.
Risk Factors
Data to clearly establish risk factors for severe COVID-19 in children are limited. Data reported to CDC
show lower hospitalization rates and ICU admission rates for children with COVID-19 than for adults
with the disease.11,13 COVID-19-related hospitalization rates for children were highest in children aged
<2 years and higher in Hispanic and Black children than in White children. The majority of hospitalized
children with acute COVID-19 had underlying conditions, with obesity, chronic lung disease, and
prematurity (data collected only for children aged <2 years) being the most prevalent.14 Risk factors such
as obesity may be more applicable to older teenagers.
In a large study of hospitalized children from the United Kingdom, age <1 month, age 10 to 14 years,
and Black race were associated with admission to critical care unit on multivariate analysis.9 Another
large multicenter study from Europe identified male sex, pre-existing medical conditions, and the
presence of lower respiratory tract disease at presentation as additional risk factors for ICU admission in
multivariable models.10
Deaths associated with COVID-19 among those aged <21 years are higher among children aged
10 to 20 years, especially young adults aged 18 to 20 years, as well as among Hispanic, Black, and
American Indian/Alaska Native persons.15 A high proportion of the fatal cases of pediatric COVID-19
are in children with underlying medical conditions, most commonly chronic lung disease, obesity, and
neurologic and developmental disorders.

Based on data for adults with COVID-19 and extrapolations from data for non-COVID-19 pediatric
respiratory viral infections, severely immunocompromised children and those with underlying
cardiopulmonary disease may be at higher risk for severe COVID-19. Initial reports of SARS-CoV-2
infection among pediatric patients with cancer and pediatric solid organ transplant recipients have
demonstrated a low frequency of infection and associated morbidity;16-20 however, similar reports for
other immunocompromised pediatric populations are limited.21 A few reports have demonstrated a
higher prevalence of asthma in pediatric COVID-19 cases, although the association of asthma with
severe disease is not clearly defined.7,8 Congenital heart disease may be associated with increased risk of
severe COVID-19, but the condition has not been consistently identified as a risk factor.22,23 Guidance on
the treatment of COVID-19 in children endorsed by the Pediatric Infectious Diseases Society specifies
additional risk factors to consider when making decisions about antiviral and monoclonal antibody
therapy for pediatric patients.24,25
Persistent symptoms after acute COVID-19 have been described in adults, although the incidence of
this sequelae in children remains unknown and is an active area of research (see Clinical Spectrum of
SARS-CoV-2 Infection). Cardiac imaging studies have described myocardial injury in young athletes
who had only mild disease;26 additional studies are needed to determine long-term cardiac sequelae.
Vertical Transmission and Infants Born to Mothers with SARS-CoV-2 Infection

Vertical transmission of SARS-CoV-2 is thought to be rare, but suspected or probable vertical
transmission has been described.27-29 Initial data on perinatal transmission of SARS-CoV-2 were limited
to small case series with conflicting results; some studies demonstrated lack of transmission, whereas
others were not able to definitively rule out this possibility.30-33 Among 100 women with SARS-CoV-2
infection who delivered 101 infants, only two infants had equivocal reverse transcription polymerase
chain reaction (RT-PCR) results that may have reflected SARS-CoV-2 infection even though most of
the infants remained with their mothers, in rooms with infection prevention measures in place, and were
breast fed.34
Infants born to individuals with SARS-CoV-2 infection may have higher risk of poor clinical
outcomes than those born to individuals without SARS-CoV-2 infection, although data are conflicting.
In a systematic review of case series in pregnant women with confirmed SARS-CoV-2 infection
(predominantly from China), the preterm birth rate was 20.1% (57 of 284 births were preterm; 95%
CI, 15.8–25.1), the cesarean delivery rate was 84.7% (33 of 392 births were by cesarean delivery;
95% CI, 80.8–87.9), there was no vertical transmission, and the neonatal death rate was 0.3% (1 of
313 neonates died; 95% CI, 0.1–1.8).35 In a prospective cohort study of 263 infants born in the United
States, the rates for preterm births, neonatal ICU admissions, and respiratory disease did not differ
between infants born to mothers with and without SARS-CoV-2 infection.36 A cohort study from
Sweden demonstrated that 5-minute Apgar scores and birth weight for gestational age did not differ
between infants born to mothers with and without SARS-CoV-2 infection.37 Coronavirus Disease 2019
(COVID-19)-Associated Hospitalization Surveillance Network (COVID-NET) data from CDC that
captured 598 hospitalized, pregnant women with SARS-CoV-2 infection showed a pregnancy loss rate
of 2% among 458 pregnancies completed during COVID-19-related hospitalizations and a preterm
birth rate of 12.9% compared to 10% for the general U.S. population.38 A systematic review and meta-
analysis of studies that included 2,567 pregnancies concluded that SARS-CoV-2-positive mothers were
at increased risk of iatrogenic preterm birth. This risk was predominantly due to caesarean sections
(21.8% of births) performed due to maternal illness and fear of maternal decompensation. In contrast,
there was no increase in the rate of spontaneous preterm birth relative to the expected rate in pregnant
individuals without SARS-CoV-2 infection.39,40 Finally, a prospective cohort study from the United
Kingdom of 66 neonates with SARS-CoV-2 infection found that 3% may have had vertically acquired

infection and 12% had suspected nosocomially acquired infection.29 Specific guidance on the diagnosis
and management of COVID-19 in neonates born to mothers with known or suspected SARS-CoV-2
infection is provided by CDC.
Treatment Considerations
There are no results available from clinical trials evaluating treatment for COVID-19 in children, and
observational data on the safety or efficacy of drug therapy in children with COVID-19 are extremely
limited. More high-quality studies, including randomized trials, are urgently needed. Guidance
for the treatment of COVID-19 in children has been published and is mostly extrapolated from
recommendations for adults with COVID-19.41,42 The older the child and the more severe the disease,
the more reasonable it is to follow recommendations for adult patients with COVID-19 (see Therapeutic
Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized
Adults With COVID-19). To address the uncertain safety and efficacy of these treatment options,
children should be enrolled in clinical trials and multicenter pragmatic trials whenever possible.
The majority of children with mild or moderate COVID-19 will not progress to more severe illness and
thus should be managed with supportive care alone (AIII). The risks and benefits of therapy should be
assessed based on illness severity, age, and the presence of risk factors outlined above.
Remdesivir
Remdesivir is the only drug approved by the Food and Drug Administration (FDA) for the treatment
of COVID-19 (see Remdesivir for detailed information). It is approved for the treatment of COVID-19
in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). It is also available
through an FDA Emergency Use Authorization (EUA) for the treatment of COVID-19 in hospitalized
pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.43 Remdesivir has
not been evaluated in clinical trials that include children, and there have been no results from systematic
evaluations of pharmacokinetics, efficacy, or toxicity in younger children, although studies are ongoing
(see ClinicalTrials.gov). However, based on adult data, the potential benefits of remdesivir are likely to
be greater for hospitalized children with COVID-19 who are at higher risk of progression due to older
age (i.e., aged ≥16 years) or medical condition than for those without these risk factors. Remdesivir
is recommended for hospitalized children aged ≥12 years with COVID-19 who have risk factors for
severe disease and have an emergent or increasing need for supplemental oxygen (BIII). Remdesivir is
also recommended for hospitalized children aged ≥16 years with COVID-19 who have an emergent or
increasing need for supplemental oxygen even in the absence of risk factors (BIII). Remdesivir can be
considered for other hospitalized children of all ages with COVID-19 who have an emergent or increasing
need for supplemental oxygen in consultation with a pediatric infectious disease specialist (CIII).
Dexamethasone
Dexamethasone is recommended for the treatment of hospitalized adults with COVID-19 who require
mechanical ventilation or supplemental oxygen through a high-flow device (see Corticosteroids and
Therapeutic Management of Hospitalized Adults With COVID-19 for detailed information). The
safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have
not been sufficiently evaluated in pediatric patients and thus caution is warranted when extrapolating
recommendations for adults to patients aged <18 years. The COVID-19 Treatment Guidelines Panel
(the Panel) recommends using dexamethasone for children with COVID-19 who require high-flow
oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane
oxygenation (ECMO) (BIII). It is not routinely recommended for pediatric patients who require only
low levels of oxygen support (i.e., via a nasal cannula only). Use of dexamethasone for the treatment of

severe COVID-19 in children who are profoundly immunocompromised has not been evaluated, may
be harmful, and therefore should be considered only on a case-by-case basis. If dexamethasone is not
available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be
considered. The dexamethasone dosing regimen for pediatric patients is dexamethasone 0.15 mg/kg/dose
(maximum dose 6 mg) once daily for up to 10 days.

Although EUAs have been issued for bamlanivimab plus etesevimab and casirivimab plus imdevimab
for the treatment of nonhospitalized, high-risk patients aged ≥12 years and weighing ≥40 kg with
mild to moderate COVID-19, there are currently no data available to determine which high-risk
pediatric patients defined in the EUAs will likely benefit from these therapies. Consequently, there
is insufficient evidence for the Panel to recommend either for or against the use of these monoclonal
antibodies in children with COVID-19 who are not hospitalized but are at high risk of severe disease
and/or hospitalization. In consultation with a pediatric infectious disease specialist, bamlanivimab plus
etesevimab or casirivimab plus imdevimab can be considered on a case-by-case basis for children who
meet the EUA criteria, but should not be considered routine care. This recommendation is primarily
based on the absence of data assessing efficacy or safety in children or adolescents, limited data with
which to identify children at the highest risk of severe COVID-19, as well as the low overall risk of
progression to serious disease in children, and the potential risk associated with infusion reactions.
Additional guidance is provided in a recent publication endorsed by the Pediatric Infectious Diseases
Society.25 There are currently no data to support the use of anti-SARS-CoV-2 monoclonal antibodies in
hospitalized children for COVID-19. Emerging data regarding the prevalence and clinical significance
of SARS-CoV-2 variants, and the efficacy of monoclonal antibodies against variants, may inform the
choice of specific anti-SARS-CoV-2 monoclonal antibody therapy in the future.
Convalescent Plasma
FDA has also issued an EUA for the use of high-titer convalescent plasma for the treatment of
hospitalized patients with COVID-19 (see Convalescent Plasma for detailed information).44 The safety
and efficacy of convalescent plasma have not been evaluated in pediatric patients with COVID-19.
There is insufficient evidence for the Panel to recommend either for or against the use of convalescent
plasma for the treatment of COVID-19 in either pediatric outpatients or in hospitalized children who do
not require mechanical ventilation. The Panel recommends against the use of convalescent plasma
for pediatric patients with COVID-19 who are mechanically ventilated (AIII). In consultation with a
pediatric infectious disease specialist, convalescent plasma may be considered on a case-by-case basis
for children who meet the EUA criteria for its use.
Baricitinib
FDA has also issued an EUA for the use of baricitinib in combination with remdesivir in hospitalized
adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive
mechanical ventilation, or ECMO.45 The safety and efficacy of baricitinib have not been evaluated in
pediatric patients with COVID-19, and pediatric data regarding its use for other conditions are extremely
limited. Thus, there is insufficient evidence for the Panel to recommend either for or against the use of
baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized children in
whom corticosteroids cannot be used (see Kinase Inhibitors for detailed information).
Tocilizumab
Data on tocilizumab use for the treatment of non-COVID-19 conditions in children are limited to very

specific clinical scenarios (e.g., chimeric antigen receptor T cell-related cytokine release syndrome).46
The use of tocilizumab for severe cases of acute COVID-19 has been described in pediatric case
series.14,47 Data on tocilizumab efficacy from trials in adults with COVID-19 are conflicting, and benefit
has only been demonstrated in a subset of hospitalized patients (see Interleukin-6 Inhibitors). There
is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab for
hospitalized children with COVID-19 or MIS-C. If used, tocilizumab should be used in combination
with dexamethasone. The Panel recommends against the use of sarilumab for hospitalized children
with COVID-19 or MIS-C, except in a clinical trial (AIII).
As for other agents outlined in these Guidelines, there is insufficient evidence for the Panel to
recommend either for or against the use of specific antivirals or immunomodulatory agents for the
treatment of COVID-19 in pediatric patients. Considerations, such as underlying conditions, disease
severity, and potential for drug toxicity or drug interactions, may inform decisions on the use of these
agents in pediatric patients with COVID-19 on a case-by-case basis. Children should be enrolled
in clinical trials evaluating COVID-19 therapies whenever possible. A number of additional drugs
are being investigated for the treatment of COVID-19 in adults; refer to the Antiviral Therapy and
Immunomodulators sections to review special considerations for use of these drugs in children and refer
to Table 2f and Table 4f for recommendations on pediatric dosing regimens.
Multisystem Inflammatory Syndrome in Children

A small subset of children and young adults with SARS-CoV-2 infection develop MIS-C. This
immune manifestation is also referred to as pediatric multisystem inflammatory syndrome–temporally
associated with SARS-CoV-2 (PMIS-TS), although the case definitions for the syndromes differ
slightly. This syndrome was first described in Europe, where previously healthy children with severe
inflammation and Kawasaki disease-like features were identified to have 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 PIMS-TS. MIS-C is consistent with a post-infectious inflammatory syndrome related
to SARS-CoV-2.48,49 Most MIS-C patients have serologic evidence of previous SARS-CoV-2 infection,
but only a minority are RT-PCR positive for SARS-CoV-2 at presentation.50,51 The peak incidence of
MIS-C lags about 4 weeks behind the peak of acute pediatric COVID-19 hospitalizations. Emerging data
suggests that adults may also develop a similar syndrome, multisystem inflammatory syndrome in adults
(MIS-A), although it is not clear if this is a postinfectious complication similar to MIS-C.50-52 Although
risk factors for MIS-C have not been established, in an analysis of MIS-C cases in the United States,
most of the children were nonwhite, and obesity was the most common comorbidity.53 Unlike in children
with acute COVID-19, the majority of children who present with MIS-C do not seem to have underlying
comorbid conditions other than obesity.
Clinical Manifestations
The current CDC case definition for MIS-C includes:
• An individual aged <21 years presenting with fever,a laboratory evidence of inflammation,b and
evidence of clinically severe illness requiring hospitalization with multisystem (i.e., more than
two) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or
neurological); and
• No alternative plausible diagnoses; and
• Positive for current or recent SARS-CoV-2 infection by RT-PCR, antigen test, or serology; or
COVID-19 exposure within the 4 weeks prior to the onset of symptoms.54
a
Fever >38.0°C for ≥24 hours or report of subjective fever lasting ≥24 hours

b
Including, but not limited to one or more of the following: an elevated C-reactive protein, erythrocyte sedimentation
rate, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, interleukin (IL)-6, or neutrophils, or reduced
lymphocytes or albumin levels
Distinguishing MIS-C from other febrile illnesses in the community setting remains challenging, but
presence of persistent fever, multisystem manifestations, and laboratory abnormalities could help
early recognition.55 The clinical spectrum of hospitalized cases has included younger children with
mucocutaneous manifestations that overlap those with Kawasaki disease, older children with more
multiorgan involvement and shock, and patients with respiratory manifestations that overlap with
acute COVID-19. Patients with MIS-C are often critically ill and up to 80% of children require ICU
admission.53 Most patients with MIS-C have markers of cardiac injury or dysfunction, including elevated
levels of troponin and brain natriuretic protein.50,51 Echocardiographic findings in these cases include
impaired left ventricular function, as well as coronary artery dilations, and rarely, coronary artery
aneurysms. Reported mortality rate in the United States for hospitalized children with MIS-C is 1% to
2%. Longitudinal studies are currently ongoing to examine the long-term sequelae of MIS-C.
The pathogenesis of MIS-C is still being elucidated. Differences have been demonstrated between
MIS-C and typical Kawasaki disease 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 acute COVID-19 in children.56-58
Management
Currently, there are only observational data available to guide treatment for MIS-C. Supportive care
remains the mainstay of therapy. There is currently insufficient evidence for the Panel to recommend
either for or against any specific therapeutic strategy for the management of MIS-C. MIS-C management
decisions should involve a multidisciplinary team of pediatric specialists including experts in intensive
care, infectious diseases, cardiology, hematology, and rheumatology. Although no clinical trial data
are available, many centers have described the use of immunomodulatory therapy (e.g., intravenous
immune globulin [IVIG], corticosteroids, IL-1 and IL-6 inhibitors). The American College of
Rheumatology has outlined initial diagnostic and treatment considerations for MIS-C, recommending
IVIG and/or corticosteroids as first-tier therapies and other biologic agents as second-line options.48,49,59
An observational study from Europe used propensity matching to compare short-term outcomes in
children with MIS-C who were treated initially with IVIG alone or IVIG and methylprednisolone. They
observed a lower risk of treatment failure (defined as persistence of fever), more rapid improvement in
hemodynamic support, less severe left ventricular dysfunction, and shorter ICU stays among children
initially treated with the combination therapy.60 These findings must be confirmed with additional
prospective studies. The role of antiviral therapy in MIS-C is not clear, therefore the use of remdesivir
should be reserved for patients who have features of acute COVID-19.
References
1. Centers for Disease Control and Prevention. COVID-19: information for pediatric healthcare providers. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html. Accessed March 26, 2021.
2. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(6).
3. Centers for Disease Control and Prevention. Coronavirus disease 2019 in children—United States, February
12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm. Accessed:
January 5, 2021.
4. Cui X, Zhang T, Zheng J, et al. Children with coronavirus disease 2019 (COVID-19): a review of
demographic, clinical, laboratory and imaging features in 2,597 pediatric patients. J Med Virol.


5. Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020;323(14):1335.
6. 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:
7. DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in children and young adults in the Washington,
DC metropolitan region. J Pediatr. 2020;223:199-203.e1. Available at:
8. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically
ill children and adolescents with coronavirus disease 2019 (COVID-19) at a tertiary care medical center in
New York City. J Pediatr. 2020;223:14-19.e2. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
9. 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.
10. 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:
11. Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged <18 years
hospitalized with laboratory-confirmed COVID-19—COVID-NET, 14 States, March 1–July 25, 2020. MMWR
Morb Mortal Wkly Rep. 2020;69(32):1081-1088. Available at:
12. Poline J, Gaschignard J, Leblanc C, et al. Systematic SARS-CoV-2 screening at hospital admission in
children: a French prospective multicenter study. Clin Infect Dis. 2020;Published online ahead of print.
13. Leidman E, Duca LM, Omura JD, Proia K, Stephens JW, Sauber-Schatz EK. COVID-19 trends among
persons aged 0–24 years—United States, March 1–December 12, 2020. MMWR Morb Mortal Wkly Rep.
14. 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.
15. 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
16. Goss MB, Galvan NTN, Ruan W, et al. The pediatric solid organ transplant experience with COVID-19: an
initial multi-center, multi-organ case series. Pediatr Transplant. 2020:e13868. Available at:
17. Bisogno G, Provenzi M, Zama D, et al. Clinical characteristics and outcome of severe acute respiratory
syndrome coronavirus 2 infection in Italian pediatric oncology patients: a study from the Infectious Diseases
Working Group of the Associazione Italiana di Oncologia e Ematologia Pediatrica. J Pediatric Infect Dis Soc.
18. Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in children with cancer in New York
City. JAMA Oncol. 2020;6(9):1459-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401276.
19. 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:
20. 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:

21. Freeman MC, Rapsinski GJ, Zilla ML, Wheeler SE. Immunocompromised seroprevalence and course of
illness of SARS-CoV-2 in one pediatric quaternary care center. J Pediatric Infect Dis Soc. 2020;Published
22. Madhusoodhan PP, Pierro J, Musante J, et al. Characterization of COVID-19 disease in pediatric oncology
patients: the New York-New Jersey regional experience. Pediatr Blood Cancer. 2021;68(3):e28843. Available
23. Lewis MJ, Anderson BR, Fremed M, et al. Impact of coronavirus disease 2019 (COVID-19) on patients with
congenital heart disease across the lifespan: the experience of an academic congenital heart disease center in
New York City. J Am Heart Assoc. 2020;9(23):e017580. Available at:
24. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter interim guidance on use of antivirals for children
with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2. J Pediatric Infect Dis Soc.
25. Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment
of COVID-19 in children and adolescents. J Pediatric Infect Dis Soc. 2021;Published online ahead of print.
26. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes
recovering from COVID-19 infection. JAMA Cardiol. 2021;6(1):116-118. Available at:
27. Demirjian A, Singh C, Tebruegge M, et al. Probable vertical transmission of SARS-CoV-2 infection. Pediatr
Infect Dis J. 2020;39(9):e257-e260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32658096.
28. Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 From an infected mother to her
newborn. JAMA. 2020;323(18):1846-1848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32215581.
29. Gale C, Quigley MA, Placzek A, et al. Characteristics and outcomes of neonatal SARS-CoV-2 infection
in the UK: a prospective national cohort study using active surveillance. Lancet Child Adolesc Health.
30. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential
of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet.
31. Fan C, Lei D, Fang C, et al. Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry?
Clin Infect Dis. 2021;72(5):862-864. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32182347.
32. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to
mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 2020;174(7):722-725. Available at:
33. Von Kohorn I, Stein SR, Shikani BT, et al. In utero severe acute respiratory syndrome voronavirus 2 infection.
J Pediatric Infect Dis Soc. 2020;9(6):769-771. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33089311.
34. 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.
35. Huntley BJF, Huntley ES, Di Mascio D, Chen T, Berghella V, Chauhan SP. Rates of maternal and perinatal
mortality and vertical transmission in pregnancies complicated by severe acute respiratory syndrome
coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol. 2020;136(2):303-312. Available
36. Flaherman VJ, Afshar Y, Boscardin J, et al. Infant outcomes following maternal infection with SARS-CoV-2:
first report from the PRIORITY study. Clin Infect Dis. 2020;Published online ahead of print. Available at:

37. Ahlberg M, Neovius M, Saltvedt S, et al. Association of SARS-CoV-2 test status and pregnancy outcomes.
JAMA. 2020;324(17):1782-1785. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32965467.
38. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized
pregnant women with laboratory-confirmed COVID-19 - COVID-NET, 13 states, March 1–August 22, 2020.
39. Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-
analysis of clinical features and pregnancy outcomes. EClinicalMedicine. 2020;25:100446. Available at:
40. Khoury R, Bernstein PS, Debolt C, et al. Characteristics and outcomes of 241 births to women with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at five New York City medical centers.
Obstet Gynecol. 2020;136(2):273-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32555034.
41. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with
COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020;9(6):701-715. Available at:
42. 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.
veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized
pediatric patients less than 12 years of age weighing at least 3.5 kg. 2020. Available at:
44. Food and Drug Administration. EUA 26382: Emergency Use Authorization (EUA) Decision Memo. 2020.
45. Food and Drug Administration. Letter of authorization: EUA for baricitinib (Olumiant), in combination
with remdesivir (Veklury), for the treatment of suspected or laboratory confirmed coronavirus disease 2019
(COVID-19). 2020. Available at: https://www.fda.gov/media/143822/download.
46. 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:
47. 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.
48. 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:
49. 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:
50. 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.
51. 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:
52. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults
associated with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR

Morb Mortal Wkly Rep. 2020;69(40):1450-1456. Available at:

53. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-associated multisystem inflammatory syndrome in
children—United States, March–-July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1074-1080.
54. 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-c/hcp/. Accessed
March 26, 2021.
55. Carlin RF, Fischer AM, Pitkowsky Z, et al. Discriminating multisystem inflammatory syndrome in children
requiring treatment from common febrile conditions in outpatient settings. J Pediatr. 2021;229:26-32 e22.
56. 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:
57. Rowley AH, Shulman ST, Arditi M. Immune pathogenesis of COVID-19-related multisystem inflammatory
syndrome in children. J Clin Invest. 2020;130(11):5619-5621. Available at:
58. Diorio C, Henrickson SE, Vella LA, et al. Multisystem inflammatory syndrome in children and COVID-19 are
distinct presentations of SARS-CoV-2. J Clin Invest. 2020;130(11):5967-5975. Available at:
59. 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. 2020;Published online ahead of print. Available at:
60. 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.

Special Considerations in Adults and Children With Cancer

• 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 or patients who are receiving treatment for cancer (AIII).
• Patients who are receiving active cancer therapy may have suboptimal responses to the current two-dose vaccine
series. Because of this, the Centers for Disease Control and Prevention recommends a third dose of an mRNA vaccine
for these patients. See the text below for additional information on the criteria for receiving a third dose and the
appropriate timing for COVID-19 vaccination in these patients.
• 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 for treatment or as post-exposure prophylaxis (PEP).
• The Panel recommends performing molecular diagnostic testing for SARS-CoV-2 in patients with cancer who develop
signs and symptoms that suggest COVID-19 (AIII) and 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 drug-drug interactions and overlapping toxicities between drugs
that are used to treat COVID-19 and cancer-directed therapies, prophylactic antimicrobials, corticosteroids, 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 during SARS-CoV-2 infection 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 were at lower risk of
death from COVID-19 than those who were receiving active treatment.6 It is unclear whether cancer
survivors are at 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 (ASH)

• 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.
Vaccination for COVID-19 in Patients With Cancer

The clinical trials that evaluated the COVID-19 vaccines that have received Emergency Use
Authorizations and/or approval from the Food and Drug Administration (FDA) excluded severely
immunocompromised patients. The Advisory Committee on Immunization Practices notes that the
authorized COVID-19 vaccines 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 or patients who are receiving treatment for cancer (AIII). The Centers for Disease
Control and Prevention (CDC) recommends a third dose of an mRNA vaccine for patients who are
receiving active cancer therapy; this third dose should be administered at least 28 days after the
completion of the initial two-dose mRNA COVID-19 vaccine series.8 ASH and NCCN have provided
additional recommendations for administering a third vaccine dose in patients with cancer based on the
patient’s tumor type and therapy.9,10
The mRNA vaccines contain polyethylene glycol (PEG), and the Johnson & Johnson (J&J)/Janssen
vaccine contains polysorbate. In patients who experience a severe anaphylactic reaction 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.11-13
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.9,14
• 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.15
• Hematopoietic stem cell and chimeric antigen receptor T cell recipients can be offered COVID-19
vaccination starting at least 3 months after therapy.14
It is unknown whether the immune response to COVID-19 vaccination can increase the risk of graft-
versus-host disease. Studies of patients who received immune checkpoint inhibitors did not report
immune-related adverse events in these patients after vaccination.16,17
Decreased immunologic responses to COVID-19 vaccination have been reported in patients who
were receiving treatment for solid tumors and hematologic malignancies.18,19 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).19
In comparison, approximately 80% to 95% of patients with solid tumors showed immunologic
responses.18,20,21 Currently, it is not known how a third dose of an mRNA vaccine affects response rates
in patients with cancer.
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 (mAbs) as post-exposure prophylaxis (PEP).
Vaccination of household members, close contacts, and health care providers who provide care for
immunocompromised patients is imperative to protect these patients from infection. All close contacts
are strongly encouraged to get vaccinated.
Testing for SARS-CoV-2 in Patients With Cancer

The Panel recommends molecular diagnostic testing for SARS-CoV-2 in patients with cancer who
develop signs and symptoms of 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.22 A retrospective study suggests that patients with cancer and
neutropenia have a higher mortality rate if they develop COVID-19.23 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.24,25 Because of this, the Panel recommends performing molecular diagnostic
testing for SARS-CoV-2 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. CDC has published a framework to
help clinicians decide whether a patient should receive in-person or virtual care during the COVID-19
pandemic; this framework accounts for factors such as the potential harm of delayed care and the
degree of SARS-CoV-2 transmission in a patient’s community.26 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.27-29 Principles of physical distancing and prevention strategies,
including masking patients and health care workers and practicing hand hygiene, apply to all in-person
interactions.30
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, treatment delays should be avoided 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.31
• 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.32
• 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.33
• 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-19.34 A retrospective
study from Italy evaluated the incidence of SARS-CoV-2 infection in patients with prostate
cancer and found that 114 of 37,161 patients (0.3%) who were treated with therapies other
than androgen deprivation therapy became infected, compared to 4 of 5,273 patients (0.08%)
who were treated with androgen deprivation therapy (OR 4.05; 95% CI, 1.55–10.59).35 A small
cohort study of patients from Finland with prostate cancer did not find an association between
androgen deprivation and the incidence of SARS-CoV-2 infection.36 The viral spike proteins that
SARS-CoV-2 uses to enter cells are primed by transmembrane serine protease 2 (TMPRSS2), an
androgen-regulated gene. Whether androgen deprivation therapy protects against SARS-CoV-2
infection requires further investigation in larger cohorts or clinical trials.35
• Radiation therapy guidelines suggest increasing the dose per fraction and reducing the number of
daily treatments to minimize the number of hospital visits.37,38
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.39 In patients with cancer, stricter transfusion thresholds
for blood products (e.g., red blood cells, platelets) in asymptomatic patients should be considered.8 At
this time, there is no evidence that COVID-19 can be transmitted through blood products.40,41
Febrile Neutropenia
Patients with cancer and febrile neutropenia should undergo molecular diagnostic testing for
SARS-CoV-2 and evaluation for other infectious agents; they should also be given empiric antibiotics, as
outlined in the NCCN Guidelines.42 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.42 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.43,44
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 serious COVID-19, and they may be eligible to receive anti-
SARS-CoV-2 mAbs as treatment if they develop mild to moderate COVID-19.

Dexamethasone treatment has been associated with a lower mortality rate in patients with COVID-19
who require supplemental oxygen or invasive mechanical ventilation.45 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.
The NCCN recommends against using G-CSF and granulocyte-macrophage colony-stimulating factor in
patients with cancer and acute SARS-CoV-2 infection who do not have bacterial or fungal infections to
avoid the hypothetical risk of increasing inflammatory cytokine levels and pulmonary inflammation.46,47
Secondary infections (e.g., invasive pulmonary aspergillosis) have been reported in critically ill patients
with COVID-19.48,49
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 duration of time between resolution of infection and initiating or restarting
cancer-directed therapy is unclear. Withholding treatment until COVID-19 symptoms have resolved is
recommended, if possible. Prolonged viral shedding (detection of SARS-CoV-2 by molecular testing)
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 drug-drug interactions and
overlapping toxicities between drugs that are used to treat COVID-19 and cancer-directed therapies,
prophylactic antimicrobials, corticosteroids, and other medications (AIII).
Several antineoplastic medications may interact with therapies that are being investigated for COVID-
19.50,51 For example, tocilizumab can interact with vincristine and doxorubicin. Any COVID-19
therapy that may cause QT prolongation must be used with caution in patients who are being treated
with venetoclax, gilteritinib, or tyrosine kinase inhibitor therapy (e.g., nilotinib). 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 cytochrome P450 (CYP) 3A4 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.52-54 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.55 Two publications include guidance for
managing specific malignancies, guidance for supportive care, and a summary of web links from expert
groups that are relevant to the care of pediatric oncology patients during the COVID-19 pandemic.55,56

Special considerations for using antivirals in immunocompromised children, including those with
malignancy, are available in a multicenter guidance statement.57
References
1. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study
during the COVID-19 outbreak. Cancer Discov. 2020;10(6):783-791. Available at:
2. Shah V, Ko Ko T, Zuckerman M, et al. Poor outcome and prolonged persistence of SARS-CoV-2 RNA in
COVID-19 patients with haematological malignancies; King’s College Hospital experience. Br J Haematol.
3. Yang K, Sheng Y, Huang C, et al. Clinical characteristics, outcomes, and risk factors for mortality in patients
with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study. Lancet Oncol.
4. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer.
Nat Med. 2020;26(8):1218-1223. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32581323.
5. Giannakoulis VG, Papoutsi E, Siempos, II. Effect of cancer on clinical outcomes of patients with COVID-19:
a meta-analysis of patient data. JCO Glob Oncol. 2020;6:799-808. Available at:
6. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a
cohort study. Lancet. 2020;395(10241):1907-1918. Available at:
7. Centers for Disease Control and Prevention. Current COVID-19 ACIP vaccine recommendations. 2021.
Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed September
30, 2021.
8. Centers for Disease Control and Prevention. COVID-19 vaccines for moderately to severely
immunocompromised people. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
recommendations/immuno.html. Accessed September 9, 2021.
9. American Society of Hematology. General principles of COVID-19 vaccines for immunocompromised
patients. 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-and-vaccines. Accessed
September 16, 2021.
10. National Comprehensive Cancer Network. Recommendations of the National Comprehensive Cancer Network
(NCCN) COVID-19 Vaccination Advisory Committee. 2021. Available at: https://www.nccn.org/docs/default-
source/covid-19/2021_covid-19_vaccination_guidance_v4-0.pdf?sfvrsn=b483da2b_68. Accessed September
16, 2021.
11. American Society of Hematology. COVID-19 and pediatric ALL: frequently asked questions. 2021. Available
at: https://www.hematology.org/covid-19/covid-19-and-pediatric-all. Accessed September 30, 2021.
12. Centers for Disease Control and Prevention. COVID-19 vaccines for people with allergies. 2021. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/specific-groups/allergies.html.
covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed September 16, 2021.
14. American Society of Hematology. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients:
frequently asked questions 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-
vaccination-for-hct-and-car-t-cell-recipients. Accessed September 16, 2021.
15. National Comprehensive Cancer Network. COVID-19 resources. 2021. Available at:
https://www.nccn.org/covid-19. Accessed September 16, 2021.

16. Chen YW, Tucker MD, Beckermann KE, Iams WT, Rini BI, Johnson DB. COVID-19 mRNA vaccines and
immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Eur J Cancer.
2021;155:291-293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34400057.
17. Waissengrin B, Agbarya A, Safadi E, Padova H, Wolf I. Short-term safety of the BNT162b2 mRNA
COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors. Lancet Oncol.
18. Barriere J, Chamorey E, Adjtoutah Z, et al. Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2
vaccine in patients treated for solid tumors. Ann Oncol. 2021;32(8):1053-1055. Available at:
19. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with
chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. Available at:
20. Massarweh A, Eliakim-Raz N, Stemmer A, et al. Evaluation of seropositivity following BNT162b2 messenger
RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer. JAMA Oncol. 2021;7(8):1133-
21. Shroff RT, Chalasani P, Wei R, et al. Immune response to COVID-19 mRNA vaccines in patients with solid
tumors on active, immunosuppressive cancer therapy. medRxiv. 2021;Preprint. Available at:
22. Becker PS, Griffiths EA, Alwan LM, et al. NCCN guidelines insights: mematopoietic growth factors, version
1.2020. J Natl Compr Canc Netw. 2020;18(1):12-22. Available at:
23. Yarza R, Bover M, Paredes D, et al. SARS-CoV-2 infection in cancer patients undergoing active treatment:
analysis of clinical features and predictive factors for severe respiratory failure and death. Eur J Cancer.
2020;135:242-250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32586724.
24. American Society of Clinical Oncology. ASCO special report: a guide to cancer care delivery during the
COVID-19 pandemic. 2021. Available at: https://www.asco.org/sites/new-www.asco.org/files/content-
files/2020-ASCO-Guide-Cancer-COVID19.pdf. Accessed September 16, 2021.
25. American Society of Anesthesiologists. The ASA and APSF joint statement on perioperative testing for the
COVID-19 virus. 2020. Available at: https://www.asahq.org/about-asa/newsroom/news-releases/2020/06/asa-
and-apsf-joint-statement-on-perioperative-testing-for-the-covid-19-virus. Accessed September 30, 2021.
26. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): framework for
healthcare systems providing non-COVID-19 clinical care during the COVID-19 pandemic. 2020. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/framework-non-COVID-care.html. Accessed August 3,
2020.
27. Wang X, Zhou Q, He Y, et al. Nosocomial outbreak of COVID-19 pneumonia in Wuhan, China. Eur Respir J.
2020;55(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32366488.
28. Luong-Nguyen M, Hermand H, Abdalla S, et al. Nosocomial infection with SARS-CoV-2 within Departments
of Digestive Surgery. J Visc Surg. 2020;157(3S1):S13-S18. Available at:
29. Rivett L, Sridhar S, Sparkes D, et al. Screening of healthcare workers for SARS-CoV-2 highlights the role of
asymptomatic carriage in COVID-19 transmission. Elife. 2020;9. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed September 30,
2021.
31. American Society of Clinical Oncology. Cancer treatment & supportive care. 2020. Available at: https://www.
asco.org/covid-resources/patient-care-info/cancer-treatment-supportive-care. Accessed September 16, 2021.

32. American Society of Hematology. COVID-19 and hodgkin lymphoma: frequently asked questions. 2021.
Available at: https://www.hematology.org/covid-19/covid-19-and-hodgkin-lymphoma. Accessed September
16, 2021.
33. Griffiths EA, Alwan LM, Bachiashvili K, et al. Considerations for use of hematopoietic growth factors in
patients with cancer related to the COVID-19 pandemic. J Natl Compr Canc Netw. 2020:1-4. Available at:
34. Lee LYW, Cazier JB, Starkey T, et al. COVID-19 mortality in patients with cancer on chemotherapy or other
anticancer treatments: a prospective cohort study. Lancet. 2020;395(10241):1919-1926. Available at:
35. Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of
infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020;31(8):1040-1045. Available
36. Koskinen M, Carpen O, Honkanen V, et al. Androgen deprivation and SARS-CoV-2 in men with prostate
cancer. Ann Oncol. 2020;31(10):1417-1418. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32615154.
37. American Society for Radiation Oncology. COVID-19 recommendations and information: COVID-19 clinical
guidance. 2020. Available at: https://www.astro.org/Daily-Practice/COVID-19-Recommendations-and-
Information/Clinical-Guidance. Accessed August 3, 2020.
38. Yahalom J, Dabaja BS, Ricardi U, et al. ILROG emergency guidelines for radiation therapy of hematological
malignancies during the COVID-19 pandemic. Blood. 2020;135(21):1829-1832. Available at:
39. Food and Drug Administration. Coronavirus (COVID-19) update: FDA provides updated guidance to
address the urgent need for blood during the pandemic. 2020. Available at: https://www.fda.gov/news-events/
press-announcements/coronavirus-covid-19-update-fda-provides-updated-guidance-address-urgent-need-
blood-during-pandemic. Accessed August 3, 2020.
40. Food and Drug Administration. COVID-19 frequently asked questions. 2020. Available at: https://www.fda.
gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-frequently-asked-
questions. Accessed August 3, 2020.
41. Centers for Disease Control and Prevention. Clinical questions about COVID-19: questions and answers.
2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html#Transmission. Accessed
Sepmtember 30, 2021.
42. 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.
43. 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:
44. 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:
46. 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:
47. 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.nccn.org/covid-19/pdf/HGF_COVID-19.pdf.
48. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-
associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020;202(1):132-135. Available at:
49. 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:
50. American Society of Hematology. COVID-19 resources. 2020. Available at:
https://www.hematology.org/covid-19. Accessed August 3, 2020.
51. University of Liverpool. COVID-19 drug interactions. 2021. Available at:
https://www.covid19-druginteractions.org/.
52. 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:
53. 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.
54. 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:
55. 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.
56. Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. 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 at: https://www.ncbi.nlm.nih.gov/pubmed/32239747.
57. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with
COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020;9(6):701-715. Available at:

Special Considerations in Solid Organ Transplant,

Hematopoietic Stem Cell Transplant, and Cellular
Immunotherapy Candidates, Donors, and Recipients
Vaccination for COVID-19
• 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,
potential donors, and recipients (AIII). See the text below for information on the appropriate timing for COVID-19
vaccination in these patients.
• A third dose of an mRNA vaccine (given at least 4 weeks after the second dose) is currently recommended by the
Centers for Disease Control and Prevention for solid organ transplant recipients who are taking immunosuppressive
medications and hematopoietic stem cell transplant (HCT) recipients who are within 2 years of transplantation or who
are taking immunosuppressive medications.
Potential Transplant and Cellular Immunotherapy Candidates
• The Panel recommends diagnostic molecular testing for SARS-CoV-2 for all potential solid organ 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
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).
• Additionally, many transplant candidates are at high risk of progressing to serious COVID-19, and they may be eligible
to receive anti-SARS-CoV-2 monoclonal antibodies (mAbs) for treatment or post-exposure prophylaxis (PEP).
Potential Transplant Donors
• The Panel recommends assessing all potential solid organ transplant and HCT donors for signs and symptoms that
are associated with COVID-19 according to guidance from medical professional organizations (AIII).
• The Panel recommends performing diagnostic molecular 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 for more information.
• Immunocompromised patients with mild to moderate COVID-19 are at high risk of progressing to serious disease,
and they may be eligible to receive anti-SARS-CoV-2 mAbs for treatment or PEP.
• The Panel recommends that clinicians who are treating COVID-19 in transplant and cellular immunotherapy patients
consult with a transplant specialist before adjusting immunosuppressive medications (AIII).
• When treating COVID-19, clinicians should pay careful attention to potential drug-drug interactions and overlapping
toxicities with immunosuppressants, prophylactic antimicrobials, and 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,
transplant-related cytopenias, and the need for chronic immunosuppressive therapy to prevent graft
rejection and graft-versus-host disease. Transplant recipients may also have increased 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 the 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,
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 for more information. The medications that are used to treat COVID-19 may present
different risks and benefits to transplant patients and nontransplant patients.
Vaccination for COVID-19 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 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 Compared to healthy vaccine recipients, solid organ
transplant recipients have a reduced antibody response following a primary two-dose vaccine series of
mRNA vaccines.5-7 Among those who had no detectable antibody response to the initial two-dose vaccine
series, 33% to 50% of patients developed an antibody response to an additional mRNA vaccine dose.8,9
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, potential donors, and recipients (AIII). Currently, the Centers for
Disease Control and Prevention recommends administering an additional dose of vaccine to moderately
to severely immunocompromised people at least 28 days after a second dose of an mRNA vaccine.10
This includes people who have:
• Received a solid organ transplant and are taking immunosuppressive medications
• Received an HCT within the last 2 years or who are taking immunosuppressive medications

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.11
• At this time, reducing the dose of immunosuppressants and holding 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.12-14 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 continue wearing a mask, maintain a distance of 6 feet from others, and avoid crowds
and poorly ventilated spaces).15
It remains unclear whether the immune responses to COVID-19 vaccines can increase the risk of graft-
versus-host disease or other immune-related complications.14,16 Outside of a clinical study, antibody
testing is not recommended to assess immunity to SARS-CoV-2 following COVID-19 vaccination in
transplant patients. It is currently unknown whether revaccination offers a clinical benefit for people
who received COVID-19 vaccines during treatment with immunosuppressive drugs.
Vaccination of household members, close contacts, and health care providers who provide care for
immunocompromised patients is imperative to protect immunocompromised patients from infection. All
close contacts are strongly encouraged to get vaccinated as soon as possible.
Post-Exposure Prophylaxis for Transplant and Cellular Immunotherapy Recipients

The Food and Drug Administration (FDA) expanded the Emergency Use Authorization (EUA)
indication for the anti-SARS-CoV-2 monoclonal antibodies (mAbs) bamlanivimab plus etesevimab
and casirivimab plus imdevimab to allow them to be used as post-exposure prophylaxis (PEP) for
selected individuals who are at high risk for disease progression. This includes immunocompromised
individuals who are not expected to mount an adequate immune response to vaccination. See Prevention
of SARS-CoV-2 Infection for more information.
Assessment of 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.

Assessment of Transplant and Cellular Immunotherapy Candidates

Diagnostic molecular testing for SARS-CoV-2 is recommended 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 in accordance with guidance
from medical professional organizations (AIII).
Clinicians should consider performing 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).
Assessment of Donors
Living solid organ donors should be counseled on strategies to prevent infection and monitored for
exposures and symptoms in the 14 days prior to a scheduled transplant.17 Living donors should undergo
respiratory tract SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing 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 (BIII).
Lower respiratory sampling for COVID-19 testing is required for potential lung transplant donors by
the United Network for Organ Sharing.18 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 group gatherings during the 28 days prior to donation.19
Recommendations for screening for HCT donors are outlined in the ASTCT and EBMT guidelines.
If SARS-CoV-2 Infection Is Detected or Is 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 (BIII). The optimal disease-free interval before
transplantation is not known. The risks of viral transmission should be balanced against the risks to the
candidate, such as progression of the underlying disease and risk of mortality if the candidate does not
receive the transplant. 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.20 For
HCT and cellular immunotherapy candidates, current guidelines recommend deferring transplants or
immunotherapy procedures, including peripheral blood stem cell mobilization, bone marrow harvest,
T cell collection, and conditioning/lymphodepletion in recipients 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-19.21,22 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).23 COVID-19 was mild in 54% of recipients, moderate in 21%
of recipients, and 25% of recipients were critically ill. Management strategies varied widely across the
transplant centers, including different ways of modifying immunosuppressive therapy and the use of

different investigational therapies to treat COVID-19. Initial reports of transplant recipients who were
hospitalized with COVID-19 suggest mortality rates of up to 28%.24-28
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.21
There are limited data on the incidence and clinical characteristics of SARS-CoV-2 infection in HCT
and cellular immunotherapy recipients. 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.29 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.30
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.31
Treatment of COVID-19 in Transplant Recipients

Currently, the antiviral agent remdesivir is the only drug that is approved by the FDA for the treatment
of COVID-19. Outpatient transplant recipients who are immunosuppressed or who have certain
underlying comorbidities are candidates for the anti-SARS-CoV-2 mAbs that are available through
EUAs (see Anti-SARS-CoV-2 Monoclonal Antibodies). Transplant recipients who are hospitalized for
reasons other than COVID-19 are also eligible to receive mAb therapy. Transplant recipients who are
hospitalized with mild to moderate COVID-19 may be considered for anti-SARS-CoV-2 mAbs that are
available through expanded access programs.
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 patients with COVID-19 who were
mechanically ventilated or who required supplemental oxygen.32 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 Interleukin-6 Inhibitors).33-35 The risks and benefits
of using dexamethasone in combination with tocilizumab or baricitinib in transplant recipients with
COVID-19 who are receiving immunosuppressive therapy are unknown. Because dexamethasone,
tocilizumab, and baricitinib are immunosuppressive agents, patients who receive these medications
should be closely monitored for secondary infections.
The Panel’s recommendations for the use of remdesivir, dexamethasone, tocilizumab, and baricitinib
in patients with COVID-19 can be found in Therapeutic Management of Hospitalized Adults With
COVID-19.
A number of other investigational agents and drugs that are approved by the FDA for other indications

are being evaluated for the treatment of COVID-19 (e.g., antiviral therapies, COVID-19 convalescent
plasma) and its associated complications (e.g., immunomodulators, antithrombotic agents). In general,
the considerations for treating COVID-19 in transplant recipients are the same as those for the general
population. When possible, treatment should be given as part of a clinical trial. The safety and efficacy of
investigational agents and drugs that have been approved by the FDA for other indications are not well-
defined in transplant recipients. Moreover, it is unknown whether concomitant use of immunosuppressive
agents to prevent allograft rejection in the setting of COVID-19 affects treatment outcomes.
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 (e.g., corticosteroids, mycophenolate, and calcineurin
inhibitors such as tacrolimus and cyclosporine), 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.25 Clinicians who are treating COVID-19 in transplant patients should
consult a transplant specialist before adjusting immunosuppressive medication (AIII).
Certain therapeutics (e.g., remdesivir, tocilizumab, baricitinib) are associated with elevated levels
of transaminases. For liver transplant recipients, the American Association for the Study of Liver
Diseases does not consider abnormal liver biochemistries a contraindication to using remdesivir.36 Close
monitoring of liver biochemistries is warranted in patients with COVID-19, especially when they are
receiving agents with a known risk of hepatotoxicity.
Calcineurin inhibitors, 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 calcineurin inhibitors 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.37 Among the drugs that are commonly used to treat COVID-19,
dexamethasone is a moderate inducer of CYP3A4, and interleukin-6 inhibitors may lead to increased
metabolism of CYP substrates. Close monitoring of serum concentration of calcineurin inhibitors should
be considered when these drugs are used.
Additional details about the adverse effects and drug interactions of antiviral medications and immune-
based therapy for COVID-19 are noted in Tables 2e, 3c, and 4e.
References
1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N
2. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N
3. Food and Drug Administration. Vaccines and related biological products advisory committee meeting. 2021.
4. Centers for Disease Control and Prevention. Current COVID-19 ACIP vaccine recommendations. 2020.
Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed January 6,
2021.
5. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series
in solid organ transplant recipients. JAMA. 2021;325(21):2204-2206. Available at:

6. Hallett AM, Greenberg RS, Boyarsky BJ, et al. SARS-CoV-2 messenger RNA vaccine antibody response and
reactogenicity in heart and lung transplant recipients. J Heart Lung Transplant. 2021;Published online ahead
7. Mazzola A, Todesco E, Drouin S, et al. Poor antibody response after two doses of SARS-CoV-2 vaccine in
transplant recipients. Clin Infect Dis. 2021;Published online ahead of print. Available at:
8. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three doses of an mRNA COVID-19
vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385(7):661-662. Available at:
9. Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine
in solid organ transplant recipients: a case series. Ann Intern Med. 2021;174(9):1330-1332. Available at:
10. Centers for Disease Control and Prevention. COVID-19 vaccine indications for patients who are
immunocompromised. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/
immunocompromised.html. Accessed September 16, 2021.
11. American Society of Transplantation. COVID-19 vaccine FAQ sheet. 2021. Available at: https://www.myast.
org/sites/default/files/2021_08_13%20COVID%20VACCINE%20FAQ-Prof8132021_FINAL.pdf. Accessed
September 16, 2021.
12. American Society of Hematology. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients:
frequently asked questions 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-
vaccination-for-hct-and-car-t-cell-recipients. Accessed September 16, 2021.
13. Ljungman P, Avetisyan G. Influenza vaccination in hematopoietic SCT recipients. Bone Marrow Transplant.
14. Ram R, Hagin D, Kikozashvilli N, et al. Safety and immunogenicity of the BNT162b2 mRNA COVID-19
vaccine in patients after allogeneic HCT or CD19-based CART therapy-a single-center prospective cohort
study. Transplant Cell Ther. 2021;27(9):788-794. Available at:
15. Centers for Disease Control and Prevention. When you’ve been fully vaccinated: how to protect yourself
and others. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.html.
16. Ali H, Ngo D, Aribi A, et al. Safety and tolerability of SARS-CoV2 emergency-use authorized vaccines for
allogeneic hematopoietic stem cell transplant recipients. Transplant Cell Ther. 2021;Published online ahead of
print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34274492.
17. American Society of Transplantation. COVID-19 resources for transplant community. 2020. Available at:
https://www.myast.org/covid-19-information. Accessed June 26, 2020.
18. United Network for Organ Sharing. Lower respiratory testing of all potential lung donors for SARS-CoV-2
now required. 2021. Available at: https://unos.org/news/sars-cov-2-lower-respiratory-testing-potential-lung-
donors-may-27/. Accessed September 16, 2021.
19. American Society for Transplantation and Cellular Therapy. ASTCT interim patient guidelines April
20, 2020. 2020. Available at: https://www.astct.org/viewdocument/astct-interim-patient-guidelines-
ap?CommunityKey=d3949d84-3440-45f4-8142-90ea05adb0e5&tab=librarydocuments. Accessed July 2,
2020.
20. Association of Organ Procurement Organizations. Information about COVID-19 (coronavirus) is being
released rapidly. We will post updates as we receive them. 2020. Available at: https://www.aopo.org/
information-about-covid-19-coronavirus-is-being-released-rapidly-we-will-post-updates-as-we-receive-them/.
21. Fix OK, Hameed B, Fontana RJ, et al. Clinical best practice advice for hepatology and liver transplant
providers during the COVID-19 pandemic: AASLD expert panel consensus statement. Hepatology.


22. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk
for severe COVID-19: information for healthcare providers. 2021. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html. Accessed September 16, 2021.
23. Boyarsky BJ, Po-Yu Chiang T, Werbel WA, et al. Early impact of COVID-19 on transplant center practices
and policies in the United States. Am J Transplant. 2020 ;20(7):1809-1818. Available at:
24. Akalin E, Azzi Y, Bartash R, et al. COVID-19 and kidney transplantation. N Engl J Med. 2020;382(25):2475-
25. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the
US epicenter. Am J Transplant. 2020;20(7):1800-1808. Available at:
26. Alberici F, Delbarba E, Manenti C, et al. A single center observational study of the clinical characteristics
and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int.
27. Montagud-Marrahi E, Cofan F, Torregrosa JV, et al. Preliminary data on outcomes of SARS-CoV-2 infection
in a Spanish single center cohort of kidney recipients. Am J Transplant. 2020;20(10):2958-2959. Available at:
28. Kates OS, Haydel BM, Florman SS, et al. COVID-19 in solid organ transplant: a multi-center cohort study.
Clin Infect Dis. 2020;Published online ahead of print. Available at:
29. Sharma A, Bhatt NS, St Martin A, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic
stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e193.
30. Shah GL, DeWolf S, Lee YJ, et al. Favorable outcomes of COVID-19 in recipients of hematopoietic cell
transplantation. J Clin Invest. 2020;130(12):6656-6667. Available at:
31. Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of viable SARS-CoV-2 after immunosuppressive
therapy for cancer. N Engl J Med. 2020;383(26):2586-2588. Available at:
36. American Association for the Study of Liver Diseases. Clinical best practice advice for hepatology
and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus
statement. 2021. Available at: https://www.aasld.org/sites/default/files/2021-03/AASLD-COVID19-
ExpertPanelConsensusStatement-March92021.pdf. Accessed September 16, 2021.
37. Elens L, Langman LJ, Hesselink DA, et al. Pharmacologic treatment of transplant recipients infected with
SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions. Ther Drug
Monit. 2020;42(3):360-368. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32304488.

Special Considerations in People With HIV

Prevention of COVID-19
• 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 two-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 HIV who have recently been in close contact with a person with SARS-CoV-2 infection are eligible to
receive anti-SARS-CoV-2 monoclonal antibodies (mAbs) as post-exposure prophylaxis (PEP); however, in situations
where there are logistical or supply constraints for administering mAbs, priority should be given to those with
advanced HIV (AIII). See Prevention of SARS-CoV-2 Infection for the specific indications for PEP.
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 are eligible to receive anti-SARS-CoV-2 mAbs for
treatment; however, in situations where there are logistical or supply constraints for administering mAbs, priority
should be given to those with advanced HIV (AIII).
• 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
antiretroviral therapy (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.
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 managing 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 Interim
Guidance for COVID-19 and Persons 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 a 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.3-10
For example, the Veterans Aging Cohort Study compared the clinical outcomes for 253 veterans with
HIV and COVID-19 and the outcomes for a matched comparator arm of 504 veterans without HIV who
developed COVID-19. More than 95% of the participants in this study were male. In this comparison, no
differences were found between the outcomes for patients with HIV and those who did not have HIV.11
In contrast, worse outcomes for patients with HIV and COVID-19, including increased COVID-19
mortality rates, have been reported by subsequent 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, invasive 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 two 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, the safety and efficacy of these vaccines in people with HIV have not been fully

reported. 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 two 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.
Guidance for using these vaccines, including guidance for people with HIV, is available through the
Advisory Committee on Immunization Practices. A patient’s HIV status should be kept confidential when
administering a vaccine.
People with HIV who have recently been in close contact with a person with SARS-CoV-2 infection are
eligible to receive anti-SARS-CoV-2 monoclonal antibodies (mAbs) as post-exposure prophylaxis (PEP);
however, in situations where there are logistical or supply constraints for administering mAbs, priority
should be given to those with advanced HIV (AIII). See Prevention of SARS-CoV-2 Infection for the
specific indications for PEP.
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) 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, tobacco use disorder, 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.3-10,31,32 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 are eligible to receive anti-SARS-
CoV-2 mAbs for treatment; however, in situations where there are logistical or supply constraints for
administering mAbs, priority should be given to those with advanced HIV (AIII). See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for more information. In hospitalized patients,
the appropriate treatment strategy depends on disease severity (see Therapeutic Management of
Hospitalized Adults With COVID-19).
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). 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 it 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 are being 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 SARS-CoV-2/HIV Coinfection

Below are some general considerations regarding the management of HIV in people with SARS-CoV-2/
HIV coinfection.
• 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 Clinical 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. Gervasoni C, Meraviglia P, Riva A, et al. Clinical features and outcomes of HIV patients with coronavirus
disease 2019. Clin Infect Dis. 2020;71(16):2276-2278. Available at:
4. 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:
5. 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:

6. 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.
7. Shalev N, Scherer M, LaSota ED, et al. Clinical characteristics and outcomes in people living with human
immunodeficiency virus hospitalized for COVID-19. Clin Infect Dis. 2020;71(16):2294-2297. Available at:
8. 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:
9. 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.
10. 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:
11. Park LS, Rentsch CT, Sigel K, et al. COVID-19 in the largest U.S. cohort. AIDS 2020 23rd International AIDS
Conference. 2020. Virtual.
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: population-based cohort
analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
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 HIV and coronavirus disease-19. Clin Infect Dis. 2021;73(7):e1964-e1972. Available
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:
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. International AIDS
Society. 2021. Virtual. Available at: https://theprogramme.ias2021.org/Abstract/Abstract/2498.
20. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N
21. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N

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). 2021. 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;Published online ahead of print.
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

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:

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
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
Carl Hinkson, MSRC Providence Health & Services, Everett, WA
Lauren Henderson, MD, MMSc Boston Children’s Hospital/Harvard Medical School, Boston, MA
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
Andrew T. Pavia, MD University of Utah School of Medicine, Salt Lake City, UT

Name Affiliation
Members, continued
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
Kevin C. Wilson, MD Boston University School of Medicine, Boston, MA
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
Consultants
Christopher Carpenter, MD, MSC Washington University, St. Louis, MO
Eric Freedman, MD Department of Veteran Affairs, Cape Coral, FL
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 National Institutes of Health, Bethesda, MD
Support)
Renee Ridzon, MD National Institutes of Health, Bethesda, MD
Kanal Singh, MD, MPH (Co-Team National Institutes of Health, Bethesda, MD
Coordinator)
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, 2020, to March 31, 2021

Financial Disclosure
Panel Member
Company Relationship
Judith Aberg, MD Atea Pharmaceuticals Research Support
Emergent BioSolutions Research Support
Frontier Technologies Research Support
Gilead Sciences Research Support
GlaxoSmithKline Advisory Board, Research Support
Janssen Research Support
Merck & Co. Advisory Board, Research Support
Pfizer Research Support
Regeneron Research Support
ViiV Healthcare Advisory Board, Research Support
Adaora Adimora, MD, MPH Merck & Co. Advisory Board, Consultant, Research Support
Jason Baker, MD, MS Gilead Sciences Research Support
Humanigen Research Support
Lisa Baumann Kreuziger, MD, MS 3M Stockholder, Spouse Is Employee
Versiti Employee
Roger Bedimo, MD, MS Merck & Co. Advisory Board
ViiV Healthcare Advisory Board
Pamela S. Belperio, PharmD None N/A
John T. Brooks, MD None N/A
Timothy Burgess, MD AstraZeneca Research Support
Danielle M. Campbell, MPH Gilead Sciences Advisory Board
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
Merck & Co. Consultant, Research Support
ViiV Healthcare 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
Gregory Eschenauer, PharmD None N/A
Laura Evans, MD, MSc None N/A

Panel Member
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 Gilead Sciences Consultant
Merck & Co. Advisory Board
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
Lauren Henderson, MD, MMSc Adaptive Biotechnologies Consultant
Bristol Myers Squibb Research Support
Cerecor Consultant
Pfizer External Panel for Grant Reviews
Sobi Consultant
Elizabeth S. Higgs, MD, DTM&H, None N/A
MIA
Carl Hinkson, MSRC None N/A
Brenna L. Hughes, MD, MSc Merck & Co. Advisory Board
Steven Johnson, MD ViiV Healthcare Advisory Board
Marla J. Keller, MD None N/A
Arthur Kim, MD None N/A
Safia Kuriakose, PharmD None N/A
H. Clifford Lane, MD None N/A
Jeffrey L. Lennox, MD ViiV Healthcare Research Support
Andrea M. Lerner, MD, MS None N/A
Mitchell M. Levy, MD Citius Pharmaceuticals Consultant
Regeneron Pharmaceuticals Consultant
Sanofi Consultant
Jonathan Li, MD, MMSc Abbvie Consultant
Gregory Martin, MD, MSc Apellis Data and Safety Monitoring Board Chair/Member
Beckman Coulter Consultant
Genentech Data and Safety Monitoring Board Chair/Member
Grifols Research Grants Review Panel
Regeneron Consultant
Henry Masur, MD None N/A

Panel Member
Susanna Naggie, MD, MHS AbbVie Research Support
Bristol Myers Squibb Event Adjudication
Vir Biotechnology Advisory Board, Stockholder
Martha C. Nason, PhD None N/A
Alice K. Pau, PharmD None N/A
Andrew T. Pavia, MD GlaxoSmithKline Consultant
Renee Ridzon, MD None N/A
Grant Schulert, MD, PhD Novartis Consultant, 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 ViiV Healthcare Research Support
Pablo Tebas, MD Inovio Pharmaceuticals Research Support
Phyllis Tien, MD, MSc Eli Lilly and Company 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
Kyorin Pharmaceutical Co. Advisory Board
Kevin C. Wilson, MD None N/A
Jinoos Yazdany, MD, MPH AstraZeneca Consultant, Research Support
Aurinia Consultant
Bristol Myers Squibb Research Support
Eli Lilly and Company Consultant
Pfizer Consultant


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COVID-19 Treatment Guidelines

Coronavirus Disease 2019 (COVID-19)

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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:

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Special Considerations in Pregnancy............................................................................... 316

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What’s New in the Guidelines

The COVID-19 Treatment Guidelines Panel’s Statement on Anticoagulation in Hospitalized

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December 30, 2021

The COVID-19 Treatment Guidelines Panel’s Statement on Potential Drug-Drug Interactions

December 23, 2021

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December 16, 2021

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Other Updates to the Guidelines

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The COVID-19 Treatment Guidelines Panel’s Statement on

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• Have a moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich

Clinical Trial Data

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The COVID-19 Treatment Guidelines Panel’s Statement on

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For Hospitalized Pregnant Adults

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The COVID-19 Treatment Guidelines Panel’s Statement on

Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Purpose of This Statement

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Ritonavir-Boosted Nirmatrelvir (Paxlovid)

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Additional Considerations When Using Ritonavir-Boosted Nirmatrelvir (Paxlovid)

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Clinical Trial Data

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The COVID-19 Treatment Guidelines Panel’s Statement on