FormalPara Key Summary Points

Risk of influenza-associated clinical burden increased with age including hospitalizations, ICU admissions, mortality, ER/outpatient visits, and use of mechanical ventilation.

Adults aged 18–64 years with underlying comorbidities (e.g., type 2 diabetes mellitus, IBD, and IPA) were at higher risk of influenza-related hospitalizations, ICU admission, and mortality compared to otherwise healthy individuals.

Limited data are available reporting the economic and humanistic burden of influenza in adults aged 18–64 years, with the identification of trends across studies extremely limited due to the small number of studies identified and high heterogeneity between study populations and methods.

Indirect costs associated with influenza in the 18–64 population were investigated by six studies, which primarily reported the impact of lost productivity and absenteeism.

Introduction

Influenza is a respiratory infection associated with significant clinical, humanistic, and economic burden for patients, caregivers, and healthcare systems worldwide [1]. Each year there are an estimated 5 million cases of severe illness worldwide, and up to 650,000 deaths attributed to influenza [2, 3]. With over half the world’s population falling in the 18–64 age bracket, significant heterogeneity appears in this demographic, from large variations in age, health status, and virus exposure, as well as socio-economic status and access to healthcare facilities [4]. Given that this group encompasses the majority of the working population, influenza can be especially disruptive, causing prolonged absence from the workplace, and reduced productivity and the ability to care for others (i.e., dependents) [2]. Furthermore, the impact of influenza in the 18–64 population is not equal with, for example, influenza incidence rates varying across differing age groups within the population. The median incidence of influenza in the United States (US) over the past decade in the 18- to 49- and 50- to 64-year-old populations were 6.8% and 11.6%, respectively [5]. Although the trend in influenza vaccine uptake has slightly increased over the past decade in the US, only 37.2% of adults who were 18–49 years old and 54.2% of adults aged 50–64 years old received the influenza vaccine in the 2020–2021 season [6].

Vaccines are central to the prevention and control of influenza [1]. Although there appears to be a lack of perceived need for vaccination in the 18–64 population exemplified by large organizations, including the World Health Organization (WHO), who only recommend annual vaccination against influenza to those aged ≥ 65 years and to those deemed at high-risk of severe influenza illness in the 18–64 population [7]. This includes individuals with chronic medical diseases, such as asthma, diabetes, heart or lung diseases, or HIV/AIDs, as well as those with increased exposure to influenza, such as healthcare workers and pregnant women [7]. In accordance, many national healthcare bodies also use these recommendations. The French, Spanish, and South African healthcare bodies recommend that all people ≥ 65 years of age receive the influenza vaccination annually [8, 9]. The UK National Health Service prioritize persons ≥ 65 years and those ≥ 18 years of age at high clinical risk of severe illness for vaccination; however, this is extended to those ≥ 50 years later in the influenza season, depending on vaccine availability [10]. Thus, the perceived importance of influenza vaccination varies across age groups. This is further reflected in the low vaccine uptake rates in the 18–49 and 50–64 populations (37.2% and 45.9%, respectively), but high uptake, 73.9%, within the US ≥ 65 population, in the 2021–2022 influenza season [11]. Importantly, although influenza vaccines do not strictly prevent transmission and infection, they do reduce the severity and incidence of further complications, thus mitigating the risk of hospitalization and death [2, 7].

A unified, global approach to increase recognition of the importance of influenza vaccine uptake in the 18–64 population may reduce the risk of hospitalization and death in this large, working-age population [7]. Furthermore, increased vaccination in the 18–64 population may mitigate workplace and productivity disruption, thus alleviating wider clinical, humanistic, and economic burden to patients, caregivers, and healthcare systems worldwide.

Currently, the global distribution of influenza vaccines comprises of those that are egg-derived [12], yet they present substantial challenges in terms of time for vaccine production. Additionally, fluctuating effectiveness and longevity of protection may result from both viral drift, manifested by differences in seasonal vaccine antigen and circulating antigen, and through adaptation of viral antigens produced in the eggs [1, 12, 13]. Consequently, these limitations can reduce vaccine effectiveness (VE) and, thus, contribute to increased burden of influenza that year, severely impacting patients, caregivers, and healthcare systems worldwide. There is an ongoing need to further mitigate disease burden year-on-year through modifying the current approach to influenza prevention.

Two alternatives to vaccine development are recombinant and messenger ribonucleic acid (mRNA) techniques. Recombinant influenza vaccines are not limited by antigen mutation, and have demonstrated improved vaccine efficacy over egg-based vaccines [14]. However, reports of suboptimal immunogenicity have impacted mass uptake [15]. Novel mRNA technology has further demonstrated precise targeting of strains, plus improved accuracy and VE, due to reduced antigen mismatch, throughout the recent COVID-19 pandemic [15, 16]. During this time, widespread utilization of mRNA vaccine technology demonstrated the proficiency of rapid, large-scale manufacturing of vaccines. These factors may help confront concerns with more traditional methods of vaccine production, provide greater protection against influenza, and alleviate further influenza disease burden [15].

While our previous work characterized the global burden of influenza among adults aged ≥ 65 years, less is known about the impact of influenza within the 18–64 population [17]. Therefore, by conducting this SLR, we sought to gain a better understanding of the clinical, humanistic and economic burden of influenza exclusively within the 18–64 population, and to identify potential limitations of current vaccines in this population.

Methods

Search Strategy

Comprehensive searches were conducted via the OVID® platform, using tailored and unique search terms for clinical, humanistic, and economic burden across two electronic databases (EMBASE and Medline). The search strategies were developed following guidance from the Cochrane Handbook for Systematic Reviews of Interventions [18], and used key terms specifying disease, clinical, humanistic, and economic burden in the general population aged 18–64 years, published between January 1, 2012 and September 20, 2022 (see Table S1 in the supplementary material for the search strategy used.) Similar methodologies have been used previously to assess the burden of influenza in an older adult (≥ 65 years) population [19].

The database searches were supplemented by conference proceedings and gray literature searches, dated from January 1, 2020 to August 21, 2022. Conference proceedings from the following congresses were deemed most relevant: International Society for Pharmacoeconomic and Outcomes Research (ISPOR), European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), American Thoracic Society (ATS), International Society for Influenza and other Respiratory Virus Diseases (ISRIV), and IDWeek (joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medical Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Recent epidemiological reports published by the WHO, ECDC, and the US CDC were also included.

Study Eligibility Criteria

Abstracts and full-text articles were fully reviewed by two independent reviewers against a pre-specified eligibility criteria and outcomes of interest with regards to the clinical, humanistic, and economic burden of influenza (Tables 1 and 2). The purpose of the eligibility criteria and outcomes of interest was to capture the most relevant clinical, humanistic, and economic outcomes of influenza within the 18–64 population. Articles published in English between January 1, 2012, and September 20, 2022 were considered. Furthermore, included studies were limited to those reporting data for the following countries: Brazil, Canada, China, France, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, UK, and the US. As the objective of this review was to assess the global burden of influenza, the authors deemed the selection of countries of interest to be representative of the variation of burden across different geographical, cultural, and economical settings. Despite influenza being a public health concern in many countries, there are substantial differences in disease surveillance infrastructure, testing and reporting, healthcare services and policy, and the availability of sufficient published literature highlighting these disparities. Therefore, the list of countries selected was the authors' best attempt at providing a balanced approach to these issues, with appropriate representation from all WHO regions.

Table 1 Eligibility criteria for the clinical, humanistic, and economic burden of influenza
Full size table
Table 2 Study outcomes of interest for the clinical, humanistic, and economic burden of influenza
Full size table

Additionally, studies reporting pandemic strains of influenza were excluded to ensure only burden relevant to seasonal influenza were identified. Given that the search time horizon spanned the outbreak and height of the COVID-19 pandemic, any data reporting influenza with COVID-19 co-infection were excluded to ensure influenza remained the focus of this study.

This article was based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The clinical, humanistic, and economic outcomes of interest, related to influenza burden, are presented in Table 2.

Study Selection and Data Extraction

Abstracts and full texts were screened via the reviewing platform DistillerSR [20] by two independent reviewers, based on the PICOS criteria detailed in Table 1. Any disagreements were resolved through discussion or involvement of a third reviewer.

Data extraction was conducted in Microsoft Excel, using a bespoke data extraction form. Publication information, study characteristics, population characteristics, and outcomes of interest, listed in Tables 1 and 2, were extracted for each study. This was carried out by a single reviewer and checked by a second reviewer. Any disagreements were resolved through discussion or involvement of a third reviewer.

Quality Assessment for Study Bias

A risk of bias assessment was conducted for each study to determine the strength and validity of findings. Similar to selection and data extraction processes, this was assessed independently by two reviewers, in accordance with the Critical Appraisal Tools developed by JBI Systematic Reviews [21]. See Tables S2–S6 of the supplementary material for the JBI critical appraisal, bias assessment checklists.

Results

Summary of Results

Of the 5895 publications identified in the database search and supplementary sources, 40 were included in the final analysis that reported clinical, humanistic, and economic burden data of influenza in adults aged 18–64 years. The number of eligible publications identified during the literature searches and screening process are presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (Fig. 1).

Fig. 1
figure 1

PRISMA flowchart of publications included in the SLR. CE cost-effectiveness, N number of, SLR systematic literature review. *Bibliographies of eligible SLR/CE studies were reviewed to identify any publications that met the eligibility criteria and were then excluded

Full size image

Study Characteristics

The clinical, economic, and humanistic burden of influenza was reported across multiple regions, and a breakdown of included studies by WHO region are presented in Fig. 2. Most studies were conducted in the Americas (n = 18), followed by the European region (n = 12), and Western Pacific (n = 8). One study was conducted in Africa and one study covered multiple countries (South Africa and US).

Fig. 2
figure 2

Included study characteristics: by burden (a), region (b) and study type (c)

Full size image

A breakdown of the studies identified by design are presented in Fig. 2. Retrospective observational studies (n = 14) and prospective observational studies (n = 5), followed by epidemiological studies (n = 5), were the most commonly used, while case–controls were the least reported on (n = 2). Most studies included in the SLR (n = 39) reported clinical burden outcomes, whereas humanistic and economic burden were reported less frequently (n = 5 and n = 15, respectively) (Fig. 2).

Clinical Burden

The SLR identified 39 studies that reported the clinical burden of seasonal influenza infection in adults aged 18–64 years. The breakdown of studies by outcome is shown in Fig. 3. Influenza-related hospitalization/emergency room (ER)/intensive care unit (ICU) admissions were the most reported outcomes of clinical burden (n = 23).

Fig. 3
figure 3

Studies reporting the clinical burden of influenza. ER Emergency room, ICU intensive care unit

Full size image

Influenza-Related Hospitalization, ER/ICU/Outpatient Visits, and Mortality

The SLR identified 23 studies that reported the clinical burden, exerted by at least one of influenza-associated hospital or ICU admissions or ER or outpatient visits, while 10 studies were identified reporting influenza-related mortality in the general population aged 18–64 years. Influenza-related hospitalization was reported in eight countries where most studies were conducted in the US (n = 5) [20, 22,23,24,25], followed by Spain (n = 3) [21, 26, 27], two in Japan [28, 29], and only one in Italy [30], Germany [31], France [32], China [33], and Brazil [34], as shown in Fig. 4.

Fig. 4
figure 4

Studies reporting the burden of influenza-associated hospitalization by country

Full size image

Overall, the findings of this SLR suggest that adults aged 50–64 years are more likely to be hospitalized due to influenza than those aged 18–49 years, of which three studies found this difference to be statistically significant (Table 3) [22,23,24,25,26, 28]. However, the seasonal variation in hospitalization rates were exemplified in Lemaitre et al., where a higher rate of influenza-associated hospitalization was reported in adults aged 20–49 years compared with adults aged 50–64 years (Fig. 5) [34]. Within the same study, the opposite was reported for influenza seasons spanning 2016–2018, when adults aged 50–64 years were more likely to be hospitalized due to influenza, highlighting the influence of seasonal variability, and the impact of differing dominant circulating strains year-on-year [34]. It should be noted that included patients had a principal diagnosis of influenza or an influenza related/associated diagnosis [34].

Table 3 Summary of studies reporting rates of hospitalization stratified by age group within the general population aged 18–64 years
Full size table
Fig. 5
figure 5

Trends in the proportion of influenza hospitalizations in patients* aged 20–49 years and 50–64 years, reported by Lemaitre et al. *Included patients had received a principal diagnosis of influenza or related/associated diagnoses. Patient comorbidities included pneumonia and influenza, respiratory, and cardiovascular disease

Full size image

Higher rates of hospitalization were reported for influenza A versus influenza B across adults aged 18–64 years [25]. Zimmerman et al. reported influenza hospitalization rate stratified by influenza strain (A(H1N1), A(H3N2) or B) and age group (18–49 years, 50–64 years) in US adults with laboratory-confirmed influenza between 2015 and 2019 [25]. Higher rates of hospitalization were reported among adults aged 50–64 years than 18–49 years, regardless of influenza strain [25]. When stratified by strain, higher rates of hospitalization were reported for influenza A than influenza B across adults aged 18–49 years and 50–64 years (119 vs. 25 and 479 vs. 120 per 100,000 population, respectively) [25]. The highest reported hospitalization rates were attributable to influenza A(H3N2), at 61 and 232 per 100,000 population for adults aged 18–49 years and 50–64, respectively [25]. Of note, a relatively small sample size was identified for the 18–49 population (n = 7623), compared with the 50–64 population (n = 14,994) [25].

Influenza-Related Use of Mechanical Ventilation

Five studies reported the use of influenza-associated mechanical ventilation [26, 36,37,38,39] (Table 4) [26, 36,37,38]. The prevalence of influenza-associated mechanical ventilation ranged from 18.7 to 60%. Chaves et al. reported a higher prevalence of mechanical ventilation use among adults aged 50–64 years across both influenza A strains (H1N1 and H3N2) at 18.2% and 9.0%, respectively, compared with patients aged 18–49 years (10.6% and 4.5%, respectively) [39]. However, among patients infected with influenza strain B, those aged 18–49 years had a similar prevalence of mechanical ventilation use with those aged 50–64 years (7.2% vs. 7.1%, respectively) [39]. These results highlight the impact of strain variability on the clinical burden within the 18–64 population.

Table 4 Studies reporting the prevalence of influenza-associated mechanical ventilation
Full size table

Influence of Comorbidities on Influenza-Related Hospitalization/ER/ICU Admissions and Mortality

Four studies reported on the clinical burden of influenza in patients with comorbidities, three of which were conducted in the US and one in Japan [36, 38, 40, 41]. This SLR found people with comorbid conditions were at higher risk of influenza-related hospitalization and death compared with individuals without comorbidities.

Samson et al. compared the prevalence of medically attended influenza events in adults with laboratory-confirmed influenza with and without type 2 diabetes mellitus (n = 54,656 and n = 113,016, respectively) [40]. The study found medically-attended influenza events were significantly higher in patients with type 2 diabetes mellitus than in the control cohort (1.96% vs. 1.37%, p < 0.001).[40] Similarly, Tinsley et al. reported on the prevalence of hospitalization, within 30 days of an influenza-related insurance claim, defined as a primary or secondary International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) diagnosis code for Crohn’s disease, ulcerative colitis and influenza [41]. Among adults with laboratory confirmed influenza with inflammatory bowel disease (IBD), prevalence of hospitalization was significantly higher compared to patients without IBD (5.40% vs. 1.85%, p < 0.001) [41].

Ishida et al. and Nam et al. reported the association between comorbidities and influenza-related mortality [36, 38]. Both studies reported adults with laboratory confirmed influenza were more at risk of death, when they had comorbid conditions compared with none. Nam et al. reported a higher mortality rate of 33.3% among patients with influenza and invasive pulmonary aspergillosis (IPA), versus 10.5% in patients with only influenza [38]. Of note, 61.6% (74/120) of the influenza cohort were immunosuppressed or had solid organ or hematological malignancy [38].

Humanistic Burden and Impact of Symptoms

The SLR identified five studies reporting the humanistic burden of seasonal influenza infection in adults aged 18–64 years. Studies reporting humanistic burden of influenza are presented in Fig. 6. Limited data on humanistic burden, symptoms of influenza and influenza-related QoL were identified in people aged 18–64 years through the SLR (n = 5). Thus, due to these limited data and heterogeneity between studies, comparison and identification of trends across studies were extremely limited.

Fig. 6
figure 6

Humanistic burden studies by country (a) and outcome (b). HRQoL Health-related quality of life, QALY quality-adjusted life year, YLL years of life lost

Full size image

Impact of Influenza Symptoms on Patient Quality of Life

Three studies reported on the duration of influenza symptoms [42,43,44]. The median duration of symptoms in adults with influenza-like illness ranged from 2 to 7 days [43, 44]. Tsuzuki et al. noted no differences in symptom duration between vaccinated and unvaccinated patients [44], while Li et al. reported duration of cough ranged from 5 to 6 days and fever from 1 to 3 days, with no differences between influenza-like illness (ILI) and influenza patients who received antiviral and supportive therapies [42].

Two studies reported influenza-associated quality of life (QoL) outcomes, both conducted in Japan with subjects stratified by influenza vaccination status [44, 45]. During January 2019 among adults with ILI [n = 72; mean age (SD) 42 (21–57)], there were no reported difference in QALYs lost or QoL score between vaccinated (n = 28) and unvaccinated (n = 44) subjects, with both subgroups reporting 0.004 QALYs lost and a QoL score of 0.66, as measured by the Short-Form 12-Item Health Status Survey – version 2 (SF-12v2) [44]. Yoshino et al. used the SF-8 questionnaire, including the physical and mental components, to assess health-related quality of life (HRQoL) in adults with laboratory-confirmed influenza (n = 79) [45]. Within the study population, 37 subjects had received the influenza vaccination. A significantly higher HRQoL physical component score was reported among the vaccinated subgroup compared to those unvaccinated (37.73 ± 9.74 vs. 29.55 ± 11.42, p = 0.001) [45]. However, there was no significant difference between vaccinated and unvaccinated subjects for the mental component (51.23 ± 8.55 vs. 50.13 ± 6.98, p = 0.287) [45]. Moreover, HRQoL score in adults with influenza was significantly higher among vaccinated than among unvaccinated patients (p = 0.001) [45]. However, there was no reported difference in QALYs lost between vaccinated (n = 28) and unvaccinated (n = 44) patients [44].

Only one study reported on the years of life lost in patients with influenza or ILI (n = 13,912), stratified by age [46]. Among the younger adult population, aged 20–44 years, a total of 115,189 (95% CI 75,481–196,497) years of life were lost due to influenza-related death [46], whereas among the older adult population, aged 45–64 years, a total of 55,356 (95% CI 32,718–106,638) years of life were lost [46].

Impact of Influenza on Patient Daily Life

This SLR identified one study that investigated the impact of influenza on the daily lives of patients among the 18- to 64-year-old working population. In a European study conducted by Vos et al., it was reported that influenza symptoms severely impacted the daily lives and activities of adults aged 36–63 years with ILI (OR 2.5; 95% CI 1.8–3.5) [43]. However, with such little evidence it is hard to derive any trends and conclusions from these data.

In conclusion, the comparison and identification of trends across studies was extremely limited in adults aged 18–64 years, due to the small number of studies identified and high heterogeneity in terms of study population and methods. Further investigation in larger and multinational study populations is required to accurately capture the humanistic burden of influenza in this adult population.

Economic Burden

Sixteen studies reported on the economic burden of seasonal influenza infection in adults aged 18–64 years [26, 29, 30, 33,34,35, 37, 38, 44, 46,47,48,49,50,51,52]. The breakdown of studies reporting economic burden by year, country, and outcome are presented in Fig. 7. The majority of studies were conducted in the US (n = 5) [38, 48, 49, 51, 52]. A limited number of studies identified influenza-related economic burden in Germany and South Africa (n = 2 and n = 1, respectively) [33, 35, 46], with none identified for Italy, Canada, China, Brazil, Saudi Arabia, or the UK.

Fig. 7
figure 7

Economic studies by country (a) and outcome (b). US United States

Full size image

Direct and Indirect Costs

A limited number of studies (n = 3) reported on influenza-related direct costs in the 18–64 population, which were limited to Germany, Spain, and the US [30, 33, 49]. Influenza-related indirect costs were reported in six studies based in Japan, South Africa, and the US [44, 46, 48, 50,51,52]. Given the size and breadth of the working adult population aged 18–64 years, these studies provide limited insight into influenza-associated costs in this age group.

Direct Costs

Trends in influenza-related direct costs were difficult to identify, due to the paucity of data. Only one study stratified direct influenza-related hospitalization costs by age and season [33]. When stratified for age, the total highest mean and median hospitalization costs per patient were reported among adults aged 50–59 years (€5,101 and €1,809, respectively; cost year: 2019) [33]. When stratified by season, from 2010 to 2019, mean hospitalization costs per patient generally decreased across all age groups year-on-year, with some seasonal fluctuation in years 2013 and 2016 [33]. However, the 50–59 years population, again incurred the highest total hospitalization costs across all seasons, for both mean and median costs [33]. Results from another study similarly reported increased median hospitalization cost per patient among the 45–64 population at €4,929.21 (cost year: 2015) [30].

A singular US study examined the direct healthcare resource utilization (HCRU) costs associated with influenza diagnosis at 30- and 90-day follow-up, from 2014 to 2016 [49]. Among patients with influenza, asthma, COPD, or respiratory infection who received an antiviral treatment (either oseltamivir, zanamivir, rimantadine, or peramivir) within 2 days of index date incurred lower total HCRU costs (excluding prescriptions), at both 30- and 90-day follow up (62 USD and 98 USD, respectively) compared to untreated patients (93 USD and 151 USD, respectively) [49]. This same trend of increased costs in untreated patients was observed when stratified into inpatient, ER, and outpatient costs, across 30-day and 90-day follow up [49].

Indirect Costs

Indirect costs associated with influenza in the 18–64 population were investigated by six studies, which were largely focused on the impact of lost productivity and absenteeism [44, 46, 48, 50,51,52].

The results presented in two US studies found that the mean cost of absenteeism and the number of work hours lost per ILI episode increased with age throughout the workforce aged 18–64 years [48, 52]. It was noted by Tsai et al. that older adults sought out more ILI-related medical visits, due to increased prevalence of comorbidities, and therefore a higher risk of ILI-related complications [48]. The severity of ILI among adults aged 20–64 years was also found in a separate study to impact the degree of absenteeism [46]. Patients with influenza-associated severe acute respiratory infection (SARI), defined as having acute or recent (within last 7 days) respiratory illness with a fever of ≥ 38°C and cough, requiring hospitalization, had higher total absenteeism than patients with ILI (1.8 days vs. 0.8 days) [46, 53]. Similarly, caregivers for patients with SARI also reported higher absenteeism than ILI-caregivers (1.3 days vs. 0.6 days) [46].

In an additional study, it was found adults with influenza (unconfirmed), who were treated with antivirals, reported losing 4.6–5.2 days of productivity during 2020 [50]. Given the unconfirmed diagnosis and period that this study was conducted, it must be noted that some COVID-19-related loss of productivity may have been attributed to influenza. Another study conducted in 2019 similarly reported a median duration of 5 days absenteeism among adults with ILI (range 4–6 days), despite 39% of subjects having received seasonal vaccination and 91% having received antiviral treatment [44]. Additionally, when the population was stratified by seasonal influenza vaccination status, there was no significant difference in median duration of absenteeism between vaccinated and unvaccinated adults [5.0 (IQR 2.5–5.5) vs. 5.0 (IQR 4.0–6.0), p = 0.51] [44].

Length of Hospitalization Stay and Associated Resource Use

Nine studies reported the economic burden of influenza-associated hospital admission, from hospital and ICU length of stay (LOS) and related resource use (Table 5) [26, 29, 30, 34, 35, 37, 38, 47, 48].

Table 5 Studies reporting length of hospitalization stay and associated resource use (n = 8)
Full size table

Two studies reported increased median length of hospitalization stay with increasing age [26, 34]. Additionally, the median length of mechanical ventilation and ICU stay were reported at 22 and 14 days, respectively, while mean length was 15 and 13 days [37, 47]. However, these studies were limited to France, Spain, and the US, and length of mechanical ventilation and ICU stay were not stratified by age, so the impact of increasing age may not apply to these outcomes.

A German study by Mohammad et al. reported on the mean hospital LOS among influenza-positive patients admitted to the emergency department, which found the opposite to Lemaitre et al. and Derqui et al. [26, 34, 35]. The younger, adult population aged 18–39 years had a higher mean hospital LOS at 7.4 days (SD 7.4) [35], whereas adults aged 40–59 years had a lower hospital LOS at 5.1 days (SD 2.5) [35].

Discussion

This SLR aimed to characterize the clinical, humanistic, and economic burden of primary influenza among adults in the general population aged 18–64 years. Although the clinical burden in this age group was widely reported, limited evidence was identified for the humanistic and economic burden.

The data identified in this SLR reflect a trend of increased influenza-associated clinical burden with increased age among those aged 18–64 years, including hospitalizations [22,23,24,25,26, 28], ICU admissions [26, 34], mortality [26, 34, 39], ER/outpatient visits [34], and use of mechanical ventilation [26, 39]. Of note, in studies that stratified by age, the ‘older’ age range with greater associated burden was most frequently 50–64 years [22, 23, 25, 26, 34, 39].

Seasonal differences in circulating influenza strain are determined by multiple factors including population-level natural and vaccine-induced immunity, surveillance, and the transmissibility of the dominant strain (most prevalent circulating strain during the influenza season). When stratified by influenza strain, higher rates of hospitalization, ICU admission, and mechanical ventilation were reported for influenza A or A subtypes (H1N1 and H3N2) than influenza B, and were reported to be exacerbated among adults aged 45–64 years [25, 39, 54]. Poor influenza outcomes have been associated with influenza A(H3N2), especially among older populations [17].

Similar to older adults, people aged 18–64 years with underlying comorbidities (e.g., type 2 diabetes mellitus, IBD, IPA, immunosuppressed) were at higher risk of influenza-related hospitalizations, ICU admission, and mortality compared to otherwise healthy individuals [36, 38, 40, 41]. The increased incidence of early onset chronic conditions such as type 2 diabetes and obesity among younger adults, largely due to lifestyle choices, means increased prevalence of comorbidities among patients aged 18–64 years [55, 56]. Further, data from the WHO suggest that the extent of influenza-related clinical burden is often underreported, and is far more detrimental to patients and healthcare systems than realized, due to influenza-related deaths from other diseases (e.g., cardiovascular) not being acknowledged [57]. Overall, with increased risk of comorbidity and general declining health in older age, extension of influenza vaccination prioritization to at least the 50–64 population may reduce the risk of hospitalization and death in this population.

Limited humanistic data were identified in the SLR that reported influenza-related outcomes (n = 5). Unlike the identified clinical burden, these studies did not stratify the humanistic burden within the adult population by age. Considering the trend of increased influenza burden with increased age, age-related differences in humanistic burden among adults aged 18–64 years warrant further investigation [7].

Interestingly, Tsuzuki et al. reported no significant difference in symptom duration, QALYs lost, or QoL score between vaccinated and unvaccinated patient subgroups [44], while Yoshino et al. reported a significantly higher HRQoL score for the physical component of the SF-8 questionnaire (p = 0.001) among vaccinated adults compared with unvaccinated adults [45]. Of note, these studies were both conducted in Japan with overlapping study periods (2018–2020), but the former among patients with influenza-like-illness and the latter among adults with laboratory-confirmed influenza [44, 45]. These findings highlight the ambiguity surrounding the benefits of influenza vaccination for assessing both the humanistic and overall burden within the general population aged 18–64 years.

Limited evidence of the economic burden in adults was identified (n = 16). Indirect costs associated with influenza were more frequently reported than direct costs (n = 6 vs. n = 3, respectively), suggesting that the impact of absenteeism and reduced productivity is more relevant and burdensome within the working population of adults [44, 46, 48, 50,51,52]. However, these identified studies still provide a limited overview of indirect costs considering the size and breadth of the working adult population aged 18–64 years.

An SLR of the economic burden of influenza among adults aged 18–64 years conducted by Courville et al. also identified an evidence gap and a focus on indirect costs in this population [58]. Currently, the WHO does not explicitly recommend seasonal vaccination against influenza in the 18–64 population. However, the organization does recognize that it can be cost-saving for patients and healthcare systems globally [59]. Interestingly, more evidence for influenza-associated direct costs has previously been reported among adults aged ≥ 65 years [17]. These SLRs in older populations reported influenza-related hospitalization, ICU admission, and ER/outpatient visits, which were also clinical outcomes reported among the 18–64 years population in this SLR. Thus, this suggests that the limited evidence of influenza-related direct costs identified in this SLR is not representative of the actual burden exerted by adults aged 18–64 years. In addition, studies investigating influenza-associated costs in those aged ≥ 65 years have demonstrated the economic benefits of preventive healthcare given the rising cost of care and limited availability of resources. These findings suggest that influenza vaccination among adults aged 18–64 years would help to reduce the burden exerted on healthcare providers.

Overall, limited and contradictory reports of influenza vaccination protection highlighted a need for further research into the benefits of seasonal influenza vaccination in adults aged 18–64 years. Given the size and breadth of this population, who form most of the global workforce, prolonged absence from the workplace has the potential to disrupt the economy and to burden healthcare providers [2].

However, seasonal influenza vaccination is currently available across several countries for adults aged 18–64 years [10, 11], but with consistently poor uptake rates. For example, vaccination coverage among US adults aged 18–64 years peaked at 43.0% between 2015–2016 and 2021–2022. Although peak uptake rate over the same period when limited to adults aged 50–64 years increased to 54.2%, these figures suggest that this population still perceives an influenza vaccination as of low importance [60].

Influenza vaccination uptake between age groups was also differentially affected by the COVID-19 pandemic. Between 2019–2020 and 2021–2022, influenza vaccination uptake increased among adults aged 50–64 years (50.6% vs. 52.4%, respectively) and decreased among adults 18–49 years (38.4 vs. 37.1%). These differences are likely due to a combination of factors, including increased distrust of vaccinations during the COVID-19 pandemic, non-prioritization while lockdown measures were in place among younger adults, and an increased feeling of vulnerability among adults aged 50–64 years. The decision to receive an influenza vaccination within the 18–64 population relies heavily on factors such as underlying comorbidities and increased occupational exposure, while attitude and trust toward healthcare, associated costs, and level of education tend to drive adults in this age group to choose not to receive a vaccination [61]. Interestingly, among unvaccinated groups, lack of knowledge was the greatest barrier to influenza vaccination [61].

A combined lack of trust in vaccine effectiveness and a perceived low risk of personal illness are reported drivers of poor influenza vaccine uptake rates [61, 62], partly owing to limitations and suboptimal effectiveness of traditional influenza vaccines. Novel vaccine production methods such as using mRNA technology may offer a solution to overcome limitations associated with current vaccine production methods [63]. The recent COVID-19 pandemic offered insight into the potential use of mRNA vaccines, highlighting the proficiency of rapid, large-scale manufacture of vaccines, and eliciting a wealth of safety and efficacy data. Improved perception of influenza vaccination effectiveness and a greater understanding of the risks of influenza illness, combined with extension of influenza vaccination prioritization to at least the 50–64 population, are necessary to reduce the risk of hospitalization and death in this population. With increased risks of comorbidity and overall declining health in older age, these aspects of vaccination are important to take into consideration, as they contextualize the burden of influenza and indicate areas to address to minimize influenza-related clinical burden within the 50–64 years population.

Study Limitations

A potential limitation of this SLR was that, during the screening process, studies that did not explicitly report data for adults aged 18–64 years within the title and/or abstract were excluded. As such, studies may have been excluded due to uncertainty of the population of interest if not disclosed within the abstract. In addition, due to the broad inclusion criteria, the ability to identify clear trends and make direct comparisons between study results were impeded by heterogeneity in study design, outcomes, and population characteristics.

Finally, the limiting of study scope to include studies reporting data for Brazil, Canada, China, France, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, UK, and the US may not be fully representative of the global burden of influenza in adults aged 18–64 years.

Conclusion

This SLR has demonstrated a clinical influenza-associated burden on patients and healthcare systems, with high levels of hospitalization and outpatient visits. Considering the size and breadth of the general population aged 18–64 years, which comprises the majority of the working population, the limited humanistic and economic findings of this SLR likely reflect an underreported burden rather than a lack thereof. This is consistent with findings from previous SLRs exploring the burden of influenza and WHO guidance [58, 59], and suggests a lack of perceived need for vaccination in the global 18–64 population.

Overall, these findings indicate that improved preventive measures, such as increased vaccination coverage, among adults aged 18–64 years is necessary to reduce the clinical burden that influenza infection exerts on patients and healthcare systems, while greater investigation into the direct costs and greater consideration of the indirect costs of disruption and prolonged absence from the workplace associated with influenza infection are required to fully understand the economic burden in this population.