Burden of Acute Respiratory Infections Caused by Influenza Virus, Respiratory Syncytial Virus, and SARS-CoV-2 with Consideration of Older Adults: A Narrative Review

Abstract

Influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are acute respiratory infections (ARIs) that can cause substantial morbidity and mortality among at-risk individuals, including older adults. In this narrative review, we summarize themes identified in the literature regarding the epidemiology, seasonality, immunity after infection, clinical presentation, and transmission for these ARIs, along with the impact of the COVID-19 pandemic on seasonal patterns of influenza and RSV infections, with consideration of data specific to older adults when available. As the older adult population increases globally, it is of paramount importance to fully characterize the true disease burden of ARIs in order to develop appropriate mitigation strategies to minimize their impact in vulnerable populations. Challenges associated with characterizing the burden of these diseases include the shared symptomology and clinical presentation of influenza virus, RSV, and SARS-CoV-2, which complicate accurate diagnosis and highlight the need for improved testing and surveillance practices. To this end, multiple regional, national, and global virologic and disease surveillance systems have been established to provide accurate knowledge of viral epidemiology, support appropriate preparedness and response to potential outbreaks, and help inform prevention strategies to reduce disease severity and transmission. Beyond the burden of acute illness, long-term health consequences can also result from influenza virus, RSV, and SARS-CoV-2 infection. These include cardiovascular and pulmonary complications, worsening of existing chronic conditions, increased frailty, and reduced life expectancy. ARIs among older adults can also place a substantial financial burden on society and healthcare systems. Collectively, the existing data indicate that influenza virus, RSV, and SARS-CoV-2 infections in older adults present a substantial global health challenge, underscoring the need for interventions to improve health outcomes and reduce the disease burden of respiratory illnesses.

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Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-024-01080-4.

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Key Summary Points

Older adults are at an increased risk for morbidity and mortality from acute respiratory infections (ARIs), including influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Influenza virus and RSV exhibit typical seasonality patterns, whereas conclusions on the seasonal dynamics of SARS-CoV-2 cannot be drawn until further circulation data are collected post-pandemic.

Clinical presentation and symptomology are similar for influenza virus, RSV, and SARS-CoV-2 infections, underscoring the importance of diagnostic testing to confirm and distinguish between these ARIs, with polymerase chain reaction-based assays being the preferred methodology.

Regional, national, and global virologic and disease surveillance systems for individual viruses, as well as integrated efforts across multiple ARIs, have been established to ensure continual viral monitoring.

The health consequences of ARIs can extend beyond the acute phase of infection, with long-term effects on numerous organ systems (including cardiovascular and pulmonary systems) and impacts on chronic sequelae, frailty, and life expectancy.

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Introduction

Influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are acute respiratory infections (ARIs) that can cause substantial morbidity and mortality among older adults [1]. The risk from ARIs is heightened in older individuals owing to an aging immune system, the presence of chronic conditions, and challenges in the ability to identify and treat these infections [1]. With the number of people aged ≥ 65 years expected to double worldwide from 761 million in 2021 to 1.6 billion in 2050, effective preventive strategies will be crucial for minimizing the risk of morbidity and mortality from ARIs in this at-risk population [2].

Characterization of the influenza, RSV, and SARS-CoV-2 disease burden in older adults is necessary to reduce morbidity and mortality, to identify unmet needs and knowledge gaps, and to support the development of optimal mitigation strategies. In this narrative review, we overview the burden of these three ARIs, summarizing epidemiology, seasonality, clinical presentation, transmission, surveillance, and diagnostic testing, as well as the long-term health and economic consequences. The older adult population will be highlighted within each of these topics, permitting available published data. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. See video 1 in the online/HTML version of the manuscript for a videographic summary of this article or follow the digital features link under the abstract.

Epidemiology

Influenza Virus

According to the World Health Organization (WHO), approximately 1 billion seasonal influenza cases occur annually, of which 3 to 5 million are severe [3]. Older adults are among those at greatest risk of severe illness and death [3]. Globally, 291,000 to 646,000 deaths are attributable to influenza annually, with 49,000–102,000 and 123,000–238,000 influenza-associated respiratory deaths among adults aged 65–74 years and ≥ 75 years, respectively (Table 1) [4]. Older age increases the likelihood of severe influenza-associated outcomes, including hospital admission and death [5].

Table 1.

Summary of select recent respiratory infection publications assessing health outcomes in the older adult population

Reference	Study design	Outcome assessed	Topline results in older adults
Influenza virus
Iuliano et al. Lancet. 2018 [4]	Model to estimate global influenza-associated respiratory deaths between 1999 and 2015; included adults aged 65–74 years and aged ≥ 75 years	Mortality	Median annual influenza-associated respiratory deaths of 48,810–102,187 per year (13.3–27.8 per 100,000) among those aged 65–74 years Highest mortality rate among those aged ≥ 75 years (median, 122,876–237,933; 51.3–99.4 per 100,000)
Paget et al. J Glob Health. 2019 [14]	Model to estimate the respiratory mortality burden of influenza globally; included adults aged ≥ 65 years	Mortality	Among adults aged ≥ 65 years:
			67% of annual influenza-associated respiratory deaths
			Influenza-associated mortality rate of 54 per 100,000
			Seasons coinciding with A/H3N2 predominance were most severe
RSV
Branche et al. Clin Infect Dis. 2022 [20]	Large, prospective, population-based surveillance study in the United States during the 2017–2018, 2018–2019, and 2019–2020 RSV seasons in 3 hospitals; included adults aged ≥ 65 years	Hospitalization	Incidence from 136.9 to 255.6 per 100,000 in patients aged ≥ 65 years:
			15 times higher than incidence in younger adults (18–49 years)
McLaughlin et al. Open Forum Infect Dis. 2022 [22]	Systematic review and meta-analysis of population-based studies in US adults; included adults aged ≥ 65 years	Medically attended RSV	Annual RSV-associated rates (per 100,000) in adults aged ≥ 65 years:
			178 hospitalizations
			133 ED admissions
			1519 outpatient visits
			After adjusting for under-detection rates (per 100,000), results increased to:
			267 hospitalizations
			200 ED admissions
			2278 outpatient visits
Li et al. Infect Dis Ther. 2023 [21]	Systematic literature review in adults aged ≥ 60 years in high-income countries including the United States, Finland, and New Zealand	RSV-associated hospitalization burden	Annual RSV-associated hospitalizations:
			Unadjusted rate was 157 per 100,000, corresponding to 356,000 hospitalizations in adults aged ≥ 65 years
			Rate adjusted for under-ascertainment was approximately 2.2 times higher
			Adjusted rate increased with age from 231 per 100,000 in adults aged 65–74 years to 692 per 100,000 in adults aged ≥ 85 years
			In-hospital RSV case fatality ratio was 6.1% in adults aged ≥ 65 years
			Total RSV-associated in-hospital deaths between 22,000 and 47,000
Savic et al. Influenza Other Respir Viruses. 2023 [19]	Systematic literature review and meta-analysis to estimate the RSV disease burden in 2019 in adults aged ≥ 60 years in high-income countries including the United States, Canada, European Union, Japan, and South Korea	RSV-associated attack rates, hospitalization rates, and in-hospital CFR	Point estimates in adults aged ≥ 60 years were:
			RSV attack rate: 1.6%; 95% CI 0.8–3.1%
			Hospitalizations: 0.2%; 95% CI 0.1–0.2%
			In-hospital deaths: 7.1%; 95% CI 5.4–9.4%
			Translates to approximately 5.2 million cases, 470,000 hospitalizations, and 33,000 in-hospital deaths
Nguyen-Van-Tam et al. Eur Respir Rev. 2022 [168]	Systematic review and meta-analysis of the burden and clinical presentation of symptomatic RSV infection and the associated healthcare utilization in developed countries in adults aged ≥ 60 years or at high risk	RSV-related CFR; proportion of symptomatic respiratory infections	Among older adults:
			RSV-related CFP was 8.2%; 95% CI 5.5–11.9%
			RSV caused 4.7% (95% CI 3.3–6.5%) of symptomatic respiratory infections in annual studies and 7.8% (95% CI 5.8–10.5%) in seasonal studies
			Among high-risk adults:
			CFP was 9.9%; 95% CI 6.7–14.4%
			RSV caused 7.0% (95% CI 5.2–9.5%) of symptomatic respiratory infections in annual studies and 7.7% (95% CI 6.2–9.5%) in seasonal studies
Influenza virus and RSV
Hansen et al. JAMA Netw Open. 2022 [11]	Cross-sectional study of death certificates in the United States from 1999–2018; included adults aged ≥ 65 years	Mortality	Mean annual mortality rate per 100,000 population adults aged ≥ 65 years:
			RSV: 14.7; 95% CI 13.8–15.5
			Influenza: 20.5; 95% CI 19.4–21.5
			In the 2017–2018 influenza season (A/H3N2 predominance), 18,739 deaths (95% CI 16,616–21,336) occurred among adults aged ≥ 65 years
SARS-CoV-2
Mefsin et al. Emerg Infect Dis. 2022 [41]	Contact-tracing data on confirmed COVID-19 cases (December 2021 to January 2022; omicron predominance) in Hong Kong; included adults aged ≥ 65 years	CFR	CFR in adults aged 65–79 years:
			Unvaccinated: 6.7%; 95% CI 4.3–9.8%
			Vaccinated: 0.7%; 95% CI 0.1–2.4%
			CFR in adults aged ≥ 80 years
			Unvaccinated: 21.7%; 95% CI 17.1–26.8%
			Vaccinated: 11.1%; 95% CI 4.2–22.6%
Tejada-Vera et al. NCHS Data Brief. 2022 [40]	Report of death certificates in the United States in 2020; included adults aged ≥ 65 years	Mortality	81% of COVID-19-associated deaths occurred in those aged ≥ 65 years (282,836) Death rate for COVID-19 among adults aged ≥ 85 years (1645.0 per 100,000) was 2.8 times higher than for those aged 75–84 years (589.8) and 7 times higher than for those aged 65–74 years (234.3)
Ahmad et al. MMWR. 2023 [37]	Analysis of death certificates from January–December 2022 in the United States; included adults aged ≥ 65 years	Mortality	COVID-19-associated deaths (number and rate per 100,000) were highest among individuals aged ≥ 85 years:
			Adults aged 65–74 years: 53,228 (158.1)
			Adults aged 75–84 years: 67,116 (414.1)
			Adults aged ≥ 85 years: 73,157 (1224.2)
Nab et al. Lancet Public Health. 2023 [45]	Observational, retrospective cohort of 5 pandemic waves from 2020–2022 in England; included adults aged ≥ 60 years	Mortality	Death rates increased during omicron predominance compared with delta predominance, with a pronounced pattern in adults aged ≥ 80 years Risk of COVID-19-related death remained increased through pandemic waves in adults aged ≥ 60 years compared with adults aged 50–59 years Decreases in COVID-19-related death were seen in older age groups in wave 3 compared with wave 1, with a 90% decrease in mortality in adults aged ≥ 80 years (vaccine program rolled out in wave 2)
Taylor et al. MMWR. 2023 [38]	Population-based surveillance of COVID-19-associated hospitalizations in 13 states in the United States from January–August 2023; included adults aged ≥ 65 years	Hospitalization, intensive care unit admissions, in-hospital deaths	COVID-19-associated rates in adults aged ≥ 65 years (% across all age groups):
			62.8% (95% CI 60.1–65.7%) of hospitalizations
			61.3% (95% CI 54.7–67.6%) of intensive care unit admissions
			87.9% (95% CI 80.5–93.2%) of in-hospital deaths
Wong et al. MMWR. 2023 [39]	Comparative analysis of COVID-19 deaths and mortality rates from 2020–2021 globally; included adults aged ≥ 60 years	Mortality	80% of COVID-19-associated deaths were in adults aged ≥ 60 years:
			60–69 years: 478,599 (40 per 100,000)
			70–79 years: 614,762 (96 per 100,000)
			≥ 80 years: 889,647 (303 per 100,000)
			Mortality was higher in older age groups regardless of income level

CFR case fatality rate, ED emergency department, RSV respiratory syncytial virus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Influenza virus exhibits seasonal circulation patterns, with “flu season” typically occurring during the fall and winter months in temperate climates (Fig. 1) [3, 6, 7]. Of the four types of influenza viruses (A, B, C, and D), seasonal epidemics are caused by types A and B [8, 9]. Historically, circulation of influenza among humans has been limited to two subtypes of influenza A (A/H1N1 and A/H3N2) and two lineages of influenza B (B/Victoria and B/Yamagata) [8, 10]. Influenza A/H3N2 has historically been associated with the highest hospitalization and mortality rates, particularly among individuals aged ≥ 65 years (Table 1) [11–14]. However, findings from a recent study assessing the severity of influenza-associated outcomes in hospitalized individuals indicated that although influenza A/H3N2 is associated with more hospitalizations, its in-hospital severity is lower compared to that of influenza B and influenza A/H1N1 [15].

Fig. 1.

Summary of the epidemiology of influenza virus, RSV, and SARS-CoV-2 ARIs in older adults [3, 6, 7, 28, 29, 50, 51, 64–68, 71–74, 173–176]. IQR interquartile range, RSV respiratory syncytial virus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, SD standard deviation. ^aThe role of fomites in viral transmission is established for influenza and RSV [177]. Although surface transmission of SARS-CoV-2 can occur, risk is considered to be low based on epidemiological data and environmental transmission studies [178]. ^bR₀, or the basic reproductive number, is defined as the average number of new infections that one case generates and is a measure of how contagious an infectious disease is in a susceptible population during the duration of the infectious period [71]

Influenza viruses undergo antigenic drift, whereby minor amino acid changes accumulate in two major antigenic sites: the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) [9]. Influenza A/H3N2 undergoes the highest rate of antigenic drift, which is approximately five- to 18-fold higher than observed in influenza A/H1N1 and B lineages [16]. Antigenic drift produces minor genetic changes in the HA and NA antigenic sites that enable evasion of humoral immunity induced by prior infection or vaccination, necessitating seasonal vaccination to protect against new circulating strains [9, 10]. If a host is simultaneously infected with antigenically diverse influenza A viruses, the result can be reassortment of the viral genome, leading to major antigenic changes in HA and/or NA, known as antigenic shift [9, 17]. Influenza viruses of pandemic potential are the result of antigenic shift, as most individuals would have little or no immunity against the new virus from past infection or vaccination, resulting in a large pool of susceptible hosts [9, 17]. Together, mutations of the influenza virus, particularly A/H3N2, are associated with an increased risk of influenza-related hospitalizations in older adults [18].

RSV

RSV is a major cause of serious respiratory disease [19], and older adults are at an increased risk of serious illness, hospitalization, and mortality from infection (Table 1) [11, 12, 19–23]. Although RSV infection is traditionally recognized as a contributor to morbidity and mortality in young children [24], a cross-sectional study from the United States reported markedly higher annual RSV mortality rates among older adults (≥ 65 years; 14.7 deaths per 100,000 population) compared with young children (< 1 year; 2.4 deaths per 100,000 population) [11]. In 2019, 5.2 million RSV-associated ARIs, 466,000 RSV-associated hospitalizations, and 33,000 RSV-associated in-hospital deaths occurred in adults aged ≥ 60 years in high-income countries, a higher burden than previously estimated (Table 1) [19]. The true RSV burden may be underestimated due to the lack of routine RSV testing, low awareness among healthcare providers of RSV in adult patients, and variations in RSV sampling, testing methodologies, and case definitions [19, 25–27].

Similar to influenza, RSV also exhibits seasonal circulation patterns; RSV activity spikes in the winter months in temperate climates, at the beginning of spring in the northernmost countries, and during the rainy season in humid equatorial and tropical regions (Fig. 1) [28, 29]. There are two major antigenic subtypes of RSV, RSV-A, and RSV-B, which differ primarily in the highly variable surface glycoprotein G [30, 31]. While subtypes can cocirculate, one subtype can predominate in a single season with temporal and geographical clustering [31, 32]. Data on subtype-related severity in older adults are lacking.

SARS-CoV-2

COVID-19 is the most consequential global health crisis to emerge since the 1918 influenza pandemic [33]. As of January 2024, over 700 million COVID-19 cases and 7 million COVID-19 deaths were reported globally [34, 35]. Age is the strongest risk factor for severe COVID-19 outcomes, including hospitalization, intensive care unit (ICU) admission, and death, with risk increasing markedly at ages > 65 years (Table 1) [36–41]. Over 80% of COVID-19-associated deaths worldwide in 2020–2021 were in adults aged ≥ 60 years (Table 1) [39].

Since its initial appearance in 2019, SARS-CoV-2 has changed markedly through genetic evolution. The evolution of SARS-CoV-2 has given rise to the five distinct variants of concern (VOC), Alpha, Beta, Gamma, Delta, and Omicron, that exhibit increased transmissibility or immune escape and caused successive waves of COVID-19 [33, 42]. Compared to the ancestral strain, the Alpha and Delta variants were associated with increased transmissibility, while Omicron infections have demonstrated reduced disease severity, potentially attributable to both lower intrinsic virulence and preexisting partial immunity from prior infection or vaccination [42, 43]. However, in Hong Kong, intrinsic severity between the ancestral strain and the Omicron BA.2 subvariant was similar [44]. Specifically, the age-stratified hospitalization fatality risk in unvaccinated individuals infected with Omicron was comparable to that of unvaccinated cases infected with the ancestral strain during earlier waves [44]. A study of approximately 19 million UK adults demonstrated that COVID-19 deaths decreased overall with successive COVID-19 waves; however, mortality rates remained higher in adults aged ≥ 60 years versus adults aged 50–59 years (Table 1) [45, 46]. Epidemiologic data from the United States also showed that although COVID-19 hospitalization rates decreased in most age groups, rates remained higher in adults aged ≥ 65 years throughout the pandemic [47].

In parallel with SARS-CoV-2 genetic evolution, population-level immunity has accumulated following infection exposure and/or immunization. This acquired population immunity may have been a driving factor behind attenuated severity, although further virologic and immunologic studies are needed to confirm these observations [44]. Hybrid immunity, derived from the combined protection of natural and vaccine-induced immunity, has been explored in the older adult population. In a Canadian test-negative case–control study during Omicron predominance, adults aged ≥ 60 years with both prior SARS-CoV-2 infection and ≥ 2 vaccine doses were well protected against hospitalization for a prolonged period [48]. A preprint study showed that, at the molecular level, hybrid immunity is more diverse against a wide range of SARS-CoV-2 epitopes and elicits both broad and potent antibody responses [49]. Additional research is needed on reformulated vaccines, varied disease severity, and hybrid immunity in at-risk populations over time in the context of new variants to determine the direction of future COVID-19 booster vaccine campaigns [48].

SARS-CoV-2 infection may also exhibit seasonal dynamics characteristic of other ARIs, although firm seasonality conclusions cannot be drawn until further post-pandemic data are available from various global regions (Fig. 1). In the United States and Europe, infections peaked in November through April during 2020 through 2022 [50]. Asynchronous surges of SARS-CoV-2 were observed across different geographical regions in the northern hemisphere (e.g., between October and January in New York City, United States, and January and March in Yamagata, Japan) [51]. The limited years of circulation, changing transmission dynamics during the pandemic, and global variation in public health interventions complicate the prediction of SARS-CoV-2 seasonality; therefore, classification should be made cautiously during the transition from pandemic to endemic disease, with sustained transmission throughout the year anticipated for the foreseeable future [51].

To date, global concerns for ARIs remain, with observed increases in the incidence of influenza virus, RSV, and SARS-CoV-2 (JN.1 strain) infections in the 2023–2024 winter season in the northern hemisphere [52]. Given the competing risk among older individuals infected with ARIs (i.e., individuals who died from COVID-19 during the pandemic who otherwise may have been infected by other respiratory viruses), mortality from respiratory infections may increase as this vulnerable population returns to pre-pandemic patterns of behavior.

Comparison of Immunity After Infection

A robust adaptive immune response following ARIs is vital for durable immunity against reinfection [53]. Key elements of this response include long-lived plasma B cells, which are responsible for maintaining high levels of neutralizing antibodies for protection against reinfection with homologous virus, as well as long-lived memory T cells, which provide functional protection by lessening disease severity caused by reinfection with variants that escape antibody-mediated immunity [53]. Gene expression profiling of individuals infected with ARIs demonstrated greater B- and T-cell production following influenza and RSV compared with SARS-CoV-2, suggesting that the former viruses elicit stronger adaptive immune responses; however, the implications of these findings on the duration of immunity against reinfection are unclear [54]. Additionally, while ARIs can elicit durable antibody responses, reinfection with antigenically drifted variants can occur for influenza virus and SARS-CoV-2 [53]. In contrast, the genetic variability of RSV is relatively low, and repeated infections therefore cannot be explained by antigenic variation; immunomodulation is another means by which viruses could shorten the duration of immunity and may contribute to reinfections [53]. Research is ongoing on the longevity of the protective immune responses generated following ARIs [53].

Clinical Presentation and Transmission

Signs and Symptoms

Influenza virus, RSV, and SARS-CoV-2 infections are associated with a wide range of symptoms and have similar clinical presentations (Table 2) [55–57]. Given that symptoms may vary from person to person and multiple symptoms overlap, with fever, cough, and runny nose especially prominent, diagnostic tests are vital to confirm and distinguish among these ARIs [55–57]. Of note, apart from the epidemiologic circumstance of a large community outbreak, clinicians experience difficulty making a differential respiratory virus diagnosis without diagnostic testing or advanced computerized screening tools [58]. The exception may be loss of smell (anosmia) and taste (ageusia) because these symptoms occur more often among patients with SARS-CoV-2 compared with those with influenza [59]. COVID-19 symptoms vary widely [57] and have changed since the beginning of the pandemic; changes in clinical presentation are anticipated to continue due to immunity from vaccination and/or repeated infection exposure, evolution of variants, and use of antivirals [60]. Similarly, the interval between SARS-CoV-2 infection and symptom onset has also shifted throughout the course of the pandemic, with incubation periods shortening as the virus evolved [61].

Table 2.

CDC-defined symptoms associated with influenza virus, RSV, and SARS-CoV-2 infections [55–57]

Symptom	Influenza virus	RSV	SARS-CoV-2
Chills	✓		✓
Cough	✓	✓	✓
Decrease in appetite		✓
Diarrhea	✓		✓
Fatigue	✓		✓
Fever	✓	✓	✓
Headaches	✓		✓
Muscle/body aches	✓		✓
Nausea			✓
New loss of taste or smell			✓
Runny nose	✓	✓	✓
Shortness of breath/difficulty breathing		✓a	✓
Sneezing	✓	✓
Sore throat	✓	✓a	✓
Vomiting	✓		✓
Wheezing	✓	✓

Influenza virus, RSV, and SARS-CoV-2 infections are associated with a wide range of symptoms and may present differently in each individual. The table presents possible symptoms for individuals regardless of age and is not intended to be exhaustive

CDC US Centers for Disease Control and Prevention, RSV respiratory syncytial virus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

^aBased on studies that assessed adults and older adults [169, 170]

Disease severity of respiratory infection ranges from mild illness or asymptomatic infection not requiring medical attention to severe illness, respiratory distress, and death, chiefly among high-risk populations [3, 62, 63]. Individuals aged ≥ 65 years are at greater risk of developing serious complications as a result of influenza infection, such as pneumonia, myocarditis, encephalitis, myositis, rhabdomyolysis, multiple organ failure, sepsis, and worsening of chronic conditions [56]. Older adults are also at increased risk of progression to worsening RSV disease; upon chest examination, 30–40% experience wheezing and rales indicative of lower respiratory tract involvement, and ≤ 10% develop pneumonia [63]. Moreover, adults aged ≥ 50 years are at increased risk of progressing to severe COVID-19, characterized by shortness of breath, decreased blood oxygen saturation, and lung infiltrates on imaging, as well as critical COVID-19 with respiratory failure, septic shock, and multiple organ failure [62]. Chronic comorbidities are key clinical risk factors that impact respiratory disease severity and outcomes, as detailed in Supplement article 2.

Viral Transmission

Influenza viruses, RSV, and SARS-CoV-2 are transmitted from person to person via respiratory droplets or aerosols contaminated with the virus that are expelled during coughing, sneezing, and/or talking and enter the eyes, throat, mouth, and respiratory tract (Fig. 1) [64–68]. Physical contact with infectious individuals or contact with contaminated surfaces or objects (fomites) can result in infection with these viruses [64–68]. The importance of airborne transmission of virus-laden aerosols is being debated among scientific and regulatory bodies and is argued to be more prevalent than previously acknowledged for respiratory pathogens [68, 69].

Respiratory viruses can be transmitted by infectious presymptomatic, asymptomatic, or symptomatic hosts [68]. Presymptomatic transmission of SARS-CoV-2 has been shown to be possible, with the potential for viral shedding thought to be modulated by the pre-existing immunity and vaccination status of the infected individual [68]. Similarly, presymptomatic influenza virus shedding also occurs, particularly among children, who are the primary drivers of influenza transmission within the population [70]. The viral transmissibility of influenza, RSV, and SARS-CoV-2 differs, as captured by the epidemiologic metric R₀ (the basic reproductive number) [71–74]. In comparison with influenza and RSV [71, 72], the R₀ for SARS-CoV-2 was higher and increased during the pandemic as variants emerged [73, 74]. Transmissibility of SARS-CoV-2 will require continual reassessment as the virus evolves and population immunity accumulates.

Disease Surveillance and Diagnostic Testing

Surveillance

Regional, national, and global virologic and disease surveillance systems have been established to ensure continual monitoring of ARIs (examples of which are listed in Table 3). Accurate knowledge of viral activity supports appropriate preparedness and response to outbreaks and informs prevention strategies to reduce disease severity and transmission. Certain networks are well established, such as the Global Influenza Surveillance and Response System, which has served as a cornerstone of viral activity monitoring for > 50 years [75]. More recently, multiple RSV surveillance platforms have been developed to better capture RSV burden, including the Global Epidemiology of RSV Network [76] and the Respiratory Syncytial Virus Hospitalization Surveillance Network [77]; the latter is a component of the larger US Centers for Disease Control and Prevention (CDC) Respiratory Virus Hospitalization Surveillance Network (or RESP-NET) that conducts population-based surveillance of US hospitalizations for laboratory-confirmed influenza (FluSurv-NET), RSV (RSV-NET), and SARS-CoV-2 (COVID-NET) infections [77–79].

Table 3.

Examples of select global and country-specific respiratory virus surveillance systems

Name	Surveillance description	Data collection time frame	Region	Additional information
Influenza virus
Global Influenza Surveillance and Response System (GISRS) [75]	Monitors influenza virus in humans through partnership between national influenza centers and WHO collaborating centers	Continuous	Global (129 WHO Member States)	Originated in 1952 Information gathered by GISRS is shared through the FluNet and FluID web-based platforms [83]
FluView [171]	Monitors influenza through multiple surveillance system components, including virologic, outpatient illness, hospitalization, mortality, and long-term care facility surveillance	Weekly	United States
Influenza Hospitalization Surveillance Network (FluSurv-NET) [78]	Collects population-based surveillance data on laboratory-confirmed influenza-associated hospitalizations in children and adults in acute-care hospitals	October 1–April 30 season each year (option to extend beyond this period)	United States (90 counties in 14 states)	Part of the Respiratory Virus Hospitalization Surveillance Network (RESP-NET) Covers approximately 9% of the US population
RSV
Global Epidemiology of RSV Network (GERi) [76]	Uses existing country-specific surveillance data to monitor RSV in primary and secondary care settings	Continuous (pending availability)	Global (Bhutan, Brazil, Cameroon, Chile, Czech Republic, Ecuador, Netherlands, New Zealand, Portugal, Romania, Russia, Singapore, South Africa, Spain, United States, Vietnam)	Launched in 2019
National Respiratory and Enteric Virus Surveillance System (NREVSS) [172]	Collects laboratory data to monitor temporal and geographic circulation patterns of RSV and 6 other viruses	Weekly	United States	Created in the 1980s to monitor seasonal trends in influenza and RSV
Respiratory Syncytial Virus Hospitalization Surveillance Network (RSV-NET) [77]	Collects population-based surveillance data on laboratory-confirmed RSV-associated hospitalizations in children and adults in acute-care hospitals	October 1–April 30 season each year	United States (58 counties in 12 states)	Part of the Respiratory Virus Hospitalization Surveillance Network (RESP-NET) Began tracking RSV-associated hospitalizations in adults in 2016–2017
SARS-CoV-2
WHO COVID-19 Dashboard [81]	Presents COVID-19 cases, deaths, and vaccine use reported by countries, territories, and areas	Weekly	Global (WHO Member State countries)	Implemented by the WHO Health Emergencies Program
COVID-19 Hospitalization Surveillance Network (COVID-NET) [79]	Collects population-based surveillance data on laboratory-confirmed COVID-19-associated hospitalizations in children and adults in acute-care hospitals	Weekly	United States (98 counties in 13 states)	Part of the Respiratory Virus Hospitalization Surveillance Network (RESP-NET) Began tracking COVID-19-associated hospitalizations in adults in 2020 Covers approximately 10% of the US population
Influenza virus, RSV, and SARS-CoV-2
European Respiratory Virus Surveillance Summary (ERVISS) [86]	Provides epidemiologic summaries for influenza virus, RSV, and SARS-CoV-2 through collaboration of the European Centre for Disease Prevention and Control and WHO Regional Office for Europe	Weekly	Europe (European Union/European Economic Area and the WHO European region)

RSV respiratory syncytial virus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, WHO World Health Organization

At the outset of the COVID-19 pandemic, the WHO in coordination with WHO regional offices implemented a global COVID-19 surveillance system to collate data on COVID-19 cases, hospitalizations, and deaths [80]; this system is presently known as the WHO COVID-19 Dashboard [81]. Existing country-level surveillance networks for influenza and RSV were leveraged early in the pandemic to enable prompt monitoring of COVID-19-associated outcomes; for example, US hospitalizations were tracked through the COVID-19 Hospitalization Surveillance Network [79, 82]. Global surveillance systems, including the WHO FluID and FluNet [83], were also adapted to capture COVID-19 cases and SARS-CoV-2 infections [80], a favorable unintended consequence of which was the ability to investigate the impact of the pandemic on other ARIs. Moreover, in most countries with routine disease surveillance, adaptations have been made to include COVID-19 on the list of diseases subject to mandatory reporting [80]. However, influenza and RSV are not always included within notifiable disease lists [84] or are only reported as viral-associated hospitalizations and mortality [85].

As we shift toward routine COVID-19 monitoring in a non-pandemic environment, integrated surveillance efforts across multiple ARIs are a desirable public health approach. For example, the European Center for Disease Prevention and Control and the WHO Regional Office for Europe have launched the European Respiratory Virus Surveillance Summary to disseminate weekly epidemiologic data on influenza virus, RSV, and SARS-CoV-2 [86]. Novel surveillance tools beyond clinical sampling are also under investigation, including wastewater-based approaches for population-level monitoring and outbreak detection that are less vulnerable to variable case ascertainment and independent of symptoms, health-seeking behavior, and clinician monitoring [87, 88].

Testing

Accurate, timely, and inexpensive viral diagnostic techniques are critical for effective surveillance efforts to determine disease burden, assess the public health impact of preventative measures, and generate accurate economic models [28]. Because the symptoms of influenza virus, RSV, and SARS-CoV-2 infection often overlap and are nonspecific, diagnostic tools are essential to confirm infection with a specific virus and to determine the appropriate therapeutic response to prevent the development of severe disease in the at-risk population [89, 90]. Available and preferred diagnostic techniques for the adult population vary across ARIs (Fig. 2). Overall, polymerase chain reaction (PCR) tests are the definitive diagnostic tests for respiratory illness [91–93], although the utility of this diagnostic approach is limited for disease surveillance and screening applications. Due to the highly sensitive nature of PCR testing, this method has limitations, such as the potential for detection of remnant genetic material from noninfectious virus and slow turnaround time [94, 95].

Fig. 2.

Common respiratory infection diagnostic techniques [91–93]. PCR polymerase chain reaction, RSV respiratory syncytial virus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2. Available methods for diagnosis of each respiratory infection are indicated by a black circle. Of these, the preferred testing approach in the adult population for each respiratory virus is indicated in pink

For influenza, direct antigen and rapid molecular assays are available; however, reverse transcription PCR (RT-PCR) tests, which require nasal or throat swabbing, are preferred [91]. Guidance on influenza testing is influenced by setting (i.e., hospital, nonhospital, nursing home) and community prevalence of influenza and other viruses [96]. Although most influenza cases are diagnosed through clinical evaluation, laboratory testing is required for confirmation [3].

Estimations of RSV incidence, hospitalization, and mortality in adults have been hampered by diagnostic challenges, lack of reliable testing, reliance on case definition for diagnosis, and low public and provider awareness [21–23, 25, 97–99]. RSV infections in adults are frequently underrecognized in clinical settings owing to low clinical suspicion; therefore, RSV-specific tests may not be requested, may be substantially delayed [100], and are often costly [101]. Additionally, because limited treatment options are available for RSV in older adults beyond supportive care, obtaining a confirmed diagnosis of RSV may not impact clinical decision-making [25]. A viral diagnosis could curtail unnecessary antibiotic use, although a meta-analysis of respiratory viral testing in emergency departments observed comparable rates of antibiotic use between tested and untested patients [102].

RSV case numbers are anticipated to increase over time due to changing respiratory viral testing practices, including the availability of rapid, real-time reverse transcriptase PCR (rRT-PCR) multiplex assays, which can differentiate RSV, SARS-CoV-2, and influenza viruses in a single panel [103], which has helped increase RSV testing capacity and awareness [104]. A shift towards multiplex testing in the years since the start of the COVID-19 pandemic led to an incidental increase of RSV detection in adults, particularly among those in the outpatient setting [105]. Similarly, a preprint study analyzing RSV epidemiology in 32 US pediatric hospitals between 2013 and 2023 showed that RSV case numbers increased while the proportion of RSV cases requiring hospitalization decreased after the lifting of pandemic restrictions; these shifts in patient volume and apparent clinical severity were associated with substantial increases in RSV testing (18.9-fold increase versus pre-pandemic), particularly in older children, and increased detection of large numbers of cases with mild clinical severity [104]. It is important to note that while the volume of detected RSV cases increased after the lifting of pandemic restrictions, the overall clinical severity of these cases (as measured by hospitalization, ICU admission, or mechanical ventilation) declined [104]. While data on the impact of the COVID-19 pandemic on RSV epidemiology in adults are limited, RSV case numbers in adults have been shown to increase after the pandemic to at least pre-pandemic levels [106].

Laboratory testing for RSV is performed on upper and lower respiratory tract specimens, with rRT-PCR and antigen tests most commonly used [92]. While the sensitivity of rapid antigen detection tests for RSV is greatest in children (estimates of 80–90%), sensitivity decreases with advancing age and infected adults, who likely have pre-existing partial immunity and do not generate a sufficient RSV antigen for a positive test result [23, 92, 107]. As such, rRT-PCR is recommended for adults owing to increased assay sensitivity [92]. Testing of a single sample type, particularly nasopharyngeal swabs of the upper respiratory tract, may lead to the under-detection of RSV [108]. In a systematic review and meta-analysis of RSV sampling methods in adults, the addition of sputum and oropharyngeal samples to nasopharyngeal/nasal swab samples for RT-PCR testing increased RSV detection rates by 52% and 28%, respectively [108]. Therefore, the addition of other sample types may help address limitations of nasopharyngeal sampling, such as detection of lower respiratory tract infections, nasal dryness, and declining nasal viral shedding by 5–6 days post RSV symptom onset [108].

The diagnosis of COVID-19 requires clinical evaluation and confirmation of SARS-CoV-2 infection by laboratory testing using nucleic acid amplification tests (NAATs) such as PCR [109, 110]. Point-of-care and at-home antigen tests are also used; although SARS-CoV-2 antigen tests have lower sensitivity than NAATs and require repeated testing ≥ 48 h apart to confirm a negative result [110], strengths include correlation with the presence of infectious virus and rapid turnaround [94]. Antibody testing is also available but is typically reserved for research settings rather than used for the diagnosis of a current infection [93]. Guidance on COVID-19 testing varies by population and is highly dependent on individual circumstances, such as the presence of symptoms and timing of exposure [93]; nevertheless, a PCR-based approach is considered the gold standard [93].

Future directions of respiratory infection testing include simultaneous detection of multiple viruses and expansion of at-home rapid antigen testing. For example, the US Food and Drug Administration issued an Emergency Use Authorization for a combination viral at-home diagnostic test that detects influenza type A and B viruses and SARS-CoV-2 from nasal swabs [111]. In addition, potential developments in ARI diagnostics include the use of other specimen types beyond nasopharyngeal swabs, such as saliva testing, with numerous benefits of this noninvasive, self-collected, cost-effective approach [112].

Impact of the COVID-19 Pandemic on Respiratory Pathogen Seasonality

A dramatic reduction in the circulation of non-SARS-CoV-2 respiratory pathogens was observed during the first year of the COVID-19 pandemic, mainly due to the introduction of nonpharmaceutical interventions aimed at limiting transmission [113]. Continual monitoring of influenza virus and RSV revealed ongoing disruptions in the usual circulation of these ARIs both during and following the acute phase of the pandemic.

Globally, the incidence of influenza infections was exceptionally low in mid to late 2020 in the wake of lockdowns and travel-related restrictions [114], and in late 2021, a resurgence began with out-of-season activity observed in the southern hemisphere [114]. Seasonal influenza patterns remained atypical in the first half of 2022, with late and protracted seasons in the northern hemisphere and early season activity in the southern hemisphere [114]. Several countries in the southern hemisphere experienced higher or earlier influenza activity in the 2022 to 2023 season compared with the activity seen pre-pandemic [115], including non-temperate regions. In Hong Kong, China, a large influenza wave followed the lifting of mask mandates on March 1, 2023 (after most other public health and social measures against COVID-19 were relaxed beginning in mid-2022) [116]. Changes in the specific circulating influenza strains have also been evident since the emergence of SARS-CoV-2; a preprint study on global surveillance of influenza B/Yamagata revealed a decline in the total number of cases, positivity rate, and prevalence as a fraction of influenza B, although it is too early to definitely declare the extinction of this lineage [117].

The COVID-19 pandemic also disrupted RSV seasonality and diversity worldwide. In the United States, a typical winter RSV epidemic was absent in the 2020–2021 season, and the timing of subsequent RSV seasons shifted; peak infections occurred in July, with an overall longer 2021–2022 season, and a peak occurred in November of the 2022–2023 season [118]. In Australia, before the emergence of SARS-CoV-2, RSV-A and -B subtypes cocirculated with similar prevalence [119, 120]. Genomic analyses of samples obtained before and after the pandemic suggested changes in RSV subtypes over time, a reduction in RSV-A sublineages, and multiple lineages associated with increased infection numbers in 2021 [119, 120]. Conversely, a genomic analysis of symptomatic patients diagnosed with RSV in the United States demonstrated a surge in RSV-A in 2022 [121]. Further sampling and analyses are required to determine if similar trends were observed in other regions and to assess whether regional RSV diversity was restored with the return of global travel [119].

Direct Comparison of Health-Related Outcomes

Numerous observational studies have compared ARI health outcomes across multiple global regions. A cross-sectional analysis compared COVID-19 and influenza outcomes across all ages during the US influenza season between October 2022 and March 2023 and found that medical encounters were more common for COVID-19 than influenza, and that non-ICU hospitalizations and ICU admissions were 4.6-fold higher for COVID-19 versus influenza [122]. In a prospective analysis of US adults aged ≥ 60 years who were hospitalized between February 2022 and May 2023, patients hospitalized with RSV experienced more severe outcomes and were more likely to receive standard-flow oxygen therapy, high-flow nasal cannula, or noninvasive ventilation, or to be admitted to the ICU; however, RSV-associated hospitalizations were less frequent than influenza- and COVID-19-associated hospitalizations (5.3% versus 12.9% and 81.8%, respectively) [123]. In Germany, the cumulative incidence was 12.6% for SARS-CoV-2, 7.9% for RSV, 5.3% for influenza A, and 0.4% for influenza B following self-testing of approximately 1400 symptomatic adults within a volunteer registry during the winter and spring 2022 to 2023 season [124]. In a Swedish retrospective cohort study of adults visiting emergency departments between August 2021 and September 2022, Omicron infections were more commonly diagnosed and associated with more severe outcomes compared with influenza and RSV; these associations were notable among unvaccinated patients with COVID-19, as demonstrated by a 30-day mortality adjusted odds ratio of 5.5 (95% CI 3.4–9.2) compared with influenza and 3.3 (95% CI 2.0–5.6) compared with RSV [125].

As described above, differences in ARI-specific trends in health-related outcomes were evident throughout the COVID-19 pandemic. COVID-19 is no longer considered a public health emergency, and although it still causes more severe disease and higher mortality in comparison to other ARIs, the differences in these rates are much smaller than those seen at the beginning of the pandemic [126]. According to US CDC data, COVID-19-related hospital admissions have declined year-over-year since 2022; in the 2023 to 2024 respiratory seasons, winter peaks in COVID-19 hospitalizations more closely resembled those of RSV and influenza [126]. The reduced threat of COVID-19 and similarities across ARIs have led public health officials to group these common viruses under one respiratory umbrella for unified guidance [126].

Simultaneous circulation and coinfection with respiratory viruses may modulate the course and severity of either infection with downstream clinical implications [127]. Virus–virus interactions, termed viral interference, can be negative (antagonistic), resulting in limited infectivity of the second virus, or positive (additive or synergistic), with more aggressive pathogenesis and disease severity [128]. Attribution of enhanced disease severity to coinfection should be made cautiously, given that the most vulnerable populations are typically studied most carefully. Among hospitalized UK adults with SARS-CoV-2 infection between 2020 and 2021, influenza virus coinfection was associated with increased odds of in-hospital mortality and use of invasive mechanical ventilation; however, SARS-CoV-2 coinfection with RSV was not associated with increased odds of adverse outcomes [129]. Of note, health-seeking behaviors and vaccination status were not captured in this study [129], limiting generalizability. In a Bulgarian study, adults aged > 65 years with SARS-CoV-2 and seasonal respiratory virus coinfection from 2020 to 2022 required hospital stays an average of 9 days longer than those required by younger individuals with co-infection [130]. The consequences of coinfection may depend on the types of viruses involved and their virus-specific cellular responses. For instance, coinfection of human lung cells with influenza A and RSV led to influenza A replication at equivalent or marginally higher titers compared with influenza A infection alone, whereas RSV replication was reduced during coinfection [131]. The impact of ARIs on one another should continue to be explored because coinfections may aggravate clinical conditions and present barriers to diagnosis and treatment for worsening prognosis [130].

Long-Term Health Consequences

Cardiovascular and Pulmonary Complications

Influenza virus, RSV, and SARS-CoV-2 infections may precipitate cardiovascular complications in both the acute and postacute phases of infection. In a self-controlled case series of patients aged ≥ 35 years, laboratory-confirmed influenza virus infection was associated with acute myocardial infarction, with an approximately sixfold higher incidence of hospital admission during the 7 days after laboratory confirmation of infection compared with a control period (incidence ratio 6.1; 95% CI 3.9–9.5) [132]. Cardiovascular complications of RSV infection have also been documented, with ≤ 22% of adults hospitalized with RSV experiencing cardiovascular events, including acute heart failure, congestive heart failure, and myocardial infarction [133, 134]. Comprehensive longitudinal assessments of long-term sequelae following SARS-CoV-2 infection revealed multiple adverse cardiovascular outcomes by 30 days after infection, with elevated risks of cerebrovascular disorders, dysrhythmias, inflammatory heart disease (including myocarditis and pericarditis), ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [135]. Notably, these associations were independent of demographic characteristics or pre-existing cardiovascular disease [135].

Respiratory infections can worsen pre-existing pulmonary conditions, including chronic obstructive pulmonary disease (COPD) and asthma. Approximately half of acute COPD exacerbations are estimated to be caused by respiratory viral infections, with influenza virus and RSV among the most commonly detected pathogens [136]. Among adults aged ≥ 45 years with comorbidities in Denmark and Scotland, rates of RSV-associated hospitalizations were five to sixfold higher in those with COPD and two to threefold higher in those with asthma compared with rates in the overall population in this age group [137]. SARS-CoV-2 infection has also been implicated in acute COPD exacerbations [138] and worsening of asthma symptoms for several months after infection, requiring treatment modification to achieve asthma control [139]. Accumulating evidence of the long-term health consequences of ARIs includes a complicated and poorly understood relationship with other organ systems beyond the heart and lungs, such as the brain [140–142].

Long COVID

Long-term sequelae following SARS-CoV-2 infection, often referred to as long COVID among other names, can present across multiple organs and systems, including the heart, lungs, immune system, pancreas, gastrointestinal tract, neurologic system, kidney, spleen, and liver [143]. One year after initial infection, the risk increases for cardiometabolic complications (including cardiac arrest, heart failure, embolism, stroke, and type 2 diabetes), myalgic encephalomyelitis/chronic fatigue syndrome, and dysautonomia [143]. The incidence of long COVID among individuals aged ≥ 65 years with a previous COVID-19 diagnosis is between 25 and 33% [144]. Data are inconsistent regarding the relationship between long COVID and older age, with some studies reporting older age as a contributor to prolonged symptomology [145] and others not reporting a positive linear association [146, 147]. This may reflect well-known research challenges in how exactly long COVID has been defined, together with its poorly understood pathogenic mechanism [143]. The long-term effects of COVID may be the result of complex inflammatory processes that remain under investigation or especially severe infections, which are more common in older adults; however, most long COVID cases occur in those with mild illness, as they represent the majority of cases [36, 143]. Notably, chronic sequalae following infection are not a phenomenon unique to SARS-CoV-2 infection; other infectious viral, bacterial, and parasitic pathogens can also cause postacute infection syndromes, albeit they are frequently overlooked and understudied [148].

Frailty

Respiratory viral infections can increase frailty in older adults, adversely affecting their ability to return to baseline health after hospital discharge. Increased frailty is observed among older hospitalized adults diagnosed with influenza illness, along with a high risk of substantial disability as a consequence of infection [13]. Acute functional decline may also be prolonged in older adults hospitalized with RSV infection [149]. In a prospective longitudinal study, a persistent functional decline during the 6 months after RSV hospitalization was reported by 33% of patients, with 8% reporting a loss of independence [149]. Frailty among older adults is a potential long-term effect after recovery from the acute phase of SARS-CoV-2 infection; although the precise mechanisms involved are not well understood, mediators of frailty may stem from the infection itself and/or enforced lack of mobility during periods of high transmission and strong interventions to restrict contact [150].

Life Expectancy

The 20th-century influenza pandemic and the recent COVID-19 pandemic both had sizeable impacts on life expectancy, although the predominantly affected age groups varied considerably [151]. The 1918 influenza pandemic resulted in exceptionally high death rates with a W-shaped mortality age profile, with a substantial impact on young- and middle-aged adults, and was responsible for an estimated 0.5% of US deaths and a reduced life expectancy at birth of 11.8 years [152]. In contrast, during 2021, COVID-19 was estimated to be an underlying or contributory cause in 13.3% of recorded deaths in the United States [153]. The 1 million COVID-19-related US deaths from February 2020 to May 2022 contributed to a decreased life expectancy of 3.1 years at birth, 3.0 years at age 35 years, and 2.1 years at age 65 years [154]. Globally, 5.9 and 10.0 million excess deaths were attributable to the COVID-19 pandemic in 2020 and 2021, respectively, with global life expectancy declining by 1.6 years between 2019 and 2021, representing the first decline in global life expectancy in over 50 years [155].

Economic Burden

Beyond the clinical burden, ARIs among older adults place a substantial financial burden on society and healthcare systems. A 2024 systematic literature review of 18 English-language studies published from 2012 through 2022 reported that the overall economic burden of influenza in North America, Europe, Asia, and Africa was high in adults aged ≥ 65 years [156]. Heterogeneity among study designs limits direct comparisons between studies [156], necessitating the exploration of cost estimates at the individual study level. In the United States, for example, the annual total economic burden of seasonal influenza on the healthcare system was estimated to be $3.2 billion (2015 USD), with the greatest share of total direct medical costs (43%) in adults aged ≥ 65 years [157]. In the US Veterans Affairs population, a predominately older male population with a high disease burden, influenza epidemics from 2010 through 2014 were responsible for $48 million in annual direct medical costs ($38 million of which was in the cohort aged 65 + years), with a projected annual society cost of $1.2 billion (costs reported in USD averaged over five respiratory seasons) [158].

RSV infection also places financial strain on the healthcare system. A global systematic literature review of 42 studies on the economic and healthcare resource utilization burden in adults with RSV found that, although data were limited in non-US countries, there was a substantial burden, including incremental cost differences in RSV cases versus controls and before versus after RSV infection [159]. In a study of US hospitalized adults aged ≥ 60 years, the mean costs per hospitalized individual were comparable for RSV and influenza infections (approximately $16,000 versus $15,000 [2013 USD], respectively) [160]. The annual US healthcare economic burden of RSV was $6.6 billion (2021 USD) among adults aged ≥ 60 years, including $2.9 billion in direct costs, $1.1 billion in indirect costs attributable to productivity losses from related morbidity, and $2.5 billion in indirect costs from related mortality [161]. Additionally, the inappropriate use of antibiotics among adults with ARIs is high (for example, approximately 75% of Norwegian adults hospitalized with respiratory tract infections receive antibiotics [162]) and is associated with substantial healthcare costs. Costs for patients with RSV who were prescribed antibiotics in the United States during the 2017 to 2018 and 2018 to 2019 RSV seasons were 49% higher than among those not treated with antibiotics [163]. Despite these estimates, the determination of the exact RSV economic burden is limited by the under-reporting of infection rates due to lack of routine testing, diagnostic testing limitations, and gaps in economic research [159].

The COVID-19 pandemic had undeniable global economic consequences. A systematic review of European studies published through 2021 on the economic burden of the pandemic found that the overall impact was substantial among patients, healthcare systems, and payers [164]. Direct costs were largely due to medical expenses from hospitalizations and ICU admissions, whereas indirect and societal costs were a product of nonpharmaceutical interventions [164]. In the US, total healthcare costs 1 month after COVID-19 diagnosis incrementally increased with patient age (a $7117 mean difference in adults versus controls aged 50–64 years [2020 USD]), with a continual burden through 5 months [165]. Economic consequences at the household level have also been explored by comparing pre- and postpandemic outcomes. For example, in a nationally representative cohort, families with a head-of-household with post-COVID-19 conditions, and to a lesser extent, those with resolved severe COVID-19, were more likely to experience economic hardship [166]. Moreover, there is an undetermined, long-term economic cost due to the substantial number of infections that occurred during the pandemic, particularly prior to the availability of vaccines. Although the precise number of individuals suffering from long COVID is unclear and dependent on definition of the syndrome, the number need not be high to make a considerable impact; for instance, if only 1% of SARS-CoV-2 infections resulted in long COVID, millions of individuals would suffer from a new, long-term chronic condition with associated increased costs. The economic costs of long COVID are just beginning to be uncovered; in a retrospective cohort study in the United Kingdom, costs of primary care consultations were approximately 40% higher among adults with long COVID for ≥ 12 weeks after infection compared with adults without long COVID [167]. Studies on the long-term economic burden of SARS-CoV-2 infection and influenza and RSV infections in at-risk populations beyond the acute stage of infection are of interest for future research.

Conclusions

In conclusion, influenza virus, RSV, and SARS-CoV-2 infections in older adults present a significant health challenge on a global scale, underscoring the need for appropriate measures to improve health outcomes and reduce disease burden. Critical future directions must include improved prevention, treatment, and management strategies, with actionable steps for meaningful change to decrease the burden in this susceptible population. Vaccination has been a critical component in limiting the impact of COVID-19 and influenza through the total number of lives saved and continues to be a key public health strategy and ongoing intervention that will provide benefits across respiratory illnesses (see Supplement articles 4 and 5 for additional details on respiratory vaccines). In conclusion, influenza virus, RSV, and SARS-CoV-2 infections in the elderly population present a significant health challenge on a global scale, underscoring the need for appropriate measures to improve health outcomes and reduce disease burden.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

William P Hanage and William Schaffner conceptualized the manuscript, provided oversight and critical evaluation of the content, and approved the submitted version.

Funding

This Supplement, including the journal’s Rapid Service Fee, was funded by Moderna, Inc.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

William P Hanage is a scientific advisor to Biobot Analytics and has consulted for Merck Vaccines, Pfizer, and Shinogi Inc. William Schaffner has nothing to disclose.

Ethical approval

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