Respiratory Syncytial Virus: An Old Foe in a New Era

(See the Major Article by Tseng et al, on pages 1298–310.)

At a time when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dominates headlines, changes our way of life completely, and is taking a devastating toll in the United States and globally, it is difficult to focus on the familiar viral respiratory pathogens. In today’s edition of the Journal of Infectious Disease, Tseng et al [1] remind us of the significant burden of one such virus, respiratory syncytial virus (RSV). Although a familiar foe to pediatricians, it has taken several decades to appreciate the morbidity and mortality due to RSV in adults. Respiratory syncytial virus infection is estimated to be associated with 43 000–177 000 hospitalizations and 10 000–14 000 deaths in older adults each winter in the United States [2–4].

In the current environment, it is hard to not to make comparisons of RSV and SARS-CoV-2-related illness (coronavirus 2019 [COVID-19]), because both viruses disproportionately affect older adults. Notable differences between the infections exist and, importantly, RSV in adults represents reinfection in contrast to a primary infection, and disease pathogenesis appears to be quite different. Nasal congestion and upper respiratory symptoms are common with RSV and can progress to a productive cough, dyspnea, and wheezing. Unlike influenza, and now with COVID-19, fever is not a common feature of RSV [5]. These observations about RSV are confirmed in the current study with more than 60% of patients having sputum production and wheezing and fewer than 40% having measured fever. In contrast, with COVID-19 illness, fever is usually present, and although dyspnea can occur, cough is frequently dry and both rhinorrhea and wheezing are infrequent [6, 7]. Chronic medical conditions predispose to severe illness with both viruses, but specific risk factors differ somewhat, with chronic cardiopulmonary illnesses (congestive heart failure [CHF] and chronic obstructive pulmonary disease [COPD]) most important with RSV, whereas, hypertension, diabetes, and obesity are leading factors for severe disease with SARS-CoV-2 [8]. Finally, both viruses can cause pneumonia, respiratory failure, and death.

In the current study of 664 adults over age 60 hospitalized with RSV, approximately half had radiologically confirmed pneumonia and 21% required ventilator support. Mortality was striking with 30-day, 3-month, 6 month, and 1-year mortality of 8.6%, 12.3%, 17.2%, and 25.8%, respectively. The 1-year death rates of patients 65–74 years old, 75–84 years old, and over 85 years old hospitalized with RSV are 7, 4, and 1.6 times higher, respectively, than rates for the same age groups based National 2018 Mortality Statistics [9]. Although these death rates may, in part, reflect overall frailty of persons hospitalized with RSV, the excess mortality certainly raises the possibility that the RSV infection and hospitalization contribute to long-term mortality and thus is potentially vaccine preventable.

A unique contribution of the current study is an analysis of variables associated with short- and long-term mortality. Not surprisingly, indications of more severe illness such as tachypnea, altered level of consciousness, pneumonia, acute renal failure, new atrial fibrillation, and neurovascular complications were associated with increased short-term mortality. Variables associated with increased mid- to long-term mortality tended to indicate more overall frailty such as advanced age, dementia, and end-stage renal disease. Interestingly, but difficult to explain, was the finding that pre-existing or exacerbated CHF during RSV illness, but not COPD, was associated with the worst 1-year survival (57%) after discharge. Notably, being hospitalized in the 6 months before the RSV hospitalization was associated with increases in both short- and long-term morbidity and appears to identify a group at highest risk for poor outcomes with RSV. Once an RSV vaccine becomes available, it may be reasonable to offer immunization during hospitalization for any reason, similar to the practice for influenza and pneumococcal vaccination.

With the current furious pace to develop a COVID 19 vaccine, it is easy to forget that significant progress had recently been made towards developing an effective RSV vaccine for adults, a goal that has been elusive for decades [10]. After many failed vaccine candidates, the stabilization of RSV prefusion protein has offered new hope [11]. Studies demonstrated markedly improved immunogenicity with prefusion F-based vaccines that can induce significantly higher levels of neutralizing antibody than prior subunit vaccines [12]. The RSV vaccine landscape has finally changed from bleak to bright, with active programs for maternal immunization to protect infants and adult programs for seniors. Although vaccine programs for pathogens other than SARS-CoV-2 have understandably been paused, it is hoped that soon focus may shift back to other important viruses when an effective COVID 19 vaccine is available. The present study not only offers additional support of need for an adult RSV vaccine by demonstrating burden, it also provides useful data for those designing vaccine studies in adults. More importantly, the average rate of positive tests over 5 seasons was 5.4% but varied from a low of 3.3% to a high of 7.6%, indicating a substantial seasonal variation that should be considered in sample size calculations for efficacy trials. The rates of RSV-related outcomes and risk groups observed in this study will inform vaccine trial design as well as implementation once a vaccine is available.

The report by Tseng et al [1] has several limitations. Foremost, the retrospective nature of the study, and the fact that testing for RSV was determined by the treating physician rather than using a standardized case definition, could introduce testing bias. Physicians typically order viral testing based on a desire to diagnosis influenza, and RSV is usually an incidental finding. When RSV and influenza epidemics overlap, the accuracy of RSV burden may be good, but it is less so during seasons when peak RSV and influenza are temporally disassociated. In addition, there may be some bias toward diagnosis of more severe illness because in the new era of “testing stewardship,” physicians may be less likely to test milder cases.

The present study offers new observations and confirms the substantial toll RSV takes in older adults. At this time, it is difficult to know how the COVID pandemic will affect the impact of RSV and other seasonal viruses. Will influenza and RSV activity lead to even more severe outbreaks of respiratory disease if cocirculating with SARS-CoV-2? Or will the efforts to mitigate the spread of coronavirus such as social distancing, masks, and hand hygiene also slow the spread of other pathogens as well. Whatever the effect, it likely will not be business as usual for several years. However, as SARS-CoV-2 hopefully recedes with development of an effective vaccine, old foes will re-emerge and once again deserve our attention.

Notes

Potential conflicts of interest. A. R. F. reports grants from Pfizer, Merck, and Janssen, and other support from Novavax outside of the submitted work. E. E. W. reports grants from Pfizer, Janssen, and Merck outside of the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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