Comparison of Respiratory Syncytial Virus Versus Influenza-Associated Acute Respiratory Illness Hospitalizations Among Adults in North America

Respiratory syncytial virus (RSV) and influenza cause substantial acute respiratory illness (ARI) and may be difficult to distinguish clinically. We compared characteristics of adults hospitalized with ARI, diagnosed with RSV versus influenza, using standardized systematic testing. The North American Multi-specimen prospective cohort study was conducted in the US and Canada during two respiratory seasons (2021–2023). Patients aged ≥ 40 years hospitalized with ARI/ARI-compatible symptoms, with symptom onset < 21 days prior to admission, who consented to provide a nasopharyngeal specimen (NPS) and ≥ 1 other specimen (saliva, sputum, or paired acute and convalescent serology) were enrolled. A patient with any specimen positive for RSV or influenza, by Luminex RT-PCR or LDT-RP, was considered positive. Characteristics were reported overall, by RSV positivity, and influenza positivity. Characteristics were compared using chi-square or Fisher’s exact tests; medians were compared using the Wilcoxon rank-sum test. A total of 3669 hospitalized adults were enrolled, 7.6% (278) influenza-positive and 6.4% (233) RSV-positive. Median age was similar for both, with a trend towards a greater proportion of RSV-positive patients aged ≥ 75 years compared to influenza (35.2% vs. 26.6%; p = 0.0837). Compared to influenza, a higher proportion of RSV patients presented with wheezing (27.9% vs. 20.1%, p = 0.040), rhinorrhea (15.0% vs. 8.3%, p = 0.0166), and a lower proportion presented with hypoxemia (18.0% vs. 27.3%, p = 0.0128). The proportion with an illness duration > 7 days trended higher for RSV (64.4% vs. 55.8%, p = 0.1267). Disease severity was similar. In a systematically tested cohort of adults with ARI, across US and Canadian sites, clinical characteristics and disease burden were largely similar for adults with influenza compared to those with RSV. These similarities highlight the need for multiplex viral testing and pathogen-specific surveillance strengthening to improve understanding of disease burden for these viruses that contribute significantly to morbidity and mortality across vulnerable populations. Additionally, with the recent licensure of older adult RSV vaccines, improved characterization of RSV-associated hospitalizations will facilitate vaccine impact evaluations and inform age-specific or risk-based vaccination strategies.