A Cluster Randomized Study to Explore Case Definitions, Clinical Course and Consequences of RSV in Community-Dwelling Adults Aged ≥ 50 Years

Introduction: In Europe, surveillance of respiratory syncytial virus (RSV) has been recently incorporated into existing influenza monitoring platforms that are based on influenza-like illness (ILI) or acute respiratory infection (ARI) case definitions. This study aims to compare RSV rates captured by ARI versus ILI case definitions and to describe the clinical and economic trajectories of RSV in older adults. Methods: The study was conducted in Italy during the 2023/2024 and 2024/2025 seasons. Thirty-eight general practitioners were randomized 1:1 to enroll individuals ≥ 50 years presenting for care and meeting the European criteria for ARI or ILI, respectively. Alternative definitions were also explored. All subjects were tested for respiratory pathogens. RSV-positive individuals were followed for up to one month. Results: Of 1431 patients (ARI: 741; ILI: 690) included, 5.2% tested positive for RSV. Odds of RSV in the ARI group (5.8%) was 26% higher than in the ILI group (4.6%) [odds ratio (OR) 1.26; 95% CI 0.60–2.65]. Exclusion of GPs with unexpectedly low enrollment rates increased the OR to 1.67 (95% CI 0.80–3.42). Conversely, adults in the ILI group showed higher rates of influenza A (OR 0.83; 95% CI 0.47–1.44) and SARS-CoV-2 (OR 0.57; 95% CI 0.34–0.95). A proposed alternative case definition, denoted as ARI with wheezing and/or productive cough and/or rhonchi and/or dyspnea was sensitive at 92.0% and specific at 30.8%. Among 75 RSV-positive outpatients, the case-complication, case-hospitalization and case-fatality rates were 30.7%, 2.7%, and 1.3%, respectively. The mean costs per RSV case were € 168.71 from the payer perspective and up to € 899.51 from the societal perspective. Conclusions: Compared to a highly sensitive ARI definition, ILI-based surveillance likely underestimates the incidence of RSV. Further qualifiers can enhance specificity of the ARI case definition. The study confirms a significant burden of RSV in older adults.