BACKGROUND: Data on the natural history of the community-acquired RSV in adult outpatients are limited. It is also unclear whether the existing influenza surveillance platforms based on influenza-like illness (ILI) case definitions are efficient for RSV. The two-season RESPIRA-50 study was established in 2023 to identify an optimal RSV case definition and to explore the natural history of RSV. Here, the first-season results are reported. METHODS: The study was conducted in Genoa (Italy) during the 2023/2024 RSV season. Twenty-four general practitioners were randomized 1:1 to enroll adults aged ≥ 50 years seeking care for acute respiratory infection (ARI) or ILI, respectively. Both syndromes were defined according to the European criteria. All subjects were tested by real-time polymerase chain reaction (RT-PCR) for RSV and other pathogens. RSV-positive adults were followed for up to 30 days. RESULTS: Of 517 subjects included, 7.0 % [95 % confidence interval (CI): 4.9-9.5 %)] tested positive for RSV. RSV prevalence in the ARI group (8.0 %
95 % CI: 5.0-12.1 %) was higher than in the ILI group (6.0 %
95 % CI: 3.5-9.5 %) with an odds ratio of 1.36 (95 % CI: 0.69-2.70). Conversely, positivity for influenza (10.4 % vs 12.4 %) and SARS-CoV-2 (12.4 % vs 16.9 %) were lower in the ARI group and the corresponding ORs were 0.82 (95 % CI: 0.48-1.42) and 0.70 (95 % CI: 0.43-1.15), respectively. The mean duration of an RSV episode was 18.8 ± 8.0 days and two thirds of individuals were prescribed antibiotics. A total of 33.3 % (95 % CI: 18.6-51.0 %) of RSV-positive individuals developed complications, of which bronchitis (13.9 %) and pneumonia (8.3 %) were the most frequent. CONCLUSIONS: Compared with ARI, ILI-based surveillance may underestimate the burden of RSV in community-dwelling adults aged ≥ 50 years. A high proportion of RSV-positive adult outpatients develops complications, which lead to substantial resource consumption.