The attributable fraction of respiratory syncytial virus among patients of different age with influenza-like illness and severe acute respiratory illness in a high HIV prevalence setting, South Africa, 2012-2016 Running title: The attributable fraction of RSV in South Africa (all ages), South Africa 2012- 2016

Introduction The detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. Calculating the attributable fraction (AF) of RSV in clinical syndromes could refine disease burden estimates. Methods Using unconditional logistic regression models, we estimated the AF of RSV-associated influenza-like illness (ILI) and severe-acute respiratory illness (SARI) cases by comparing RSVdetection prevalence among ILI and SARI cases to those of healthy controls in South Africa, 2012-2016. The analysis, stratified by HIV serostatus, was conducted in the age categories <1, 1-4, 5-24, 25-44, 45-64, ≥65 years. Results We included 12,048 individuals: 2,687 controls, 5,449 ILI cases and 5,449 SARI cases. RSVAFs for ILI were significant in <1, 1-4, 5-24, 25-44-year age groups: 84.9%(95% confidence interval (CI) 69.3%-92.6%), 74.6%(95%CI 53.6%-86.0%), 60.8%(95%CI 21.4%-80.5%) and 64.1%(95%CI 14.9%-84.9%), respectively. Similarly, significant RSV-AFs for SARI were 95.3%(95%CI 91.1%-97.5) and 83.4%(95%CI 70.9-90.5) in the <1 and 1-4-year age groups respectively. In HIV-infected persons, RSV was significantly associated with ILI cases versus controls in individuals aged 5-44 years. Conclusion High RSV-AFs in young children confirm RSV detection is associated severe respiratory illness in South African children, specifically infants. These estimates will assist with refining burden estimates and cost effectiveness models
Attributable Fraction; Respiratory syncytial virus; Burden of disease