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

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 RSV-detection 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. RSV-AFs 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. Key point The attributable fraction of illness is key to accurate burden estimates, specifically in the presents of sensitive PCR testing. Burden and cost burden estimates are key to cost-effectiveness model for new prevention technologies in the pipeline for respiratory syncytial virus. ### Competing Interest Statement Prof Cheryl Cohen and Anne von Gottberg has received institutional funding support from US CDC related to the current work and also received funding from Bill and Melinda Gates Foundation (BMGF), PATH, Sanofi, Wellcome Trust and South African MRC outside of the submitted work. Dr Moyes received institutional funding from Sanofi and PATH for work outside of this current work. Dr Dawood reports personal fees from Sanofi-South Africa. In addition, she reports workshop attendance sponsorship from Biomieruex-South Africa. ### Funding Statement The data collection for this manuscript was funded through a grant to the NICD from the Centers for Disease Control (CDC), Atlanta Georgia. Collaborative Research on Influenza, Coronavirus Diseases 2019 (COVID-19), and Other Respiratory Pathogens in South Africa (Cooperative Agreement Number: 1U01IP001160) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the hospital-based surveillance was obtained from the University of the Witwatersrand Human Research Ethics Committee (HREC) for the Klerksdorp site and form the University of KwaZulu-Natal Human Biomedical Research Ethics Committee (BREC) for the Pietermaritzburg site; protocol numbers M081042 and BF157/08, respectively. The ILI and control enrolment protocol was approved by HREC and BREC (protocol numbers M120133 and BF080/12, respectively). This surveillance was deemed non-research by the US Centers for Disease Control and Prevention (non-research determination number: 2012-6197). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors