Circulating Biomarkers Associated with Severe Respiratory Syncytial Virus Infection in Infants Under 2 Years: A Systematic Review

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in infants, but circulating biomarkers for severity stratification remain insufficiently validated. This systematic review evaluated circulating biomarkers associated with acute RSV disease severity in children aged≤ 24 months. PubMed, Web of Science, and Scopus were searched for English-language reports published between 1 January 2016 and 1 March 2026, with the last searches performed on 1 March 2026. Study-level risk of bias was assessed using the Newcastle–Ottawa Scale or the Joanna Briggs Institute checklist, according to study design. Findings were synthesized descriptively using study-level effect estimates and reported severity-discrimination measures. Twenty-four studies contributed 174 extractable comparisons. Biomarker associations varied across populations, age strata, sampling times, and severity definitions, and reproducibility across independent cohorts was limited. In one cohort, fibrinogen and the fibrinogen-to-albumin ratio (FAR) showed large differences between severity groups; FAR had a reported AUC of 0.875. These findings do not establish comparative superiority or external validity. Important limitations include heterogeneous clinical comparisons, limited confounder adjustment, and predominantly single-cohort evidence. Current evidence does not support using FAR, the neutrophil-to-lymphocyte ratio (NLR), or other circulating biomarkers alone to predict subsequent clinical deterioration. Whether these markers add useful information to clinical assessment requires prospective validation. Registration: PROSPERO, CRD420261471336.