CCL5 Levels, Disease Progression, and Mortality in Respiratory Viral Infections: A Systematic Review and Meta-Analysis.

IMPORTANCE: The role of chemokine C-C motif ligand 5 (CCL5) in respiratory viral infections remains controversial; although essential for viral clearance, it is also implicated in pathogenic hyperinflammation. OBJECTIVE: To quantify associations between CCL5 levels and unfavorable disease progression and mortality in respiratory viral infections. DATA SOURCES: Medline and PubMed, Embase, Scopus, Web of Science, the Cochrane Library, CABI Digital Library, and Global Health (Ovid) were searched from inception to October 1, 2025. STUDY SELECTION: Observational studies evaluating the association of CCL5 levels with clinical severity or survival in patients with confirmed respiratory viral infections. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed risk of bias (Newcastle-Ottawa Scale) and certainty of evidence (GRADE). Data were pooled using a random-effects model following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analysis was performed from September 2025 to December 2025. MAIN OUTCOMES AND MEASURES: Unfavorable disease progression (severity) and all-cause mortality. RESULTS: The meta-analysis included 18 studies (2376 patients; median age, 58.2 [range, 0.08-65.0] years; 1278 of 2126 male [60.1%]); 12 studies (67%) were of high methodological quality. Eleven studies (1214 patients) evaluated disease progression and 7 (1162 patients) evaluated mortality. Elevated CCL5 levels were associated with reduced odds of unfavorable disease progression (OR, 0.78; 95% CI, 0.71-0.85; I2 = 0%) and mortality (OR, 0.65; 95% CI, 0.55-0.76; I2 = 23.1%). The protective association had significantly larger effect sizes for mortality than for disease progression (P = .047 for interaction). Subgroup analyses for disease progression demonstrated consistent protective associations without significant interaction by virus type (coronavirus: OR, 0.80 [95% CI, 0.70-0.90] vs noncoronavirus: OR, 0.74 [95% CI, 0.63-0.87]) or age group (pediatric: OR, 0.79 [95% CI, 0.69-0.90] vs adult: OR, 0.75 [95% CI, 0.63-0.88]). Results remained consistent in sensitivity analyses. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of 18 observational studies, elevated CCL5 levels were associated with favorable outcomes and survival in respiratory viral infections, reflecting a competent antiviral immune response rather than pathogenic hyperinflammation. These findings suggest that CCL5 may serve as a prognostic biomarker for risk stratification.