DOI: 10.1001/jamanetworkopen.2026.28987 ISSN: 2574-3805

CCL5 Levels, Disease Progression, and Mortality in Respiratory Viral Infections

Carlos Pita-Martínez, Daniel Sepúlveda-Crespo, Jesús F. Bermejo-Martín, Isidoro Martínez, Salvador Resino
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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; I 2  = 0%) and mortality (OR, 0.65; 95% CI, 0.55-0.76; I 2  = 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.

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