Blood-based biomarkers associated with long COVID: an updated systematic review

Clinicians currently lack a validated biomarker-based approach to classify Long COVID (LC) patients. This limits standardized evaluation, treatment planning, and follow-up. We systematically searched PubMed, CINAHL, and Embase for peer-reviewed studies that evaluated blood-based biomarkers in adults with LC. Eligible studies included LC patients and either healthy donors (HD) or recovered individuals without LC (Re), with extractable biomarker data measured in serum or plasma. Across 57 eligible studies, 144 biomarkers differed significantly between LC patients and HD or Re comparators. Among 31 studies comparing LC with HD, four reported C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) as elevated. Among 36 studies comparing LC with Re, interleukin (IL)-6 (six studies), TNF-α (five studies), IL-1β (four studies), and CRP (four studies) were most frequently reported as elevated. These findings are consistent with recurrent inflammatory abnormalities in subsets of individuals with LC. Building on these results and our previous review, we propose a candidate framework for prioritizing routinely available and exploratory biomarkers for longitudinal and prospective clinical validation.