Distinct inflammatory biomarkers associated with rheumatological outcomes in chronic chikungunya disease

Chikungunya virus (CHIKV) poses an enduring public health threat in endemic regions and can progress from acute febrile illness to chronic, disabling rheumatologic disease. We performed an unmatched case-control study of 20 patients sampled during the acute phase (< 14 days) and 20 recruited ≥ 90 days after onset who met criteria for chronic chikungunya disease (CCD). At enrolment we quantified 45 serum cytokines/chemokines by multiplex assay; clinical data were recorded for all, and chronic cases were re-evaluated at 3, 12 and 24 months. CCD participants were older, reported greater initial pain and more often received symptomatic corticosteroids. Acute CHIKV infection showed a focused antiviral signature characterized by higher CCL2, CXCL10, IFN-α and IL-1RA, whereas CCD displayed a broader, non-resolving profile enriched for IL-21, GM-CSF, IL-23, LT-α, IL-4, IL-9, IL-31 and FGF-2. Over follow-up, many CCD cases improved; however, in time-to-discharge analyses, higher IL-23, baseline rheumatoid arthritis, and higher VAS were associated with persistence, whereas higher FGF-2 and IL-4, arthrosis, and anti-CHIKV IgG were associated with earlier resolution. Acute and chronic chikungunya exhibit distinct soluble-mediator signatures. A targeted early antiviral response aligns with recovery, while a broad Th2/Th17-skewed milieu aligns with chronicity. IL-23, for risk, and FGF-2/IL-4, for resolution, emerge as candidate biomarkers for risk stratification and therapeutic trials, alongside clinical factors.