Acute Immunological Profile and Prognostic Biomarkers of Persistent Joint Pain in Chikungunya Fever: A Systematic Review

Chikungunya virus infection (CHIKV) increases the risk of persistent arthralgia; however, there is no consistent evidence regarding prognostic biomarkers of progression to chronic arthropathy. This systematic review provides an overview of currently available literature about the potential role of the acute immunologic response in predicting long-term joint pain in patients with a diagnosis of CHIKV. We searched for observational studies using the terms “chikungunya,” “cytokines,” “biomarkers,” and “joint pain” in PubMed/MEDLINE, LILACS, Cochrane Library Plus, and SCOPUS databases, restricting to articles published in English and up to April 2024. PROSPERO registration number: CRD42021279400. Thirty-eight studies were selected for qualitative synthesis with a maximum duration from diagnosis to clinical evaluation of 60 months. The sample sizes ranged from 8 to 346 participants (age range: 0-90 years). We identified an immunologic profile during the acute phase of CHIKV that includes increased levels of proinflammatory cytokines (IFN-α, IFN-γ, IL-2R, IL-6, IL-7, and IL-8), anti-inflammatory cytokines (IL1Ra and IL-4), chemokines (MCP-1, MIG, and IP-10) and growth factors (VEGF and G-CSF). Only one out of two studies reported differences in cytokine levels during the acute phase, predicting persistent joint pain at 20 months of follow-up. Also, persistence of anti-CHIKV IgG seemed to be a potential prognostic marker. The evidence suggests the existence of an inflammatory response in the acute phase of CHIKV that persists during its chronic phase; however, there is no unequivocal candidate set of biomarkers of progression toward long-term articular sequelae.