Proinflammatory Cytokines and Chemokines as Biomarkers of Persistent Arthralgia and Severe Disease After Chikungunya Virus Infection: A 5-Year Follow-Up Study in Southern Thailand

Abstract

Chikungunya fever is a re-emerging viral disease caused by chikungunya virus (CHIKV). The disease is generally self-limiting, but chronic arthralgia/arthritis may persist for months or years. We evaluated the expression of 12 cytokines/chemokines and matrix metalloproteinases (MMP)-1 and MMP-3 using enzyme-linked immunosorbent assays (ELISAs) and compared among patients who still had arthralgia (persistent arthralgia), patients who had fully recovered, and healthy controls. There was a significant increase in interleukin (IL)-1<i>β</i>, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), MMP-1, and MMP-3 levels in patients with persistent arthralgia in comparison to healthy controls (<i>p</i> < 0.05) and a significant increase in tumor necrosis factor-alpha (TNF-<i>α</i>), MMP-1, and MMP-3 levels in patients with persistent arthralgia in comparison to patients who had fully recovered (<i>p</i> < 0.05). Interferon (IFN)-<i>γ</i>, IL-6, and transforming growth factor beta (TGF-<i>β</i>) levels tended to be increased in patients with chronic CHIKV-induced arthritis compared with fully recovered. TNF-<i>α</i>, IL-12, and MCP-1 levels were elevated (<i>p</i> < 0.05), whereas regulated on activation, normal T cell expressed and secreted (RANTES) levels were decreased in patients with severe pain compared with patients with nonsevere pain (<i>p</i> < 0.05). IFN-<i>γ</i>, IL-1<i>β</i>, IL-6, and IL-8 levels tended to be elevated in patients with severe pain compared with patients with nonsevere pain. We proposed a role played by TNF-<i>α</i>, IL-6, IL-8, and MCP-1 in persistent arthralgia or chronic disease through the activation of MMP-1 and MMP-3. The increase in TNF-<i>α</i>, IL-12, and MCP-1 levels (and the tendency toward an increase in IFN-<i>γ</i>, IL-1<i>β</i>, IL-6, and IL-8 levels) in patients with severe pain compared with patients with nonsevere pain suggests the role of these inflammatory markers in chronic disease and severity of the disease.