Brendan Mueller

Introduction.  Chikungunya disease is an acute-febrile illness, caused by the Chikungunya virus (CHIKV), which is debilitating, arthritic, and transmitted by mosquitoes in the genus Aedes¹.  Within the past 15 years, there has been a re-emergence of CHIKV outbreaks in temperate regions, as opposed to tropical regions in which the disease is endemic and maintained by a sylvatic cycle¹. CHIKV has a viral incubation period of 3-7 days, presenting with symptoms of fever, myalgias, polyarthralgias, and a maculopapular rash².  Approximately 72-97% of patients are symptomatic, which distinguishes CHIKV from other arboviruses³. Many symptoms disappear with a week; however, polyarthralgias may persist in about 33% of patients for 4 months, 15% of patients for 20 months, and 12% of patients for 3-5 years^2,4. There are several theories for pathogenesis of viral persistence and associated chronic joint disease, although lack of accurate animal models has slowed progress and treatment development^5,10.  Methods. Studies utilizing mouse models have described both acute and chronic histopathological findings which may be responsible for persistent disease⁵.  Additionally, these studies analyze CHIKV persistence in wild-type versus Rag1-/- mice with deficient adaptive immune response to quantify tissue-specific clearing of CHKIV, using RNA from joint-associated tissues to identify chronic forms of disease⁶.  Longitudinal studies following CHIKV outbreaks have led to further analysis of cytokine profiles in both acute and chronic stages of disease^7,8.  Results.  CHIKV-infected mice had a 100% rate of acute myofiber degeneration, leading to cartilage necrosis and periosteal bone proliferation, which may manifest as polyarthralgia and mimic degenerative osteoarthritis⁵. Initial viremia may determine chronic disease status, with high levels of pro-inflammatory cytokines (Interferon-alpha, IL-6) in acute infection and high levels of IL-17 and IL-12 in chronic infection, driving chronic inflammation through macrophage activation^7,8. Chronic CHIKV persistence may be under control of cell-mediated immunity, due to sustained levels of CHIKV RNA in joint-specific tissues in mice lacking B and T cells⁶.  Conclusions. Persistence of joint disease following CHIKV infection may have multiple methods of pathogenesis.  Months after acute infection, local inflammation and pro-inflammatory cytokine production in joint-associated tissues continues to attract monocytes, T-cells, and other proposed immune cells^5,9.  Severity of initial infection, indicated by high viral load, may be predictive of chronic disease and has been associated with high levels of IL-6 and interferon-alpha^7,8. Some animal models have laid the groundwork for future research, but continued studies to analyze mechanism of persistence and aspects of human disease manifestation are necessary.

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