Chronic chikungunya virus musculoskeletal disease: what are the underlying mechanisms?

Chikungunya virus (CHIKV) is a positive-sense enveloped RNA virus that causes large epidemics of musculoskeletal disease, including acute and chronic forms of arthritis. Starting in 2005, CHIKV re-emerged to cause outbreaks of unprecedented scale in islands of the Indian Ocean, India, South East Asia, and Europe [1–5]. In 2013, CHIKV reached the Western Hemisphere, where it is responsible for outbreaks in the Americas that have affected millions [6]. Acute CHIKV infection generally presents with fever, severe joint pain, muscle aches and rash, which subside in 7–10 days. However, up to two-thirds of infected individuals experience an incapacitating arthralgia, which often includes signs of joint inflammation and tenosynovitis that persists for months or years after the acute phase [7,8]. These persistent disease signs and symptoms cause a substantial economic burden and loss of quality of life [7]. Vaccines and antiviral agents are not currently available for CHIKV infection, and treatment is limited to managing symptoms with a nalgesics and anti-inflammatory drugs. Given the high percentage of patients with persistent symptoms following previous CHIKV outbreaks on other continents, it is likely that there will be a substantial population in the Americas with long-lasting pain and disability as a result of chronic CHIKV disease. Initial reports from ongoing outbreaks indicate that chronic disease is already prevalent in parts of the Americas [9–11]. Despite this growing public health concern, the underlying mechanisms of chronic musculoskeletal pain and inflammation following acute CHIKV infection are not well understood. The factors that contribute to the development of chronic CHIKV disease in individual patients are complex and may include: genetic predispositions; pre-existing arthropathy or other co-morbidities; direct virus-induced tissue damage; longterm persistence of CHIKV infection in tissues with concomitant inflammation; and activation of autoimmune responses. Thus, more research in humans and animal models is needed, as identifying effective therapies for the wide spectrum of chronic CHIKV disease manifestations will be challenging without an improved understanding of the molecular mechanisms that contribute to chronic CHIKV disease pathogenesis.