Emergence and Clinical Insights into the Pathology of Chikungunya Virus Infection

Marie Christine Jaffar-Bandjee; Duksha Ramful; Bernard Alex Gauzere; Jean Jacques Hoarau; Pascale Krejbich-Trotot; Stephanie Robin; Anne Ribera; Jimmy Selambarom; Philippe Gasque

Disclosures

Expert Rev Anti Infect Ther. 2010;8(9):987-996. 

In This Article

Chronic Arthralgia, Pain & Arthritis Post-CHIK

Several reports on chronic pain related to CHIKV infection have been published. Many of these patients do not respond well to usual analgesics, suggesting that the nature of chronic pain may be not only nociceptive, but also neuropathic. A cross-sectional study at the end of the major two-wave outbreak in La Réunion assessed pain in 106 patients visiting general practitioners with confirmed infection with CHIKV, and evaluated its impact on quality of life.[69] A total of 56 patients fulfilled the definition of chronic pain. Pain was neuropathic in 18.9% of patients. The mean pain interference in life activities calculated from the Brief Pain Inventory was significantly higher in patients with chronic pain than in patients without it. This score was also significantly higher in patients with neuropathic pain than in those without.

Persistent symptoms, mainly joint and muscular pain and depression, have been reported several months after CHIKV infection. A retrospective cohort study on 199 patients[70] described the frequency of prolonged clinical manifestations of CHIKV infection and measured the impact on quality of life and healthcare resource consumption in comparison with that of an unexposed population, more than 1 year post-infection (PI). More than 1 year following the acute phase of infection, CHIK-positive subjects reported more disabilities than those who were CHIK-negative. These persistent disabilities, however, have no significant influence on medical consumption, and the impact on quality of life was moderate. In the acute phase, as most normal antalgic and anti-inflammatory treatments failed, many patients were given various doses of prednisone (0.5–1 mg/kg), since during the chronic phase, low-dose prednisone (≤10 mg/day) was used.

Long-term CHIKV rheumatic manifestations seem to be a frequent underlying post-epidemic condition. At the 15-month-evaluation period after diagnosis, 84 out of 147 participants (57%) reported rheumatic symptoms. Of these 84 patients, 53 (63%) reported permanent trouble, while 31 (37%) had recurrent symptoms. Age 45 years or older, severe initial joint pain and presence of underlying osteoarthritis comorbidity were predictors of nonrecovery.[7]

Particularly in elderly patients (those over 60 years of age), CHIKV had rather profound acute arthritogenic activities and could contribute to chronic incapacitating arthritis as described for several alphaviruses.[71–75] Rheumatic manifestations in up to 50% of the adult patients (6 months–1 year PI) typically consisted of a febrile arthritis mainly affecting the extremities (ankles, wrists and phalanges).[7,76–80] Typically, the joint symptoms occurred in a relapsing manner but involved the same anatomical location. Pain within or around tendons was also a common trait and evolved to tenosynovitis. Chopra et al. reported high levels of CHIKV IgM antibodies in a cohort of Indian patients with post-CHIKV rheumatoid arthritis (RA)-like illnesses.[81] These patients were clearly naive for musculoskeletal disorders prior to CHIKV infection. Surprisingly, few were positive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Tenosynovitis/enthesopathy rather than synovitis was evidenced by ultrasonography in several cases, and these unique observations are in agreement with our x-ray imaging of enthesitis in post-CHIK RA patients in La Réunion [Ribera A, Pers. Comm.]. The ongoing cohort studies of Chopra et al. and ourselves (6 months–1 year PI) did not reveal any major RA classic erosions of the cartilage and bones, and hence the post-CHIK RA is reminiscent of, but distinguishable from, autoimmune RA. Nevertheless, some inflammatory processes were suggested in the Indian study by high levels of C-reactive protein (in over 70% of the cohort), necessitating effective treatment regimes. Patients with a diagnosis of RA following CHIKV infection were given a classical disease-modifying anti-rheumatic drug therapy with methotrexate (up to 0.3 mg/kg/week), salazopyrine (1.5 g–3 g/day), leflunomide (10–20 mg/day) or hydroxychloroquine (200–600 mg/day). In case of inadequate response to methotrexate, treatment was successful with TNF-α blockers (etanercept and adalimumab).[82]

As the chronic disease progresses, more severe cases of arthritis were reported 1–2 years post-CHIKV infection. Some patients with chronic associated rheumatism developed progressive erosive arthritis.[76,80,83] In the study of Manimunda et al., it was confirmed that the level of rheumatoid factor and anti-cyclic citrullinated peptide antibodies was not elevated, in contrast to what is known in canonical autoimmune RA.[80] In the same study, a third of the patients who had joint pain met the American College of Rheumatology criteria to classify them as having RA. The MRI findings were joint effusion, erosion of the bone, marrow edema, synovial thickening, tendinitis and tenosynovitis. The authors conclude that CHIK arthritis is a chronic inflammatory erosive arthritis.

It has recently been demonstrated that CHIKV infection in cynomolgus macaques mimics CHIKV infection in humans. The viral, clinical and pathological features observed in human disease can be observed in these animals.[84] Moreover, viral antigens and RNA (3 months PI) was observed in joints, muscles, lymphoid organs and liver. This seminal study suggests that arthritogenic CHIKV could persist for extended periods, despite the presence of antiviral antibodies and T-cell responses. The same conclusions were drawn in a longitudinal study of 49 hospitalized CHIKV patients from La Réunion subsequently categorized into two distinct groups at 12 months PI.[57] Comprehensive analyses of the clinical and immunological parameters throughout the disease course were studied in either the 'recovered' or the 'chronic' groups to identify prognostic markers of arthritis-like pathology post-CHIKV disease. It was found that the 'chronic' group consisted mainly of more elderly patients (over 60 years) and with much higher viral load (up to 1010 viral RNA/ml) during the acute phase. Interestingly, the antiviral immune response witnessed by high levels of IFN-α mRNA in peripheral blood mononuclear cells and circulating IL-12 persisted for months only in the 'chronic' group. Remarkably, CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 months PI. We found that CHIKV persisting in the synovial tissue was associated with fibroblast hyperplasia and strong angiogenesis, leading to cell apoptosis (identification of cleaved poly[ADP-ribose]-positive polymerase cells) and tissue lesions as evidenced by high levels of matrix metalloproteinase 2.[57] These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment, but with immunosuppressive function in the context of viral persistence. As the development and characterization of primate models for CHIK fever represent a significant advance that has already increased our understanding of the disease, it is hoped that this model of CHIKV physiopathology could allow the development of new therapeutic and prophylactic strategies. It provides a possible explanation for the long-lasting symptoms observed in humans and demonstrates the existence of a relationship between the amount of inoculated virus, the viremia and the disease.

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