Persisting Mixed Cryoglobulinemia in Chikungunya Infection

Case Western Reserve University School of Medicine, United States of America
PLoS Neglected Tropical Diseases (Impact Factor: 4.45). 02/2009; 3(2):e374. DOI: 10.1371/journal.pntd.0000374
Source: PubMed

ABSTRACT Chikungunya virus (CHIKV), an arbovirus, is responsible for a two-stage disabling disease, consisting of an acute febrile polyarthritis for the first 10 days, frequently followed by chronic rheumatisms, sometimes lasting for years. Up to now, the pathophysiology of the chronic stage has been elusive. Considering the existence of occasional peripheral vascular disorders and some unexpected seronegativity during the chronic stage of the disease, we hypothesized the role of cryoglobulins.
From April 2005 to May 2007, all travelers with suspected CHIKV infection were prospectively recorded in our hospital department. Demographic, clinical and laboratory findings (anti-CHIKV IgM and IgG, cryoglobulin) were registered at the first consultation or hospitalization and during follow-up.
Among the 66 travelers with clinical suspicion of CHIKV infection, 51 presented anti-CHIKV IgM. There were 45 positive with the serological assay tested at room temperature, and six more, which first tested negative when sera were kept at 4 degrees C until analysis, became positive after a 2-hour incubation of the sera at 37 degrees C. Forty-eight of the 51 CHIKV-seropositive patients were screened for cryoglobulinemia; 94% were positive at least once during their follow-up. Over 90% of the CHIKV-infected patients had concomitant arthralgias and cryoglobulinemia. Cryoglobulin prevalence and level drop with time as patients recover, spontaneously or after short-term corticotherapy. In some patients cryoglobulins remained positive after 1 year.
Prevalence of mixed cryoglobulinemia was high in CHIKV-infected travelers with long-lasting symptoms. No significant association between cryoglobulinemia and clinical manifestations could be evidenced. The exact prognostic value of cryoglobulin levels has yet to be determined. Responsibility of cryoglobulinemia was suspected in unexpected false negativity of serological assays at room temperature, leading us to recommend performing serology on pre-warmed sera.

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    • "From our study, the fact that non-linearity characterizes the positive association between CHIK-R and specific IgG levels argues for the contribution of other factors. The possibility of mixed cryoglobulinemia has been suggested [45] but not replicated in observational studies [18]. Long-term persistence of IgM has been reported with CHIKV [27], sometimes associated with erosive arthritis [46], so that it is the timing of antibody commutation rather its significance (putative persistence of CHIKV antigens) that would be of critical importance. "
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    ABSTRACT: Introduction Long-lasting relapsing or lingering rheumatic musculoskeletal pain (RMSP) is the hallmark of Chikungunya virus (CHIKV) rheumatism (CHIK-R). Little is known on their prognostic factors. The aim of this prognostic study was to search the determinants of lingering or relapsing RMSP indicative of CHIK-R. Methods Three hundred and forty-six infected adults (age ≥ 15 years) having declared RMSP at disease onset were extracted from the TELECHIK cohort study, Reunion island, and analyzed using a multinomial logistic regression model. We also searched for the predictors of CHIKV-specific IgG titres, assessed at the time of a serosurvey, using multiple linear regression analysis. Results Of these, 111 (32.1%) reported relapsing RMSP, 150 (43.3%) lingering RMSP, and 85 (24.6%) had fully recovered (reference group) on average two years after acute infection. In the final model controlling for gender, the determinants of relapsing RMSP were the age 45-59 years (adjusted OR: 2.9, 95% CI: 1.0, 8.6) or greater or equal than 60 years (adjusted OR: 10.4, 95% CI: 3.5, 31.1), severe rheumatic involvement (fever, at least six joints plus four other symptoms) at presentation (adjusted OR: 3.6, 95% CI: 1.5, 8.2), and CHIKV-specific IgG titres (adjusted OR: 3.2, 95% CI: 1.8, 5.5, per one unit increase). Prognostic factors for lingering RMSP were age 45-59 years (adjusted OR: 6.4, 95% CI: 1.8, 22.1) or greater or equal than 60 years (adjusted OR: 22.3, 95% CI: 6.3, 78.1), severe initial rheumatic involvement (adjusted OR: 5.5, 95% CI: 2.2, 13.8) and CHIKV-specific IgG titres (adjusted OR: 6.2, 95% CI: 2.8, 13.2, per one unit increase). CHIKV specific IgG titres were positively correlated with age, female gender and the severity of initial rheumatic symptoms. Conclusions Our data support the roles of age, severity at presentation and CHIKV specific IgG titres for predicting CHIK-R. By identifying the prognostic value of the humoral immune response of the host, this work also suggest a significant contribution of the adaptive immune response to the physiopathology of CHIK-R and should help to reconsider the paradigm of this chronic infection primarily shifted towards the involvement of the innate immune response.
    Arthritis research & therapy 01/2013; 15(1):R9. DOI:10.1186/ar4137 · 3.75 Impact Factor
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    • "Commercial enzyme immunoassays and immunofluorescence assays are available, but are of poor performance when expertized [30•]. Interpretation of serological results must be cautious because of 1) possible false negativity due to CHIKV-induced mixed cryoglobulinemia [25], 2) cross-reactivity with viruses of the Semliki Forest serocomplex requiring seroneutralization, and 3) long-term persistence of anti-CHIKV IgM months after disease onset. Synchronous testing of a sample from the acute stage and a sample collected at least 3 weeks later is sufficient to demonstrate a recent CHIKV infection in most cases. "
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    ABSTRACT: Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes, mostly Aedes aegypti and Aedes albopictus. After half a century of focal outbreaks of acute febrile polyarthralgia in Africa and Asia, the disease unexpectedly spread in the past decade with large outbreaks in Africa and around the Indian Ocean and rare autochthonous transmission in temperate areas. This emergence brought new insights on its pathogenesis, notably the role of the A226V mutation that improved CHIKV fitness in Ae. albopictus and the possible CHIKV persistence in deep tissue sanctuaries for months after infection. Massive outbreaks also revealed new aspects of the acute stage: the high number of symptomatic cases, unexpected complications, mother-to-child transmission, and low lethality in debilitated patients. The follow-up of patients in epidemic areas has identified frequent, long-lasting, rheumatic disorders, including rare inflammatory joint destruction, and common chronic mood changes associated with quality-of-life impairment. Thus, the globalization of CHIKV exposes countries with Aedes mosquitoes both to brutal outbreaks of acute incapacitating episodes and endemic long-lasting disorders.
    Current Infectious Disease Reports 04/2011; 13(3):218-28. DOI:10.1007/s11908-011-0180-1 · 1.68 Impact Factor
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    • "Although we did not collect blood samples from unaffected areas (control) for comparison purposes, the possibility of the persistence of IgM anti-CHIKV for one year cannot be ruled out. This apparent persistence of anti-CHIKV IgM is consistent with the observations of both Fourie & Morrison and Gauzere [19,20] who described such persistence of IgM antibodies for up to 12 months in patients suffering from polyarthritis or rheumatoid arthritis after CHIKV infection; and with those of Olivier et al. [21] who recorded 75 and 42% of anti-CHIKV IgM positives, respectively after 7 and 10 months, in French patients with imported CHIKV between 2005 and 2007. These observations closely match the situation in our study where many people were still complaining of recurrent arthralgia (joint pains). "
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    ABSTRACT: Although arboviral infections including Chikungunya virus (CHIKV) are common in sub-Saharan Africa, data on their circulation and prevalence are poorly documented. In 2006, more than 400 cases of dengue-like fever were reported in Kumbo (Northwest Region of Cameroon). The aim of this study was to identify the aetiology of this fever and to define its extent in the area. We conducted a cross-sectional seroprevalence survey one year after clinical investigations to define the extent of the infection. An entomological survey consisted of the collection and identification of mosquito immature stages in water containers in or around human dwellings. A total of 105 sera were obtained from volunteers and tested for CHIKV, O'Nyong-nyong virus (ONNV) and Dengue virus (DENV) specific IgM and IgG antibodies by enzyme-linked immunosorbent assays (ELISA). CHIKV infection was defined as the presence of IgM antibodies to CHIKV. There was serological evidence for recent Chikungunya infection, as 54 subjects (51.4%) had detectable IgM anti-CHIKV in their sera. Amongst these, 52 showed both anti-CHIKV IgM and IgG, and 2 (1.9%) had IgM anti-CHIKV in the absence of IgG. Isolated anti-CHIKV IgG positives were detected in 41 (39%) cases. No anti-ONNV and anti-DENV IgM antibodies were found amongst the sample tested. Out of 305 larvae collected in the different breeding sites, 87 developed to the adult stage; 56 (64.4%) were Aedes africanus and the remaining Culex spp. These findings suggest that the outbreak of febrile illness reported in three villages of Western Cameroon was due to CHIKV. The issue of a possible persistence of anti-CHIKV IgM antibodies is discussed. Ae. africanus which was found to be relatively abundant among the raffia palm bushes probably plays a role in the transmission of CHIKV along the chain of sylvatic/domestic mosquito species in this rural area. Particular attention should therefore be given to arbovirus infections in the Central African sub-region where these infections are becoming an emerging public health threat.
    BMC Research Notes 05/2010; 3(1):128. DOI:10.1186/1756-0500-3-128
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