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      Chikungunya Fever: A Clinical and Virological Investigation of Outpatients on Reunion Island, South-West Indian Ocean

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          Abstract

          Background

          Chikungunya virus (CHIKV) is responsible for acute febrile polyarthralgia and, in a proportion of cases, severe complications including chronic arthritis. CHIKV has spread recently in East Africa, South-West Indian Ocean, South-Asia and autochthonous cases have been reported in Europe. Although almost all patients are outpatients, medical investigations mainly focused on hospitalised patients.

          Methodology/Principal Findings

          Here, we detail clinico-biological characteristics of Chikungunya (CHIK) outpatients in Reunion Island (2006). 76 outpatients with febrile arthralgia diagnosed within less than 48 hours were included by general practitioners during the CuraChik clinical trial. CHIK was confirmed in 54 patients and excluded in 22. A detailed clinical and biological follow-up was organised, that included analysis of viral intrahost diversity and telephone survey until day 300. The evolution of acute CHIK included 2 stages: the ‘viral stage’ (day 1–day 4) was associated with rapid decrease of viraemia and improvement of clinical presentation; the ‘convalescent stage’ (day 5–day 14) was associated with no detectable viraemia but a slower clinical improvement. Women and elderly had a significantly higher number of arthralgia at inclusion and at day 300. Based on the study clinico-biological dataset, scores for CHIK diagnosis in patients with recent febrile acute polyarthralgia were elaborated using arthralgia on hands and wrists, a minor or absent myalgia and the presence of lymphopenia (<1G/L) as major orientation criteria. Finally, we observed that CHIKV intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with increased number of arthralgia and intensity of sequelae at day 300.

          Conclusions/Significance

          This study provided a detailed picture of clinico-biological CHIK evolution at the acute phase of the disease, allowed the elaboration of scores to assist CHIK diagnosis and investigated for the first time the impact of viral intra-host genetic diversity on the disease course.

          Author Summary

          The mosquito-transmitted chikungunya virus is responsible for acute febrile polyarthralgia and, in a proportion of cases, complications including chronic arthritis. Since 2005, it has massively re-emerged in the Old World. Although the large majority of patients are outpatients, the most detailed studies have focused previously on hospitalised patients ( i.e., severe cases). Here, we report the detailed clinico-biological characteristics of ‘standard’ clinical presentations in patients followed-up by general practitioners in Reunion Island (2006) during the CuraChik clinical trial. At the onset of the disease, two stages were observed: (i) a ‘viral stage’ during the first 4 days, associated with an acute febrile polyarthralgic syndrome and a subsequent rapid clinical improvement; the main clinico-biological characteristics during that period were used to elaborate supportive chikungunya diagnostic scores, ( ii) a ‘convalescent stage’ (days 5–14) with no detectable viraemia but a slower clinical improvement. Woman and elderly patients were found at risk for more symptomatic forms of the disease at both the acute and late stages (day 300) and we observed that the viral intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with more symptomatic illness at the late stage of the disease.

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          Most cited references29

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          The impact of confounder selection criteria on effect estimation.

          Much controversy exists regarding proper methods for the selection of variables in confounder control. Many authors condemn any use of significance testing, some encourage such testing, and other propose a mixed approach. This paper presents the results of a Monte Carlo simulation of several confounder selection criteria, including change-in-estimate and collapsibility test criteria. The methods are compared with respect to their impact on inferences regarding the study factor's effect, as measured by test size and power, bias, mean-squared error, and confidence interval coverage rates. In situations in which the best decision (of whether or not to adjust) is not always obvious, the change-in-estimate criterion tends to be superior, though significance testing methods can perform acceptably if their significance levels are set much higher than conventional levels (to values of 0.20 or more).
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            Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients.

            Chikungunya is a reemerging disease. In 2005-2006, a severe outbreak occurred on Reunion Island in the southwestern part of the Indian Ocean. Other islands in this area were affected during the same period. Adult patients with acute chikungunya (defined as onset of fever and/or polyarthralgia in the 5 days preceding consultation) and laboratory-confirmed chikungunya who were referred to Groupe Hospitalier Sud Reunion during the period from March 2005 through April 2006 were included in this retrospective study. Their clinical and laboratory features are reported. Laboratory-confirmed acute chikungunya was documented in 157 patients. The mean age of patients was 57.9 years, and the ratio of male to female patients was 1.24 : 1. Sixty percent of patients had at least 1 comorbidity. Ninety-seven patients (61.8%) were hospitalized, and 60 (38.2%) were treated as outpatients. Five fatalities were reported. One hundred fifty-one patients (96.1%) experienced polyarthralgia, and 129 (89%) experienced fever. Gastrointestinal symptoms were reported by 74 patients (47.1%), and skin rash was reported by 63 (40.1%). Hemorrhagic signs were rare. Lymphopenia and hypocalcemia were the prominent laboratory findings. Severe thrombocytopenia was rarely observed. Chikungunya virus can be responsible for explosive outbreaks of disease. Polyarthralgia and fever are the 2 main clinical features. In this era of travel and globalization, chikungunya should be considered in the differential diagnosis of febrile polyarthralgia with an abrupt onset.
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              Persistent Arthralgia Induced by Chikungunya Virus Infection is Associated with Interleukin-6 and Granulocyte Macrophage Colony-Stimulating Factor

              Background. Chikungunya virus (CHIKV) infection induces arthralgia. The involvement of inflammatory cytokines and chemokines has been suggested, but very little is known about their secretion profile in CHIKV-infected patients. Methods. A case-control longitudinal study was performed that involved 30 adult patients with laboratory-confirmed Chikungunya fever. Their profiles of clinical disease, viral load, and immune mediators were investigated. Results. When patients were segregated into high viral load and low viral load groups during the acute phase, those with high viremia had lymphopenia, lower levels of monocytes, neutrophilia, and signs of inflammation. The high viral load group was also characterized by a higher production of pro-inflammatory cytokines, such as interferon-α and interleukin (IL)–6, during the acute phase. As the disease progressed to the chronic phase, IL-17 became detectable. However, persistent arthralgia was associated with higher levels of IL-6 and granulocyte macrophage colony-stimulating factor, whereas patients who recovered fully had high levels of Eotaxin and hepatocyte growth factor. Conclusions. The level of CHIKV viremia during the acute phase determined specific patterns of pro-inflammatory cytokines, which were associated with disease severity. At the chronic phase, levels of IL-6, and granulocyte macrophage colony-stimulating factor found to be associated with persistent arthralgia provide a possible explanation for the etiology of arthralgia that plagues numerous CHIKV-infected patients.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                January 2013
                17 January 2013
                : 7
                : 1
                : e2004
                Affiliations
                [1 ]UMR 190, Emergence des Pathologies Virales, Aix-Marseille Univ-IRD-EHESP French School of Public Health, University Hospital Institute for Infectious Disease and Tropical Medicine, Marseille, France
                [2 ]Infectious Disease and Tropical Medicine, AP-HM CHU Nord, University Hospital Institute for Infectious Disease and Tropical Medicine, Marseille, France
                [3 ]Department of Medical Intensive Care, CHU South Site, Saint Pierre, Reunion, France
                [4 ]Aix-Marseille Univ, UMR192, SESSTIM (AMU, IRD, INSERM), Marseille, France
                [5 ]Department of Infectious Diseases and Tropical Medicine, Laveran Military Teaching Hospital, Marseille, France
                [6 ]EHESP French School of Public Health, Rennes-Sorbonne Paris Cité, Paris, France
                University of Texas Medical Branch, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SDT XDL AF. Performed the experiments: SDT VB. Analyzed the data: SDT XDL JG FS. Contributed reagents/materials/analysis tools: SDT XDL VB AF. Wrote the paper: SDT XDL.

                Article
                PNTD-D-12-00661
                10.1371/journal.pntd.0002004
                3547841
                23350006
                c4dd6697-0106-47b8-966c-b4fcb5d18b33
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 May 2012
                : 28 November 2012
                Page count
                Pages: 13
                Funding
                This study was funded by the French government, the University of Marseille, the “Pôle de Compétitivité Orpheme” (public structure) and Sanofi-Aventis France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Microbiology
                Emerging Infectious Diseases
                Medicine
                Epidemiology
                Infectious Disease Epidemiology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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