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      Chikungunya in Indonesia: Epidemiology and diagnostic challenges

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          Abstract

          Background

          Chikungunya virus (CHIKV) is often overlooked as an etiology of fever in tropical and sub-tropical regions. Lack of diagnostic testing capacity in these areas combined with co-circulation of clinically similar pathogens such as dengue virus (DENV), hinders CHIKV diagnosis. To better address CHIKV in Indonesia, an improved understanding of epidemiology, clinical presentation, and diagnostic approaches is needed.

          Methodology/Principal findings

          Acutely hospitalized febrile patients ≥1-year-old were enrolled in a multi-site observational cohort study conducted in Indonesia from 2013 to 2016. Demographic and clinical data were collected at enrollment; blood specimens were collected at enrollment, once during days 14 to 28, and three months after enrollment. Plasma samples negative for DENV by serology and/or molecular assays were screened for evidence of acute CHIKV infection (ACI) by serology and molecular assays. To address the co-infection of DENV and CHIKV, DENV cases were selected randomly to be screened for evidence of ACI. ACI was confirmed in 40/1,089 (3.7%) screened subjects, all of whom were DENV negative. All 40 cases initially received other diagnoses, most commonly dengue fever, typhoid fever, and leptospirosis. ACI was found at five of the seven study cities, though evidence of prior CHIKV exposure was observed in 25.2% to 45.9% of subjects across sites. All subjects were assessed during hospitalization as mildly or moderately ill, consistent with the Asian genotype of CHIKV. Subjects with ACI had clinical presentations that overlapped with other common syndromes, atypical manifestations of disease, or persistent or false-positive IgM against Salmonella Typhi. Two of the 40 cases were possibly secondary ACI.

          Conclusions/Significance

          CHIKV remains an underdiagnosed acute febrile illness in Indonesia. Public health measures should support development of CHIKV diagnostic capacity. Improved access to point-of-care diagnostic tests and clinical training on presentations of ACI will facilitate appropriate case management such as avoiding unneccessary treatments or antibiotics, early response to control mosquito population and eventually reducing disease transmission.

          Author summary

          Chikungunya virus (CHIKV) is often-overlooked as an etiology of fever in tropical and sub-tropical regions. Lack of diagnostic testing capacity in these areas combined with co-circulation of clinically similar pathogens such as dengue virus (DENV), hinders CHIKV diagnosis. The present study characterized the epidemiology, clinical presentation, and diagnostic approaches to better understand the CHIKV in Indonesia. We screened blood samples collected from children and adults with acute fever admitted to 8 hospitals in Indonesia from 2013–2016. Blood samples negative for DENV infection and a subset blood samples from confirmed DENV cases were then screened for acute CHIKV infection (ACI). ACI was confirmed in 40/1,089 (3.7%) screened patients, of whom initially received other diagnoses such as dengue fever, typhoid fever, and leptospirosis. All patients were considered as mildly or moderately ill, consistent with the Asian genotype of CHIKV. Given the unspecific clinical presentations of ACI, public health measures should support development of CHIKV diagnostic capacity. Improved access to point-of-care diagnostic tests will facilitate appropriate case management, such as avoiding unnecessary treatments or antibiotics, early response to control mosquito population, and eventually reducing disease transmission.

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          Most cited references32

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          Tracking the re-emergence of epidemic chikungunya virus in Indonesia.

          Twenty-four distinct outbreaks of probable chikungunya (CHIK) etiology were identified throughout Indonesia from September 2001 to March 2003, after a near 20-year hiatus of epidemic CHIK activity in the country. Thirteen outbreak reports were based on clinical observations alone, and 11 confirmed by serological/virological methods. Detailed epidemiological profiles of two investigated outbreaks in Bogor and Bekasi are presented. Human sera were screened using an ELISA for IgM and IgG anti-CHIK antibodies. Additionally, reverse transcriptase PCR and virus isolation were attempted for virus identification. The mean age of cases was 37 +/- 18 years in Bogor and 33 +/- 20 years in Bekasi. There was no outstanding case-clustering, although outbreak-affected households were observed to be geographically grouped within villages. The attack rates in Bogor and Bekasi were 2.8/1000 and 6.7/1000 inhabitants respectively. Both outbreaks started in the rainy season following increased Aedes aegypti and A. albopictus densities.
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            Chikungunya virus: evolution and genetic determinants of emergence.

            Chikungunya virus (CHIKV) causes a severe and often persistent arthralgic disease that is occasionally fatal. A mosquito-borne virus, CHIKV exists in enzootic, non-human primate cycles in Africa, but occasionally emerges into urban, human cycles to cause major epidemics. Between 1920 and 1950, and again in 2005, CHIKV emerged into India and Southeast Asia, where major urban epidemics ensued. Unlike the early introduction, the 2005 emergence was accompanied by an adaptive mutation that allowed CHIKV to exploit a new epidemic vector, Aedes albopictus, via an A226V substitution in the E1 envelope glycoprotein. However, recent reverse genetic studies indicate that lineage-specific epistatic restrictions can prevent this from exerting its phenotype on mosquito infectivity. Thus, the A. albopictus-adaptive A226V substitution that is facilitating the dramatic geographic spread CHIKV epidemics, was prevented for decades or longer from being selected in most African enzootic strains as well as in the older endemic Asian lineage.
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              Chikungunya Virus–Vector Interactions

              Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes chikungunya fever, a severe, debilitating disease that often produces chronic arthralgia. Since 2004, CHIKV has emerged in Africa, Indian Ocean islands, Asia, Europe, and the Americas, causing millions of human infections. Central to understanding CHIKV emergence is knowledge of the natural ecology of transmission and vector infection dynamics. This review presents current understanding of CHIKV infection dynamics in mosquito vectors and its relationship to human disease emergence. The following topics are reviewed: CHIKV infection and vector life history traits including transmission cycles, genetic origins, distribution, emergence and spread, dispersal, vector competence, vector immunity and microbial interactions, and co-infection by CHIKV and other arboviruses. The genetics of vector susceptibility and host range changes, population heterogeneity and selection for the fittest viral genomes, dual host cycling and its impact on CHIKV adaptation, viral bottlenecks and intrahost diversity, and adaptive constraints on CHIKV evolution are also discussed. The potential for CHIKV re-emergence and expansion into new areas and prospects for prevention via vector control are also briefly reviewed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Writing – original draft
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – original draft
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Supervision
                Role: Data curationRole: InvestigationRole: ResourcesRole: Supervision
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Supervision
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Supervision
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                1 June 2020
                June 2020
                : 14
                : 6
                : e0008355
                Affiliations
                [1 ] Faculty of Medicine, Universitas Hasanuddin/Dr. Wahidin Sudirohusodo Hospital, Makassar, Indonesia
                [2 ] *Indonesia Research Partnership on Infectious Disease (INA-RESPOND), Jakarta, Indonesia
                [3 ] Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
                [4 ] National Institute of Health Research and Development (NIHRD), Ministry of Health, Jakarta, Indonesia
                [5 ] Sulianti Saroso Hospital, Jakarta, Indonesia
                [6 ] Hasan Sadikin Hospital–Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia
                [7 ] Dr. Kariadi Hospital–Diponegoro University, Semarang, Indonesia
                [8 ] Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [9 ] Tangerang District Hospital, Tangerang, Indonesia
                [10 ] Dr. Soetomo Academic General Hospital–Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
                [11 ] Medical Faculty, Udayana University and Sanglah General Hospital, Denpasar, Indonesia
                [12 ] National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland, United States of America
                Johns Hopkins Bloomberg School of Public Health, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-1095-3422
                http://orcid.org/0000-0001-9348-7046
                Article
                PNTD-D-19-01916
                10.1371/journal.pntd.0008355
                7289446
                32479497
                4b3a4b30-84de-4984-9129-acc9de6f9496

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 13 November 2019
                : 4 May 2020
                Page count
                Figures: 4, Tables: 2, Pages: 18
                Funding
                Funded by: National Institute of Allergy and Infectious Disease, National Institutes of Health
                Award ID: HHSN261200800001E; HHSN261201500003I
                Award Recipient :
                This study was conducted by INA-RESPOND, a collaborative research network of NIHRD, Ministry of Health, Indonesia, and US-NIAID, NIH. This project has been funded in whole or in part with Federal funds from the NIAID, NIH, under contract Nos. HHSN261200800001E and HHSN261201500003I. NIAID collaborators contributed to design of the study; collection, analysis, and interpretation of data; and writing of the manuscript. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
                Categories
                Research Article
                Biology and life sciences
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                Viruses
                RNA viruses
                Togaviruses
                Alphaviruses
                Chikungunya Virus
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                Tropical Diseases
                Neglected Tropical Diseases
                Dengue Fever
                Medicine and Health Sciences
                Infectious Diseases
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                Dengue Fever
                Medicine and Health Sciences
                Pain Management
                Arthralgia
                Custom metadata
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                2020-06-11
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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