Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

A scoping review of published literature on chikungunya virus

  • Mariola Mascarenhas ,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing

    mariola.mascarenhas@canada.ca

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯
  • Sophiya Garasia,

    Roles Data curation, Formal analysis, Project administration, Validation

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯
  • Philippe Berthiaume,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – review & editing

    Affiliation National Microbiology Laboratory at St. Hyacinthe, Public Health Agency of Canada, St. Hyacinthe, Quebec, Canada

    ⨯
  • Tricia Corrin,

    Roles Data curation, Writing – review & editing

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯
  • Judy Greig,

    Roles Conceptualization, Methodology, Writing – review & editing

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯
  • Victoria Ng,

    Roles Conceptualization, Methodology, Writing – review & editing

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯
  • Ian Young,

    Roles Data curation, Methodology, Writing – review & editing

    Affiliation School of Occupational and Public Health, Ryerson University, Toronto, Ontario, Canada

    ⨯
  • Lisa Waddell

    Roles Conceptualization, Methodology, Software, Writing – review & editing

    Affiliation National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, Ontario, Canada

    ⨯

Abstract

Chikungunya virus (CHIKV) has caused several major epidemics globally over the last two decades and is quickly expanding into new areas. Although this mosquito-borne disease is self-limiting and is not associated with high mortality, it can lead to severe, chronic and disabling arthritis, thereby posing a heavy burden to healthcare systems. The two main vectors for CHIKV are Aedes aegypti and Aedes albopictus (Asian tiger mosquito); however, many other mosquito species have been described as competent CHIKV vectors in scientific literature. With climate change, globalization and unfettered urban planning affecting many areas, CHIKV poses a significant public health risk to many countries. A scoping review was conducted to collate and categorize all pertinent information gleaned from published scientific literature on a priori defined aspects of CHIKV and its competent vectors. After developing a sensitive and specific search algorithm for the research question, seven databases were searched and data was extracted from 1920 relevant articles. Results show that CHIKV research is reported predominantly in areas after major epidemics have occurred. There has been an upsurge in CHIKV publications since 2011, especially after first reports of CHIKV emergence in the Americas. A list of hosts and vectors that could potentially be involved in the sylvatic and urban transmission cycles of CHIKV has been compiled in this scoping review. In addition, a repository of CHIKV mutations associated with evolutionary fitness and adaptation has been created by compiling and characterizing these genetic variants as reported in scientific literature.

Citation: Mascarenhas M, Garasia S, Berthiaume P, Corrin T, Greig J, Ng V, et al. (2018) A scoping review of published literature on chikungunya virus. PLoS ONE 13(11): e0207554. https://doi.org/10.1371/journal.pone.0207554

Editor: Abdallah M. Samy, Faculty of Science, Ain Shams University (ASU), EGYPT

Received: September 20, 2018; Accepted: November 1, 2018; Published: November 29, 2018

Copyright: © 2018 Mascarenhas et al. 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.

Data Availability: All relevant extracted data are contained within the manuscript and supporting information files. The dataset of our raw data underlying this study have been uploaded to Dryad and are accessible at https://doi.org/10.5061/dryad.qd65020.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Chikungunya disease is caused by chikungunya virus (CHIKV), a mosquito-borne alphavirus belonging to the family Togaviridae. The virus was first isolated from a patient in Tanzania during an outbreak of a dengue-like illness that had been circulating in that area between 1952 and 1953. Frequent descriptions of this illness had been reported in earlier years in other parts of Africa, including Mozambique [1]. The virus got its name from a word in the local dialect of the Makonde area in Tanzania and is literally translated as “bent over in pain” [2], describing the stooped posture of many chikungunya afflicted patients due to severe joint pains and arthralgias, both hallmark features of the disease. The proportion of asymptomatic CHIKV infections during epidemics has been reported to be between 3 to 28% [3–5]. Together with severe joint pain, patients typically exhibit febrile exanthema with a saddleback fever pattern, symptoms also seen with Dengue virus (DENV) and Zika virus (ZIKV) infections [6]. This makes CHIKV diagnosis difficult, particularly since there are many reports of co-circulating CHIKV, DENV and ZIKV in many areas with co-infected patients [7–14].

CHIKV is an enveloped, positive strand RNA virus with a genome usually a little less than 12000 nucleotides. Its genome consists of five structural proteins; E1, E2, E3, C (Capsid protein), 6K, and four non-structural proteins; non-structural proteins 1 (nsP1), 2 (nsP2), 3 (nsP3) and 4 (nsP4) [15–16]. Evolutionary studies on the virus provide evidence that the West African lineage of CHIKV originated in Africa and subsequently moved into Asia where it evolved into a distinct Asian lineage. The CHIKV isolate from the epidemic in Reunion Island in 2005 showed that the virus evolved into the East/Central/South African (ECSA) lineage with more recent Indian Ocean strains forming an Indian Ocean sub-lineage within ECSA [17–20]. The large chikungunya epidemic in Brazil that started in late 2013 was reported to be the outcome of two separate introductions of two individual CHIKV lineages; Asian and ECSA [21–23].

CHIKV is maintained in a sylvatic cycle involving wild primates and arboreal mosquitoes in Africa, and a mosquito to (and from) human urban cycle in countries with human epidemics [24]. The urban cycle of CHIKV has been responsible for several large CHIKV epidemics in countries spanning many continents. During the 2005–2006 epidemics in the Indian Ocean Islands and India, more than a third of the population in Reunion Island were infected with CHIKV (34.3%) resulting in many severe clinical cases, while case-fatality rates of 4.5% and 4.9% were reported in Mauritius and India respectively [25–26]. There have been sweeping epidemics throughout Asia for a number of years following the Indian Ocean Islands epidemics [27–29]. In late 2013, CHIKV emerged in the Caribbean for the first time and caused an epidemic in St. Martin, followed by its expansion into other islands in close proximity [30–33]. Around the same time, CHIKV also spread across South and Central America causing major epidemics throughout the region where competent vectors were already established.

The two main competent vectors of CHIKV are considered to be Aedes aegypti and Aedes albopictus, although the virus has been isolated from other mosquitoes [34–36]. Ae. aegypti mosquitoes thrive in tropical and arid areas but cannot withstand cool temperatures. These mosquitoes were responsible for all the recorded CHIKV epidemics until the Indian Ocean Islands epidemic in 2005–2006 when a point mutation occurred in the outer membrane E1 glycoprotein of CHIKV, causing an amino acid change with an Alanine to Valine substitution at position 226 [37]. This variant offered Ae. albopictus the propensity to emerge as a highly competent CHIKV vector with enhanced transmission capability [37–38]. Ae. albopictus mosquitoes are highly invasive and have successfully established populations in temperate climates [39–41]. With climate change, there is a strong concern that these vectors will expand into new areas.

A scoping review (ScR) on CHIKV and its competent vectors was conducted to identify, characterize, categorize, and elucidate global evidence from published research on this topic. The product of this ScR is a comprehensive report of the evidence and knowledge gaps that exist on this important emerging public health issue. A ScR utilizes reproducible, systematic and rigorous knowledge synthesis methodology to identify and summarize the extent and range of knowledge on a particular topic or issue [42–44]. Results generated from this ScR can inform policy-makers, as well as the scientific community, and facilitate decision-making on mitigation of chikungunya and/or CHIKV competent vectors.

Methods

A ScR protocol was created a priori to ensure transparency, reproducibility and consistency during all stages of our review; S1 Protocol. We followed the general framework outlined by Arksey and O’Malley [42] which included: 1) establishing a research question, 2) conducting a stringent literature search, 3) relevance screening of captured articles, 4) characterizing all relevant articles, and 5) collating and summarizing results from extracted data. This ScR was designed and executed to be reproducible by employing good synthesis research practices, which included a complete search strategy. Screening and data characterization tools were developed a priori and uniformly implemented on all citations and articles included in the review by two independent reviewers [42–44]. The reporting of this ScR is aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [45].

Expert consultation

Prior to finalizing the research question, we solicited input from an expert advisory team from Canada and South America consisting of four government and two academic scientists with expertise on the topic. Our topic experts consented to help us frame the scope of this study by answering a questionnaire in writing; S1 Expert Questionnaire. All but one expert also participated in a teleconference call aimed to discuss key issues and information needs required for public health professionals to assess and address this emerging issue. Subsequent discussions were held with the experts whenever clarification was needed. The finalized protocol was shared with our topic experts before commencing our review.

Research question

This review had two main research questions:

“What is the current state of research knowledge on chikungunya virus (CHIKV), including its pathogenesis, attributes of clinical infection and diagnosis, surveillance and epidemiology, economic burden, prevention and control strategies, risk factors for developing CHIKV infection, societal attitudes and perceptions regarding CHIKV infection, in humans and other vertebrate hosts.”

And,

“What vectors are competent for transmission of CHIKV, what are the parameters for effective CHIKV transmission and vector competence, what ecological risk factors contribute to CHIKV competent vector abundance, and what vector mitigation strategies can prevent and control CHIKV vectors?”

Search strategy.

A comprehensive and stringent search algorithm was developed and pretested to capture relevant literature. The final search algorithm included two parts, one encompassing chikungunya research and the other to capture additional research on CHIKV vectors:

(Chikungunya OR CHIK OR CHIKV)

OR

(alphavirus AND mosquito* AND control)

The search was conducted on May 27, 2015 and updated on January 6, 2017 in the following databases: Scopus, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Centre for Agriculture and Biosciences International (CABI), Literatura Latino Americana em Ciências da Saúde (LILACS), Agricola and Cochrane library. The update was conducted to include more recent studies from Central and South America due to the recent emergence of chikungunya in those regions. To verify that our search algorithm had an optimal degree of sensitivity to capture all relevant articles pertaining to our research question, we hand-searched reference lists from 10 relevant narrative reviews for missed citations [46–55]. The grey literature search was conducted in October 2015 and included targeted, iterative hand searching of 22 government and/or research organization websites that were suggested during the expert consultation and are listed in S1 Protocol. Twenty two additional citations were added to the review from the grey literature search.

Inclusion/Exclusion criteria.

Articles included in this ScR reported primary data that were generated by the authors, or through reliable government and/or research organizations. Included articles had to be relevant to one or more aspects of the review question: i.e., information on CHIKV and chikungunya disease, competence parameters of CHIKV vectors, or control of CHIKV vectors. Articles in languages other than English, French, Spanish or Portuguese were excluded due to limited translation resources. Documents without primary data, such as whole conference proceedings, books, literature reviews, systematic reviews, meta-analyses and some types of grey literature were also excluded from the review.

Relevance screening and data characterization.

Relevance screening was conducted in two stages. The first screening tool comprised of two questions to determine whether the citation could potentially be relevant to the review based on the title and abstract. We erred on the side of inclusiveness by including citations whenever their relevance remained unclear. Full-text articles of citations that passed through the first relevance screening stage were procured and assigned to a second level of relevance screening. The purpose of this step was to exclude articles after full text assessment, so that only relevant articles in full alignment with the research question remained for further characterization. At the second level of relevance screening, articles were excluded after full text assessment if they did not report on: 1) the impact of CHIKV on humans, hosts or vectors, 2) CHIKV studies including phylogeny and molecular characterization of genetic determinants for fitness and other evolutionary markers, CHIKV pathogenesis and infection mechanisms, 3) mitigation strategies to prevent and control CHIKV infections including strategies for CHIKV vector prevention and control, 4) clinical aspects of CHIKV infection and risk factors contributing to such infections, and 5) vector competence parameters—both behavioural and physiologic, as well as environmental factors associated with CHIKV transmission, 6) economic burden of chikungunya disease, or 7) modeling studies on chikungunya or CHIKV vectors. Articles that did not meet the inclusion criteria for language and primary data were also excluded at this stage. For articles that met the inclusion criteria, questions were answered at this level to broadly categorize articles by publication period, study location, study population (stratified as human and non-human hosts, vectors and/or virus) and research focus. This stage in the ScR process allowed us to gauge the quantity and breadth of research within the different focus areas and ensure that the data characterization and utility (DCU) tool would adequately capture relevant data from all studies.

The third stage of the ScR was data characterization of all relevant articles using the DCU tool; S1 Protocol. Questions included general information on when and where the research was conducted, the study population and genotype of CHIKV. The research focus area(s) was selected at this step and reviewers could access a unique set of questions tailored to each focus area, which aided in efficient characterization of the research. In vitro studies examining pathogenesis and/or immunomodulatory mechanisms associated with CHIKV infection in hosts and vectors were identified at the second stage of screening; however, due to the large number of articles on this single focus area, these studies were not characterized in detail at the third stage of the ScR as this was logistically unfeasible for completion within a reasonable timeframe.

Review management.

All citations captured using the search algorithm were imported from the bibliographic databases to RefWorks (ProQuest, LLC), an online citation management program. The citation database was de-duplicated so that only unique citations remained. The citations were then imported into an online systematic review software, Distiller SR (Evidence Partners, Ottawa, Canada), which is specifically designed to manage all aspects of scoping reviews. All stages of the ScR were conducted by two reviewers working independently using the a priori developed data collection tools within Distiller SR. All forms were pre-tested by all reviewers to confirm reproducibility, clarity and consistency between reviewers on each form. Reviewers pre-tested the Relevance Screening Level 1 (RS1) form with 36 citations, the Relevance Screening Level 2 (RS2) form was pre-tested with ten articles and the Data Extraction and Utility (DCU) form was pre-tested on ten articles representing all the main focus areas of the review question, (kappa >0.8); S1 Protocol. After pre-testing, any necessary adjustments were made to the forms to improve clarity and consistency between reviewers. Any discrepancies on extracted data between reviewers were resolved by consensus, or with the help of a third reviewer. The completed dataset was exported into Microsoft Excel for data cleaning, categorization, descriptive analysis and charting.

Results

From 6815 unique citations captured by the search, 3422 potentially relevant articles were procured and 2326 were considered primary research relevant to the research question (Fig 1). Four percent (148/3422) of potentially relevant articles were excluded from the review on the basis of language: 57 Chinese, 23 German, 20 Russian, 14 Japanese, 9 Italian, 6 Dutch, 4 Croatian, 3 Danish, 3 Norwegian, 2 Czech, 1 Romanian, 1 Polish, 1 Turkish, 1 Malay, 1 Korean, 1 Thai, and 1 Albanian. We were unable to procure 15 articles despite contacting the authors. Additionally, 74 citations were excluded that were either correspondence or abstracts referencing articles that we were unable to procure or review.

thumbnail
Download:
Fig 1. PRISMA chart of the flow of articles through the ScR.

See S1 Checklist.

https://doi.org/10.1371/journal.pone.0207554.g001

The focus area researched most extensively was epidemiology of chikungunya related to hosts and vectors, with a total of 912/2326 (39%) studies. A little over one third of the articles (764/2326; 33%) reported on signs, symptoms and diagnosis of CHIKV in humans. Treatment for chikungunya in humans was reported in 283/2326 (12%) studies, and mitigation strategies against CHIKV in both humans and vectors comprised 323/2326 (14%) studies. There were 410/2326 (18%) vector studies with relevance to vector competence for transmitting CHIKV and vector behavioural characteristics, while 256/2326 (11%) studies examined phylogeny and signature evolutionary mutations of CHIKV. Also included were 208/2326 (9%) studies describing surveillance programs for CHIKV in humans, other hosts and vectors. The accuracy of CHIKV diagnostic tests was evaluated in 167/2326 (7%) studies. Research areas with fewer studies included modeling studies with relevance to CHIKV and/or its vectors; 103/2326 (4%), social impact examining knowledge, attitudes and perceptions of chikungunya in various target human populations in 46/2326 (2%) studies, and 23/2326 (1%) studies on the economic burden of chikungunya. There were 406/2326 (17%) pathogenesis studies on pathways or mechanisms at the cellular level and detailed study characterization (DCU) was not conducted on these studies. Many studies reported on multiple focus areas. Table 1 is a heat chart of the number of studies in each major and minor focus area by study population category and is referenced throughout the manuscript to aid the reader in tracking the quantity of research underpinning different areas of chikungunya research. This ScR focuses on the detailed characteristics of the 1510 /2326 (65%) articles on vertebrate hosts for CHIKV, while only high level category information is presented for 406/2326 (17%) articles on pathogenesis and immunity related pathways of CHIKV infection. Results from CHIKV vector studies (410/2326; 18%) on important competence and behavioural vector characteristics will be summarized in a subsequent article.

thumbnail
Download:
Table 1. Heat Chart of study numbers captured by focus area (multiple focus areas in some studies; article numbers associated with colour density).

https://doi.org/10.1371/journal.pone.0207554.t001

Publications by continent and time

Generally, interest in CHIKV research increased in regions soon after they were affected by epidemics (Fig 2). The majority of research has been conducted since 2000 across Asia, North America, Europe and the Indian Ocean Islands. Many of the articles that reported on the major CHIKV epidemic in Reunion Island and other nearby Indian Ocean Islands during 2005–2006 were published by authors in both France and the affected islands. There were major CHIKV epidemics reported in India and Southeast Asia from 2006 onwards and multiple articles have described various aspects of these epidemics. Autochthonous transmission of CHIKV was reported in Italy [56]; and France [57] between 2007 and 2010 and many studies reported on these locally transmitted outbreaks. Since the emergence of CHIKV in the Americas, there have been several reports on autochthonous CHIKV transmission in newly affected areas [58–59].

thumbnail
Download:
Fig 2. Publications (n = 2326) on CHIKV or its competent vectors by decade of publication and continent of research.

Study numbers for each category represented by bubble size and reported with corresponding bubbles.

https://doi.org/10.1371/journal.pone.0207554.g002

Chikungunya virus

Of the 1920 studies fully characterized in this ScR, lineage of the CHIKV strains isolated or used in experiments was reported in 324 articles; West African lineage (62/324), ECSA lineage (176/324) and Asian lineage (106/324). The Indian Ocean sub-lineage of ECSA was reported in 69/176 (39%) articles and two articles reported a new Caribbean clade [60–61]. Many gene mutations that contribute to evolutionary adaptation and fitness of CHIKV have been reported in scientific literature [62–65]. A repository of these mutations has been created from results gathered in this ScR; S1 Table.

Diagnostic testing for CHIKV.

Data were captured from three types of testing for CHIKV, predominantly in humans (687/2326; 30%), to: 1) diagnose active CHIKV infection in patients, 2) screen sample populations of hosts for antibodies to CHIKV to detect prior exposure and 3) studies related to the evaluation of the performance of diagnostic tests; Table 1. Results show that 126/687 (18%) studies reported the use of clinical signs and symptoms alone for diagnosis, mostly in resource limited countries with large ongoing epidemics. CHIKV diagnosis in humans reported in the earliest research was conducted by using a suckling mouse animal model to grow and test for the virus, but antigenic tests were soon developed. More recently, molecular tests have been developed and utilized to detect viral RNA, some offering results with a quick turnaround time. Details on the number of studies reporting on each category of CHIKV tests are available in S2 Table.

The vast majority of studies reported CHIKV testing on blood or cerebrospinal fluid (CSF); S2 Table. Uncommon samples that were successfully tested for CHIKV included corneas [66], oral secretions [67–69], peritoneal, gastric and blister fluids [70–73], urine and semen [74]. Saliva was found to be useful in molecular testing only for a week post symptom onset and was reported to be less sensitive than blood samples in one study [69]. Another study reported identifying viable virus in urine and semen samples even up to 30 days post infection [74].

There were 167/2326 (7%) studies on determining the accuracy of CHIKV tests by comparing the sensitivity and specificity of one or more tests; Table 1. Evaluating various diagnostic algorithms based on clinical symptoms to reach an accurate clinical diagnosis was conducted in 16 /167 (10%) studies to help with rapid diagnosis, mainly in regions where laboratory testing is not easily accessible or feasible. Diagnostic accuracy studies for CHIKV included 15/167 (9%) articles assessing virus isolation and culture tests, 90/167 (54%) evaluating serological tests, and 88/167 (53%) on molecular tests; S3 Table.

CHIKV in non-human vertebrate hosts.

Chikungunya infection was studied in non-human primates (NHPs) (51/1920; 3% studies), other vertebrates such as rodents (12/1920; 1% studies), reptiles (4/1920; 0.2% studies), bats (6/1920; 0.3% studies), wild birds (12/1920, 0.6% studies), farm animals (33/1920; 2% studies) and domestic pets (8/1920; 0.4% studies); Table 1. Surveillance for CHIKV in animals was identified in 7/208 (3%) surveillance studies; Table 1. All non- human vertebrate surveillance studies were conducted during non-epidemic periods and investigated exposure to CHIKV infection.

Epidemiological studies on potential sylvatic hosts for CHIKV.

The potential contribution of non-human vertebrate hosts towards sylvatic transmission of CHIKV was investigated in 12 observational studies (Table 1) with 11/12 (92%) articles on NHPs, 3/12 (25%) on domestic and farm animals, 1/12 (8%) on wild birds, and 4/12 (33%) on non-primate wild animals and reptiles. Sylvatic transmission has only been reported in Africa where early studies implicated primates, rodents and bats as possible sylvatic hosts; Table 2. Outside Africa, a few surveys have provided some evidence for a number of monkey species, small rodents and bats to possibly play a role as sylvatic hosts for CHIKV; Table 2.

thumbnail
Download:
Table 2. Results from observational studies evaluating potential vertebrate sylvatic hosts for CHIKV*.

https://doi.org/10.1371/journal.pone.0207554.t002

Transmission of CHIKV in non-human vertebrate hosts.

Very few studies have been conducted outside Africa to investigate sylvatic transmission, but evidence from Africa has shown cyclic surges in CHIKV circulating among arboreal mosquitoes and vertebrate host populations [81]. A study on sylvatic transmission of CHIKV among Bornean orangutans was inconclusive as there was no evidence for CHIKV infection in the orangutans or humans from the local areas [82]. One experimental study demonstrated that genetically modified mice with deficiencies in their type 1 interferon response (IRF3/7-/-) were able to transmit CHIKV mouse-to-mouse without an arthropod vector. In addition, results from the same study showed that saliva from several infected monkeys was positive for the presence of viral RNA and infectious virus, which could potentially lead to CHIKV transmission without a vector [67].

The observational studies above provide data on possible sylvatic hosts and the ecology of CHIKV within the studied areas. Many experimental studies were conducted to understand the potential contribution of diverse non-human vertebrate hosts to CHIKV transmission by investigating the susceptibility of these hosts to the virus. A susceptible vertebrate host in these studies is defined as an animal that exhibits symptoms of CHIKV infection and/or detectible levels of viremia within the experimental host. There were 20 studies that looked at several NHP species and other vertebrate hosts listed in Table 3. General observations included higher susceptibility in infant mice, chicks, rats and rabbits, although this was not consistent across all studies. Several studies demonstrated that a number of NHP species, some rodents and bats were susceptible to CHIKV infection, while most wild birds, domestic and farm animals and adult experimental rodents were not susceptible hosts.

thumbnail
Download:
Table 3. Results from challenge trials investigating host susceptibility to CHIKV in non-human vertebrate hosts.

https://doi.org/10.1371/journal.pone.0207554.t003

CHIKV in humans

Chikungunya in humans was studied in 1159/2326 (50%) articles: 1040 observational and 49 experimental studies. The experimental studies comprised 3/49 (6%) challenge trials for potential vaccine candidates. Of the controlled trials (17/49; 35%), four studied vaccination in humans. All vaccination studies were at the experimental or trial stages. The efficacy of drugs to treat chikungunya symptoms was assessed in 3/17 (18%) controlled trial studies in humans. Other controlled trials included in vitro studies using human blood cells from volunteers to assess potential antiviral or vaccine candidates (11/17; 65%).

Epidemiology and surveillance in humans.

There were 126/208 (61%) surveillance articles reporting on CHIKV in humans (Table 1), including 36/126 (29%) articles on travel-related syndromic surveillance and 2/126 (2%) articles on surveillance for CHIKV in the blood donor system. Active surveillance for CHIKV in humans during epidemics was reported in 26/126 (21%) studies, often in a hospital or tertiary care setting. Some results originated from resource limited countries where large epidemics were occurring and the surveillance protocol involved public health staff going door-to-door in impoverished neighbourhoods to identify CHIKV cases [106–108]. Monitoring programs in epidemic settings were reported in 6/126 (5%) human surveillance studies. These were systematic and purposeful programs mainly focussed on collecting numbers of chikungunya patients without a rigid action plan. Passive surveillance, mainly syndromic surveillance for CHIKV during epidemics was reported in 14/126 (11%) articles where data on chikungunya patients were collected in a hospital or other healthcare setting. In non-epidemic settings, there were 43/126 (34%) active surveillance articles for CHIKV in humans, 17/126 (13%) articles on monitoring programs, and 57/126 (45%) articles on passive surveillance.

Most of the epidemiological studies were on humans (848/912; 93%); Table 1. These included 117/848 (14%) epidemic investigations and 242/848 (29%) prevalence surveys. Human CHIKV prevalence results representing the burden of CHIKV during epidemics were reported in 16/242 (6.6%) studies, while 134/242 (55%) studies investigated the presence of antibodies against CHIKV in populations after an epidemic. Incidence was reported in 51/848 (6%) studies with 12/848 (1%) studies reporting CHIKV incidence during epidemics, while attack rates were reported in 31/848 (4%) studies soon after the epidemic. CHIKV related mortality was reported in 36/848 (4%) studies and in many cases death was associated with a pre-existing chronic morbidity [109–110]. The viremic period for CHIKV infection was reported in 30 studies and ranged from the first day of illness to 23 days (one report of prolonged viremia in a pediatric case detected at day 23 of illness [111]. The intrinsic incubation period reported in 13 studies also varied between studies and ranged from two to twelve days. One study reported evidence of possible sequential CHIKV infection [112].

Risk factors for developing chikungunya infection in humans were investigated in 345 studies. Landscape associated risk factors were reported in 100/345 (29%) studies with variables such as coastal (8/100), inland (3/100), elevated (5/100), urban (24/100), suburban or peri-urban (8/100), rural (21/100), farm or agricultural land (3/100), forest (5/100), parks (2/100), private gardens (7/100) and type of dwelling (19/100) investigated. Climatic indices as risk factors were investigated in 75/345 (22%) studies with precipitation (28/75; 37%), season (34/75; 45%) and temperature (9/75; 12%) predominantly studied. Other risk factors studied were occupation (26/345; 8%), outdoor recreational activities (4/345; 1%), storage of tires (4/345; 1%) and stagnant water on property, in containers, vases and flower pots (23/345; 7%). Travel to and from endemic areas was reported as a risk factor in 215/345 (62%) studies. Chikungunya incidence was reported to be highest in individuals aged 55–64 years and lowest in the 0–14 age group [113]. Other risk factors for chikungunya were pre-existing chronic conditions such as Type 2 diabetes, cardiovascular disease [114–117] and obesity [118–119].

CHIKV epidemics.

Over 70 chikungunya epidemics have occurred in several countries across many continents between 1959 and 2016 and were documented in 141articles; Tables 1 and 4. The number of large epidemics increased steadily since the E1:A226V mutation occurred in CHIKV when Ae. albopictus became another and more efficient competent vector. During the epidemics in the Indian Ocean Islands in 2005–2006, a third of the population was estimated to be infected [120–122] and both Ae. aegypti and Ae. albopictus were found to carry the virus [123]. Over half the population was reported to be infected with CHIKV during a 2007 epidemic in Kerala, India [124–125]. Several articles described results from major epidemics across the Indian subcontinent from 2006 onwards (39/141; 28%). Epidemic investigation reports after CHIKV emergence in the Caribbean and South America also indicated high prevalence of exposure [92, 126–127]. These results depict the spread of CHIKV over time, either as an emerging pathogen in a new area, or a re-emerging public health risk in previously affected regions.

thumbnail
Download:
Table 4. Human CHIKV epidemics reported between 1959 and 2016.

https://doi.org/10.1371/journal.pone.0207554.t004

Travel-related chikungunya.

There were 215/1159 (19%) articles reporting travel-related CHIKV infections; Table 1. These results included 74/215 (34%) studies where travelers acquired their infections during travel to endemic countries, while 81/215 (38%) studies reported that travelers developed clinical symptoms days after returning to their home countries from a chikungunya endemic country where they were exposed to the virus. Of the travel-related studies, 29/215 (13%) studied prevalence of chikungunya infection among travelers.

Clinical manifestation of acute phase CHIKV infection in humans

A total of 764/2326 (33%) articles reported clinical signs and symptoms of chikungunya infection, of which 269/764 (35%) were case or case series reports; Table 1. The commonly accepted triad of CHIKV symptoms is fever (539/764, 71%), itchy rash (410/764, 54%) and joint pain (506/764, 66%), however, the literature reports many other frequently reported symptoms of CHIKV including: headache (291/764, 38%), myalgia or muscle ache (246/764, 32%), conjunctivitis (82/764, 11%), gastrointestinal symptoms such as nausea, vomiting, diarrhea or abdominal pain (218/764, 29%), and fatigue, malaise or weakness (117/764, 15%); Fig 3. Although described more often in association with DENV infections, 57/764 (7%) articles reported retro-orbital pain, 107/764 (14%) reported hemorrhagic disorders and 95/764 (12%) articles described neurological symptoms associated with chikungunya disease. These results do not represent the frequency of occurrence of these signs and symptoms as some articles reported exclusively on a single disease manifestation.

thumbnail
Download:
Fig 3. Number of studies reporting each sign or symptom of clinical CHIKV disease in humans*.

*Multiple signs and symptoms reported in many articles.

https://doi.org/10.1371/journal.pone.0207554.g003

Atypical signs and symptoms.

Atypical signs and symptoms of chikungunya infection were described in 121/764 (16%) articles, all with case / case series or cross-sectional study designs. Hyperpigmentation was reported as an atypical observation in 38/764 (5%) articles, and was first reported after the 2005–2006 epidemics in the Indian Ocean Islands. Other atypical observations seen increasingly after the Indian Ocean Island epidemics included severe ocular (15/764, 2%) [251–253] and neurological conditions (95/764, 12%) [254–256]; S4 Table.

Sequelae following CHIKV infection in humans.

There were 239/764 (21%) articles describing long term sequelae associated with CHIKV; Table 1. Persistent post-infection morbidities included tendinitis (5/239; 2%), synovitis (14/239; 6%), balance disorders (1/239; 0.4%), and tunnel syndromes (11/239; 5%). There were 9/239 (4%) articles that reported Guillaine-Barré Syndrome (GBS) associated with chikungunya infection. Other long term complications reported were chronic arthritis (163/239; 68%), neurological disorders such as encephalopathies (18/239; 8%), acute disseminated encephalomyelitis (ADEM) (5/239; 2%), and ocular disorders (17/239; 7%). These post-chikungunya long term sequelae were reported to last from a few months to several years. A recent study suggests that hyperferritinemia may be a potential marker of chronic chikungunya disease [257].

Co-infections with CHIKV in humans.

Chikungunya co-infections with either single or multiple co-infecting pathogens were reported in the literature. There were 109/1159 (9%) articles reporting co-infections with chikungunya: dengue (77/109; 71%), malaria (13/109, 12%) and zika (9/109; 8%); Table 1. There were four articles from the Americas that reported triple concurrent co-infections with CHIKV, DENV and ZIKV, all viruses that are transmitted by the same vectors [9,14, 258–259]. Other co-infections reported with CHIKV were Japanese Encephalitis, West Nile Virus, Tuberculosis, Human Immunodeficiency Virus (HIV), Leptospirosis, Yellow Fever, Klebsiella pneumoniae and Pseudomonas aeruginosa. A complete list of co-infections reported with CHIKV is compiled in S5 Table.

Treatment for chikungunya infections in humans

Chikungunya disease is generally managed through supportive treatment and treatment strategies were reported in 283/2326 (12%) studies. Prescribed analgesics and anti-pyretics were reported in 87/283 (31%) studies, non-steroidal anti-inflammatory drugs (NSAIDs) in 80/283 (28%) studies and steroids in 70/283 (25%) studies; Table 1. Antibiotics were prescribed as treatment for chikungunya in 30/283 (11%) studies. There were 7/283 (2%) studies that described the use of antiviral drugs for chikungunya treatment and 29/283 (10%) studies described using an anti-malarial agent such as hydroxychloroquine to treat chikungunya symptoms. A randomized controlled trial examining the effectiveness of chloroquine to treat chikungunya concluded that there is no justification for its use during the acute stage of the illness [260]. Physical therapy or acupuncture were prescribed in 9/283 (3%) studies and 14/283 (5%) studies described the use of traditional medicine for treating chikungunya and its symptoms. The efficacy of plant-based drugs (19 studies), NSAIDs (17 studies), corticosteroids (19 studies), antivirals (17 studies) chloroquines (12 studies) and traditional medicines (8 studies) for treating acute and chronic symptoms of chikungunya was assessed in experimental studies.

CHIKV transmission in humans.

All the major epidemics reported in Table 4 were due to the CHIKV urban transmission cycle where the virus is reported to be maintained between humans and Ae. aegypti and Ae. albopictus mosquitoes in tropical and sub-tropical regions of the world. Other potential modes of CHIKV transmission have been reported, including human exposure through infected blood transfusions (2/1159; 0.2%), or needle pricks with infected blood (3/1159; 0.3%); Table 1. Accidental CHIKV transmission was reported in three articles; two in laboratory staff working with infected mosquitoes [261–262], and one report of an infected nurse who was potentially exposed while drawing blood from an infected patient [263]. No studies investigated human sexual transmission of CHIKV as is frequently reported for ZIKV. One study found evidence of CHIKV transmission through corneal grafts and the authors propose banning cornea donations in CHIKV endemic areas [66].

Several studies (49/1159; 4%) reported mother-to-child or vertical transmission of CHIKV and many investigated fetal outcomes in neonates infected in utero or post partum; S6 Table. Pregnant women and neonates were the study subjects in 34/49 (69%) studies, while 13/49 (27%) studies reported on neonates alone. The impact of congenital CHIKV infection in neonates was reported in 16/49 (33%) studies and 6/49 (12%) studies investigated pregnancy outcomes due to CHIKV infection [5, 264–267]. One article recommended close monitoring of viremic pregnant mothers in maternity units. The same study reported that 12% of newborns are symptomatic, with many neonates requiring prolonged or intensive care due to complications such as meningoencephalits and intravascular coagulation [265].

Public knowledge, attitudes and perceptions of chikungunya disease and CHIKV vectors

Knowledge, attitudes and perceptions about CHIKV, mosquito-borne diseases and their prevention were investigated in 46/2326 (2%) cross-sectional articles; Table 1. Articles on attitudes and perceptions to chikungunya disease focused on concerns about toxic or environmental effects of chemical control measures (3/46; 7%), perception about the severity and risks associated with chikungunya disease (16/46; 35%), and perception on the efficacy of various protective measures (13/46; 28%). Several studies evaluated knowledge on chikungunya disease (29/46; 63%), CHIKV vectors (27/46; 59%) and behavioral mitigation practices for CHIKV (33/46; 72%). A single study examined willingness to pay for protection against CHIKV [268].

Economic burden of CHIKV

A total of 23/2326 (1%) studies investigated the economic burden of CHIKV, of which 19/23 (83%%) studied the economic burden of chikungunya disease in humans, 3/23 (13%) examined the cost-benefit of implemented vector control measures during epidemics and 1/23 (4%) reported the cost effectiveness of interventions to prevent the transmission of CHIKV through blood transfusions in Canada; Table 1, S7 Table. Publications on the economic burden due to CHIKV were predominantly from countries impacted by major epidemics and used data collected from surveillance during epidemics to estimate costs [122, 182, 269–271]. The epidemics from these areas were reported to have high attack rates, case fatalities and many severe long term sequelae, posing a burden to healthcare systems. All but one study were published after 2005; S7 Table. The 1980 study from Fiji calculated the cost effectiveness of vector control mitigation strategies in general [272].

Mitigation strategies to prevent and control CHIKV and its vectors

A total of 323/2326 (14%) articles reported on mitigation or prevention and control strategies for CHIKV, mainly focusing on vaccination against CHIKV (78/323; 24%), personal protective measures (79/323; 25%), the use of insecticides (156/323; 48%), public education (48/323; 15%), quarantine of infected individuals (5/323; 2%) and biological control of mosquitoes (51/323; 16%); Table 1.

Vaccination: There were 78 studies evaluating potential vaccine candidates. Twenty-one included in vitro experiments, 42 used laboratory animals (mice and rabbits), seven used non-human primates and eight reported results from testing the potential vaccine on humans; Table 1. There was no validated and approved ready-to-use vaccine against chikungunya for humans identified from our data analyses. However, there were articles on two potential vaccine candidates. One demonstrated complete immunity against CHIKV in mice and NHPs [273], while the other, a novel live-attenuated vaccine candidate, has undergone a phase II clinical trial and is suggested as an option for emergency CHIKV vaccinations, in addition to being a potential vaccine candidate that can be further developed [274].

Behavioral protective measures: The 79/323 articles on personal protective measures included using insect repellant (38 articles), wearing full coverage clothing that prevents mosquito access to skin while outdoors (8 articles), using mosquito bed nets and window screens (36 articles), avoiding practices that lead to collecting stagnant water and removing suitable vector habitats, such as emptying pots, containers or tires (64 articles). The use of many of the protective interventions were evaluated before and/or after an education program to teach the general public or targeted population group about CHIKV (12 articles), personal and/or behavioral protective measures (7 articles), insecticides (5 articles) or all three aforementioned categories of measures (22 articles). Study designs varied from quasi-experiments and cross-sectional studies to predictive models of the various protective measures. Few articles report data on the effectiveness of personal protection interventions (38/79, 48%).

Insecticidal use: Insecticide use to control CHIKV vector populations was reported in 156/323 (48%) articles. Ten used a targeted ovicide (10/156; 6%),105/156 (67%) used a larvicide and 49/156 (31%) used an adulticide. Of all the articles reporting on insecticidal use, 24/156 (15%) articles evaluated the insecticide for its efficacy at the community level, while the remaining investigated plant extracts and other compounds experimentally for their efficacy as a potential insecticide. Two articles described the use of lethal ovitraps as a successful mitigation strategy against CHIKV vectors [275–276]. The use of larvivorous fish, beetles, nematodes or other copepods as a vector mitigation strategy was reported in 7/323 (2%) studies [277–283].

Biological control strategies: There were 51/323 (16%) articles describing biologic control of vectors as a mitigation strategy against CHIKV. Of these, 7/51 (14%) reported on Sterile Insect Technology (SIT), 14/51 (27%) were on Incompatible Insect Technique (IIT or Cytoplasmic incompatibility) and 2/51 (2%) articles described Release of Insects with Dominant Lethal mosquitoes (RIDL) as an effective strategy to mitigate CHIKV transmission through vectors. Infection of mosquito vectors with bacteria for controlling or reducing CHIKV replication was reported in 23/51 (45%) studies, with 12/51 (24%) studies examining the efficacy of Wolbachia and 11/51 (22%) investigating the role of Bacillus thuringiensis for effective control of CHIKV transmission through CHIKV carrying vectors. One study investigated silver particles synthesized by the fungus Trichoderma atroviride as a potential nanolarvicide against Ae. aegypti larvae and found this to be a very effective strategy for killing the larvae [284].

Modeling studies

There were 103/2326 (4%) modeling studies including quantitative risk assessment articles on chikungunya disease or competent CHIKV vectors. Exposure to CHIKV, illness, or costs attributed to chikungunya disease in humans was the outcome modeled in 58/103 (56%) articles, 1/103 (1%) article modeled CHIKV spread through birds [285], while 70/103 (68%) modeled CHIKV vectors; mainly Ae. aegypti, Ae. albopictus, or both. Of these, 40/103 (39%) were spatio-temporal models, 48/103 (47%) were temporal models without a spatial component, 8/103 (8%) were spatial models without a time component and 7/103 (7%) models did not incorporate time or space. There were 9/103 (9%) risk assessment models estimating reproductive numbers or the magnitude of the threat posed by CHIKV to the general population. Modeling results were relevant to North America (Canada, USA and Mexico) (10/103, 10%), Central/South America and the Caribbean (15/103, 15%), Africa (3/103, 3%), Europe (21/103, 20%), Asia (17/103, 17%), Australia and New Zealand (2/103, 2%), Oceania (2/103, 2%) and Reunion Island (15/103, 15%). We reviewed 27/103 (26%) modeling articles that were general transmission models applicable to any region. Studies also included those that predicted an outcome, such as number of cases, incidence or prevalence rates (69/103, 67%), generated a better understanding of disease transmission (41/103, 40%), evaluation of mitigation measures or programs (28/103, 27%), or evaluation of the economic burden of CHIKV outbreaks (6/103, 6%). Other studies included travel associated importation models (11/103; 11%), models assessing risk through blood donation (9/103; 9%) and a single model on spread of CHIKV through transportation of cargo (1/103; 1%). Many modeling studies generated results that fell under more than one of the above mentioned categories.

Discussion

Although CHIKV was first isolated in 1953, it is postulated that some epidemics dating back to the eighteenth century could have been caused by CHIKV and had been incorrectly attributed to DENV [134, 286]. Our chronological analysis of published CHIKV epidemic reports depicts the emergence and re-emergence of CHIKV across continents over time. A single mutation in the viral genome of CHIKV resulted in advantageous changes to the virus by increasing its fitness and ability to adapt to Ae. albopictus, a new vector that is more tolerant to cold temperature, subsequently changing the global distribution and risk profile of CHIKV [19].

Transmission

Many studies report sylvatic transmission in Africa, where the virus is thought to be maintained by circulating between NHPs, rodents, reptiles and bats, with arboreal mosquitoes as vectors in the sylvatic cycle [24], however, there is limited research on sylvatic transmission outside Africa. While the urban transmission cycle between humans and mosquitoes is well understood, sylvatic cycles in areas outside Africa likely exist and may not be elucidated at the present time. Due to the hypermutability of CHIKV, it is conceivable that the virus could have adapted to new hosts and vectors in areas where CHIKV has expanded recently, thereby introducing a substantial risk for CHIKV to initiate a sylvatic cycle in the Americas [287]. A knowledge gap exists in our full understanding of vertebrate hosts that may contribute to the sylvatic transmission cycle and maintenance of CHIKV in endemic areas. Future research can focus on filling current knowledge gaps that could facilitate a better understanding of the roles of various hosts and vectors in CHIKV transmission cycles contributing to the spread, emergence and maintenance of CHIKV globally, as this knowledge is important for developing effective mitigation strategies and more accurate risk analyses.

Vertical transmission of CHIKV was observed in humans [146,149, 244, 288]. The impact of intra-uterine CHIKV infection on the fetus and neonates is not clearly understood with conflicting results from several studies. One study looked at dizygous twins born to a mother infected during pregnancy and reported one healthy neonate, while the other twin was severely ill due to congenitally acquired chikungunya [267]. Another study examining outcomes of CHIKV infection to the fetus during each trimester of pregnancy until post-partum reported vertical transmission in all three trimesters, with more serious outcomes to neonates when mothers were viremic at delivery [289]. It is important to keep in mind that vertical transmission of chikungunya in an asymptomatic infected mother or neonate can also trigger a cluster of cases among pregnant women or new mothers and neonates in maternity units. A single case of microcephaly in a neonate born to a mother with gestational chikungunya infection has been described [290]. Microcephaly is believed to be an outcome associated with ZIKV infections [291]. We acknowledge that this could be a coincidental finding, but CHIKV associated microcephaly certainly warrants future research given that CHIKV and ZIKV co-circulate in many regions. There has been no research on sexual transmission of CHIKV, despite evidence for this with ZIKV. Interestingly, viable CHIKV has been isolated from an individual’s semen and urine sample up to 30 days post-infection [74] and one study provided experimental evidence for the presence of infectious CHIKV in human saliva [67], so the possibility of sexual transmission of CHIKV in humans needs to be clearly elucidated.

The risk of viremic travelers importing CHIKV into non-endemic regions with competent vectors is quite high, as highlighted by locally transmitted epidemics in France [230–231]; Italy [182–183] and many more recent travel- related importations into the Americas [54, 59]. In non-endemic areas where CHIKV vectors are present, it is important for public health authorities and physicians to be aware of chikungunya disease and the possible epidemic risks associated with the importation of the virus into new areas through viremic travelers. Large epidemics are costly but can be controlled with proper prevention and control strategies such as personal protection against vectors and vector mitigation.

CHIKV diagnostics

Although there are diagnostic tests to confirm clinical diagnosis, there is evidence for antigenic cross reactivity between CHIKV and other alphaviruses [292–293]. A rapid, field-ready and cost effective gold standard diagnostic test with high sensitivity and specificity for CHIKV has not been reported in the literature and would be useful, especially in resource limited settings. A wide array of samples have been successfully tested for CHIKV using currently available tests. While the most common sample was blood, others included corneas and minimally invasive samples such as urine and semen [74].

Pre-existing risk factors for developing chronic sequelae

Although chikungunya is a self-limiting disease, it can result in long term sequelae, most often resulting in chronic arthritis. Researchers have postulated that pre-existing morbidities can predispose an individual to more severe chikungunya disease and chronic sequelae post-CHIKV infection [110] and that initial clinical manifestation of CHIKV illness can predict progression to chronic arthritis [294]. The list of pre-existing morbidities in CHIKV patients compiled from the literature can broadly be categorized as chronic respiratory, cardiovascular, immunological disorders, and Type 2 Diabetes. Further analysis of the literature on the relationship between pre-existing morbidities and the development of chronic sequelae could be explored in a systematic review to summarize the magnitude and confidence in any potential association that might exist.

Atypical chikungunya disease

Several studies described atypical and severe forms of chikungunya disease during both acute and convalescent phases, as well as chronic morbidities associated with CHIKV infection. Many articles from India reporting on epidemics from 2006 onwards frequently describe hyperpigmentation as an atypical observation during and after the infection [295–297]. A study from Venezuela described unexpected nasal skin necrosis in a few patients with severe chikungunya disease [298]. It remains unclear whether this atypical sign is linked to a particular mutation in the virus or to host genetics. Interestingly, observations from our results show that hyperpigmentation is always reported in individuals with darker skin. In addition to hyperpigmentation, we observed several reports of severe ocular disease associated with chikungunya, ranging from varied forms of uveitis and other manifestations, to complete blindness [299–300]. Five studies described acute disseminated encephalomyelitis (ADEM) in CHIKV patients from India [256, 301–304]. It remains to be determined if any pre-existing morbidity is associated with these outcomes. Other neurological complications were infrequently observed across early chikungunya outbreaks, however, Guillain Barré Syndrome (GBS) is a relatively new complication associated with CHIKV infection reported in the literature since the Indian Ocean Island epidemics of CHIKV [27, 156, 247, 305–306]. A study on a chikungunya epidemic in French Polynesia reported an increase in the number of GBS cases [233]. These observations may be a result of larger epidemics with better reporting, or due to newly acquired genomic changes that contribute to higher virulence in the virus. ZIKV which often co-circulates with CHIKV has also been reported to be associated with GBS [307].

Treatment

Management of chikungunya illness is predominantly supportive, with analgesics, steroids and NSAIDs that alleviate the symptoms of CHIKV rather than specifically target the virus. Chloroquine, an antimalarial, was often prescribed to manage CHIKV symptoms, even though its efficacy in alleviating symptoms during the acute phase of infection is questioned [260]. Some studies reported the use of antibiotics to treat CHIKV infections [30, 308–311], but their efficacy as an effective treatment option was not evaluated in any study.

CHIKV lineages and genomic plasticity

Many outbreaks in India have been linked to different CHIKV lineages [312–313]. Since there is evidence for two separate virus introductions in Brazil with different lineages of CHIKV during the same epidemic period [21, 23, 314], it is important to keep in mind that there may be a strong likelihood that this can also occur elsewhere. With many reports of co-circulating CHIKV, DENV and ZIKV [8, 249, 259], it would be interesting to examine whether there is evidence for possible horizontal acquisition of genetic elements for virulence between co-circulating viruses in endemic areas. There has been a lot of research on CHIKV mutations and phylogeny for investigating the evolutionary relatedness of CHIKV isolates across epidemics in different geographical areas, as well as to identify genetic changes in the virus as it evolves over time. Many articles reported an important amino acid change in the EI outer membrane glycoprotein region of the virus with an alanine to valine substitution at position 226 [315–316]. This mutation reportedly allowed the virus to gain Ae. albopictus as a new and highly competent vector to aid in its transmission more efficiently [317]. This mutation contributed significantly to the global expansion of risk areas for chikungunya and also highlights the plasticity of CHIKV and its potential to mutate, adapt and emerge or re-emerge in different areas. There is great concern that more selective mutations in the virus will facilitate its success in efficiently gaining more competent vectors and host reservoirs from invasive species [316], and if this occurs, public health risks from CHIKV could increase globally. At the same time, there is also evidence of genetic stability in CHIKV isolates, where isolates that share a common origin but were collected over many years and in different regions maintained a high degree of identity [18, 318]. Several CHIKV mutations associated with adaptation and fitness were reported in the literature and are compiled in this ScR.

Burden of chikungunya disease

One of the challenges of estimating the true burden of CHIKV is due to a high proportion of asymptomatic and mild cases who may not seek medical attention. This underestimation can affect results for predictive models, mitigation strategies and other analyses that use surveillance data as inputs. Misclassification of chikungunya as dengue or zika infections could also occur as these infections are often co-circulating and share overlapping symptoms [7, 319–320], therefore prevalence results reported on the basis of clinical signs and symptoms should be considered with caution. A complete understanding of whether co-infections with CHIKV can lead to altered symptoms or sequelae is also required. One study reported evidence of possible sequential CHIKV infection [112] and more studies are needed to validate this.

CHIKV epidemics can result in great financial burdens to affected countries. The 2014 CHIKV epidemic in Colombia was estimated to cost at least 73.6 million USD and put an enormous burden on that country’s economy [238]. It is imperative for countries at risk for CHIKV to have effective and efficient surveillance systems and mitigation strategies to alleviate the potential impact from future epidemics. The best way to mitigate public health risks from CHIKV is by preventing exposure to the virus through personal protective measures and the implementation of efficient vector control strategies to curb viral transmission.

Limitations of this study

This ScR was conducted by using rigorous and reproducible synthesis research methodology, however, it is possible that some articles were not identified by our search or search verification strategy. Excluding articles that were not in English, French, Spanish or Portuguese could contribute to potential language bias and may have resulted in an underrepresentation of some geographic regions in our results. The impact of these exclusions is unknown. The lapse in time between the updated search and the completion of the analysis for this study has certainly resulted in our inability to capture information from many recently published papers and is a limitation of our study. However, we believe that this limitation is offset by the rigour and thoroughness of our methodology and the included literature adequately represents affected areas around the world. We presume that the impact of missing research is minimal. The articles used for data extraction and the dataset generated from this project mailto:are available in the DRYAD digital repository and can be accessed using the review link: DOI: https://doi.org/10.5061/dryad.qd65020.

Conclusion

In conclusion, this ScR identified and characterized all available literature on CHIKV and allowed us to capture important information from the many epidemic waves observed with CHIKV infection over time. We have reported important observations relating to trends in disease manifestation, long term sequelae associated with CHIKV infection, plasticity of the viral genome, important epidemiological characteristics, as well as characteristics of surveillance and monitoring programs typically used. In addition, our results describe the extent of research on treatment strategies, mitigation methods for preventing or controlling CHIKV disease and/or CHIKV vectors. Global evidence on treating and preventing CHIKV can be used to inform future public health initiatives. The ScR repository also includes a comprehensive list of research on important mutations that are potentially linked to evolution, adaptation and fitness of the virus. Within these results, knowledge gaps and areas with abundant research were noted. In-depth knowledge synthesis projects and a risk assessment project have used data generated from this ScR as inputs [321–322].

Results from this ScR can be used to inform policy-makers and researchers on the evidence base for CHIKV and point to where additional research is needed to close knowledge gaps.

Supporting information

S1 Checklist. PRISMA checklist.

https://doi.org/10.1371/journal.pone.0207554.s001

(DOC)

S1 Protocol. ScR on Chikungunya infections—Protocol.

https://doi.org/10.1371/journal.pone.0207554.s002

(DOCX)

S1 Expert Questionnaire. Expert Questionnaire.

https://doi.org/10.1371/journal.pone.0207554.s003

(DOCX)

S1 Table. List of CHIKV genetic variants for fitness and adaptation.

https://doi.org/10.1371/journal.pone.0207554.s004

(DOCX)

S2 Table. Diagnostic tests and samples.

*Multiple diagnostic tests reported in many articles.

https://doi.org/10.1371/journal.pone.0207554.s005

(DOCX)

S3 Table. Diagnostic test evaluation.

*Multiple tests evaluated in many articles.

https://doi.org/10.1371/journal.pone.0207554.s006

(DOCX)

S4 Table. Atypical signs and symptoms.

https://doi.org/10.1371/journal.pone.0207554.s007

(DOCX)

S5 Table. Coinfections with CHIKV.

*Pathogen not specified.

https://doi.org/10.1371/journal.pone.0207554.s008

(DOCX)

S6 Table. Materno-fetal transmission.

https://doi.org/10.1371/journal.pone.0207554.s009

(DOCX)

S7 Table. Economic burden of CHIKV.

https://doi.org/10.1371/journal.pone.0207554.s010

(DOCX)

Acknowledgments

The authors would like to thank the following advisors for helping us frame the scope of this project: Dr. Nicholas Ogden (PHAC), Dr. Harvey Artsob (Retired—PHAC), Dr. Martin Petric (Retired—BCCDC), Dr. Raymond Tellier (U Calgary), Dr. Victor Ng (PHAC) and Dr. Pablo Martinez de Salazar (CARPHA). We would also like to thank Danielle Reimer and Catherine Hierlihy for their help with reviewing articles, together with Janet Harris and the PHAC librarians for their assistance with library services.

References

  1. 1. Gudo ES, Black JF, Cliff JL. Chikungunya in Mozambique: A Forgotten History. PLoS Negl Trop Dis 2016 Nov 17;10(11):e0005001. pmid:27855168
  2. 2. Halstead SB. Reappearance of chikungunya, formerly called dengue, in the Americas. Emerging Infectious Diseases 2015;21(4):557–561. 40 ref. pmid:25816211
  3. 3. Manimunda SP, Sugunan AP, Rai SK, Vijayachari P, Shriram AN, Sharma S, et al. Short report: Outbreak of chikungunya fever, Dakshina Kannada District, South India, 2008. Am J Trop Med Hyg 2010;83(4):751–754.
  4. 4. Ayu Said Mas, Lai Li Rong, Chan YokeFun, Hatim Ahmad, Hairi Noran Naqiah, Asiah Ayob, et al. Seroprevalence survey of Chikungunya virus in Bagan Panchor, Malaysia. Am J Trop Med Hyg 2010;83(6):1245–1248. 21 ref. pmid:21118929
  5. 5. Robillard PY, Boumahni B, Gerardin P, Michault A, Fourmaintraux A, Schuffenecker I, et al. Vertical maternal-fetal transmission of chikungunya virus: ten cases on Reunion among 84 pregnant women. Presse Medicale 2006;35(5(Cahier 1):785–788. 3 ref.
  6. 6. Ng DHL, Ho HJ, Chow A, Wong J, Kyaw WM, Tan A, et al. Correlation of clinical illness with viremia in Zika virus disease during an outbreak in Singapore. BMC Infectious Diseases 2018;18(201).
  7. 7. Ali U, Isahak I, Rahman MM. Chikungunya confused with dengue in Malaysia: Clinical, serological and molecular perspective. Internet Journal of Microbiology 2011;9(2).
  8. 8. Cabral-Castro MJ, Cavalcanti MG, Peralta RH, Peralta JM. Molecular and serological techniques to detect co-circulation of DENV, ZIKV and CHIKV in suspected dengue-like syndrome patients. J Clin Virol 2016 Sep;82:108–111. pmid:27479173
  9. 9. Calvo EP, Sanchez-Quete F, Duran S, Sandoval I, Castellanos JE. Easy and inexpensive molecular detection of dengue, chikungunya and zika viruses in febrile patients. Acta Trop 2016 Nov;163:32–37. pmid:27477452
  10. 10. Rodriguez-Morales AJ, Villamil-Gomez WE, Franco-Paredes C. The arboviral burden of disease caused by co-circulation and co-infection of dengue, chikungunya and Zika in the Americas. Travel Med Infect Dis 2016 May-Jun;14(3):177–179. pmid:27224471
  11. 11. Carey DE. Chikungunya and dengue: a case of mistaken identity? J Hist Med Allied Sci 1971 Jul;26(3):243–262. pmid:4938938
  12. 12. Suharti C, van Gorp EC, Dolmans WM, Groen J, Hadisaputro S, Djokomoeljanto RJ, et al. Hanta virus infection during dengue virus infection outbreak in Indonesia. Acta medica Indonesiana 2009;41(2):75–80. pmid:19390126
  13. 13. Edwards T, Signor LD, Williams C, Donis E, Cuevas LE, Adams ER. Co-infections with Chikungunya and Dengue Viruses, Guatemala, 2015. Emerg Infect Dis 2016 Nov;22(11):2003–2005. pmid:27767914
  14. 14. Villamil-Gomez WE, Rodriguez-Morales AJ, Uribe-Garcia AM, Gonzalez-Arismendy E, Castellanos JE, Calvo EP, et al. Zika, dengue, and chikungunya co-infection in a pregnant woman from Colombia. Int J Infect Dis 2016 Oct;51:135–138. pmid:27497951
  15. 15. Khan AH, Morita K, Parquet MdC, Hasebe F, Mathenge EGM, Igarashi A. Complete nucleotide sequence of chikungunya virus and evidence for an internal polyadenylation site. J Gen Virol 2002;83(12):3075–3084. 36 ref.
  16. 16. Kawashima KD, Suarez LAC, Labayo HKM, Liles VR, Salvoza NC, Klinzing DC, et al. Complete genome sequence of chikungunya virus isolated in the Philippines. Genome Announcements 2014;2(3):e00336–14. 9 ref. pmid:24970822
  17. 17. Volk SM, Chen RB, Tsetsarkin KA, Adams AP, Garcia TI, Sall AA, et al. Genome-scale phylogenetic analyses of Chikungunya virus reveal independent emergences of recent epidemics and various evolutionary rates. J Virol 2010;84(13):6497–6504. 63 ref. pmid:20410280
  18. 18. Powers AM, Brault AC, Tesh RB, Weaver SC. Re-emergence of chikungunya and o’nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships. J Gen Virol 2000;81(2):471–479. 54 ref.
  19. 19. Schuffenecker I, Iteman I, Michault A, Murri S, Frangeul L, Vaney MC, et al. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Medicine 2006;3(7):e263. 44 ref. pmid:16700631
  20. 20. Powers AM, Logue CH. Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus. Journal of General Virology 2007;88:2363. pmid:17698645
  21. 21. Rodrigues Faria N, Lourenco J, Marques de Cerqueira E, Maia de Lima M, Pybus O, Carlos Junior Alcantara L. Epidemiology of Chikungunya Virus in Bahia, Brazil, 2014–2015. PLoS Curr 2016 Feb 1;8: pmid:27330849
  22. 22. Kautz TF, Diaz-Gonzalez EE, Erasmus JH, Malo-Garcia IR, Langsjoen RM, Patterson EI, et al. Chikungunya Virus as Cause of Febrile Illness Outbreak, Chiapas, Mexico, 2014. Emerg Infect Dis 2015 Nov;21(11):2070–2073. pmid:26488312
  23. 23. Nunes MRT, Faria NR, de Vasconcelos JM, Golding N, Kraemer MUG, de Oliveira LF, et al. Emergence and potential for spread of Chikungunya virus in Brazil; pmid:25976325. BMC Medicine 2015;13(1).
  24. 24. Townson H, Nathan MB. Resurgence of chikungunya. Trans R Soc Trop Med Hyg 2008;102(4):308–309. 5 ref. pmid:18178232
  25. 25. Renault P, Josseran L, Pierre V. Chikungunya-related fatality rates, Mauritius, India, and Reunion Island. Emerg Infect Dis 2008 Aug;14(8):1327.
  26. 26. Josseran L, Paquet C, Zehgnoun A, Caillere N, Tertre Al, Solet JL, et al. Chikungunya disease outbreak, Reunion Island. (Special Issue: Zoonotic diseases.). Emerging Infectious Diseases 2006;12(12):1994–1995. 4 ref. pmid:17354339
  27. 27. Suryawanshi SD, Dube AH, Khadse RK, Jalgaonkar SV, Sathe PS, Zawar SD, et al. Clinical profile of chikungunya fever in patients in a tertiary care centre in Maharashtra, India. Indian J Med Res 2009;129(4):438–441. 14 ref. pmid:19535840
  28. 28. Noridah O, Paranthaman V, Nayar SK, Masliza M, Ranjit K, Norizah I, et al. Outbreak of Chikungunya due to virus of Central/East African genotype in Malaysia. Med J Malaysia 2007;62(4):323–328. 17 ref. pmid:18551938
  29. 29. Yoosuf AA, Shiham I, Mohamed AJ, Ali G, Luna JM, Pandav R, et al. First report of chikungunya from the Maldives. Trans R Soc Trop Med Hyg 2009;103(2):192–196. 14 ref. pmid:18930301
  30. 30. Murhekar MV, Manickam P, Kumar RM, Ganesakumar SRB, Ramachandran V, Ramakrishnan R, et al. Treatment practices & laboratory investigations during Chikungunya outbreaks in South India. Indian J Med Res 2011;133(5):546–547. 4 ref.
  31. 31. Omarjee R, Prat CM, Flusin O, Boucau S, Tenebray B, Merle O, et al. Importance of case definition to monitor ongoing outbreak of chikungunya virus on a background of actively circulating dengue virus, St Martin, December 2013 TO January 2014. Eurosurveillance 2014;19(13).
  32. 32. Ledrans M, Cassadou S, Boucau S, HucAnais P, LeparcGoffart I, Prat C, et al. Emergence of chikungunya in the French overseas territories of the Americas: organization and results of epidemiological surveillance, April 2014. Bulletin Epidemiologique Hebdomadaire 2014(21/22):368–379. 18 ref.
  33. 33. Wv Bortel, Dorleans F, Rosine J, Blateau A, Rousset D, Matheus S, et al. Chikungunya outbreak in the Caribbean region, December 2013 to March 2014, and the significance for Europe. Eurosurveillance; 2014 0759;19(13):2; 81 ref.
  34. 34. Yamanishi H, Sawayama T, Matsumura T. Multiplication of chikungunya virus in male Culex pipiens molestus. Jap J Sanit Zool 1980;31(1):69–70. 4 ref.
  35. 35. Viennet E, Knope K, Faddy HM, Williams CR, Harley D. Assessing the threat of chikungunya virus emergence in Australia. Commun Dis Intell Q Rep 2013 Jun 30;37(2):E136–43. pmid:24168087
  36. 36. Tilston N, Skelly C, Weinstein P. Pan-European Chikungunya surveillance: designing risk stratified surveillance zones. International Journal of Health Geographics; 2009 2009 October;8(61):(31;). 65 ref.
  37. 37. Tsetsarkin KA, Vanlandingham DL, McGee CE, Higgs S. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog 2007 Dec;3(12):e201. pmid:18069894
  38. 38. Vazeille M, Moutailler S, Coudrier D, Rousseaux C, Khun H, Huerre M, et al. Two Chikungunya isolates from the outbreak of La Reunion (Indian Ocean) exhibit different patterns of infection in the mosquito, Aedes albopictus. PLos One 2007(November):e1168. 34 ref.
  39. 39. Medlock Jolyon M., Avenell David, Barrass Iain, and Leach Steve. Analysis of the potential for survival and seasonal activity of Aedes albopictus (Diptera: Culicidae) in the United Kingdom. 2006;31(2):292.
  40. 40. Gratz NG. Critical review of the vector status of Aedes albopictus. Med Vet Entomol 2004 Sep;18(3):215–227. pmid:15347388
  41. 41. Schaffner F, Bellini R, Petric D, Scholte EJ, Zeller H, Rakotoarivony LM. Development of guidelines for the surveillance of invasive mosquitoes in Europe. Parasites and Vectors; 2013 2013 July;6(209):(18;). 35 ref.
  42. 42. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. International Journal of Social Research Methodology 2005 02/01;8(1):19–32.
  43. 43. Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implementation Science 2010;5(69).
  44. 44. Tricco AC, Lillie E, Zarin W, O’Brien K, Colquhoun H, Kastner M, et al. A scoping review on the conduct and reporting of scoping reviews. BMC Medical Research Methodology 2016;16(15).
  45. 45. Moher D, Liberati A, Tetzlaff J, Altman DG, The Prisma Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann Intern Med 2009;6(7):264–269.
  46. 46. Mowatt L, Jackson ST. Chikungunya in the Caribbean: An Epidemic in the Making. Infect Dis Ther 2014 Sep 23.
  47. 47. Roques P, Gras G. Chikungunya fever: focus on peripheral markers of pathogenesis. J Infect Dis 2011 Jan 15;203(2):141–143. pmid:21288810
  48. 48. Higgs S, Ziegler SA. A nonhuman primate model of chikungunya disease. J Clin Invest 2010 Mar;120(3):657–660. pmid:20179348
  49. 49. Ogden NH, Lindsay LR, Coulthart M. Is there a risk of chikungunya transmission in Canada? (Special Issue: Chikungunya virus.). Canada Communicable Disease Report 2015;41(1):11–14. 11 ref. pmid:29769915
  50. 50. Straetemans M. Vector-related risk mapping of the introduction and establishment of Aedes albopictus in Europe. Euro surveillance: bulletin européen sur les maladies transmissibles = European communicable disease bulletin 2008;13(7).
  51. 51. Weitzel A, Rega PP, Bork CE. Chikungunya virus: An emerging condition in the industrialized world. Journal of the American Academy of Physician Assistants 2012;25(1):E1–E5.
  52. 52. Parida MM, Santhosh SR, Dash PK, Lakshmana Rao PV. Rapid and real-time assays for detection and quantification of Chikungunya virus. Future Virology 2008;3(2):179–192.
  53. 53. Kar PK, Nagpal BN, Dua VK, Ghosh SK, Raghavendra K, Bhatt RM, et al. Molecular characterization of chikungunya virus from Andhra Pradesh, India. Indian J Med Res 2009 Mar;129(3):335–7; author reply 337. pmid:19491431
  54. 54. Cassadou S, Boucau S, PetitSinturel M, Huc P, LeparcGoffart I, Ledrans M. Emergence of chikungunya fever on the French side of Saint Martin Island, October to December 2013. Eurosurveillance; 2014 0752;19(13):2; 12 ref.
  55. 55. Kaur P, Chu JJH. Chikungunya virus: An update on antiviral development and challenges. Drug Discov Today 2013;18(19–20):969–983. pmid:23684571
  56. 56. Angelini P, Macini P, Finarelli AC, Po C, Venturelli C, Bellini R, et al. Chikungunya epidemic outbreak in Emilia-Romagna (Italy) during summer 2007. Parassitologia (Roma) 2008;50(1/2):97–98. 6 ref.
  57. 57. Gould EA, Gallian P, De Lamballerie X, Charrel RN. First cases of autochthonous dengue fever and chikungunya fever in France: from bad dream to reality! Clin Microbiol Infect 2010 Dec;16(12):1702–1704. pmid:21040155
  58. 58. McCarthy M. First case of locally acquired chikungunya is reported in US. BMJ 2014;349.
  59. 59. Yactayo S, Staples JE, Millot V, Cibrelus L, Ramon-Pardo P. Epidemiology of Chikungunya in the Americas. J Infect Dis 2016 Dec 15;214(suppl 5):S441–S445. pmid:27920170
  60. 60. Bocanegra C, Anton A, Sulleiro E, Pou D, Salvador F, Roure S, et al. Imported cases of Chikungunya in Barcelona in relation to the current American outbreak. J Travel Med 2016 Mar 16;23(3): Print 2016 Mar. pmid:26984354
  61. 61. Wang C, Saborio S, Gresh L, Eswarappa M, Wu D, Fire A, et al. Chikungunya Virus Sequences Across the First Epidemic in Nicaragua, 2014–2015. Am J Trop Med Hyg 2016 Feb;94(2):400–403. pmid:26643533
  62. 62. Failloux A-. Chikungunya virus adaptation to a mosquito vector correlates with only few point mutations in the viral envelope glycoprotein. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 2014 01 Jun 2014;24:116–126. pmid:24681263
  63. 63. Agarwal A, Sharma AK, Sukumaran D, Parida M, Dash PK. Two novel epistatic mutations (E1:K211E and E2:V264A) in structural proteins of Chikungunya virus enhance fitness in Aedes aegypti. Virology 2016 Oct;497:59–68. pmid:27423270
  64. 64. Rodas JD, Kautz T, Camacho E, Paternina L, Guzman H, Diaz FJ, et al. Genetic Characterization of Northwestern Colombian Chikungunya Virus Strains from the 2014–2015 Epidemic. Am J Trop Med Hyg 2016 Sep 7;95(3):639–646. pmid:27430542
  65. 65. Tsetsarkin KA, Chen RB, Yun RM, Rossi SL, Plante KS, Guerbois M, et al. Multi-peaked adaptive landscape for chikungunya virus evolution predicts continued fitness optimization in Aedes albopictus mosquitoes. Nature Communications; 2014 4084;5(6):57 ref.
  66. 66. Couderc T, Gangneux N, Chretien F, Caro V, Le Luong Tan, Ducloux B, et al. Chikungunya virus infection of corneal grafts. J Infect Dis 2012;206(6):851–859. 30 ref. pmid:22706183
  67. 67. Gardner J, Rudd PA, Prow NA, Belarbi E, Roques P, Larcher T, et al. Infectious Chikungunya Virus in the Saliva of Mice, Monkeys and Humans. PLoS One 2015 Oct 8;10(10):e0139481. pmid:26447467
  68. 68. Bandeira AC, Campos GS, Sardi SI, Rocha VF, Rocha GC. Neonatal encephalitis due to Chikungunya vertical transmission: First report in Brazil. IDCases 2016 Jul 25;5:57–59. pmid:27500084
  69. 69. Musso D, Teissier A, Rouault E, Teururai S, de Pina JJ, Nhan TX. Detection of chikungunya virus in saliva and urine. Virol J 2016 Jun 16;13:102-016-0556-9.
  70. 70. Kee ACL, Yang S, Tambyah P. Atypical Chikungunya virus infections in immunocompromised patients. Emerging Infectious Diseases 2010;16(6):1038–1040. 10 ref. pmid:20507772
  71. 71. Robin S, Ramful D, Zettor J, Benhamou L, JaffarBandjee MC, Riviere JP, et al. Severe bullous skin lesions associated with Chikungunya virus infection in small infants. Eur J Pediatr 2010;169(1):67–72. pmid:19401826
  72. 72. Grivard P, Roux Kl, Laurent P, Fianu A, Perrau J, Gigan J, et al. Molecular and serological diagnosis of Chikungunya virus infection. Pathologie Biologie 2007;55(10):490–494. 30 ref. pmid:17920211
  73. 73. Iborra C, Thia-Thiong-Fat C, Assouere M-, Fite S. Febrile bullous eruptions revealing a Chikungunya infection: Report of 6 cases. Nouvelles Dermatologiques 2007;26(4 SPEC. ISS.):6–8.
  74. 74. Bandeira AC, Campos GS, Rocha VF, Souza BS, Soares MB, Oliveira AA, et al. Prolonged shedding of Chikungunya virus in semen and urine: A new perspective for diagnosis and implications for transmission. IDCases 2016 Nov 4;6:100–103. pmid:27882301
  75. 75. McIntosh BM, Paterson HE, McGillivray G, DeSousa J. Further Studies on the Chikungunya Outbreak in Southern Rhodesia in 1962. I. Mosquitoes, Wild Primates and Birds in Relation to the Epidemic. Ann Trop Med Parasitol 1964 Mar;58:45–51. pmid:14147664
  76. 76. Brès P, Camicas JL, Cornet M, Robin Y, Taufflieb R. Epidemiology of arbovirus diseases in Senegal. Bull Soc Pathol Exot Filiales 1969;62(2):253–259. pmid:4996397
  77. 77. McCrae AWR, Henderson BE, Kirya BG, Sempala SDK. Chikungunya virus in the entebbe area of Uganda: Isolations and epidemiology. Trans R Soc Trop Med Hyg 1971;65(2):152–168. pmid:4997499
  78. 78. Chikungunya virus in southern Africa: distribution and epidemiology. Rotterdam, The: A.A. Balkema.; 1976.
    • 79. McIntosh BM, Jupp PG, Dos Santos I. Rural epidemic of Chikungunya in South Africa with involvement of Aedes (Diceromyia) furcifer (Edwards) and baboons. S Afr J Sci 1977;73(9):267–269. 6 ref.
    • 80. Guilherme JM, GonellaLegall C, Legall F, Nakoume E, Vincent J. Seroprevalence of five arboviruses in zebu cattle in the Central African Republic. Trans R Soc Trop Med Hyg 1996;90(1):31–33. 5 ref. pmid:8730305
    • 81. Diallo M, Thonnon J, TraoreLamizana M, Fontenille D. Vectors of chikungunya virus in Senegal: current data and transmission cycles. Am J Trop Med Hyg 1999;60(2):281–286. 28 ref. pmid:10072152
    • 82. Wolfe ND, Kilbourn AM, Karesh WB, Rahman HA, Bosi EJ, Cropp BC, et al. Sylvatic transmission of arboviruses among Bornean orangutans. Am J Trop Med Hyg 2001;64(5/6):310–316. 37 ref.
    • 83. Kading RC, Borland EM, Cranfield M, Powers AM. Prevalence of antibodies to alphaviruses and flaviviruses in free-ranging game animals and nonhuman primates in the greater Congo basin. J Wildl Dis 2013;49(3):587–599. 32 ref. pmid:23778608
    • 84. Vourc’h G, Halos L, Desvars A, Boue F, Pascal M, Lecollinet S, et al. Chikungunya antibodies detected in non-human primates and rats in three Indian Ocean islands after the 2006 ChikV outbreak. Veterinary Research; 2014 2014 May;45(52):(1;). 25 ref.
    • 85. Nakgoi K, Nitatpattana N, Wajjwalku W, Pongsopawijit P, Kaewchot S, Yoksan S, et al. Dengue, Japanese encephalitis and Chikungunya virus antibody prevalence among captive monkey (Macaca nemestrina) colonies of Northern Thailand. Am J Primatol 2014;76(1):97–102. 43 ref. pmid:24105916
    • 86. Sam IC, Chua CL, Rovie-Ryan JJ, Fu JY, Tong C, Sitam FT, et al. Chikungunya Virus in Macaques, Malaysia. Emerg Infect Dis 2015 Sep;21(9):1683–1685. pmid:26291585
    • 87. Weger-Lucarelli J, Chu H, Aliota MT, Partidos CD, Osorio JE. A novel MVA vectored Chikungunya virus vaccine elicits protective immunity in mice. PLoS Negl Trop Dis 2014 Jul 24;8(7):e2970. pmid:25058320
    • 88. Myers RM, Carey DE. Concurrent isolation from patient of two arboviruses, Chikungunya and dengue type 2. Science 1967 Sep 15;157(3794):1307–1308. pmid:6038994
    • 89. Bedekar SD, Pavri KM. Studies with Chikungunya virus. I. Susceptibility of birdsand small mammals. Indian J Med Res 1969;57(7):1181–1192. pmid:5357149
    • 90. Chakravarty SK, Sarkar JK. Susceptibility of new born and adult laboratory animals to Chikungunya virus. Indian J Med Res 1969;57(7):1157–1164. pmid:5357148
    • 91. Tiawsirisup S, Navavichit PRW, Ratpiyapaporn Hemmarat. Experimental infection of mice and baby chickens with Thailand strain of Chikungunya virus. Thai Journal of Veterinary Medicine 2012;42(2):353–358. 19 ref.
    • 92. Hugo LE, Prow NA, Tang B, Devine G, Suhrbier A. Chikungunya virus transmission between Aedes albopictus and laboratory mice. Parasit Vectors 2016 Oct 19;9(1):555. pmid:27760560
    • 93. Bosco-Lauth AM, Nemeth NM, Kohler DJ, Bowen RA. Viremia in North American Mammals and Birds After Experimental Infection with Chikungunya Viruses. Am J Trop Med Hyg 2016 Mar;94(3):504–506. pmid:26666699
    • 94. Jupp PG, McIntosh BM. Aedes furcifer and other mosquitoes as vectors of chikungunya virus at Mica, northeastern Transvaal, South Africa. J Am Mosq Control Assoc 1990;6(3):415–420. 13 ref. pmid:1977875
    • 95. Nakao E, Hotta S. Immunogenicity of purified, inactivated chikungunya virus in monkeys. Bull World Health Organ 1973 May;48(5):559–562. pmid:4204490
    • 96. Binn LN, Harrison VR, Randall R. Patterns of viremia and antibody observed in rhesus monkeys inoculated with chikungunya and other serologically related group A arboviruses. Am J Trop Med Hyg 1967;16(6):782–785. pmid:4965218
    • 97. Boorman JPT, Draper CC. Isolations of arboviruses in the Lagos area of Nigeria, and a survey of antibodies to them in man and animals. Trans R Soc Trop Med Hyg 1968;62(2):269–277. pmid:4384491
    • 98. McIntosh BM, Sweetnam J, McGillivray GM, De Sousa J. Laboratory transmission of chikungunya virus by Mansonia (Mansonioides) africana (Theobald). Ann Trop Med Parasitol 1965;59(4):390–392. pmid:4379371
    • 99. McIntosh BM. Susceptibility of some African wild rodents to infection with various arthropod-borne viruses. Trans R Soc Trop Med Hyg 1961;55(1):63–68.
    • 100. Paul SD, Singh KR. Experimental infection of Macaca radiata with Chikungunya virus and transmission of virus by mosquitoes. Indian J Med Res 1968;56(6):802–811. pmid:4971384
    • 101. Weinbren MP. The occurrence of Chikungunya virus in Uganda. II. In man on the. Trans R Soc Trop Med Hyg 1958;52(3):258–259. pmid:13556870
    • 102. Chen ChingI, Clark DC, Pesavento P, Lerche NW, Luciw PA, Reisen WK, et al. Comparative pathogenesis of epidemic and enzootic Chikungunya viruses in a pregnant Rhesus macaque model. Am J Trop Med Hyg 2010;83(6):1249–1258. 49 ref. pmid:21118930
    • 103. Jupp PG, McIntosh BM, Santos Id, Moor P. Laboratory vector studies on six mosquito and one tick species with chikungunya virus. Trans R Soc Trop Med Hyg 1981;75(1):15–19. 12 ref. pmid:6115488
    • 104. Sempala SDK, Kirya BG. Laboratory transmission of chikungunya virus by Aedes (Stegomyia) apicoargenteus Theobald (Diptera, Culicidae). Am J Trop Med Hyg 1973;22(2):263–266. 9 ref. pmid:4631766
    • 105. Ross RW. The Newala Epidemic III. The Virus: Isolation, Pathogenic Properties and Relationship to the Epidemic. Journal of Hygiene 1956;54(2):177. pmid:13346078
    • 106. Jain Ruchi, Acharya AS, Jyoti Khandekar, Jais Manoj. Entomo-epidemiological investigations of chikungunya outbreak in Delhi, India. Annals of Tropical Medicine and Public Health 2013;6(3):297–300. 18 ref.
    • 107. Puwar Tapasvi, Sheth JK, Kohli Vijay, Yadav Rajpal. Prevalence of chikungunya in the city of Ahmedabad, India, during the 2006 outbreak: a community-based study. (Special Issue: Cost and burden of dengue and chikungunya from the Americas to Asia.). Dengue Bulletin; 2010.34:40–45 14 ref.
    • 108. Kannan M, Rajendran R, Sunish IP, Balasubramaniam R, Arunachalam N, Paramsivan R, et al. A study on chikungunya outbreak during 2007 in Kerala, south India. Indian J Med Res 2009;129(3):311–315. 26 ref. pmid:19491425
    • 109. Economopoulou A, Dominguez M, Helynck B, Sissoko D, Wichmann O, Quenel P, et al. Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005–2006 outbreak on Reunion. Epidemiol Infect 2009;137(4):534–541. 21 ref. pmid:18694529
    • 110. Torres JR, Leopoldo Códova G., Castro JS, Rodríguez L, Saravia V, Arvelaez J, et al. Chikungunya fever: Atypical and lethal cases in the Western hemisphere: A Venezuelan experience. IDCases 2015;2(1):6–10. pmid:26793440
    • 111. Lewthwaite P, Vasanthapuram Ravi, Osborne JC, Begum Ashia, Plank JLM, Shankar MV, et al. Chikungunya virus and central nervous system infections in children, India. Emerging Infectious Diseases 2009;15(2):329–331. 19 ref. pmid:19193287
    • 112. Kosasih H, de Mast Q, Widjaja S, Sudjana P, Antonjaya U, Ma’roef C, et al. Evidence for endemic chikungunya virus infections in Bandung, Indonesia. PLoS Negl Trop Dis 2013 Oct 24;7(10):e2483. pmid:24205417
    • 113. Feldstein LR, Ellis EM, Rowhani-Rahbar A, Halloran ME, Ellis BR. The First Reported Outbreak of Chikungunya in the U.S. Virgin Islands, 2014–2015. Am J Trop Med Hyg 2016 Oct 5;95(4):885–889. pmid:27402523
    • 114. Jean-Baptiste E, von Oettingen J, Larco P, Raphael F, Larco NC, Cauvin MM, et al. Chikungunya Virus Infection and Diabetes Mellitus: A Double Negative Impact. Am J Trop Med Hyg 2016 Dec 7;95(6):1345–1350. pmid:27729569
    • 115. Perti T, Lucero-Obusan CA, Schirmer PL, Winters MA, Holodniy M. Chikungunya Fever Cases Identified in the Veterans Health Administration System, 2014. PLoS Negl Trop Dis 2016 May 4;10(5):e0004630. pmid:27144588
    • 116. Borgherini G, Poubeau P, Staikowsky F, Lory M, Moullec Nl, Becquart JP, et al. Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients. Clinical Infectious Diseases 2007;44(11):1401–1407. 31 ref. pmid:17479933
    • 117. Tandale BV, Sathe PS, Arankalle VA, Wadia RS, Kulkarni Rahul, Shah SV, et al. Systemic involvements and fatalities during Chikungunya epidemic in India, 2006. Journal of Clinical Virology 2009;46(2):145–149. 18 ref. pmid:19640780
    • 118. Padmakumar B, Jayan JB, Menon Rejeesh, Kottarathara AJ. Clinical profile of chikungunya sequelae, association with obesity and rest during acute phase. Southeast Asian J Trop Med Public Health 2010;41(1):85–91. 20 ref. pmid:20578486
    • 119. Schwarz NG, Girmann M, Randriamampionona N, Bialonski A, Maus D, Krefis AC, et al. Seroprevalence of antibodies against chikungunya, dengue, and Rift Valley fever viruses after febrile illness outbreak, Madagascar. Emerging Infectious Diseases 2012;18(11):1780–1786. 26 ref. pmid:23092548
    • 120. Setbon M, Raude J. Chikungunya on Réunion Island: Social, environmental and behavioural factors in an epidemic context. Population 2008;63(3):491–518.
    • 121. Larrieu S, Balleydier E, Renault P, Baville M, Filleul L. Epidemiological surveillance du chikungunya on Reunion Island from 2005 to 2011. (Special chikungunya.) [French]. Revue Medecine Tropicale 2011;72(Special):38–42. 14 ref.
    • 122. Flahault A, Aumont G, Boisson V, Lamballerie Xd, Favier F, Fontenille D, et al. An interdisciplinary approach to controlling chikungunya outbreaks on French islands in the south-west Indian Ocean. (Special chikungunya.). Revue Medecine Tropicale 2011;72(Special):66–71. 27 ref.
    • 123. de Lamballerie X, Leroy E, Charrel RN, Ttsetsarkin K, Higgs S, Gould EA. Chikungunya virus adapts to tiger mosquito via evolutionary convergence: a sign of things to come? Virol J 2008 Feb 27;5:33-422X-5-33. pmid:18304328
    • 124. Vijayakumar KP, Nair Anish TS, George B, Lawrence T, Muthukkutty SC, Ramachandran R. Clinical Profile of Chikungunya Patients during the Epidemic of 2007 in Kerala, India. J Glob Infect Dis 2011 Jul;3(3):221–226. pmid:21887052
    • 125. Vijayakumar K, Anish TS, Sreekala KN, Ramachandran R, Philip RR. Environmental factors of households in five districts of Kerala affected by the epidemic of chikungunya fever in 2007. Natl Med J India 2010 Mar-Apr;23(2):82–84. pmid:20925203
    • 126. Blettery M, Brunier L, Polomat K, Moinet F, Deligny C, Arfi S, et al. Brief Report: Management of Chronic Post-Chikungunya Rheumatic Disease: The Martinican Experience. Arthritis Rheumatol 2016 Nov;68(11):2817–2824. pmid:27273928
    • 127. Macpherson C, Noel T, Fields P, Jungkind D, Yearwood K, Simmons M, et al. Clinical and Serological Insights from the Asian Lineage Chikungunya Outbreak in Grenada, 2014: An Observational Study. Am J Trop Med Hyg 2016 Oct 5;95(4):890–893. pmid:27527629
    • 128. Rodger LM. An outbreak of suspected Chikungunya fever in Northern Rhodesia. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 1961;35:126–128. pmid:13742532
    • 129. MCIntosh BM, Harwin RM, Paterson HE, Westwater ML. An Epidemic of Chikungunya in South-Eastern Southern Rhodesia. Cent Afr J Med 1963 Sep;43:351–359.
    • 130. Halstead SB, Udomsakdi S, Singharaj P, Nisalak A. Dengue chikungunya virus infection in man in Thailand, 1962–1964. 3. Clinical, epidemiologic, and virologic observations on disease in non-indigenous white persons. Am J Trop Med Hyg 1969 Nov;18(6):984–996. pmid:5355244
    • 131. Sarkar JK, Chatterjee SN, Chakravarty SK. Three-year study of mosquito-borne haemorrhagic fever in Calcutta. Trans R Soc Trop Med Hyg 1967;61(5):725–735. pmid:4383288
    • 132. Thiruvengadam KV, Kalyanasundaram V, Rajgopal J. Clinical and pathological studies on chikungunya fever in Madras city. Indian J Med Res 1965;53(8):729–744. pmid:5830407
    • 133. Reuben R. Some entomological and epidemiological observations on the 1964 outbreak of Chikungunya fever in South India. Indian J Med Res 1967;55(1):1–12. pmid:6036047
    • 134. Carey DE, Myers RM, Deranitz CM, Jadhav M, Reuben R. The 1964 chikungunya epidemic at vellore, South India, including observations on concurrent dengue. Trans R Soc Trop Med Hyg 1969;63(4):434–445. pmid:5821266
    • 135. Mendis NM. Epidemiology of dengue-like fever in Ceylon. Ceylon Med J 1967;12(2):67–74. pmid:5588663
    • 136. Rodrigues FM, Dandawate CN. The 1965 epidemic of febrile illness in Saugar town, Madhya Pradesh: a retrospective diagnosis of the probable aetiology. Indian J Med Res 1974 Jul;62(7):1005–1010. pmid:4435911
    • 137. Ghosh SN, Sheikh BH. Investigations on the outbreak of dengue fever in Ajmer City, Rajasthan in 1969. Part II: Result of serological tests. Indian J Med Res 1974;62(4):523–533. pmid:4435862
    • 138. Padbidri VS, Gnaneswar TT. Epidemiological investigations of chikungunya epidemic at Barsi, Maharashtra state, India. J Hyg Epidemiol Microbiol Immunol 1979;23(4):445–451. pmid:575900
    • 139. Fourie ED, Morrison JG. Rheumatoid arthritic syndrome after chikungunya fever. South African Medical Journal 1979;56(4):130–132. pmid:494034
    • 140. Saluzzo JF, Cornet M, Digoutte JP. Outbreak of a Chikungunya virus epidemic in western Senegal in 1982. Dakar Med 1983;28(3):497–500. pmid:6323109
    • 141. Lam SK, Chua KB, Hooi PS, Rahimah MA, Kumari S, Tharmaratnam M, et al. Chikungunya infection—an emerging disease in Malaysia. Southeast Asian J Trop Med Public Health 2001;32(3):447–451. 17 ref. pmid:11944696
    • 142. MuyembeTamfum JJ, Peyrefitte CN, Yogolelo R, Basisya EM, Koyange D, Pukuta E, et al. Epidemics of Chikungunya virus in 1999 and 2000 in the Democratic Republic of Congo. Med Trop 2003;63(6):637–638. 6 ref.
    • 143. Laras K, Sukri NC, Larasati RP, Bangs MJ, Kosim R, Djauzi , et al. Tracking the re-emergence of epidemic chikungunya virus in Indonesia. Trans R Soc Trop Med Hyg 2005;99(2):128–141. 27 ref. pmid:15693148
    • 144. Sergon K, Njuguna C, Kalani R, Ofula V, Onyango C, Konongoi LS, et al. Seroprevalence of Chikungunya virus (CHIKV) infection on Lamu Island, Kenya, October 2004. Am J Trop Med Hyg 2008;78(2):333–337. 24 ref. pmid:18256441
    • 145. Cordel H, Investigation Group. Chikungunya outbreak on Reunion: update. Euro Surveill 2006 Mar 2;11(3):E060302.3.
    • 146. Paquet C, Quatresous I, Solet JL, Sissoko D, Renault P, Pierre V, et al. Chikungunya outbreak in Reunion: epidemiology and surveillance, 2005 to early January 2006. Euro Surveill 2006 Feb 2;11(2):E060202.3.
    • 147. Quatresous I, Investigation Group. E-alert 27 January: Chikungunya outbreak in Reunion, a French overseas department. Euro Surveill 2006 Feb 2;11(2):E060202.1.
    • 148. Paquet C, Quatresous I, Solet JL, Sissoko D, Renault P, Pierre V, et al. Epidemiology of chikungunya virus infection on the Island of Reunion: situation on 8 January 2006. (Infection par le virus Chikungunya a l’Ile de la Reunion) [French]. Bulletin Epidemiologique Hebdomadaire 2006(hors serie):2–3. 5 ref.
    • 149. Ledrans M, Quatresous I, Renault P, Pierre V. Outbreak of chikungunya in the French Territories, 2006: lessons learned. Euro surveillance: bulletin européen sur les maladies transmissibles = European communicable disease bulletin 2007;12(9).
    • 150. Renault P, Solet JL, Sissoko D, Balleydier E, Larrieu S, Filleul L, et al. A major epidemic of chikungunya virus infection on Reunion Island, France, 2005–2006. Am J Trop Med Hyg 2007;77(4):727–731. 23 ref. pmid:17978079
    • 151. Sergon K, Yahaya AA, Brown J, Bedja SA, Mlindasse M, Agata N, et al. Seroprevalence of Chikungunya virus infection on Grande Comore Island, Union of the Comoros, 2005. Am J Trop Med Hyg 2007;76(6):1189–1193. 22 ref. pmid:17556634
    • 152. Josseran L, Solet JL, Renault P, Caillere N, Fouillet A, Tertre Al, et al. Description of mortality fluctuations in the Reunion Island population in the context of the 2005–2006 chikungunya outbreak. (Special issue—What did we learn from the chikungunya outbreak in the Indian Ocean in 2005–2006?) [French]. Bulletin Epidemiologique Hebdomadaire 2008(38/40):353–357. 9 ref.
    • 153. Dominguez M, Economopoulou A, Sissoko D, Boisson V, Gauzere BA, Pierre V, et al. Atypical forms of chikungunya in epidemic period, Reunion Island, France, 2005–2006. (Special issue—What did we learn from the chikungunya outbreak in the Indian Ocean in 2005–2006?) [French]. Bulletin Epidemiologique Hebdomadaire 2008(38/40):349–352. 14 ref.
    • 154. Brottet E, Renault P, GlorieuxMontury S, Franco JM, Turquet M, Balleydier E, et al. Epidemic of chikungunya virus infection on the Reunion Island, France, 2005–2006: description of cases reported by practitioners of a surveillance network. (Special issue—What did we learn from the chikungunya outbreak in the Indian Ocean in 2005–2006?) [French]. Bulletin Epidemiologique Hebdomadaire 2008(38/40):346–349. 9 ref.
    • 155. Staikowsky F, Talarmin F, Grivard P, Souab A, Schuffenecker I, Le Roux K, et al. Prospective study of chikungunya virus acute infection in the Island of La Réunion during the 2005–2006 outbreak. PLoS ONE 2009;4(10).
    • 156. Tournebize P, Charlin C, Lagrange M. Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island. Rev Neurol 2009;165(1):48–51. pmid:18835614
    • 157. Sissoko D, Malvy D, Giry C, Delmas G, Paquet C, Gabrie P, et al. Outbreak of Chikungunya fever in Mayotte, Comoros archipelago, 2005–2006. Trans R Soc Trop Med Hyg 2008;102(8):780–786. 27 ref. pmid:18400240
    • 158. Kaur P, Ponniah M, Murhekar MV, Ramachandran V, Ramachandran R, Raju HK, et al. Chikungunya outbreak, South India, 2006. Emerg Infect Dis 2008 Oct;14(10):1623–1625. pmid:18826830
    • 159. Prashant S, Kumar A, Mohammed Basheeruddin D, Chowdhary T, Madhu B. Cutaneous manifestations in patients suspected of chikungunya disease. Indian J Dermatol 2009;54(2):128–131. pmid:20101307
    • 160. Jain S, Kadri S, Venkatesh S, Lal S, Katyal R. Epidemiological investigation of an outbreak of chikungunya in hyderabad and nalgonda districts of andhra pradesh, India. Int J Health Sci (Qassim) 2007 Jul;1(2):303–308.
    • 161. Ratsitorahina M, Harisoa J, Ratovonjato J, Biacabe S, Reynes JM, Zeller H, et al. Outbreak of dengue and chikungunya fevers, Toamasina, Madagascar, 2006. Emerging Infectious Diseases 2008;14(7):1135–1137. 8 ref. pmid:18598641
    • 162. Kumarasamy V, Prathapa S, Zuridah H, Chem YK, Norizah I, Chua KB. Re-emergence of Chikungunya virus in Malaysia. Med J Malaysia 2006;61(2):221–225. 10 ref. pmid:16898316
    • 163. Selvavinayagam TS. Chikungunya fever outbreak in Vellore, South India. Indian Journal of Community Medicine 2007;32(4):286–287. 3 ref.
    • 164. Kirte RC, Naik DB, Khamgaonkar MB. Clinico-epidemiological profile of fever cases admitted during epidemics of Chikungunya fever. J Commun Dis 2007;39(1):33–35. 6 ref. pmid:18338714
    • 165. Jain SK, Kumar Kaushal, Bhattacharya D, Venkatesh S, Jain DC, Shiv Lal. Chikungunya viral disease in district Bhilwara (Rajasthan) India. J Commun Dis 2007;39(1):25–31. 11 ref. pmid:18338713
    • 166. Showkath Ali MK, Rajendran R, Regu K, Mohanan MK, Bora D, Dhariwal AC, et al. Study on the eco-epidemiology of chikungunya in U.T of Lakshadweep. J Commun Dis 2009;41(2):81–92. pmid:22010495
    • 167. Samuel PP, Krishnamoorthi R, Hamzakoya KK, Aggarwal CS. Entomo-epidemiological investigations on chikungunya outbreak in the Lakshadweep islands, Indian Ocean. Indian J Med Res 2009;129(4):442–445. 13 ref. pmid:19535841
    • 168. Dilip C, Saraswathi R, Krishnan PN, Azeem AK, Raseena , Azeez Abdul, et al. Comparitive evaluation of different systems of medicines and the present scenario of chikungunya in Kerala. Asian Pacific Journal of Tropical Medicine 2010;3(6):443–447. 15 ref.
    • 169. Dwibedi Bhagirathi, Mohapatra Namita, Beuria MK, Kerketta AS, Sabat Jyotsna, Kar SK, et al. Emergence of Chikungunya virus infection in Orissa, India. Vector Borne and Zoonotic Diseases 2010;10(4):347–354. 40 ref. pmid:19874187
    • 170. Doke PP, Dakhure DS, Patil AV. A clinico-epidemiological study of chikungunya outbreak in Maharashtra state, India. Indian J Public Health 2011;55(4):313–316. 10 ref. pmid:22298142
    • 171. Dwibedi B, Sabat J, Mahapatra N, Kar SK, Kerketta AS, Hazra RK, et al. Rapid spread of chikungunya virus infection in Orissa: India. Indian J Med Res 2011;133(3):316–321. 21 ref.
    • 172. Seyler T, Sakdapolrak P, Sanjeevi Prasad S, Dhanraj R. A chikungunya outbreak in the metropolis of Chennai, India, 2006. J Environ Health 2012;74(6):8–13. pmid:22329203
    • 173. Kularatne SAM, Weerasinghe SC, Gihan C, Wickramasinghe S, Dharmarathne S, Abeyrathna A, et al. Epidemiology, clinical manifestations, and long-term outcomes of a major outbreak of Chikungunya in a Hamlet in Sri Lanka, in 2007: A longitudinal cohort study. Journal of Tropical Medicine 2012.
    • 174. Razmy AM. Clinical features of chikungunya infection in Sri Lanka. Asian Pacific Journal of Tropical Disease 2014;4(2):131–134.
    • 175. Nair PMC. Chikungunya in neonates. Indian Pediatr 2008;45(7):605.
    • 176. Sharma RS, Showkath Ali MK, Dhillon GPS. Epidemiological and entomological aspects of an outbreak of chikungunya in Lakshadweep Islands, India, during 2007. Dengue Bulletin 2008;32:178–185.
    • 177. Santhosh SR, Dash PK, Parida MM, Khan M, Tiwari M, Rao PVL. Comparative full genome analysis revealed E1: A226V shift in 2007 Indian Chikungunya virus isolates. Virus Res 2008;135(1):36–41. 30 ref. pmid:18384900
    • 178. Goel MK, Malik JS, Khanna P, Gaur DR, Behera BK, Yadav RK. Sero-epidemiological investigation of an outbreak of fever in rural area of Rohtak. J Commun Dis 2009 Sep;41(3):215–217. pmid:22010491
    • 179. Bandyopadhyay B, Pramanik N, De R, Mukherjee D, Mukherjee H, Neogi DK, et al. Chikungunya in west bengal, India. Trop Doct 2009 Jan;39(1):59–60. pmid:19211436
    • 180. Angelini R, Finarelli AC, Angelini P, Po C, Petropulacos K, Macini P, et al. An outbreak of chikungunya fever in the province of Ravenna, Italy. Euro Surveill 2007 Sep 6;12(9):E070906.1.
    • 181. Rezza G, Nicoletti L, Angelini R, Romi R, Finarelli AC, Panning M, et al. Infection with chikungunya virus in Italy: an outbreak in a temperate region. Lancet (British edition) 2007;370(9602):1840–1846. 26 ref.
    • 182. Liumbruno GM, Calteri D, Petropulacos K, Mattivi A, Po C, Macini P, et al. The Chikungunya epidemic in Italy and its repercussion on the blood system. Blood Transfus 2008 Oct;6(4):199–210. pmid:19112735
    • 183. Seyler T, Rizzo C, Finarelli AC, Po C, Alessio P, Sambri V, et al. Autochthonous chikungunya virus transmission may have occurred in Bologna, Italy, during the summer 2007 outbreak. Euro Surveill 2008 Jan 17;13(3):8015. pmid:18445394
    • 184. Moro ML, Grilli E, Corvetta A, Silvi G, Angelini R, Mascella F, et al. Long-term chikungunya infection clinical manifestations after an outbreak in Italy: a prognostic cohort study. J Infect 2012;65(2):165–172. pmid:22522292
    • 185. Pages F, Peyrefitte CN, Mve MT, Jarjaval F, Brisse S, Iteman I, et al. Aedes albopictus mosquito: the main vector of the 2007 Chikungunya outbreak in Gabon. PLos One 2009(March):e4691. 27 ref.
    • 186. Leroy EM, Nkoghe D, Ollomo B, NzeNkogue C, Becquart P, Grard G, et al. Concurrent chikungunya and dengue virus infections during simultaneous outbreaks, Gabon, 2007. Emerging Infectious Diseases 2009;15(4):591–593. 14 ref. pmid:19331740
    • 187. Manimunda SP, Vijayachari Paluru, Uppoor Raghuraj, Sugunan AP, Singh SS, Rai SK, et al. Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. Trans R Soc Trop Med Hyg 2010;104(6):392–399. 25 ref. pmid:20171708
    • 188. Bhat RM, Rai Yashaswi, Ramesh Amitha, Nandakishore B, Sukumar D, Martis Jacintha, et al. Mucocutaneous manifestations of Chikungunya fever: a study from an epidemic in coastal Karnataka. Indian J Dermatol 2011;56(3):290–294. 12 ref. pmid:21772590
    • 189. First identified outbreak of Chikungunya in Bangladesh, 2008. HSB (Health Science Bulletin) 2009;7(1):En1-En6, Benga1-6. 8 ref.
    • 190. Ng LeeChing, Tan LiKiang, Tan CheongHuat, Tan SSY, Hapuarachchi HC, Pok KwoonYong, et al. Entomologic and virologic investigation of chikungunya, Singapore. Emerging Infectious Diseases 2009;15(8):1243–1249. 21 ref. pmid:19751586
    • 191. Leo YS, Chow ALP, Tan LiKiang, Lye DC, Lin Li, Ng LC. Chikungunya outbreak, Singapore, 2008. Emerging Infectious Diseases 2009;15(5):836–837. 10 ref. pmid:19402989
    • 192. Win MK, Chow A, Dimatatac F, Go CJ, Leo YS. Chikungunya fever in Singapore: acute clinical and laboratory features, and factors associated with persistent arthralgia. Journal of Clinical Virology 2010;49(2):111–114. 14 ref. pmid:20674479
    • 193. Ho KaiWei, Ang LiWei, Tan BoonHian, Tang ChoonSiang, Ooi PengLim, James L, et al. Epidemiology and control of chikungunya fever in Singapore. J Infect 2011;62(4):263–270. pmid:21315108
    • 194. Sam IChing, Chan YokeFun, Chan ShieYien, Loong ShihKeng, Chin HockKhim, Hooi PohSim, et al. Chikungunya virus of Asian and Central/East African genotypes in Malaysia. Journal of Clinical Virology 2009;46(2):180–183. 23 ref. pmid:19683467
    • 195. Thavara U, Tawatsin A, Pengsakul T, Bhakdeenuan P, Chanama S, Anantapreecha S, et al. Outbreak of chikungunya fever in Thailand and virus detection in field population of vector mosquitoes, Aedes aegypti (L.) and Aedes albopictus Skuse (Diptera: Culicidae). Southeast Asian J Trop Med Public Health 2009;40(5):951–962. many ref. pmid:19842379
    • 196. Theamboonlers A, Rianthavorn P, Praianantathavorn K, Wuttirattanakowit N, Poovorawan Y. Clinical and molecular characterization of Chikungunya virus in South Thailand. Jpn J Infect Dis 2009;62(4):303–305. 13 ref. pmid:19628911
    • 197. Chusri S, Siripaitoon P, Silpapojakul K. Chikungunya outbreak in Southern Thailand, December 2008 to October 2009. J Infect Dis Antimicrobial Agents 2011;28(1):25–34. 19 ref.
    • 198. Nakkhara P, Chongsuvivatwong V, Thammapalo S. Risk factors for symptomatic and asymptomatic chikungunya infection. Trans R Soc Trop Med Hyg 2013;107(12):789–796. 30 ref. pmid:24052594
    • 199. Chakravarti A, Malik S, Tiwari S, Ashraf A. A study of Chikungunya outbreak in Delhi. J Commun Dis 2011 Dec;43(4):259–263. pmid:23781642
    • 200. Patil SS, Patil SR, Durgawale PM, Patil AG. A study of the outbreak of Chikungunya fever. J Clin Diagn Res 2013 Jun;7(6):1059–1062. pmid:23905103
    • 201. Shoukry NM, Elwan MA, Morsy TA. Aedes aegypti (Linnaeus) re-emerging in southern Egypt. J Egypt Soc Parasitol 2012;42(1):41–50. 39 ref. pmid:22662594
    • 202. Paupy C, Kassa Kassa F, Caron M, Nkoghe D, Leroy EM. A chikungunya outbreak associated with the vector Aedes albopictus in remote villages of Gabon. Vector Borne Zoonotic Dis 2012 Feb;12(2):167–169. pmid:22141733
    • 203. Nkoghe D, Kassa RF, Caron M, Grard G, Mombo I, Bikié B, et al. Clinical forms of Chikungunya in Gabon, 2010. PLoS Neglected Tropical Diseases 2012;6(2).
    • 204. Zhang QiaoLi, He JianFeng, Wu De, Wang ZiJun, Zhong XinGuang, Zhong HaoJie, et al. Maiden outbreak of Chikungunya in Dongguan City, Guangdong Province, China: epidemiological characteristics. PLoS ONE; 2012 2830;7(8):e4; 19 ref.
    • 205. De Wu, Jie Wu, Zhang QiaoLi, Zhong HaoJie, Ke ChangWen, Deng XiaoLing, et al. Chikungunya outbreak in Guangdong Province, China, 2010. Emerging Infectious Diseases 2012;18(3):493–495. 13 ref. pmid:22377135
    • 206. De Wu, Zhang YongHui, ZhouHui Qiong, Jing Kou, Liang WenJia, Zhang Huan, et al. Chikungunya virus with E1-A226V mutation causing two outbreaks in 2010, Guangdong, China. Virology Journal; 2013 2013 June;10(174):(2;). 35 ref.
    • 207. D’Ortenzio E, Grandadam M, Balleydier E, JaffarBandjee MC, Michault A, Brottet E, et al. A226V strains of Chikungunya virus, Reunion Island, 2010. Emerging Infectious Diseases 2011;17(2):309–311. 10 ref. pmid:21291616
    • 208. Vilain P, Larrieu S, Renault P, Baville M, Filleul L. How to explain the re-emergence of chikungunya infection in Reunion Island in 2010? Acta Trop 2012;123(2):85–90. 25 ref. pmid:22525433
    • 209. Gurav YK, Gopalkrishna V, Shah PS, Patil DR, Mishra M, Paingankar MS, et al. An outbreak of chikungunya in Jamshedpur, Jharkhand in 2011. Indian J Med Res 2012;136(5):886–889. 19 ref. pmid:23287142
    • 210. Bhagwati C, M M, Mehta KD, Y SG. Profile of The Chikungunya Infection: A Neglected Vector Borne Disease which is Prevalent In The Rajkot District. J Clin Diagn Res 2013 Jun;7(6):1008–1011. pmid:23905091
    • 211. An outbreak of Chikungunya in Dohar Upazila, Bangladesh, 2011. HSB (Health Science Bulletin) 2012;10(4):1–8 (En), 1–8 (Benga). 23 ref.
    • 212. Khatun S, Chakraborty A, Rahman M, Nasreen Banu N, Rahman MM, Hasan SM, et al. An Outbreak of Chikungunya in Rural Bangladesh, 2011. PLoS Negl Trop Dis 2015 Jul 10;9(7):e0003907. pmid:26161995
    • 213. DupontRouzeyrol M, Caro V, Guillaumot L, Vazeille M, D’Ortenzio E, Thiberge JM, et al. Chikungunya virus and the mosquito vector Aedes aegypti in New Caledonia (South Pacific Region). Vector Borne and Zoonotic Diseases 2012;12(12):1036–1041. 29 ref. pmid:23167500
    • 214. Mombouli JV, Bitsindou P, Elion DOA, Grolla A, Feldmann H, Niama FR, et al. Chikungunya virus infection, Brazzaville, Republic of Congo, 2011. Emerging Infectious Diseases 2013;19(9):1542–1543. 10 ref. pmid:23968609
    • 215. Moyen N, Thiberville S-, Pastorino B, Nougairede A, Thirion L, Mombouli J-, et al. First reported chikungunya fever outbreak in the republic of Congo, 2011. PLoS ONE 2014;9(12).
    • 216. Malik MR, Mnzava A, Mohareb E, Zayed A, Al Kohlani A, Thabet AAK, et al. Chikungunya outbreak in Al-Hudaydah, Yemen, 2011: Epidemiological characterization and key lessons learned for early detection and control. Journal of Epidemiology and Global Health 2014;4(3):203–211.
    • 217. Sy AK, Saito-Obata M, Medado IA, Tohma K, Dapat C, Segubre-Mercado E, et al. Molecular Characterization of Chikungunya Virus, Philippines, 2011–2013. Emerg Infect Dis 2016 May;22(5):887–890. pmid:27088593
    • 218. Horwood P, Bande G, Dagina R, Guillaumot L, Aaskov J, Pavlin B. The threat of chikungunya in Oceania. Western Pac Surveill Response J 2013 Jun 4;4(2):8–10. pmid:24015365
    • 219. Horwood PF, Reimer LJ, Dagina R, Susapu M, Bande G, Katusele M, et al. Outbreak of Chikungunya virus infection, Vanimo, Papua New Guinea. Emerging Infectious Diseases 2013;19(9):1535–1538. 14 ref. pmid:23965757
    • 220. Soulaphy C, Souliphone P, Phanthavong K, Phonekeo D, Phimmasine S, Khamphaphongphane B, et al. Emergence of Chikungunya in Moonlapamok and Khong Districts, Champassak Province,the Lao People’s Democratic Republic, May to September 2012. Western Pac Surveill Response J 2013 Mar 18;4(1):46–50.
    • 221. Wangchuk S, Chinnawirotpisan P, Dorji T, Tobgay T, Dorji T, Yoon InKyu, et al. Chikungunya fever outbreak, Bhutan, 2012. Emerging Infectious Diseases 2013;19(10):1681–1684. 13 ref. pmid:24047543
    • 222. Robinson M, Conan A, Duong V, Ly S, Ngan C, Buchy P, et al. A model for a chikungunya outbreak in a rural Cambodian setting: implications for disease control in uninfected areas. PLoS Negl Trop Dis 2014 Sep 11;8(9):e3120. pmid:25210729
    • 223. Gutierrez-Rubio AK, Magbitang A-D, Penserga EG. A three-month follow up of musculoskeletal manifestions in chikungunya fever. 2014.
      • 224. Ballera JE, Zapanta MJ, de los Reyes VC, Sucaldito MN, Tayag E. Investigation of chikungunya fever outbreak in Laguna, Philippines, 2012. Western Pac Surveill Response J 2015 Aug 10;6(3):8–11. pmid:26668759
      • 225. Salje H, Lessler J, Paul KK, Azman AS, Rahman MW, Rahman M, et al. How social structures, space, and behaviors shape the spread of infectious diseases using chikungunya as a case study. Proc Natl Acad Sci U S A 2016 Nov 22;113(47):13420–13425. pmid:27821727
      • 226. Phommanivong V, Kanda S, Shimono T, Lamaningao P, Darcy AW, Mishima N, et al. Co-circulation of the dengue with chikungunya virus during the 2013 outbreak in the southern part of Lao PDR. Trop Med Health 2016 Aug 4;44:24-016-0020-y. eCollection 2016. pmid:27524929
      • 227. Nsoesie EO, Ricketts RP, Brown HE, Fish D, Durham DP, Ndeffo Mbah ML, et al. Spatial and Temporal Clustering of Chikungunya Virus Transmission in Dominica. PLoS Negl Trop Dis 2015 Aug 14;9(8):e0003977. pmid:26274813
      • 228. Kendrick K, Stanek D, Blackmore C. Transmission of chikungunya virus in the continental United States—Florida, 2014. Morbidity and Mortality Weekly Report; 2014 1137;63(48):3 ref.
      • 229. Dumpala Suguna, Kondagunta Nagaraj, Malhotra VM, Venna GP, Jothula KY. An outbreak investigation of suspected Chikungunya fever in Nalgonda District, Telangana state. Journal of Clinical and Scientific Research 2014;3(4):219–223. 14 ref.
      • 230. Delisle E, Rousseau C, Broche B, Leparc-Goffart I, Ambert G, Cochet A, et al. Chikungunya outbreak in Montpellier, France, September to October 2014. Euro Surveill 2015 Apr 30;20(17):21108. pmid:25955774
      • 231. Septfons A, Noel H, Leparc-Goffart I, Giron S, Delisle E, Chappert JL, et al. Monitoring of chikungunya and dengue in metropolitan France, 2014. 2015;. Accessed 13.
        • 232. Aubry M, Teissier A, Roche C, Richard V, Shan Yan, Zisou K, et al. Chikungunya outbreak, French Polynesia, 2014. Emerging Infectious Diseases 2015;21(4):724–726. 10 ref. pmid:25811534
        • 233. Oehler E., Fournier E., Leparc-Goffart I., Larre P., Cubizolle S., Sookhareea C., et al. Increase in cases of guillain-barre syndrome during a chikungunya outbreak, French Polynesia, 2014 to 2015. 2015;. Accessed 48, 20.
          • 234. Sharp TM, Roth NM, Torres J, Ryff KR, Rodriguez NMP, Mercado C, et al. Chikungunya cases identified through passive surveillance and household investigations—Puerto Rico, May 5-August 12, 2014. Morb Mortal Weekly Rep 2014;63(48):1121–1128. 19 ref.
          • 235. Ahmed S, Francis L, Ricketts RP, Christian T, Polson-Edwards K, Olowokure B. Chikungunya virus outbreak, dominica, 2014. Emerg Infect Dis 2015 May;21(5):909–911. pmid:25898214
          • 236. Jimenez-Canizales CE, Medina-Gaitan DA, Mondragon-Cardona AE, Rodriguez-Morales AJ. From imported to an endemic disease: impact of chikungunya virus disease in the hospital epidemiology, Tolima, Colombia, 2014–2015. Recent Pat Antiinfect Drug Discov 2015 Apr 14.
          • 237. Campo Carey AR, Martinez Duran ME, Benavides Ocampo M, Constanza Cuellar N. Chikungunya outbreak in the municipality of San Juan Nepomuceno, Bolivar, Colombia, 2014. Informe Quincenal—Epidemiologico Nacional 2015;20(1):2–20. 17 ref.
          • 238. Cardona-Ospina JA, Villamil-Gomez WE, Jimenez-Canizales CE, Castaneda-Hernandez DM, Rodriguez-Morales AJ. Estimating the burden of disease and the economic cost attributable to chikungunya, Colombia, 2014. Trans R Soc Trop Med Hyg 2015 Dec;109(12):793–802. pmid:26626342
          • 239. Mattar S, Miranda J, Pinzon H, Tique V, Bolanos A, Aponte J, et al. Outbreak of Chikungunya virus in the north Caribbean area of Colombia: clinical presentation and phylogenetic analysis. J Infect Dev Ctries 2015 Oct 29;9(10):1126–1132. pmid:26517488
          • 240. Campo Carey AR, Benavides Ocampo M, Martinez Duran ME, Caro Nunez OA, Gomez Amaya JA, Nieto Sanchez DL, et al. Chikungunya outbreak in the municipality of Mahates, Bolivar, 2014. Informe Quincenal—Epidemiologico Nacional 2014;19(21):342–367. 21 ref.
          • 241. Martinez Duran M, Gomez Romero SE, Mercado Reyes M, Campo Carey A, Alarcon Cruz A. Autochthonous transmission of chikungunya in Colombia, October 2014. Informe Quincenal—Epidemiologico Nacional 2014;19(20):312–340. 13 ref.
          • 242. Cardona-Ospina JA, Henao-SanMartin V, Paniz-Mondolfi AE, Rodriguez-Morales AJ. Mortality and fatality due to Chikungunya virus infection in Colombia. J Clin Virol 2015 Sep;70:14–15. pmid:26305812
          • 243. Castillo Pabon JO, Walteros Acero DM, Herrera Gutierrez N, Cochero Bustamante S. Research cases of Chikungunya fever virus in communities, September 2014, Ovejas, Sucre. 2015;. Accessed 11, 20.
            • 244. Pimentel R, SkewesRamm R, Moya J. Chikungunya in the Dominican Republic: lessons learned in the first six months. Rev Panam Salud Publica/Pan Am J Public Health 2014;36(5):336–341. 19 ref.
            • 245. Langsjoen RM, Rubinstein RJ, Kautz TF, Auguste AJ, Erasmus JH, Kiaty-Figueroa L, et al. Molecular Virologic and Clinical Characteristics of a Chikungunya Fever Outbreak in La Romana, Dominican Republic, 2014. PLoS Negl Trop Dis 2016 Dec 28;10(12):e0005189. pmid:28030537
            • 246. Kumar A, Best C, Benskin G. Epidemiology, Clinical and Laboratory Features and Course of Chikungunya among a Cohort of Children during the First Caribbean Epidemic. J Trop Pediatr 2016 Aug 10.
            • 247. Crosby L, Perreau C, Madeux B, Cossic J, Armand C, Herrmann-Storke C, et al. Severe manifestations of chikungunya virus in critically ill patients during the 2013–2014 Caribbean outbreak. Int J Infect Dis 2016 Jul;48:78–80. pmid:27208636
            • 248. Rapidly Evolving Outbreak of a Febrile Illness in Rural Haiti: The Importance of a Field Diagnosis of Chikungunya Virus in Remote Locations. 2015;. Accessed 11, 15.
              • 249. Pessoa R, Patriota JV, Lourdes de Souza M, Felix AC, Mamede N, Sanabani SS. Investigation Into an Outbreak of Dengue-like Illness in Pernambuco, Brazil, Revealed a Cocirculation of Zika, Chikungunya, and Dengue Virus Type 1. Medicine (Baltimore) 2016 Mar;95(12):e3201.
              • 250. Genderen FT, Krishnadath I, Sno R, Grunberg MG, Zijlmans W, Adhin MR. First Chikungunya outbreak in Suriname; clinical and epidemiological features. 2016;. Accessed 4, 10.
                • 251. Vishwanath S, Badami K, Sriprakash KS, Sujatha BL, Shashidhar SD, Shilpa YD. Post-fever retinitis: a single center experience from south India. Int Ophthalmol 2014 Aug;34(4):851–857. pmid:24362635
                • 252. Babu K, Kini R, Philips M, Subbakrishna DK. Clinical profile of isolated viral anterior uveitis in a South Indian patient population. Ocul Immunol Inflamm 2014 Oct;22(5):356–359. pmid:24111839
                • 253. Babu K, Adiga M, Govekar SR, Kumar BR, Murthy KR. Associations of Fuchs heterochromic iridocyclitis in a South Indian patient population. J Ophthalmic Inflamm Infect 2013 Jan 15;3(1):14-5760-3-14.
                • 254. Hayek S, Rousseau A, Bouthry E, Prat CM, Labetoulle M. Chikungunya Virus Infection and Bilateral Stromal Keratouveitis. JAMA Ophthalmol 2015 Apr 9.
                • 255. Kashyap RS, Morey S, Bhullar S, Baheti N, Chandak N, Purohit H, et al. Determination of Toll-like receptor-induced cytokine profiles in the blood and cerebrospinal fluid of Chikungunya patients. Neuroimmunomodulation 2014;21(6):338–346. pmid:24776821
                • 256. Das Suman, Sarkar Nirmalya, Majumder Jayitri, Chatterjee Kaushani, Bholanath A. Acute disseminated encephalomyelitis in a child with chikungunya virus infection. Journal of Pediatric Infectious Diseases 2014;9(1):37–41. 15 ref.
                • 257. Anfasa F, Provacia L, GeurtsvanKessel C, Wever R, Gerstenbluth I, Osterhaus AD, et al. Hyperferritinemia is a potential marker of chronic chikungunya: A retrospective study on the Island of Curacao during the 2014–2015 outbreak. J Clin Virol 2017 Jan;86:31–38. pmid:27912127
                • 258. Waggoner JJ, Gresh L, Mohamed-Hadley A, Ballesteros G, Davila MJ, Tellez Y, et al. Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 2016 Jul;22(7):1295–1297. pmid:27184629
                • 259. Waggoner JJ, Gresh L, Vargas MJ, Ballesteros G, Tellez Y, Soda KJ, et al. Viremia and Clinical Presentation in Nicaraguan Patients Infected With Zika Virus, Chikungunya Virus, and Dengue Virus. Clin Infect Dis 2016 Dec 15;63(12):1584–1590. pmid:27578819
                • 260. d Lamballerie X, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, et al. On chikungunya acute infection and chloroquine treatment. Vector Borne and Zoonotic Diseases 2008;8(6):837–840. 10 ref. pmid:18620511
                • 261. Paterson HE, McIntosh BM. Further studies on the chikungunya outbreak in southern Rhodesia in 1962. II. Transmission experiments with the Aedes Furcifer-Taylori group of mosquitoes and with a memver of the Anopheles gambiae complex. Ann Trop Med Parasitol 1964;58:52–55. pmid:14147665
                • 262. Shah KV, Baron S. Laboratory infection with chikungunya virus: a case report. Indian J Med Res 1965;53(7):610–613. pmid:5827506
                • 263. Parola P, Lamballerie Xd, Jourdan J, Rovery C, Vaillant V, Minodier P, et al. Novel chikungunya virus variant in travelers returning from Indian Ocean islands. Emerging Infectious Diseases 2006;12(10):1493–1499. 37 ref. pmid:17176562
                • 264. Baudin M, Jumaa AM, Jomma HJ, Karsany MS, Bucht G, Naslund J, et al. Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study. Lancet Glob Health 2016 Nov;4(11):e864–e871. pmid:27692776
                • 265. Torres JR, Falleiros-Arlant LH, Duenas L, Pleitez-Navarrete J, Salgado DM, Castillo JB. Congenital and perinatal complications of chikungunya fever: a Latin American experience. Int J Infect Dis 2016 Oct;51:85–88. pmid:27619845
                • 266. Fritel X, Rollot O, Gerardin P, Gauzere BA, Bideault J, Lagarde L, et al. Chikungunya virus infection during pregnancy, Reunion, France, 2006. Emerging Infectious Diseases 2010;16(3):418–425. 28 ref.
                • 267. Gerardin P, Barau G, Michault A, Bintner M, Randrianaivo H, Choker G, et al. Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the Island of La Reunion. PLoS Medicine 2008;5(3):e60. 42 ref. pmid:18351797
                • 268. Chebabi Abramides G, Roiz D, Guitart R, Quintana S, Gimenez N. Control of the Asian tiger mosquito (Aedes albopictus) in a firmly established area in Spain: risk factors and people’s involvement. Trans R Soc Trop Med Hyg 2013;107(11):706–714. 41 ref. pmid:24114673
                • 269. Thuilliez J, Bellia C, Dehecq JS, Reilhes O. Household-level expenditure on protective measures against mosquitoes on the island of La Réunion, France. PLoS neglected tropical diseases 2014;8(1).
                • 270. Custer B, Agapova M, Martinez RH. The cost-effectiveness of pathogen reduction technology as assessed using a multiple risk reduction model. Transfusion 2010;50(11):2461–2473. 45 ref. pmid:20497512
                • 271. Seyler T, Hutin Y, Ramanchandran V, Ramakrishnan R, Manickam P, Murhekar M. Estimating the burden of disease and the economic cost attributable to chikungunya, Andhra Pradesh, India, 2005–2006. Trans R Soc Trop Med Hyg 2010;104(2):133–138. 17 ref. pmid:19709705
                • 272. Goettel MS, Toohey MK, Pillai JS. The urban mosquitoes of Suva, Fiji: seasonal incidence and evaluation of environmental sanitation and ULV spraying for their control. J Trop Med Hyg 1980 Aug;83(4):165–171. pmid:7411679
                • 273. Erasmus JH, Auguste AJ, Kaelber JT, Luo H, Rossi SL, Fenton K, et al. A chikungunya fever vaccine utilizing an insect-specific virus platform. Nat Med 2016 Dec 19.
                • 274. Edelman R, Tacket CO, Wasserman SS, Bodison SA, Perry JG, Mangiafico JA. Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218. Am J Trop Med Hyg 2000;62(6):681–685. 30 ref. pmid:11304054
                • 275. Jenyoshikawa M, Tang CS, Nishibuchi M. Incidence of chikungunya fever in Singapore: Implications of public health measures and transnational movements of people. Tropical Medicine and Health 2010;38(1):39–45.
                • 276. Lorenzi OD, Major C, Acevedo V, Perez-Padilla J, Rivera A, Biggerstaff BJ, et al. Reduced Incidence of Chikungunya Virus Infection in Communities with Ongoing Aedes Aegypti Mosquito Trap Intervention Studies—Salinas and Guayama, Puerto Rico, November 2015-February 2016. MMWR Morb Mortal Wkly Rep 2016 May 13;65(18):479–480. pmid:27171600
                • 277. Moulay D, Aziz-Alaoui MA, Kwon H-. Optimal control of chikungunya disease: Larvae reduction, treatment and prevention. Mathematical Biosciences and Engineering 2012;9(2):369–392. pmid:22901069
                • 278. Kumar NP, Bashir A, Abidha S, Sabesan S, Jambulingam P. Predatory potential of Platynectes sp. (Coleoptera: Dytiscidae) on Aedes albopictus, the vector of dengue/chikungunya in Kerala, India. Tropical Biomedicine 2014;31(4):736–741. 20 ref. pmid:25776599
                • 279. Paily KP, Chandhiran K, Vanamail P, Kumar NP, Jambulingam P. Efficacy of a mermithid nematode Romanomermis iyengari (Welch) (Nematoda: Mermithidae) in controlling tree hole-breeding mosquito Aedes albopictus (Skuse) (Diptera: Culicidae) in a rubber plantation area of Kerala, India. Parasitol Res 2013;112(3):1299–1304. 23 ref. pmid:23306387
                • 280. Ghosh SK, Chakaravarthy Preethi, Panch SR, Pushpalata K, Tiwari Satyanarayan, Ojha VP, et al. Comparative efficacy of two poeciliid fish in indoor cement tanks against chikungunya vector Aedes aegypti in villages in Karnataka, India. BMC Public Health; 2011 2011 July;11(599):(28;). 18 ref.
                • 281. Surendran SN, Kajatheepan Arunasalam, Jude PJ, Ramasamy Ranjan. Use of tilapia, Oreochromis mossambicus, for the control of mosquito breeding in water storage tanks in the Jaffna district of Sri Lanka. Tropical Medicine and Health 2008;36(2):107–110. 9 ref.
                • 282. Thaung U, Khai Ming C, Thein Myint. Dengue haemorrhagic fever in Burma. Southeast Asian J Trop Med Public Health 1975;6(4):580–591. 7 ref. pmid:131977
                • 283. Murugan K, Priyanka V, Dinesh D, Madhiyazhagan P, Panneerselvam C, Subramaniam J, et al. Predation by Asian bullfrog tadpoles, Hoplobatrachus tigerinus, against the dengue vector, Aedes aegypti, in an aquatic environment treated with mosquitocidal nanoparticles. Parasitol Res 2015 Oct;114(10):3601–3610. pmid:26091763
                • 284. Singh G, Prakash S. Virulency of novel nanolarvicide from Trichoderma atroviride against Aedes aegypti (Linn.): a CLSM analysis. Environ Sci Pollut Res Int 2015 Apr 25.
                • 285. Cummins B, Cortez R, Foppa IM, Walbeck J, Hyman JM. A spatial model of mosquito host-seeking behavior. PLoS Comput Biol 2012;8(5):e1002500. pmid:22615546
                • 286. Pile JC, Henchal EA, Christopher GW, Steele KE, Pavlin JA. Chikungunya in a North American traveler. Journal of Travel Medicine 1999;6(2):137–139. 15 ref. pmid:10381967
                • 287. Lourenco-de-Oliveira R, Failloux A. High risk for chikungunya virus to initiate an enzootic sylvatic cycle in the tropical Americas. PLoS Negl Trop Dis 2017;11(6).
                • 288. Villamil-Gomez W, Alba-Silvera L, Menco-Ramos A, Gonzalez-Vergara A, Molinares-Palacios T, Barrios-Corrales M, et al. Congenital Chikungunya Virus Infection in Sincelejo, Colombia: A Case Series. J Trop Pediatr 2015 Oct;61(5):386–392. pmid:26246086
                • 289. Senanayake MP, Senanayake SM, Vidanage KK, Gunasena S, Lamabadusuriya SP. Vertical transmission in chikungunya infection. Ceylon Med J 2009 Jun;54(2):47–50. pmid:19670548
                • 290. Peter R, Krishnan L, Anandraj V, Kuruvila S. Chikungunya in a newborn. Journal of Clinical Neonatology 2015 01 Apr 2015;4(2):145–146.
                • 291. de Araújo Thália Velho Barreto, Ximenes Ricardo Arraes Alencar, Miranda-Filho Demócrito de Barros, Souza Wayner Vieira, Montarroyos Ulisses Ramos, de Melo Ana Paula Lopeset al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect Dis 2018;18:328. pmid:29242091
                • 292. YiuWing K, KwoonYong P, KaiEr E, LiKiang T, Kaur S, Lee WWL, et al. Sero-prevalence and cross-reactivity of Chikungunya virus specific anti-E2EP3 antibodies in arbovirus-infected patients. 2015;. Accessed 1, 9.
                  • 293. Hassing RJ, Leparc-Goffart I, Tolou H, van Doornum G, van Genderen PJ. Cross-reactivity of antibodies to viruses belonging to the Semliki forest serocomplex. Eurosurveillance 2010;15(23).
                  • 294. Larrieu S, Pouderoux N, Pistone T, Filleul L, Receveur MC, Sissoko D, et al. Factors associated with persistence of arthralgia among chikungunya virus-infected travellers: report of 42 French cases. Journal of Clinical Virology 2010;47(1):85–88. 15 ref. pmid:20004145
                  • 295. Mishra AK, George AA, Sadhasiv M, Sathyendra S. Sign in Chikungunya Fever. Journal of Association of Physicians of India 2016;64:74.
                  • 296. Vasani R, Kanhere S, Chaudhari K, Phadke V, Mukherjee P, Gupta S, et al. Congenital Chikungunya-A Cause of Neonatal Hyperpigmentation. Pediatr Dermatol 2016 Mar-Apr;33(2):209–212. pmid:26205895
                  • 297. Mishra K, Rajawat V. Chikungunya-induced genital ulcers. Indian J Dermatol Venereol Leprol 2008 Jul-Aug;74(4):383–384. pmid:18797064
                  • 298. Torres JR, Cordova LG, Saravia V, Arvelaez J, Castro JS. Nasal Skin Necrosis: An Unexpected New Finding in Severe Chikungunya Fever. Clin Infect Dis 2016 Jan 1;62(1):78–81. pmid:26423381
                  • 299. Sebastian MR, Lodha R, Kabra SK. Chikungunya infection in children. Indian J Pediatr 2009 Feb;76(2):185–189. pmid:19330307
                  • 300. Rampal , Sharda M, Meena H. Neurological complications in Chikungunya fever. J Assoc Physicians India 2007 Nov;55:765–769. pmid:18290551
                  • 301. Paul BJ, Pannarkady G, Moni SP, Thachil EJ. Clinical profile and long-term sequelae of Chikungunya fever. Indian Journal of Rheumatology 2011;6(1 SUPPL.):12–19.
                  • 302. Taraphdar D, Roy BK, Chatterjee S. Chikungunya virus infection amongst the acute encephalitis syndrome cases in West Bengal, India. Indian Journal of Medical Microbiology 2015;33(5(Suppl.):153–156. 13 ref.
                  • 303. Maity P, Roy P, Basu A, Das B, Ghosh US. A case of ADEM following Chikungunya fever. J Assoc Physicians India 2014 May;62(5):441–442. pmid:25438499
                  • 304. Mohamed Musthafa AK, Abdurahiman P, Jose J. A case of ADEM following Chikungunya fever. Journal of Association of Physicians of India 2008;56(JUNE):473.
                  • 305. Lemant J, Boisson V, Winer A, Thibault L, Andre H, Tixier F, et al. Serious acute Chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005–2006. Crit Care Med 2008;36(9):2536–2541. 35 ref. pmid:18679124
                  • 306. Lebrun G, Chadda K, Reboux AH, Martinet O, Gauzere BA. Guillain-Barre syndrome after chikungunya infection. Emerging Infectious Diseases 2009;15(3):495–496. 8 ref. pmid:19239775
                  • 307. Benoît Rozé, Fatiha Najioullah, Fergé Jean-Louis, Dorléans Frédérique, Apetse Kossivi, Barnay Jose-Luis et al. Guillain-Barré Syndrome Associated With Zika Virus Infection in Martinique in 2016: A Prospective Study. Clinical Infectious Diseases 2017;65(9):1462. pmid:29020245
                  • 308. Bhuvaneshwari S, Manjari K, Bhuvaneswari K. Usage of antimicrobials in Chikungunya at a tertiary care hospital. International Journal of Pharmaceutical and Biological Archives 2013;4(5):965–967. 4 ref.
                  • 309. Kiran LJ, Jyothi CH, Narendranath S, Gokul CG, Shivashankaramurthy KG, Srinivas LD, et al. Prescribing patterns in clinically suspected chikungunya: a retrospective study. Journal of Pharmacy Research 2012;5(3):1704–1705. 7 ref.
                  • 310. Prasad SS, Venugopal K, Anusha B, Dadapeer S, Hamidulla SD, Manasa T, et al. A study on Chikungunya prevalence during 2009 in the state of Andhra Pradesh, South India. International Journal of Chemical Sciences 2012;10(1):175–181. 20 ref.
                  • 311. Mukadam AM, Chauhan KG, Topia SY, Bhise KS. Occurrence of Chikungunya and prescribing patterns for its treatment in Maharashtra state. Journal of Pharmacy Research 2009;2(9):1370–1372. 10 ref.
                  • 312. Chem YK, Zainah S, Berendam SJ, Rogayah Tengku, Khairul AH, Chua KB. Molecular epidemiology of chikungunya virus in Malaysia since its first emergence in 1998. Med J Malaysia 2010;65(1):31–35. 10 ref. pmid:21265245
                  • 313. Nyari N, Maan HS, Sharma S, Pandey SN, Dhole TN. Identification and genetic characterization of chikungunya virus from Aedes mosquito vector collected in the Lucknow district, North India. Acta Trop 2016 Jun;158:117–124. pmid:26943997
                  • 314. Conteville LC, Zanella L, Marin MA, Filippis AM, Nogueira RM, Vicente AC, et al. Phylogenetic analyses of chikungunya virus among travelers in Rio de Janeiro, Brazil, 2014–2015. Mem Inst Oswaldo Cruz 2016 May;111(5):347–348. pmid:27120007
                  • 315. Lo Presti A, Ciccozzi M, Cella E, Lai A, Simonetti FR, Galli M, et al. Origin, evolution, and phylogeography of recent epidemic CHIKV strains. Infect Genet Evol 2012 Mar;12(2):392–398. pmid:22244786
                  • 316. Vazeille M, Zouache K, Vega-Rua A, Thiberge JM, Caro V, Yebakima A, et al. Importance of mosquito "quasispecies" in selecting an epidemic arthropod-borne virus. Sci Rep 2016 Jul 7;6:29564. pmid:27383735
                  • 317. Kumar NP, Mitha MM, Krishnamoorthy N, Kamaraj T, Joseph R, Jambulingam P. Genotyping of virus involved in the 2006 Chikungunya outbreak in South India (Kerala and Puducherry). Curr Sci 2007;93(10):1412–1416. 7 ref.
                  • 318. Peyrefitte CN, Rousset D, Pastorino BAM, Pouillot R, Bessaud M, Tock F, et al. Chikungunya virus, Cameroon, 2006. Emerging Infectious Diseases 2007;13(5):768–771. 15 ref. pmid:17553262
                  • 319. Peper SM, Monson BJ, Van Schooneveld T, Smith CJ. That Which Bends Up: A Case Report and Literature Review of Chikungunya Virus. J Gen Intern Med 2016 May;31(5):576–581. pmid:26194641
                  • 320. Dayakar S., Goud I.K, Pillai H, Remadevi V., Dharmaseelan S., Nair R.R, et al. Molecular Diagnosis of Chikungunya virus (CHIKV) and Dengue virus (DENV) and its concomitant circulation in South Indian population. 2015;, 5.
                  • 321. Corrin T, Waddell L, Greig J, Young I, Hierlihy C, Mascarenhas M. Risk perceptions, attitudes, and knowledge of chikungunya among the public and health professionals: a systematic review. Trop Med Health, 2017;45(21).
                  • 322. Ng V, Fazil A, Gachon P, Deuymes G, Radojević M, Mascarenhas M, et al. Assessment of the Probability of Autochthonous Transmission of Chikungunya Virus in Canada under Recent and Projected Climate Change. Environmental Health Perspectives 2017;06701.