Skip to main content
Advertisement
  • Loading metrics

The global burden of Chikungunya fever among children: A systematic literature review and meta-analysis

  • Doris K. Nyamwaya ,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing

    dnyamwaya@kemri-wellcome.org

    Affiliations KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom

  • Samuel M. Thumbi,

    Roles Conceptualization, Formal analysis, Supervision, Validation, Writing – review & editing

    Affiliations Paul G Allen School for Global Health, Washington State University, Pullman, Washington, United States of America, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom, Center for Epidemiological Modelling and Analysis, Institute of Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya

  • Philip Bejon,

    Roles Formal analysis, Funding acquisition, Investigation, Supervision, Validation, Writing – review & editing

    Affiliations KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom

  • George M. Warimwe,

    Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing

    Affiliations KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom

  • Jolynne Mokaya

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

    Affiliations KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom

Abstract

Chikungunya fever (CHIKF) is an arboviral illness that was first described in Tanzania (1952). In adults, the disease is characterised by debilitating arthralgia and arthritis that can persist for months, with severe illness including neurological complications observed in the elderly. However, the burden, distribution and clinical features of CHIKF in children are poorly described. We conducted a systematic literature review and meta-analysis to determine the epidemiology of CHIKF in children globally by describing its prevalence, geographical distribution, and clinical manifestations. We searched electronic databases for studies describing the epidemiology of CHIKF in children. We included peer-reviewed primary studies that reported laboratory confirmed CHIKF. We extracted information on study details, sampling approach, study participants, CHIKF positivity, clinical presentation and outcomes of CHIKF in children. The quality of included studies was assessed using Joanna Briggs Institute Critical Appraisal tool for case reports and National Institute of Health quality assessment tool for quantitative studies and case series. Random-effects meta-analysis was used to estimate the pooled prevalence of CHIKF among children by geographical location. We summarised clinical manifestations, laboratory findings, administered treatment and disease outcomes associated with CHIKF in children. We identified 2104 studies, of which 142 and 53 articles that met the inclusion criteria were included in the systematic literature review and meta-analysis, respectively. Most of the selected studies were from Asia (54/142 studies) and the fewest from Europe (5/142 studies). Included studies were commonly conducted during an epidemic season (41.5%) than non-epidemic season (5.1%). Thrombocytopenia was common among infected children and CHIKF severity was more prevalent in children <1 year. Children with undifferentiated fever before CHIKF was diagnosed were treated with antibiotics and/or drugs that managed specific symptoms or provided supportive care. CHIKF is a significant under-recognised and underreported health problem among children globally and development of drugs/vaccines should target young children.

Introduction

Chikungunya fever (CHIKF) is an acute febrile illness caused by the mosquito-borne chikungunya virus (CHIKV) [1]. CHIKV is a positive-sense single-stranded RNA virus of approximately 11 kilobases that is mainly transmitted to humans by Aedes aegypti and Aedes albopictus mosquitoes [2, 3].

There are three main CHIKV genotypes, the west African (WA) , the east central and southern African (ECSA) and the Asian genotypes [4]. The strains of the WA lineage are maintained in a sylvatic cycle in western Africa countries with small focal spill-over outbreaks of human infections reported [5, 6]. The ECSA strains are enzootic in East, Central and Southern Africa but they have been detected in samples from a broader geographical range [7]. Mutations in the ECSA genotype resulted in the Indian ocean lineage (IOL) [7].

The first CHIKF outbreak was reported in Tanzania (1952) and was followed by several sporadic and major epidemics in tropical and subtropical regions; Africa, Asia, Europe, the Pacific islands and the Americas [8]. Epidemics were mostly experienced in 1960s and 1990s but the 2004 CHIKV epidemic (caused by genotype ECSA), emerged in coastal Kenya and is the largest on record reporting over 1.3 million cases [5, 9]. It spread along the Kenyan coast from Lamu to Mombasa and islands on the Indian Ocean [10, 11], India and subsequently to Southeast Asia and Europe [5, 12, 13]. This rapid expansion into new ecological niches was enhanced by adaptation of CHIKV to new mosquito vectors, its introduction into temperate regions [14, 15] , as well as travel-associated importation of the virus into naïve populations [13] resulting in outbreaks associated with high morbidity and mortality [16]. ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬

CHIKV is inoculated by an infected mosquito bite either on human resident dermal cells i.e. fibroblasts and macrophages, or directly unto the blood circulatory system [17, 18]. Initial replication takes place in these skin cells triggering an immune response. It then disseminates to draining lymph nodes for further replication, and spread to other peripheral organs including muscle, peripheral joints, and tendons [19]. In severe cases, the virus invades the brain and liver [19, 20].

CHIKF is characterised by a sudden rise in body temperature and debilitating joint pain that may resolve within weeks or persist for months to years [21]. Other symptoms include; headache, maculo-papular rash, fatigue, myalgia, backache and tachycardia [5, 22]. Severe complications like encephalitis, myocarditis, kidney dysfunction, hepatitis, oculitis, cardiovascular and respiratory disorders have been observed, and are more common among the elderly, infants and immunosuppressed individuals [21, 23]. There are currently no specific antivirals or approved vaccines for CHIKV infection, though efforts towards vaccine development are underway [2428].

Accurate diagnosis of CHIKF remains a challenge due to non-specific symptoms that are similar to those of other common endemic illnesses such as malaria and dengue [29]. In addition, the general lack of awareness of the disease as well as lack of resources impedes efforts towards active surveillance and inclusion of CHIKF in routine screening of febrile illness. As a result, the burden of CHIKF remains underestimated, with diminished attention on its public health impact [29].

There are few studies that have described the clinical manifestations of paediatric CHIKF, which tend to differ from manifestations described in adults [3033]. After an incubation period ranging 1 to 12 days, there is a sudden onset of high-grade fever. In adults, this is usually preceded by musculoskeletal manifestations including myalgia, back pain and symmetric arthropathy affecting distal joints that can be sometimes chronic [33]. In contrast, children exhibit a broader range of cutaneous manifestations like pigmentation, bullous rash and blistering [34]. Neurological manifestations including seizures, encephalopathies and meningoencephalitis are common among children. Haemorrhagic manifestations associated with thrombocytopenia and lymphopenia are commonly reported in paediatric CHIKF [35]. With delayed medical attention, infected neonates have increased risk of developing severe complications including status epilepticus and multiorgan failure due to sepsis and intracerebral haemorrhage [36]. Nevertheless, there remains limited descriptions of the clinical spectrum and epidemiology of paediatric CHIKF, particularly in Africa. We therefore set out to describe the epidemiology of CHIKF among children (aged <18 years) globally by describing the proportion of acutely unwell children who tested positive for CHIKV, geographical distribution, and clinical manifestations through a systematic literature review and meta-analysis.

Methods

Search strategy and selection criteria

Our systematic review protocol was developed in line with the Preferred Reporting Items of Systematic Review and Meta-Analyses protocols (PRISMA-P). We searched published peer-reviewed literature in PUBMED, SCOPUS, EMBASE and Web of Science electronic databases for relevant articles without date or language restrictions. We divided search terms into group A; those defining studies in children and group B; terms that define studies focusing on Chikungunya infection as detailed in Table 1. Searches were done for individual groups using the Boolean operator ‘OR’ and a combined search done for groups A and B using the ‘AND’ operator as follows: #1 AND #2. PRISMA checklist is provided in (S1 Checklist).

thumbnail
Table 1. Details of search strategy used to identify studies on epidemiology of chikungunya infections among children globally, from PubMed, Scopus, Embase and Web of Science databases.

https://doi.org/10.1371/journal.pgph.0000914.t001

Two researchers (DKN and JM) independently screened titles and abstracts matching the search terms and included studies that reported on laboratory-confirmed CHIKV infection among children (age <18 years), and that presented original data and had undergone peer review. We carried out initial screening of titles and abstracts using the Ryyan software (https://rayyan.ai). Disagreements in the eligibility assessment were resolved through consensus between the two researchers or discussion with a third review author (SMT and/or GMW).

Data extraction and analysis

Following the selection of eligible studies, DKN and JM independently extracted relevant data using a uniform data extraction tool in Google Sheets (S1 Table). For each study, we extracted the following information: first author and year of publication, study site (country/ geographical location), study setting (hospital vs community), duration of study, whether study was conducted during epidemic or non-epidemic season, study design, sampling method, sample size, diagnostic technique, diagnostic tool sensitivity and specificity, case definition, type of study population, age of study participants, sex of study participants, patient symptoms, clinical/laboratory findings, treatment, disease outcome, detected viral strain, estimated prevalence/incidence and a statement on the key findings. Non-English language studies were translated into English using Google Translate before data extraction.

We used the Joanna Briggs Institute Critical Appraisal tool checklist to assess for quality of case reports (joannabriggs.org) (S2 Table). For assessment of quantitative studies and case series, we used the National Institute of Health quality assessment tool for Observational Cohort and Cross-Sectional Studies (S3 Table), and quality assessment tool for Case Series studies (S4 Table), respectively (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools).

We summarised the clinical manifestations, laboratory diagnostics, treatment administration and disease outcome of CHIKF among children. We estimated the proportion of children with acute CHIKF by pooling all studies with a defined sample size and study population, that screened participants for CHIKF using reverse-transcriptase polymerase chain reaction (RT-PCR) to detect viral RNA in body fluids and/or serologic tests for CHIKV specific immunoglobulin M (IgM). We performed meta-analysis of reported CHIKF among children using the metaprop package in R [37]. Overall estimates were calculated using random effects model to take account of between-study heterogeneity [38]. The restricted maximum likelihood estimator [39] was used to calculate the heterogeneity variance τ2 while the Knapp-Hartung adjustments [40] were used to calculate 95% confidence intervals (CI) around the pooled effect. CHIKF prevalence data were pooled using logit-transformed proportions in a generalised linear mixed-effect model (GLMM). Test for heterogeneity was applied using the Cochran’s Q, I2, and H statistics, with an I2 of more than 75% indicating substantial heterogeneity [41]. We performed sensitivity analysis by checking for outlier and influential cases [42] to determine their impact on the validity and robustness of the effect size estimate. We performed meta-regression using multimodel inference to obtain a comprehensive look at which predictors were more or less important for predicting differences in effect sizes. The test statistics and 95% CIs were computed using Knapp-Hartung adjustment. For model evaluation, we applied corrected Akaike’s information criterion (AICc). We did not consider any interactions between included predictors (S5 Table). We checked for existence of publication bias by using a funnel plot whose asymmetry was measured by Egger’s linear regression test (p<0.05 levels were considered statistically significant for publication bias) [43].

Results

Our search identified 2104 unique articles. After screening the titles, abstracts and full texts, 142 articles met the inclusion criteria; following exclusion of articles that; did not focus on children, did not describe acute CHIKV infections, were inaccessible, reviews, conference abstracts and general outbreak descriptions (Fig 1). Most studies (32.4%) were hospital-based descriptions of individual cases from an epidemic period (Table 2 and S1 Table). The geographical and temporal distribution of studies included in this review are summarised in Fig 2 and S1 Fig. Most of the studies were from India (n=48) and Brazil (n=17) with only eight countries in Africa represented. There were a number of studies from the Indian Ocean Islands, especially from La Reunion (n=10), a constituent part of France that was severely affected by a CHIKF epidemic in 2005 – 2006 [44]. There were 11 studies from Europe and North America, nine of which were reports on traveller-associated importation of CHIKV [4553]. Studies from the Carribbean islands and Central America,(n=16) were mainly descriptive of epidemic waves after introduction of CHIKV into the presumably immunologically naïve population [34, 5468]. Case series and case reports represented 76% of the studies from South America.

thumbnail
Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram illustrating identification and inclusion of studies for a systematic review of Chikungunya disease among children.

https://doi.org/10.1371/journal.pgph.0000914.g001

thumbnail
Fig 2. A global map depicting the geographical distribution of reviewed articles for CHIKV infection in children.

The map was generated using open-source data in the R statistical package “spData” (https://cran.r-project.org/web/packages/spData/index.html). Despite the absence of data from most parts of the globe, most of the studies were from Asia and South America.

https://doi.org/10.1371/journal.pgph.0000914.g002

thumbnail
Table 2. Summary of studies included in a systematic literature review to collate evidence for the global prevalence and clinical manifestation of chikungunya infection among children.

https://doi.org/10.1371/journal.pgph.0000914.t002

Among the case reports and observational studies and case series, 18 studies [32, 47, 66, 6983], seven studies [54, 57, 61, 64, 8486], and one study [87], were of high quality respectively, while the remaining studies had a fair rating (S2S4 Tables).

To determine the proportion of children with acute CHIKF, we focused on studies (n=53) that had a defined numerator (number of CHIKF cases) and denominator (the total sample size) (S1 Table). We excluded case-reports, case series and observational studies that only reported on children with CHIKF; these studies did not sample from a wider population of individuals with and without the disease. Prevalence rates of CHIKV among children in endemic regions range approximately 5–40% [29, 8890]. The highest rates were recorded during epidemic seasons (Table 3) with highest positivity observed in the Carribbean islands at 56% (154/275).

thumbnail
Table 3. The rates of CHIKV cases reported among children from various continents in different seasons.

https://doi.org/10.1371/journal.pgph.0000914.t003

Higher estimates of clinical CHIKF are reported among older children [61, 91, 92]. However, the younger children may lack the verbal ability to describe clinical symptoms like myalgia and joint pains. In the absence of effective diagnostics, most cases in this age group remain unrecognized or are misdiagnosed.

Detection of CHIKV RNA by RT-PCR was a frequently used diagnostic method (n=22/53 studies) followed by detection of anti-CHIKV IgM antibodies by ELISA (n=19 studies). Most studies (27/53 studies) were carried out during an epidemic season, and they provided the highest prevalence estimate at 18% (95% CI 10-30, n=27) when compared to those carried out during the non-epidemic seasons, 3.86% (95% CI 2-8, n=6) (Table 4). The percentage of children with acute CHIKF was highest in South America at 22.8% (95%CI 7.5, 51.9) while the percentage in Asia and Africa were comparable at approximately 9% (Table 4). The generated funnel plot was symmetrical implying an absence of evidence of publication bias as suggested by Egger’s linear regression test (Intercept= -0.438 [95%CI; -3.33–2.45], t-value= -0.297, p-value= 0.77) (Fig 3).

thumbnail
Fig 3. Funnel plot showing the precision of 53 reviewed studies included in the meta-analysis of CHIKV prevalence among children against their effect estimates.

https://doi.org/10.1371/journal.pgph.0000914.g003

thumbnail
Table 4. Results of sub-group analysis for prevalence of CHIKV infection among children based on continent, study setting, diagnostic technique, study design and season.

https://doi.org/10.1371/journal.pgph.0000914.t004

CHIKF among children can affect various body organs as shown in Fig 4. Fever, rash and arthralgia were the most common symptoms reported in 80, 55 and 40 studies, respectively. The clinical presentation of paediatric CHIKF varies with geographical location and the circulating strain of CHIKV. In La Reunion island where epidemics were predominantly due to the IOL, majority of infected neonates had thrombocytopenia , deranged coagulation, seizures , hemodynamic disorders and hemorrhagic syndromes [93]. In contrast, circulatory failure was common among CHIKV infected infants in Kerala where the ECSA strain circulated [94]. The Asia genotype introduced to the Carribbean islands and central America induced weaker pro-inflammatory effect with a milder clinical course among infected neonates. It was not associated with thrombocytopaenia and clinical neurological sequelae, however the case fatality rate was comparably high [68, 95].

thumbnail
Fig 4. A summary of symptoms/complications of CHIKV infection in children.

The number in brackets represents the number of studies that reported on this symptom/complication.

https://doi.org/10.1371/journal.pgph.0000914.g004

Of 59 studies that reported on laboratory findings among children with CHIKF, thrombocytopenia was the most commonly observed in 40 studies. Other laboratory findings also reported included: neutrophilia, leukopenia, lymphopenia, hypokalemia, hyponatremia, hypocalcemia, hyperbilirubinemia, anaemia, elevated C-reactive protein, transaminases (aspartate, alanine and oxaloacetic glutamic), elevated cellularity and neutrophil predominance, elevated creatinine kinase, reduced prothrombin concentration (Fig 5). Cerebrospinal fluid (CSF) examination was reported in nine studies [68, 71, 73, 96100], and showed pleocytosis (n=7 studies), increased protein levels (n=7 studies) and hypoglycorrhachia (n=3 studies). Radiological, CT and MRI scans presented abnormal findings indicating diffuse brain lesions, cerebral edema, soft tissue resorption and haemorrhagic leukoencephalopathy.

thumbnail
Fig 5. A summary of the treatments administered to CHIKV infected children and the reported laboratory investigation findings among studies included in this review.

https://doi.org/10.1371/journal.pgph.0000914.g005

Sixty-five of one hundred forty-two studies described treatment therapies for CHIKF. Antibiotic prescription was predominantly given to children presenting with undifferentiated fever before CHIKF was diagnosed as reported in 35/65 studies. Treatment was supportive through management of aches using analgesics, volume resuscitation by intravenous hydration and mechanical ventilation in cases of respiratory distress. Neurological symptoms were managed using anticonvulsant therapy in 12 studies. Abnormal haematological values were corrected by transfusion of either platelets, red blood cells or plasma in 14 studies. Immunoglobulin, antivirals, antimalarial and corticosteroid therapies were also reported (Fig 5). None of these treatments are supported by randomized controlled trials, or by nationally recognized guidelines.

Fifty-five studies did not describe the disease outcome. After pooling all the cases in the included studies (n=3093), 34.5% (n=1068) underwent full recovery within an average of 11 days. 1.2% (n=36) developed a severe form of the disease that necessitated hospitalisation and special care. The severity included long-term neurological and dermatological sequelae, severe cerebral bleeding, neurocognitive delay, cerebral palsy with ataxia and blindness, ocular and behavioural or postural deficiencies (dysconjugate gaze), language delay, axial hypotonia, aphasia, tenosynovitis causing fixed flexion deformity of thumb, hypotonic cerebral palsy with mental retardation, deafness, persistent seizures, visual impairment, tone abnormalities, strabismus, persistent itchy rash, arthralgia, progressive sclerosis of digital skin with limited range of motion and further tapering of distal fingertips, postnatal microcephaly and retinopathy, ptosis and myosis, ataxia, pallesthesia and hyperflexia in lower limbs associated with persistent clonus and urinary incontinence, bulging fontanelle, convulsion and dyspnea. A case fatality rate of 1% (n=33 cases) was observed. The causes of death included respiratory stress, cardiac arrest, intraventricular, gastrointestinal or cerebral haemorrhage, renal failure, cerebral edema, pleural and pericardial effusion, enterocolitis, coma and collapse of the circulatory system.

Discussion

In this study, we set out to understand the global epidemiology of CHIKF among children (aged <18 years) by describing its geographical distribution, percentage of positive cases among children presenting with fever, and clinical manifestations. CHIKF is common among febrile children with a wide geographical range of transmission given that it has been reported in five continents. Several studies were from India during the CHIKF epidemic wave in 2005-6 [101103], and an initial study from the Americas was published after 2013 when CHIKF was first reported in the region [22]. There were relatively few studies published from Africa and Southeast Asia despite a high prevalence of CHIKV in these settings [29].

Spread of CHIKV into naïve populations in the Indian ocean islands, south east Asia and then to the Americas and the Caribbean islands, resulted into rapid establishment of local transmission and high clinical attack rates among children [61, 62, 94]. The intensity of transmission has been associated with disease severity [54]. The CHIKV force of infection and associated clinical manifestations are influenced by the exposure dose [62, 94]. The epidemics resulted into significant absenteeism among school-going children, excessive demand for health care, marked economic losses and significant morbidity and mortality [62]. Neonates were disproportionately affected owing to their developing immune system [62].

The precise prevalence rate of CHIKF among children with acute illness remains undetermined. This is due to scarcity of data from most CHIKF endemic regions. Underreporting of CHIKF cases could be due to exclusion of CHIKF from routine screening of undifferentiated febrile illness in many low- and middle-income countries, absence of affordable diagnostic infrastructure, general lack of awareness among healthcare professionals and absence of an efficient surveillance system. Limited epidemiological data on CHIKV among children calls for more efforts towards control, prevention and management within the clinical and public health sector.

There is no specific clinical sign that is discriminatory for CHIKF in children to aid in its diagnosis, and hence CHIKF may be missed in many countries that lack testing capacity. CHIKF manifests with a wide range of clinical symptoms affecting most parts of the body including musculoskeletal, nervous, cardio- respiratory, renal, cutaneous and gastrointestinal systems. Neonates may become infected during the peri-partum period if born to viremic mothers, and in rare cases may develop long-term neuro-cognitive impairment or fatal pathological progression [35]. The rate of vertical transmission among CHIKV-infected pregnant women was estimated at 48.5% during an epidemic [104].

CHIKF clinical manifestations among children vary with geographical location and the infecting CHIKV genotype. CHIKF associated thrombocytopenia in children is dependent on the infecting CHIKV genotype. It was observed more among children infected by the ECSA and IOL genotypes [35, 72, 82,105–]. Clinical investigations of CHIKF among children in the Carribbean island and Central America noted absence of this common hematological parameter reported in most studies from Asia, Indian ocean islands and Africa [34, 62, 68].

Surveillance and detection of CHIKV infections among children is rare within community setups as most studies in this review were hospital-based reports. Community surveillance could inform transmission trends and enable timely detection of epidemics. Children travellers from affected areas can contribute in the importation of CHIKV to new niches as indicated by the case reports from Europe [46, 51, 53, 106]. This could be detrimental among CHIKV immunologically naïve populations. An effective surveillance system can detect transmission trends and help in prediction and identification of epidemic seasons.

We recognise some limitations in our review that calls for caution when interpreting our results. Differential representation of various geographical zones in terms of publications could lead to bias. Scarcity of data from endemic regions may lead to an underestimate of the proportion of positive cases in this review, or a bias towards studies during epidemics may lead to an overestimate. We acknowledge that there would be differences/biases based on socio-demographic conditions of different settings which can impact on transmission dynamics and disease severity.

Conclusions

CHIKF is a significant unrecognised and underreported health problem among children globally and should be included in routine screening of febrile illnesses. Efforts towards treatment therapy and vaccine development should target the vulnerable children <1 year of age who are at an increased risk of developing severe CHIKV-associated neurological complications and require adequate monitoring for potentially fatal outcomes.

Supporting information

S1 Checklist. PRISMA criteria for Chikungunya disease among children systematic literature review.

https://doi.org/10.1371/journal.pgph.0000914.s001

(DOCX)

S1 Fig. The distributions of the included studies versus their year of publication.

https://doi.org/10.1371/journal.pgph.0000914.s002

(TIF)

S1 Table. Full details of 142 studies identified by a systematic literature search for Chikungunya infection among children published between 1983 and 2021 inclusive.

https://doi.org/10.1371/journal.pgph.0000914.s003

(XLSX)

S2 Table. Quality appraisal using Joanna Briggs Institute Critical Appraisal tool checklist for 58 studies identified for a systematic literature review of Chikungunya infection among children.

https://doi.org/10.1371/journal.pgph.0000914.s004

(XLSX)

S3 Table. Quality appraisal using National Institute of Health quality assessment tool for 53 longitudinal and cross-sectional studies identified for a systematic literature review of Chikungunya infection among children.

https://doi.org/10.1371/journal.pgph.0000914.s005

(XLSX)

S4 Table. Quality appraisal using National Institute of Health quality assessment tool for 13 case series identified for a systematic litertaure review of Chikungunya infection among children.

https://doi.org/10.1371/journal.pgph.0000914.s006

(XLSX)

S5 Table. Characteristics of the best five models fitted by the multimodel inference in metaregeression.

https://doi.org/10.1371/journal.pgph.0000914.s007

(DOCX)

Acknowledgments

This manuscript was submitted for publication with permission from the Director of the Kenya Medical Research Institute.

References

  1. 1. Staples JE, Breiman RF, Powers AM. Chikungunya Fever: An Epidemiological Review of a Re‐Emerging Infectious Disease. Clin Infect Dis. 2009;49: 942–948. pmid:19663604
  2. 2. Weaver SC, Lecuit M. Chikungunya Virus and the Global Spread of a Mosquito-Borne Disease. Campion EW, editor. N Engl J Med. 2015;372: 1231–1239. pmid:25806915
  3. 3. Powers AM, Brault AC, Shirako Y, Ellen G, Kang W, Strauss JH, et al. Evolutionary Relationships and Systematics of the Alphaviruses Evolutionary Relationships and Systematics of the Alphaviruses. J Virol. 2001;75: 10118–10131.
  4. 4. 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: 471–479. pmid:10644846
  5. 5. Powers AM, Logue CH. Changing patterns of chikunya virus: Re-emergence of a zoonotic arbovirus. J Gen Virol. 2007;88: 2363–2377. pmid:17698645
  6. 6. Monlun E, Zeller H, Le Guenno B, Traoré-Lamizana M, Hervy JP, Adam F, et al. Surveillance of the circulation of arbovirus of medical interest in the region of eastern Senegal. Bull Soc Pathol Exot. 1993;86: 21–8.
  7. 7. Sara Volk M, Chen R, Tsetsarkin KA, Paige Adams A, 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: 6497–6504. pmid:20410280
  8. 8. Wahid B, Ali A, Rafique S, Idrees M. Global expansion of chikungunya virus: mapping the 64-year history. Int J Infect Dis. 2017;58: 69–76. pmid:28288924
  9. 9. 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: 333–337. 78/2/333 [pii] pmid:18256441
  10. 10. Kariuki Njenga M, Nderitu L, Ledermann JP, Ndirangu A, Logue CH, Kelly CHL, et al. Tracking epidemic Chikungunya virus into the Indian Ocean from East Africa. pmid:18931072
  11. 11. Breiman RF. Seroprevalence of Chikungunya virus infection on Grande Comore Island, union of the Comoros, 2005. Kenya Med Res Inst Int Emerg Infect Program–Kenya.
  12. 12. Ligon BL. Reemergence of an Unusual Disease: The Chikungunya Epidemic. Semin Pediatr Infect Dis. 2006;17: 99–104. pmid:16822471
  13. 13. Weaver SC. Arrival of Chikungunya Virus in the New World: Prospects for Spread and Impact on Public Health. PLoS Negl Trop Dis. 2014;8: 6–9. pmid:24967777
  14. 14. Burt FJ, Rolph MS, Rulli NE, Mahalingam S, Heise MT. Chikungunya: A re-emerging virus. The Lancet. 2012. pmid:22100854
  15. 15. Zeller H, Van Bortel W, Sudre B. Chikungunya: Its History in Africa and Asia and Its Spread to New Regions in 2013–2014. J Infect Dis. 2016;214: S436–S440. pmid:27920169
  16. 16. Berry IM, Eyase F, Pollett S, Konongoi SL, Joyce MG, Figueroa K, et al. Global Outbreaks and Origins of a Chikungunya Virus Variant Carrying Mutations Which May Increase Fitness for Aedes aegypti: Revelations from the 2016 Mandera, Kenya Outbreak. Am J Trop Med Hyg. 2019;100: 1249–57. pmid:30860010
  17. 17. Madariaga M, Ticona E, Resurrecion C, Madariaga M, Ticona E, Resurrecion C. Chikungunya: bending over the Americas and the rest of the world. Brazilian J Infect Dis. 2016;20: 91–98. pmid:26707971
  18. 18. Sourisseau M, Schilte C, Casartelli N, Trouillet C, Guivel-Benhassine F, Rudnicka D, et al. Characterization of Reemerging Chikungunya Virus. PLoS Pathog. 2007;3: e89. pmid:17604450
  19. 19. Silva LA, Dermody TS. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest. 2017;127. pmid:28248203
  20. 20. Chusri S, Siripaitoon P, Hirunpat S, Silpapojakul K. Short report: Case reports of neuro-chikungunya in Southern Thailand. Am J Trop Med Hyg. 2011;85: 386–389. pmid:21813863
  21. 21. Thiberville S-D, Moyen N, Dupuis-Maguiraga L, Nougairede A, Gould EA, Roques P, et al. Chikungunya fever: Epidemiology, clinical syndrome, pathogenesis and therapy. Antiviral Res. 2013;99: 345–370. pmid:23811281
  22. 22. Feldstein LR, Rowhani-Rahbar A, Staples JE, Weaver MR, Halloran ME, Ellis EM. Persistent arthralgia associated with chikungunya virus outbreak, US Virgin Islands, december 2014–february 2016. Emerg Infect Dis. 2017;23: 673–676. pmid:28322703
  23. 23. Mason PJ, Haddow AJ. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952–1953. Trans R Soc Trop Med Hyg. 1957;51: 238–240.
  24. 24. Couderc T, Khandoudi N, Grandadam M, Visse C, Gangneux N, Bagot S, et al. Prophylaxis and therapy for Chikungunya virus infection. J Infect Dis. 2009;200: 516–523. pmid:19572805
  25. 25. Gorchakov R, Wang E, Leal G, Forrester NL, Plante K, Rossi SL, et al. Attenuation of Chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein. J Virol. 2012;86: 6084–6096. pmid:22457519
  26. 26. Saraswat S, Athmaram TN, Parida M, Agarwal A, Saha A, Dash PK. Expression and Characterization of Yeast Derived Chikungunya Virus Like Particles (CHIK-VLPs) and Its Evaluation as a Potential Vaccine Candidate. PLoS Negl Trop Dis. 2016;10: e0004782. pmid:27399001
  27. 27. Plante KS, Rossi SL, Bergren NA, Seymour RL, Weaver SC. Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate. PLoS Negl Trop Dis. 2015;9: e0004007. pmid:26340754
  28. 28. Schwameis M, Buchtele N, Wadowski PP, Schoergenhofer C, Jilma B. Chikungunya vaccines in development. Hum Vaccin Immunother. 2016;12: 716–31. pmid:26554522
  29. 29. Crump JA, Morrissey AB, Nicholson WL, Massung RF, Stoddard RA, Galloway RL, et al. Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study. PLoS Negl Trop Dis. 2013;7: e2324. pmid:23875053
  30. 30. Scheld ML Hughes JMW MG, editor. Chikungunya virus infection is causing acute febrile illness among children in Kenya. Am J Trop Med Hyg. 2017;10: 47. http://dx.doi.org/10.4269/ajtmh.abstract2016
  31. 31. Gresh L, Ojeda S, Sanchez N, Narvaez F, Lopez B, D., Elizondo D, et al. Characterization of chikungunya virus infections in children in Managua, Nicaragua. Am J Trop Med Hyg. 2015;93: 41.
  32. 32. Sharma PK, Kumar M, Aggarwal GK, Kumar V, Srivastava RD, Sahani A, et al. Severe Manifestations of Chikungunya Fever in Children, India, 2016. Emerg Infect Dis. 2018;24: 1737–1739. pmid:30124414
  33. 33. Ritz N, Hufnagel M, Gerardin P. Chikungunya in Children. Pediatr Infect Dis J. 2015;34: 789–791. pmid:26069950
  34. 34. Van Keulen V, Huibers M, Manshande M, Van Hensbroek MB, Van Rooij L. Chikungunya Virus Infections among Infants-Who Classification Not Applicable. Pediatr Infect Dis J. 2018;37: e83–e86. pmid:29135829
  35. 35. Gérardin 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. Chretien J-P, editor. PLOS Med. 2008;5: 413–423. pmid:18351797
  36. 36. Rollé A, Schepers K, Cassadou S, Curlier E, Madeux B, Hermann-Storck C, et al. Severe Sepsis and Septic Shock Associated with Chikungunya Virus Infection, Guadeloupe, 2014. Emerg Infect Dis. 2016;22: 891–894. pmid:27088710
  37. 37. Harrer M, Cuijpers P, Furukawa TA, Ebert DD. Doing Meta-Analysis With R: A Hands-On Guide. Chapman & Hall/CRC Press; 2021.
  38. 38. Borenstein M, Hedges L, Higgins J, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1: 97–111. pmid:26061376
  39. 39. Viechtbauer W. Bias and Efficiency of Meta-Analytic Variance Estimators in the Random-Effects Model. J Educ Behav Stat. 2005;30: 261–293.
  40. 40. Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med. 2003;22: 2693–2710. pmid:12939780
  41. 41. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327: 557–560. pmid:12958120
  42. 42. Viechtbauer W, Cheung MW-L. Outlier and influence diagnostics for meta-analysis. Res Synth Methods. 2010;1: 112–125. pmid:26061377
  43. 43. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315: 629–634. pmid:9310563
  44. 44. Cordel H. Chikungunya outbreak on Reunion: update. Euro Surveill. 2006;11: E060302.3. pmid:16804222
  45. 45. Dubrocq G, Wang K, Spaeder MC, Hahn A. Septic Shock Secondary to Chikungunya Virus in a 3-Month-Old Traveler Returning From Honduras. J Pediatric Infect Dis Soc. 2017;6: e158–e160. pmid:28903519
  46. 46. Simon F, Parola P, Grandadam M, Fourcade S, Oliver M, Brouqui P, et al. Chikungunya infection: An emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore). 2007;86: 123–137. pmid:17505252
  47. 47. Nguyen DK, Navarro A, Zangwill KM. Pruritic Rash in a Recent Traveler to Central America. J Pediatric Infect Dis Soc. 2015;4: 280–282. pmid:26407434
  48. 48. Landis ET, Strowd LC, Taxter AJ. Post-Chikungunya Rheumatic Disease in a 13-Year-Old Boy. Pediatr Dermatol. 2017;34: e294–e295. pmid:28884916
  49. 49. Swaminathan P, Swaminathan S. Nail findings in Chikungunya infection. Open Forum Infect Dis. 2020;7: ofaa031. pmid:32104718
  50. 50. Shiferaw B, Lam P, Tuthill S, Choudhry H, Syed S, Ahmed S, et al. The Chikungunya Epidemic: A look at five cases. IDCases. 2015;2: 89–91. pmid:26793467
  51. 51. Kantele A. Travellers as sentinels of chikungunya epidemics: a family cluster among Finnish travellers to Koh Lanta, Thailand, January 2019. EUROSURVEILLANCE. 2019;24: 2–5. pmid:30892179
  52. 52. Tini ML, Rezza G. Morbilliform skin rash with prominent involvement of the palms in Chikungunya fever. IDCases. 2018;13: e00421. pmid:30101066
  53. 53. Pfeffer M, Hanus I, Löscher T, Homeier T, Dobler G. Chikungunya fever in two German tourists returning from the Maldives, September, 2009. Euro Surveill. 2010;15. pmid:20394712
  54. 54. Gordon A, Gresh L, Ojeda S, Chowell G, Gonzalez K, Sanchez N, et al. Differences in Transmission and Disease Severity Between 2 Successive Waves of Chikungunya. Clin Infect Dis. 2018;67: 1760–1767. pmid:29697796
  55. 55. Gordon A, Kuan G, Gresh L, Sanchez N, Ojeda S, Saborio S, et al. Attack rate of chikungunya in Nicaraguan children during the first two waves of the epidemic , 2014-2016. Am J Trop Med Hyg. 2017;95: 199–200.
  56. 56. Michlmayr D, Rahman A, Gresh L, Kim-Schulze S, Thomas GP, Pak T, et al. Immune profiling and network modeling of chikungunya infection in a hospital-based study in nicaragua. Am J Trop Med Hyg. 2016;95: 225. http://dx.doi.org/10.4269/ajtmh.abstract2016
  57. 57. Ball JD, Elbadry MA, Telisma T, White SK, Chavannes S, Anilis MG, et al. Clinical and Epidemiologic Patterns of Chikungunya Virus Infection and Coincident Arboviral Disease in a School Cohort in Haiti, 2014-2015. Clin Infect Dis. 2019;68: 919–926. pmid:30184178
  58. 58. Dorléans F, Hoen B, Najioullah F, Herrmann-Storck C, Schepers KM, Abel S, et al. Outbreak of Chikungunya in the French Caribbean Islands of Martinique and Guadeloupe: Findings from a Hospital-Based Surveillance System (2013–2015). Am J Trop Med Hyg. 2018;98: 1819. pmid:29692295
  59. 59. Bustos Carrillo F, Collado D, Sanchez N, Ojeda S, Lopez Mercado B, Burger-Calderon R, et al. Epidemiological Evidence for Lineage-Specific Differences in the Risk of Inapparent Chikungunya Virus Infection. J Virol. 2019;93: 1622–1640. pmid:30463967
  60. 60. Ramírez-Zamora M, Veliz-Martínez V, Barahona GE, Mena ID, Ortez CI, Nolasco-Tovar GA, et al. [Hemicerebellitis due to chikungunya associated with refractory status epilepticus in the paediatric age]. Revista de neurologia Rev Neurol; Aug 1, 2020 pp. 123–124. pmid:32672351
  61. 61. Balmaseda A, Gordon A, Gresh L, Ojeda S, Saborio S, Tellez Y, et al. Clinical Attack Rate of Chikungunya in a Cohort of Nicaraguan Children. Am J Trop Med Hyg. 2016;94: 397–399. pmid:26643531
  62. 62. Christie C, Melbourne-Chambers R, Ennevor J, Young-Peart S, Buchanan T, Scott-Brown P, et al. Article in The West Indian medical journal. 2016.
  63. 63. Hsu CH, Cruz-Lopez F, Vargas Torres D, Perez-Padilla J, Lorenzi OD, Rivera A, et al. Risk factors for hospitalization of patients with chikungunya virus infection at sentinel hospitals in Puerto Rico. PLoS Negl Trop Dis. 2019;13: e0007084. pmid:30640900
  64. 64. 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. 2017;63: 43–49. pmid:27516419
  65. 65. Enter BJD Van, Huibers MHW, Rooij L Van, Steingrover R, Hensbroek MB Van, Voigt RR, et al. Perinatal Outcomes in Vertically Infected Neonates During a Chikungunya Outbreak on the Island of Curaçao. Am J Trop Med Hyg. 2018;99: 1415–1418. pmid:30328407
  66. 66. Evans-Gilbert T. Chikungunya and Neonatal Immunity: Fatal Vertically Transmitted Chikungunya Infection. Am J Trop Med Hyg. 2017;96: 913–915. pmid:28167590
  67. 67. White SK, Mavian C, Elbadry MA, Beau De Rochars VM, Paisie T, Telisma T, et al. Detection and phylogenetic characterization of arbovirus dual-infections among persons during a chikungunya fever outbreak, Haiti 2014. PLoS Negl Trop Dis. 2018;12: e0006505. pmid:29851952
  68. 68. Torres JR, Falleiros-Arlant LH, Dueñas L, Pleitez-Navarrete J, Salgado DM, Castillo JB-D, et al. Congenital and perinatal complications of chikungunya fever: a Latin American experience. Int J Infect Dis. 2016;51: 85–88. pmid:27619845
  69. 69. Luz Gunturiz M, Cortes L, Liliana Cuevas E, Enrique Chaparro P, Lucia Ospina M. Congenital cerebral toxoplasmosis, Zika and chikungunya virus infections: A case report. BIOMEDICA. 2018;38: 144–152. pmid:30184357
  70. 70. Vasani R, Kanhere S, Chaudhari K, Phadke V, Mukherjee P, Gupta S, et al. Congenital Chikungunya--A Cause of Neonatal Hyperpigmentation. Pediatr Dermatol. 2016;33: 209–212. pmid:26205895
  71. 71. Nóbrega PR, Morais NM de M, Braga-Neto P, Barros LS da S, Honório FPP, Dellavance A, et al. NMDAR Encephalitis Associated With Acute Chikungunya Virus Infection: A New Trigger? Front Pediatr. 2020;8: 176. pmid:32426307
  72. 72. Shrivastava A, Waqar Beg M, Gujrati C, Gopalan N, Rao PVL, Mirza &, et al. Management of a vertically transmitted neonatal Chikungunya thrombocytopenia. Indian J Pediatr. 2011;78: 1008–1009. pmid:21328079
  73. 73. Bandeira AC, Campos GS, Sardi SI, Rocha VFD, Rocha GCM. Neonatal encephalitis due to Chikungunya vertical transmission: First report in Brazil. IDCases. 2016;5: 57–59. pmid:27500084
  74. 74. Passi RG, Khan YZ, Chitnis DS. Chikungunya infection in neonates. Indian Pediatr. 2008;45: 240–242. pmid:18367775
  75. 75. Lee YS, Quek SC, Koay ESC, Tang JW-TJW-T. Chikungunya mimicking atypical Kawasaki disease in an infant. Pediatr Infect Dis J. 2010;29: 275–277. pmid:19935121
  76. 76. Ferreira F, Silva A, M A, Patricia P. Late Identification of Chikungunya Virus in the Central Nervous System of a 2-Month-Old Infant: Persistence of Maternal-Neonatal Infection? J Pediatric Infect Dis Soc. 2019;8: 374–377. pmid:30657982
  77. 77. Ramos R, Viana R, Brainer-Lima A, Floreâncio T, Carvalho MD, Van Der Linden V, et al. Perinatal Chikungunya Virus-associated Encephalitis Leading to Postnatal-Onset Microcephaly and Optic Atrophy. Pediatr Infect Dis J. 2018;37: 94–95. pmid:28737626
  78. 78. Kumar Sharma P, Kumar M, Bhandari N, Kushwaha A. Severe sepsis and septic shock associated with chikungunya fever in an adolescent. J Trop Pediatr. 2018;64: 557–559. pmid:29325169
  79. 79. Lyra PPR, Campos GSGSG, Bandeira IDD, Sardi SI, Costa LF de M, Santos FRFR, et al. Congenital Chikungunya Virus Infection after an Outbreak in Salvador, Bahia, Brazil. AJP Rep. 2016;6: E299–E300. pmid:27555980
  80. 80. Alves LV, da Câmara FMP, Batista Granha M, Meneses Neto A, Alves JG B. Chikungunya infection and horner syndrome. IDCases. 2018;14. pmid:30510900
  81. 81. Chandorkar N, Raj D, Kumar R, Warsi S. Fever, marked tachycardia and vesiculobullous rash in an infant with Chikungunya fever. BMJ Case Rep. 2017;2017: bcr–2016–218687. pmid:28942395
  82. 82. Kalane S, Joshi R, Rajhans A. Congenital Chikungunya with Centro-facial Pigmentation and Persistent Thrombocytopenia: A Case Report. Int J Pediatr. 2015;3: 575–578.
  83. 83. Mendez-Dominguez N, Augusto Achach-Asaf J, Manuel Basso-Garcia L, Berenice Quinones-Pacheco Y, Gomez-Carro S, Méndez-Domínguez N, et al. Septic shock secondary to non-congenital chikungunya fever in a young infant: A clinical case. Rev Chil Pediatr. 2016;87: 143–147. pmid:27032486
  84. 84. Gavotto A, Muanza B, Delion F, Dusacre J-A, Amedro P. Chikungunya disease among infants in French West Indies during the 2014 outbreak. Arch Pediatr. 2019;26: 259–262. pmid:31281036
  85. 85. Proesmans S, Katshongo F, Milambu J, Fungula B, Muhindo Mavoko H, Ahuka-Mundeke S, et al. Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study. PLoS Negl Trop Dis. 2019;13: e0007047–e0007047. pmid:31487279
  86. 86. Capeding MR, Chua MN, Hadinegoro SR, Hussain IIHM, Nallusamy R, Pitisuttithum P, et al. Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLoS Negl Trop Dis. 2013;7: e2331. pmid:23936565
  87. 87. Alvarado-Socarras JL, Ocampo-Gonzalez M, Vargas-Soler JA, Rodriguez-Morales AJ, Franco-Paredes C. Congenital and neonatal chikungunya in Colombia. J Pediatric Infect Dis Soc. 2016;5: E17–E20. pmid:27125272
  88. 88. Nyamwaya DK, Otiende M, Omuoyo DO, Githinji G, Karanja HK, Gitonga JN, et al. Endemic chikungunya fever in Kenyan children: a prospective cohort study. BMC Infect Dis 2021 211. 2021;21: 1–10. pmid:33602147
  89. 89. Simo FBN, Bigna JJ, Well EA, Kenmoe S, Sado FBY, Weaver SC, et al. Chikungunya virus infection prevalence in Africa: a contemporaneous systematic review and meta-analysis. Public Health. 2019;166: 79–88. pmid:30468973
  90. 90. Hertz JT, Munishi OM, Ooi EE, Howe S, Lim WY, Chow A, et al. Chikungunya and dengue fever among hospitalized febrile patients in northern Tanzania. Am J Trop Med Hyg. 2012;86: 171–177. pmid:22232469
  91. 91. 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: 751–754. pmid:20889860
  92. 92. Qiaoli Z, Jianfeng H, De W, Zijun W, Xinguang Z, Haojie Z, et al. Maiden outbreak of chikungunya in Dongguan city, Guangdong province, China: epidemiological characteristics. PLoS One. 2012;7: e42830. pmid:22916166
  93. 93. Ramful D, Carbonnier M, Pasquet MM, Bouhmani B, Ghazouani J, Noormahomed T, et al. Mother-to-child transmission of Chikungunya virus infection. Pediatr Infect Dis J. 2007;26: 811–815. pmid:17721376
  94. 94. Elenjickal MG, Sushamabai S. Outbreak of Chikungunya disease in Kerala in 2007. Indian pediatrics. India; 2009. pp. 440–441. pmid:19478364
  95. 95. Torres JR, Có L, Castro JS, Rodríguez L, Saravia V, Arvelaez J, et al. Chikungunya fever: Atypical and lethal cases in the Western hemisphere A Venezuelan experience. 2015. pmid:26793440
  96. 96. Horwood PF, Duong V, Laurent D, Mey C, Sothy H, Santy K, et al. Aetiology of acute meningoencephalitis in Cambodian children. 2017;6: 35. pmid:28536430
  97. 97. Beserra FLCN, Oliveira GM, Marques TMA, Farias LABG, Santos JR, Dos Daher EDF, et al. Short Communication Clinical and laboratory profiles of children with severe chikungunya infection. Rev Soc Bras Med Trop. 2019;52: e20180232. pmid:30994798
  98. 98. Le Bomin A, Hebert JC, Marty P, Delaunay P. [Confirmed chikungunya in children in Mayotte. Description of 50 patients hospitalized from February to June 2006]. Med Trop (Mars). 2008;68: 491–495.
  99. 99. Teixeira AAR, Ferreira LF, Pires Neto R da J. Acute Disseminated Encephalomyelitis after Chikungunya Infection. JAMA Neurol. 2019;76: 619. pmid:30830174
  100. 100. Maria A, Vallamkonda N, Shukla A, Bhatt A, Sachdev N. Encephalitic presentation of Neonatal Chikungunya: A Case Series. Indian Pediatr. 2018;55: 671–674. http://dx.doi.org/10.1007/s13312-018-1356-7 pmid:30218513
  101. 101. Kaur P, Ponniah M, Murhekar M V, Ramachandran V, Ramachandran R, Raju HK, et al. Chikungunya outbreak, South India, 2006. Emerg Infect Dis. 2008;14: 1623–1625. pmid:18826830
  102. 102. Sengupta S, Mukherjee S, Haldar SK, Bhattacharya N, Tripathi A, S S., et al. Re-emergence of Chikungunya virus infection in Eastern India. Brazilian J Microbiol [publication Brazilian Soc Microbiol. 2020;51: 177–182. pmid:31898249
  103. 103. Seyler T, Sakdapolrak P, Prasad SS, Dhanraj R. A chikungunya outbreak in the metropolis of Chennai, India, 2006. J Environ Health. 2012;74: 8–13; quiz 64. pmid:22329203
  104. 104. Lenglet Y, Barau G, Robillard P-Y, Randrianaivo H, Michault A, Bouveret A, et al. [Chikungunya infection in pregnancy: Evidence for intrauterine infection in pregnant women and vertical transmission in the parturient. Survey of the Reunion Island outbreak]. J Gynecol Obstet Biol Reprod (Paris). 2006;35: 578–583.
  105. 105. Reddy VS, Jinka DR. A case of neonatal thrombocytopenia and seizures: Diagnostic value of hyperpigmentation. Neoreviews. 2018;19: e502–e506.
  106. 106. Parola P, de Lamballerie X, Jourdan J, Rovery C, Vaillant V, Minodier P, et al. Novel chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis. 2006;12: 1493–1499. pmid:17176562