REVIEW

Chikungunya Virus Disease

An Emerging Challenge for the Rheumatologist
Vini Vijayan, MD* and Sukesh Sukumaran, MD, DPMR
Abstract: Chikungunya is caused by an alphavirus that is transmitted to
humans via the Aedes species mosquito. Chikungunya is endemic to tropical Africa and South and Southeast Asia, but over the past decade, the geographic distribution of the virus has been expanding rapidly. The disease is
characterized by fever and severe polyarthritis, and although symptoms
typically resolve within 7 to 10 days, some patients experience persistent
arthritis and arthralgias for months to years.
In December 2013, the first local transmission of chikungunya virus in
the Americas was identified in the Caribbean Island of Saint Martin. Since
then, the number of afflicted individuals has spread throughout the Caribbean
and Central America, as well as into South America. The United States reported 2788 chikungunya virus disease cases among travelers returning from
affected areas in 2014. In addition, 11 locally acquired cases were reported in
Florida. Further spread and establishment of the disease in the Americas are
likely considering the high levels of viremia in infected individuals, widespread distribution of effective vectors, lack of immunity among people living in the Americas, and the popularity of international travel.
Considering the prominent rheumatic manifestations of chikungunya,
rheumatologists are likely to encounter patients with the disease in their
practice. We recommend that rheumatologists consider chikungunya in
their differential diagnosis when evaluating patients presenting with fever
and joint pain following travel to a chikungunya endemic area. Early diagnosis would ensure timely management and reduction of polypharmacy
and its associated complications. In this article, we briefly describe the epidemiology of chikungunya, the clinical features, laboratory testing, prevention, and treatment of disease.
(J Clin Rheumatol 2016;22: 203211)

hikungunya virus disease (CHIK) is a mosquito-borne illness

that is characterized by acute onset of fever, joint pain, and
frequently rash. Joint symptoms are usually bilateral and symmetric and can be severe and debilitating.1,2 Following acute infection, patients with CHIK may develop prolonged joint pain,
similar to inflammatory rheumatic diseases such as rheumatoid arthritis (RA) or psoriatic arthritis.3,4 Persistent chikungunya rheumatic disorders (CHIK-R) can severely affect the quality of life
of individuals with the disease, and hence large outbreaks of
CHIK can have serious socioeconomic consequences in endemic
countries.4,5 There is no specific treatment for CHIK, and emphasis is on acute symptomatic care and preventive measures focused
on vector control and avoidance of mosquito bites by use of repellents, mosquito nets, and protective clothing.
Although previously thought to be a tropical illness, over the
past decade the geographic distribution of the virus has been
expanding rapidly.68 An increasing number of cases of CHIK
From the Divisions of *Infectious Diseases and Rheumatology, Department of
Pediatrics, University of Arkansas for Medical Sciences, Arkansas Childrens Hospital, Little Rock, AR.
This study has no sources of funding.
The authors declare no conflict of interest.
Correspondence: Vini Vijayan, MD, Division of Infectious Diseases Arkansas
Childrens Hospital, 1 Childrens Way, Slot 512-11, Little Rock, AR 72202.
E-mail: VVijayan@uams.edu.
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1076-1608
DOI: 10.1097/RHU.0000000000000396

have been reported among travelers returning to the United

States from endemic countries.911 The prominent joint manifestations of this disease present a unique challenge for rheumatologists in the United States as travel history may not be obtained, and
hence the diagnosis may be overlooked. In addition, some patients
with chikungunya viral arthritis may fit the 2010 American College of RheumatologyEuropean League Against Rheumatism
(ACR-EULAR) classification criteria for seronegative RA, making the diagnosis and treatment decisions more difficult.12,13
Rheumatologists in the Americas should be able to identify, diagnose, and treat patients with CHIK and CHIK-R in order to improve quality of life and prevent progression to deforming arthritis.
In this review, we briefly describe the epidemiology of CHIK,
the clinical features, laboratory testing, prevention, and treatment
of disease.

EPIDEMIOLOGY AND SPREAD

Chikungunya virus disease was first described by Robinson14,15
and Lumsden14,15 in 1955, following an outbreak in 1952 on the
Makonde Plateau, along the border between Mozambique and
Tanganyika (modern-day Tanzania). The word chikungunya is
derived from the Makonde language, meaning that which bends
up, describing the contorted position of patients with the debilitating joint pain associated with this disease.14,15 Chikungunya virus disease is endemic to tropical Africa and South and Southeast
Asia. Since its discovery, CHIK has been reported in West Africa,
from Senegal to Cameroon and in many other African countries
(Democratic Republic of Congo, Nigeria, Angola, Uganda, Guinea,
Malawi, Central African Republic, Burundi, and South Africa).1417
In Asia, epidemics occurred in Burma, Thailand, Cambodia,
Vietnam, Sri Lanka, Timor, Indonesia, and the Philippines
between the 1960s to the 1990s.3,1719 Sporadic outbreaks
continue to appear cyclically in these endemic areas.
In May 2004, an outbreak of CHIK affecting the population
of coastal Kenya, on Lamu Island, announced the resurgence of
the disease. The epidemic peak was achieved in July 2004, and
an estimated 75% of the population was seropositive.20 Among
the 115 symptomatic seropositive cases, 84% reported missing
work or school for a mean of 7 days (range, 190 days; median,
7 days). Prolonged debilitating arthritis requiring bed rest for a
mean of 7 days (range, 190 days) was also described among these
cases, emphasizing the considerable economic and social impact
of CHIK.20 The epidemic then appeared on Comoros Islands21
in December 2004 and later encompassed islands in the Indian
Ocean (Madagascar, Reunion Island, Seychelles, Mayotte, and
Mauritius) and the Indian subcontinent.2225
Chikungunya virus disease reached La Reunion Island in the
Indian Ocean in March-April 2005, where a massive epidemic occurred. More than 266,000 of the 770,000 inhabitants were infected, and 254 deaths attributed directly or indirectly to CHIK
were reported.24,25Aedes albopictus emerged as a major vector
of the chikungunya virus (CHIKV) in the Reunion Island outbreak. This was attributed to a point mutation in the E1 gene of
CHIKV, which facilitated enhanced viral uptake, replication, and
transmission by A. albopictus.26,27 The epidemic also spread to

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.jclinrheum.com

203

Vijayan and Sukumaran

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

India, where it is estimated that more than 1.5 million people

were infected.28
Subsequently, imported cases from infected travelers returning from areas with high incidence of CHIK were identified
in Europe29,30 and the United States.31 From 2006 to 2013, studies
identified an average of 28 people per year in the United States
with positive tests for recent CHIKV infection (range, 565 per year),
all of whom were travelers who arrived in the United States from
areas known to be epidemic or endemic for CHIK.10 Although there
was no evidence for autochthonous transmission, the potential for the
virus to disseminate to temperate areas of the world was confirmed.
In 2007, the first established outbreak of autochthonous of
CHIKV in a temperate area was reported in northeastern Italy.32
In September 2010, autochthonous transmission of CHIKV was
recorded in southeastern France33 with 2 confirmed cases. In
December 2013, the first local transmission of CHIKV in the
Americas was identified in the Caribbean Island of Saint Martin.34
Since then, local transmission has been identified in 44 countries
or territories throughout the Americas with more than 1.2 million
suspected cases reported to the Pan American Health Organization from affected areas35 (Fig. 1).
Beginning in 2014, CHIK cases were reported among US
travelers returning from affected areas in the Americas, and local
transmission was identified in Florida, Puerto Rico, and the US
Virgin Islands. In 2014, a total of 2799 CHIK cases were reported
to the ArboNET, the national surveillance system for arthropodborne diseases, from US states. Eleven locally transmitted cases
were reported from Florida. All other cases occurred in travelers
returning from affected area. A total of 4702 CHIK cases were reported to ArboNET from US territories for 2014. Of these, 4651
were locally transmitted cases reported from Puerto Rico and the
US Virgin Islands. The remaining 51 cases occurred in travelers
returning from other affected areas.9 As of September 15, 2015,
433 CHIK cases have already been reported from 39 US states.

All reported cases occurred in travelers returning from affected

areas. No locally transmitted cases have been reported from US
states9 in 2015 as of September 15, 2015 (Fig. 2).
Given the relatively widespread presence of mosquito vectors
in the United States and high level of viremia among infected individuals, the virus could replicate to sufficient levels in humans to
initiate localized transmission cycles among a naive population
leading to establishment of the CHIKV in the United States.36

THE VIRUS
The CHIKV is an arthropod-borne virus of the alphavirus genus
of the Togaviridae family. The members of the genus alphavirus cause
a wide range of diseases in humans and animals. Many Old World viruses, including the Ross River virus, Barmah Forest, Mayaro virus
disease, onyong-nyong virus, CHIKV, and Sindbis virus, cause arthralgias, whereas the New World viruses, Venezuelan equine virus,
eastern equine encephalitis virus, and western equine encephalitis
virus cause encephalitis.1 Chikungunya virus is a single-stranded,
positive-sense RNA molecule with 60- to 70-nm-diameter capsid
and a phospholipid envelope, in which multiple copies of 2 major
virus-encoded glycoproteins El and E2 are embedded.1,2
Three lineages with distinct genotypic and antigenic characteristics have been identified from phylogenetic analysis based on
the E1 gene and complete genome sequences of CHIKV strains
isolates from Africa and Asia and during the outbreaks in 2005
to 2007 in the islands of the Indian Ocean and in India. These include the (1) West African genotype, (2) Asian genotype, and
(3) the East, Central, and Southern African (ECSA) genotype. It
is thought that CHIKV originated in West Africa, colonized other
African areas, and was primarily introduced into Asia before
1960. The major CHIK outbreaks in the Indian Ocean in the
2000s were caused by strains of the Indian Ocean lineage, which
evolved from the ECSA genotype.26,27,37

FIGURE 1. Countries and territories where chikungunya cases have been reported* (as of March 10, 2015).

204

www.jclinrheum.com

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Chikungunya and the Rheumatologist

FIGURE 2. States reporting CHIK casesUnited States, 2015 (September 15, 2015).

The unexpected appearance of an adaptive mutation in the

ECSA genotype led to the outbreak in La Reunion Island. This
point mutation, an alanine-to-valine substitution at position 226
in the E1 glycoprotein, caused the mutated CHIKV to lose cholesterol dependence for growth and enhanced its infectivity. This
mutation also enhanced the transmissibility of CHIKV by A.
albopictus.26,27,37 The adaptation of CHIKV to this new vector,
the A. albopictus mosquito, is a major factor contributing to the
worldwide re-emergence of CHIK.

Transmission of the Virus

Chikungunya virus is typically maintained by 2 distinct transmission cycles: (1) sylvatic cycle in Africa and (2) urban humanmosquito-human virus transmission cycle seen in Asia, Africa,
and Europe.17,38 Within epidemic periods, human beings serve as
reservoir hosts for the virus, whereas during interepidemic periods,
primates, and perhaps other animals, serve as reservoirs.1,17,38
While most cases are vector-borne, vertical transmission from
mother to child39 has been reported as well. Parola et al40 described nosocomial transmission, wherein a nurse was infected
after direct contact with the blood of a traveler in metropolitan
France. Chikungunya virus infects the human cornea and potentially could be transmitted via corneal grafts.41 Transmission from
blood transfusion or organ donation is theoretically possible.42

Vectors
Chikungunya virus is transmitted from human to human by
the bites of infected female mosquitoes. There are 2 main
vectors of CHIKV, namely, the Aedes aegypti and A. albopictus.

Both mosquito species are widely distributed throughout the tropical regions of Africa and Asia.14,17,37 Until recently, A. aegypti
was considered the primary vector for CHIKV transmission, but
in 2006, A. albopictus was surprisingly identified as a second major vector of the virus, in places where A. aegypti is considered to
be less prevalent. Aedes albopictus is native to East Asia, but over
the past decades, the mosquito has invaded many countries through
international travel and transport of goods especially used tires.17,43,44
Both species are well established in the southeastern and parts of
the southwestern United States. Aedes albopictus can also be
found in the Mid-Atlantic and lower Midwest states as well.45
Adult mosquitoes rest in cool, shady areas and bite primarily
during the day. Aedes aegypti breeds mainly in stored fresh water
in urban and semiurban environments. Artificial or natural water
containers (water storage containers, flower pots, discarded tires,
plates under potted plants, clogged rain gutters, ornamental fountains, water bowls for pets) are ideal larval habitats for this mosquito. Aedes albopictus is a container-inhabiting species that
lays its eggs in any water-containing receptacle in urban, suburban, rural, and forested areas.4345

Susceptibility and Immunity

Infection with CHIKV induces long-lasting protective immunity, and the epidemic peak drops as an increasing percentage of
the population gains immunity.13,20 As with all arboviruses,
CHIKV outbreaks are heavily dependent on mosquito density,
which is influenced by rainfall but also varies based on other environmental factors such as climate, relative humidity, wind direction,
vegetation, and ground water levels. Virus evolution, climate

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.jclinrheum.com

205

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Vijayan and Sukumaran

change, absence of herd immunity, and lack of vector control are

other factors that have been implicated in the re-emergence of
CHIKV infection.14,44,45

CLINICAL MANIFESTATIONS
Chikungunya virus affects males and females equally and occurs in all age groups. The incubation period is 3 to 7 days (range,
112 days), after which acute disease ensues.46 Approximately
3% to 28% of people infected with CHIKV will remain asymptomatic.42 The potential for an infected individual to transmit
CHIKV to a susceptible Aedes mosquito is greatest during the first
2 to 6 days of illness, during the viremic phase.47 Chikungunya virus is generally a self-limited illness, and death is rare.48

Acute Presentation
Chikungunya virus is most often characterized by acute onset
of fever (typically >39C [102F]) and polyarthritis. High-grade
fevers (39C40C) occur abruptly and are accompanied with
chills and rigors. Fevers usually last from 3 to 5 days (range,
110 days) and can be continuous or intermittent.46,48,49 Bilateral
symmetric polyarthritis begins 2 to 5 days after onset of fever and
commonly involves the distal joints (wrists, ankles, phalanges),
but proximal joints can also be affected (shoulders, elbows, and
knees). The pain is worse in the morning and improves with mild
exercise but may be intense and disabling, leading to immobilization. Involvement of the axial skeleton was noted in 34% to 52%
of patients. The pain can be severe and debilitating, and tenosynovitis of fingers has also been reported. On physical examination
of afflicted individuals, periarticular edema or swelling has been
observed among 32% to 95%. In 1 series, large joint effusions
were noted in 15% of patients.4953
Cutaneous manifestations of CHIK are highly variable but
are reported in approximately 40% to 75% of cases. The most
common manifestation is appearance of a maculopapular rash
predominantly on the face, trunk, and extremities 2 to 5 days after
onset of fever. Rash may be pruritic and involve the palms and
soles. The rash typically lasts 3 to 7 days and resolves completely
but in some may result in hyperpigmentation.52,54,55 Other cutaneous findings noted during the acute phase of CHIK include diffuse
erythema of the face and trunk, hyperpigmentation of face, pinna,
and extremities and vasculitic lesions.5456 Several mucocutaneous manifestations, such as intertrigo, penoscrotal, or perianal ulceration, have been described in patients with CHIK.56,57
Ocular manifestations can be seen with CHIK and include
iridocyclitis and retinitis, conjunctivitis, and less frequently
episcleritis.58 Other nonspecific signs and symptoms consist
of lymphadenopathy, pruritus and myalgias, nausea, fatigue,
and diarrhea.52

Chronic Disease
After the acute phase of illness (usually 710 days), persistent
or relapsing arthralgias occur mainly affecting the distal extremities
such as ankles, wrists, and phalanges. Morning stiffness and severe
tenosynovitis are also common features of the secondary phase
of CHIK.5961
The duration of persistent arthralgia and arthritis varies substantially by study. Schilte et al61 found that during the 3 years
following acute CHIK 60% of patients experienced arthralgia with
episodic relapse and recovery. Arthralgias typically involved multiple joints (70%) and were symmetrical (90%) and highly incapacitating (77%). They were often associated with local swelling
(63%), asthenia (77%), or depression (56%).60,61 In a study of
47 adult patients in Marseilles, France, nearly 82% of the affected
patients had persisting joint pains after 10 days, and 88%, 86%,

206

www.jclinrheum.com

and 48% of these patients had symptoms at the end of 1, 3, and

6 months.62 In contrast, data from La Reunion outbreak have
found that as many as 80% to 93% of patients complained of persistent symptoms at 3 months after CHIK, 57% at 15 months, and
47% at 2 years.59 Brighton et al50 reported a high prevalence of
chronic arthralgia occurring 3 years after disease onset. Risk factors for long-term arthralgia included age older than 35 years and
the presence of arthralgia 4 months after the disease onset, as well
as presence of comorbidities.4
Chikungunya rheumatic disorders can mimic seronegative
RA by joint distribution and duration of joint pain in up to 50%
of patients. The 2 entities may be difficult to distinguish, considering that there are no specific clinical or radiological features
for persistent CHIK-R.13,6366 Miner et al65 describe 10 travelers
who developed CHIK after returning to the United States from
Haiti. Eighty percent developed persistent arthritis, none of whom
had positive rheumatoid factor (RF) or anticyclic citrullinated
peptide (anti-CCP) antibodies but met the 2010 ACR-EULAR
classification criteria for a diagnosis of RA. Three patients had
positive antinuclear antibodies, 1 had elevated C-reactive protein,
and none had familial history of rheumatic disease. Chikungunya
virus disease was suspected secondary to travel history, and serological testing confirmed the diagnosis of CHIK.67 Javelle et al66
found that approximately 95% of patients who have pain beyond
3 months after acute CHIK infection have varied musculoskeletal features and responded to treatment with nonsteroidal antiinflammatory drugs and physical therapy. However, 5% of patients
met the 2010 ACR-EULAR criteria for chronic inflammatory rheumatism (RA, spondyloarthritis, or unclassified polyarthritis) and
required disease-modifying antirheumatic drugs (DMARDs) such
as methotrexate.68 The prevalence of RF and anti-CCP positivity
was 30% in this study.
In the majority of patients with rheumatic symptoms, radiological findings were normal, but few reports describe progressive
erosive arthritis 1 to 2 years after infection.6365 These patients did
not display elevated RF and anti-CCP antibodies as typically
found in autoimmune or rheumatoid diseases. Chopra et al67 described a cohort of Indian patients with CHIK-R that not only had
high levels of CHIKV IgM antibodies but a few also were positive
for RF and anti-CCP antibodies. Manimunda et al68 performed a
longitudinal follow-up study of 94 patients with persistent arthritis
following serologically confirmed CHIK, of which one-third (34/94)
met the ACR-EULAR criteria to classify them as having RA. A subpopulation of patients with joint pain (20/94) was tested for RF and
anti-CCP antibody and underwent radiographic imaging. All tested
negative for RF, and 1 patient tested positive for anti-CCP. The magnetic resonance imaging findings were joint effusion, bony erosion,
marrow edema, synovial thickening, tendinitis, and tenosynovitis.
These patients were naive for musculoskeletal disorders prior to
CHIK infection.68
Myalgia, chronic neuropathic pain, Raynaud syndrome, depression, fatigue, weakness, and other sequelae have been reported several months following CHIK. Lymphedema may also
appear 2 to 3 weeks after the appearance of fever. Hyperpigmentation of skin may persist for months after the remission of CHIK,
and new dermatological manifestations may appear weeks after
the other changes have subsided.55,62

Severe Manifestations
Severe CHIK can manifest as encephalitis, encephalopathy,
myocarditis, hepatitis, and multiorgan failure. These are rare forms
but can be fatal. Severe and atypical manifestations of CHIK have
been observed particularly during the 20052006 Indian Ocean
outbreaks wherein the mortality rate from CHIK was estimated
to be 0.3% to 1%.25,69 Severe CHIK was observed to be more
2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

common in neonates, the elderly, and those with coexisting conditions such as cardiovascular, respiratory, neurological disorders.70,71
In La Reunion Island, the estimated incidence of severe disease (e.g., hospitalized patients with complications, such as respiratory failure, meningoencephalitis, acute hepatitis, or kidney failure)
was 17 per 100,000 population.24,25 Meningoencephalitis was the
most common neurologic complication; other manifestations include acute flaccid paralysis and Guillain-Barr syndrome.24,72,73
Ocular abnormalities (iridocyclitis, retinitis, episcleritis, macular
choroiditis) and sensorineural hearing loss have also been described.58 Hemorrhagic complications such as petechiae, purpura,
epistaxis, mucosal bleeding, hematemesis, and melena are rare and
should prompt the consideration of an alternative diagnosis such
as coinfection with dengue.74,75

Pregnant Women and Neonates

Most CHIK viral infections that occur during pregnancy do not
result in the virus being transmitted to the fetus, although few reports
of spontaneous abortions exist.76 Infection during the intrapartum
period was associated with the highest transmission risk. During
the 20052006 La Reunion Island outbreaks, vertical transmission
rates of 48% were reported in the context of intrapartum viremia,
despite the method of delivery.39,76 Data from a populationbased series of 47 cases of perinatal mother-to-child CHIK found
that mothers could transmit CHIKV to their infants during the
perinatal period (day 4 to day +1), and this was associated with
a high degree of morbidity in the infant.39 A similar study by
Gerardin et al76 reported 19 cases of neonatal infection associated
with intrapartum maternal viremia secondary to vertical transmission from infected mothers. There is no evidence that the virus is
transmitted through breast milk.39,76,77
Infants are typically asymptomatic at birth and then develop
fever, pain, rash, and peripheral edema. Severe illness was observed in 53% of newborns and mainly consisted of neurologic
disease (e.g., meningoencephalitis, white matter lesions, seizures,
and intracranial hemorrhage) with resultant long-term disabilities.
Cardiac complications such as myocardial hypertrophy, ventricular dysfunction, pericarditis, and coronary artery dilatation were
also reported.39,76,77

Chikungunya and the Rheumatologist

during the outbreak in India in 2007 wherein peripheral cyanosis

without hemodynamic abnormalities was found in 42 (75%) of
the infants. Edema of the lower extremities was noted in 11
(20%) of the infants by the third day of illness. Most skin manifestations resolved, but hyperpigmentation persisted in some cases.77
Other clinical features including vomiting, diarrhea, and minor
hemorrhagic signs have also been reported in infants with CHIK.77
Death is rare in children, and in La Reunion Island, only 3
deaths were reported (1 neonatal infection, 1 case of acute disseminated encephalomyelitis, and 1 case of acute hemorrhagic
shock syndrome).78

DIFFERENTIAL DIAGNOSIS
The acute presentation of CHIK must be distinguished from
dengue as both have common clinical symptoms and areas of geographic distribution. A key feature shared by both diseases is that
the fever occurs abruptly and lasts for 5 to 7 days. Dengue fever
classically is accompanied by a headache, retro-orbital pain, severe myalgias, and adenopathy. Similarly, chikungunya features
prominent headache and adenopathy, but instead of the myalgia
that is so characteristic of dengue, CHIK is characterized by severe
symmetric migratory polyarthritis. Maculopapular rash beginning
on approximately day 3 of illness is a frequently associated finding
in patients with CHIK, especially so in children. Serious hemorrhagic manifestations (hemoconcentration, lymphopenia, thrombocytopenia) and shock are more frequent with dengue.6,8284
However, as both diseases are transmitted by the same vectors,
co-infections have been reported and should be considered in endemic areas. Other diagnoses to consider include leptospirosis,
malaria, rickettsia, group A streptococcus, rubella virus, measles,
parvovirus, enterovirus, adenovirus, and other alphavirus infections (e.g., Mayaro virus, Ross River virus, Barmah Forest,
onyong-nyong virus, and Sindbis virus) and postinfectious arthritis.6,82,83 Prolonged CHIK can mimic seronegative RA, spondylarthropathy, psoriatic arthritis, undifferentiated polyarthritis,
viral polyarthritis, polyarticular gout or calcium pyrophosphate
deposition disease, and systemic lupus erythematosus.13

DIAGNOSIS
Infants and Children
Chikungunya virus disease is usually benign in children, and
fever, polyarthritis, and rash are found in more than 50% of patients. In children, the arthritis is well known to be better tolerated
than in adulthood, but severe and atypical manifestations of CHIK
can occur.78,79
Pediatric hospital-based studies from La Reunion Island and
India have reported a spectrum of neurological and dermatological
manifestations among children following CHIK.80,81 Robin et al80
describe a case series of 122 children with confirmed CHIK, of
whom 30 (24.6%) had neurological involvement during the epidemic in La Reunion Island. The range of presentations included
encephalitis (n = 12), febrile seizures (n = 10), meningeal syndrome (n = 4), and acute encephalopathy (n = 4). Cerebrospinal
fluid analyses were unremarkable, and magnetic resonance imaging was performed in 14 patients (46.6%), 5 (35.7%) of whom
were abnormal.80
In infants, a high prevalence of dermatological manifestations
including hyperpigmentation, generalized erythema, maculopapular
rash, and peeling has been reported. Vesiculobullous lesions were
noted to be quite specific of infants younger than 6 months, sometimes affecting more than 10% of the total body surface area and
requiring hospitalization.55,77,78 Valamparampil et al77 describe a
series of 56 infants with serologically confirmed chikungunya

Laboratory abnormalities included raised liver function tests,

reduced platelet and lymphocyte counts, and decreased prothrombin levels. Hematologic testing in CHIK may reveal leukopenia
with relative lymphocytosis by days 3 to 6 of illness. Thrombocytopenia is rare. Erythrocyte sedimentation rate and C-reactive protein are increased during the acute phase and may remain elevated
for a few weeks.82,83
Specific laboratory diagnosis is generally accomplished by
serology, viral culture, and molecular techniques.84,85 Enzymelinked immunosorbent assay detects antichikungunya IgM and
IgG antibodies in the serum. Immunoglobulin M antibodies are
detectable after a mean period of 5 to 7 days from the onset of
the fever and persist for several weeks up to 3 months, whereas
IgG antibodies begin to appear approximately 2 weeks from onset
of symptoms and persist for years.8587 The enzyme-linked immunosorbent assay is specific with little cross reactivity with other
alphaviruses in different antigenic complexes. However, CHIKV
IgM antibodies may cross-react with other viruses within the same
antigenic complex, including Semliki Forest, onyong-nyong virus, Ross River virus, or Mayaro virus.37 Other tests described
for the detection of CHIKV antibodies include immunofluorescence assays86 and plaque reduction neutralization test. Plaque reduction neutralization test is quite specific for alphaviruses and
used for confirmation of serological tests.

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.jclinrheum.com

207

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Vijayan and Sukumaran

Reverse transcriptionpolymerase chain reaction is a specific

and sensitive tool for diagnosing detection of CHIKV RNA in the
early phase of illness. Chikungunya virus disease results in high
levels of viremia that typically last 8 days but can last up to 12 days
after disease onset.11,30 Reverse transcriptionpolymerase chain
reaction can also be used to screen cerebrospinal fluid and tissues,
including corneas or other graft tissues. Chikungunya virus can be
isolated from samples on C6/36 or Vero cell lines within the first
3 days of illness, but this method is performed only in biosafety
level 3 laboratories and is therefore mainly used for epidemiological purposes and research studies.11,30 There is no specific assay
for assessing chronic signs and symptoms associated with CHIK,
although elevated levels of C-reactive protein and proinflammatory cytokines correlate with disease activity.61
Currently, CHIK testing is performed at the Centers for Disease Control and Prevention, several state health departments, and
1 commercial laboratory. Health care providers should contact
their state or local health department or the Centers for Disease
Control and Prevention for assistance with diagnostic testing.9

TREATMENT AND PREVENTION

Treatment is supportive and consists of rest, hydration, and
use of analgesics and antipyretics.4,66 Acetaminophen is preferred
over aspirin so as to avoid the theoretical risk of hemorrhage or
Reye syndrome. No antiviral agents have been shown to be effective in human infection, although ribavirin and interferon appear
to have in vitro activity against virus replication.87,88
Chronic arthralgia or arthritis may require treatment with nonsteroidal anti-inflammatory drugs and graduated physiotherapy.
Chloroquine sulfate, corticosteroids, DMARDs, and antitumor
necrosis factor agents have been suggested for chronic arthritis
following CHIK because of their anti-inflammatory properties
but have not been demonstrated to be effective, and further studies
are required.89,90 A single, randomized controlled study, comparing chloroquine with meloxicam, failed to demonstrate any advantage of chloroquine over meloxicam.90 Mouse models of
Ross River virus disease have indicated that etanercept treatment
given prior to the development of antiviral antibodies resulted in
mortality, suggesting that antitumor necrosis factor agents are
not suitable during the acute phase of the disease.91 The persistence of CHIKV in target tissues during the chronic phase of CHIK
has been demonstrated in humans and experimental animals, and
hence immunosuppression could potentially be deleterious.92
A few studies have described the efficacy of methotrexate in
treatment of chronic arthritis after CHIK.13,66,93,94 Javelle et al66
have developed a diagnostic and therapeutic algorithm for management of patients with chronic rheumatic manifestations of CHIK in
which for patients with a defined inflammatory polyarthritis lasting
more than 3 months DMARDs (methotrexate) are proposed.
Currently, there is no licensed vaccine for prevention of
CHIK, but strategies are underway to develop a vaccine.95,96 A
virus-like particle vaccine has undergone a National Institutes of
Health phase 1 trial.97 Administration of polyvalent immunoglobulins purified from human plasma samples of convalescent
chikungunya-infected patients has been reported as a potential
prevention strategy and treatment for individuals exposed to
CHIKV who are at risk of severe infection, such as neonates born
to viremic mothers and adults with underlying conditions.98 Active work is also underway to develop monoclonal antibodies
for treatment.99,100
Prevention consists of minimizing mosquito exposure by a
combination of vector control and human behavioral modifications. Travelers to disease endemic areas should use personal protective measures in the form of mosquito repellants, mosquito

208

www.jclinrheum.com

nets, and protective clothing such as long-sleeved shirts, long

pants, socks, and shoes to prevent bites.9 Measures to control
mosquito breeding include covering of water tanks, cisterns, and
other water storage equipment; removal of tires and coconut shells
that may collect water; regular emptying of bird baths and pet water bowls; trimming of tall grass/weeds; and the introduction of
larvivorous fish such as the guppy in ornamental water tanks.45
Patients with CHIK who are receiving care in an area inhabited
by effective vectors should be treated in mosquito-free areas or
use insect repellent to avoid spread.

CONCLUSIONS
Chikungunya virus disease represents a major public health
threat in the Western hemisphere, an area that has never before experienced the disease. Given the popularity of international travel,
high levels of viremia in infected individuals, lack of immunity,
and the presence of the mosquito vectors in the United States, further spread and establishment of CHIK are likely. Chikungunya
virus disease shares many clinical features with inflammatory
rheumatic diseases, and hence rheumatologists in the United
States should consider CHIK in patients presenting with fever
and joint pain following travel to a CHIK endemic area such as
the Caribbean, Central and South America, Africa, India, or other
areas where the virus is prevalent. Suspected cases should be reported to the state or local health department to facilitate diagnostic testing and mitigate the risk of local transmission of the
disease. There is no specific treatment or licensed vaccines for
CHIK currently, and evidence-based recommendations are needed
to guide treatment approaches.
REFERENCES
1. Jupp PG, Monath TP. Chikungunya virus disease. In: Monath TP, ed.
The Arboviruses: Epidemiology and Ecology. Vol. II. Boca Raton, FL:
CRC Press; 1988. p. 137157.
2. Ross RW. The Newala epidemic. III. The virus: isolation, pathogenic
properties and relationship to the epidemic. J Hyg (Lond). 1956;54:
177191.
3. Pialoux G, Gauzere B-A, Jaureguiberry S, et al. Chikungunya, an
epidemic arbovirosis. Lancet Infect Dis. 2007;7:319327.
4. Grardin P, Fianu A, Malvy D, et al. Perceived morbidity and community
burden after a chikungunya outbreak: the TELECHIK survey, a
population-based cohort study. BMC Med. 2011;9:5.
5. Krishnamoorthy K, Harichandrakumar KT, Krishna Kumari A, et al.
Burden of chikungunya in India: estimates of disability adjusted life years
(DALY) lost in 2006 epidemic. J Vector Borne Dis. 2009;46:2635.
6. Staples JE, Breiman RF, Powers AM. Chikungunya fever: an
epidemiological review of a re-emerging infectious disease. Clin Infect
Dis. 2009;49:942948.
7. Burt FJ, Rolph MS, Rulli NE, et al. Chikungunya: a re-emerging virus.
Lancet. 2012;379:662671.
8. Fischer M, Staples JE. Arboviral Diseases Branch, National Center for
Emerging and Zoonotic Infectious Diseases, CDC. Notes from the field:
chikungunya virus spreads in the AmericasCaribbean and South
America, 20132014. MMWR Morb Mortal Wkly Rep. 2014;63:500501.
9. Centers for Disease Control and Prevention. Chikungunya virus in the
United States. Available at: http://www.cdc.gov/chikungunya/geo/
united-states.html. Accessed September 13, 2015.
10. Gibney KB, Fischer M, Prince HE, et al. Chikungunya fever in the
United States: a fifteen year review of cases. Clin Infect Dis. 2011;52:
e121e126.
11. Lanciotti RS, Kosoy OL, Laven JJ, et al. Chikungunya virus in US
travelers returning from India, 2006. Emerg Infect Dis. 2007;13:764767.

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

12. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis

classification criteria: an American College of Rheumatology/European
League Against Rheumatism collaborative initiative. Arthritis Rheum.
2010;62:25692581.
13. Bouquillard E, Combe B. Rheumatoid arthritis after chikungunya fever: a
prospective follow-up study of 21 cases. Ann Rheum Dis. 2009;68:
15051506.
14. Lumsden WH. An epidemic of virus disease in Southern Province,
Tanganyika Territory, in 195253. II. General description and
epidemiology. Trans R Soc Trop Med Hyg. 1955;49:3357.
15. Robinson MC. An epidemic of virus disease in Southern Province,
Tanganyika Territory, in 195253. I. Clinical features. Trans R Soc Trop
Med Hyg. 1955;49:2832.
16. Muyembe-Tamfum JJ, Peyrefitte CN, Yogolelo R, et al. Epidemic of
chikungunya virus in 1999 and 2000 in the Democratic Republic of the
Congo. Med Trop. 2003;63:637638.
17. Powers AM, Logue CH. Changing patterns of chikungunya virus:
re-emergence of a zoonotic arbovirus. J Gen Virol. 2007;88(pt 9):
23632377.
18. Halstead SB, Scanlon JE, Umpaivit P, et al. Dengue and chikungunya
virus infection in man in Thailand, 19621964 IV. Epidemiologic studies
in the Bangkok metropolitan area. Am J Trop Med Hyg. 1969;18:
9971021.

Chikungunya and the Rheumatologist

33. Grandadam M, Caro V, Plumet S, et al. Chikungunya virus,

southeastern France. Emerg Infect Dis. 2011;17:910913.
34. Cassadou S, Boucau S, Petit-Sinturel M, et al. Emergence of
chikungunya fever on the French side of Saint Martin island,
October to December 2013. Euro Surveill. 2014;19.
35. Pan American Health Organization and CDC. Preparedness and
Response for Chikungunya Virus Introduction in the Americas.
Washington, DC: Pan American Health Organization; 2011. Available at:
http://new.paho.org/hq/index.php?option=com_content&view=
article&id=3545&Itemid=2545&lang=en.
36. Vega-Rua A, Zouache K, Girod R, et al. High level of vector competence
of Aedes aegypti and Aedes albopictus from ten American countries
as a crucial factor in the spread of chikungunya virus. J Virol. 2014;88:
62946306.
37. Powers AM, Brault AC, Tesh RB, et al. Re-emergence of chikungunya
and onyong-nyong viruses: evidence for distinct geographical lineages
and distant evolutionary relationships. J Gen Virol. 2000;81(pt 2):
471479.
38. Inoue S, Morita K, Matias RR, et al. Distribution of three arbovirus
antibodies among monkeys (Macaca fascicularis) in the Philippines.
J Med Primatol. 2003;32:8994.
39. Ramful D, Carbonnier M, Pasquet M, et al. Mother-to-child transmission
of chikungunya virus infection. Pediatr Infect Dis J. 2007;26:811815.

19. Kariuki Njenga M, Nderitu L, Ledermann JP, et al. Tracking epidemic

chikungunya virus into the Indian Ocean from East Africa. J Gen Virol.
2008;89:27542760.

40. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus

variant in travelers returning from Indian Ocean islands. Emerg Infect Dis.
2006;12:14931499.

20. Sergon K, Njuguna C, Kalani R, et al. Seroprevalence of chikungunya

virus (CHIKV) infection on Lamu Island, Kenya, October 2004.
Am J Trop Med Hyg. 2008;78:333.

41. Couderc T, Gangneux N, Chretien F, et al. Chikungunya virus infection of

corneal grafts. J Infect Dis. 2012;206:85185915.

21. Sergon K, Yahaya AA, Brown J, et al. Seroprevalence of chikungunya

virus infection on Grande Comore Island, union of the Comoros, 2005.
Am J Trop Med Hyg. 2007;76:11891193.
22. Sissoko D, Moendandze A, Malvy D, et al. Seroprevalence and risk
factors of chikungunya virus infection in Mayotte, Indian Ocean,
20052006: a population-based survey. PLoS One. 2008;3:e3066.
23. Beesoon S, Funkhouser E, Kotea N, et al. Chikungunya fever, Mauritius,
2006. Emerg Infect Dis. 2008;14:337338.
24. Paquet C, Quatresous I, Solet JL, et al. Chikungunya outbreak in Reunion:
epidemiology and surveillance, 2005 to early January 2006. Euro Surveill.
2006;11:E060202.3.
25. Renault P, Solet JL, Sissoko D, et al. A major epidemic of chikungunya
virus infection on Reunion Island, France, 20052006. Am J Trop
Med Hyg. 2007;77:727731.
26. Tsetsarkin KA, Vanlandingham DL, McGee CE, et al. A single mutation
in chikungunya virus affects vector specificity and epidemic potential.
PLoS Pathog. 2007;3:e201.
27. Dash PK, Parida MM, Santhosh SR, et al. East Central South African
genotype as the causative agent in reemergence of chikungunya outbreak
in India. Vector Borne Zoonotic Dis. 2007;7:519527.

42. Brouard C, Bernillon P, Quatresous I, et al. Estimated risk of chikungunya

viremic blood donation during an epidemic on Reunion Island in the
Indian Ocean, 2005 to 2007. Transfusion. 2008;48:1333.
43. Reiter P, Fontenille D, Paupy C. Aedes albopictus as an epidemic vector
of chikungunya virus: another emerging problem? Lancet Infect Dis.
2006;8:463464.
44. Benedict MQ, Levine RS, Hawley WA, et al. Spread of the tiger:
global risk of invasion by the mosquito Aedes albopictus. Vector Borne
Zoonotic Dis. 2007;7:7685.
45. Rochlin I, Ninivaggi DV, Hutchinson ML, et al. Climate change and
range expansion of the Asian tiger mosquito (Aedes albopictus) in
Northeastern USA: implications for public health practitioners.
PLoS One. 2013;8:e60874.
46. Rudolph KE, Lessler J, Moloney RM, et al. Incubation periods of
mosquito-borne viral infections: a systematic review. Am J Trop Med Hyg.
2014;90:882891.
47. Thiberville SD, Boisson V, Gaudart J, et al. Chikungunya fever: a
clinical and virological investigation of outpatients on Reunion Island,
South-West Indian Ocean. PLoS Negl Trop Dis. 2013;7:e2004.
48. Taubitz W, Cramer JP, Kapaun A, et al. Chikungunya fever in travelers:
clinical presentation and course. Clin Infect Dis. 2007;45:e1e4.

28. Mavalankar D, Shastri P, Raman P. Chikungunya epidemic in India: a

major public-health disaster. Lancet Infect Dis. 2007;7:306307.

49. Suhrbier A, Jaffar-Bandjee MC, Gasque P. Arthritogenic

alphavirusesan overview. Nat Rev Rheumatol. 2012;8:420429.

29. Krastinova E1, Quatresous I, Tarantola A. Imported cases of chikungunya

in metropolitan France: update to June 2006. Euro Surveill. 2006;
11:E060824.1.

50. Brighton SW, Prozesky OW, de la Harpe AL. Chikungunya virus

infection. A retrospective study of 107 cases. S Afr Med J. 1983;63:
313315.

30. Panning M, Grywna K, van Esbroeck M, et al. Chikungunya fever in

travelers returning to Europe from the Indian Ocean region, 2006.
Emerg Infect Dis. 2008;14:416422.

51. Borgherini G, Poubeau P, Staikowsky F, et al. Outbreak of chikungunya

on Reunion Island: early clinical and laboratory features in 157 adult
patients. Clin Infect Dis. 2007;44:14011407.

31. Lindsey NP, Prince HE, Kosoy O, et al. Chikungunya virus infections
among travelersUnited States, 20102013. Am J Trop Med Hyg.
2015;92:8287.

52. Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection

in travelers. Emerg Infect Dis. 2006;12:15651567.

32. Angelini R, Finarelli AC, Angelini P, et al. An outbreak of chikungunya

fever in the province of Ravenna, Italy. Euro Surveill. 2007;12:E070906.1.

53. Parola P, Simon F, Oliver M. Tenosynovitis and vascular disorders

associated with chikungunya virusrelated rheumatism. Clin Infect Dis.
2007;45:801802.

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.jclinrheum.com

209

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Vijayan and Sukumaran

54. Prashant S, Kumar AS, Mohammed Basheeruddin DD, et al. Cutaneous

manifestations in patients suspected of chikungunya disease. Indian J
Dermatol. 2009;54:128131.

75. Lee VJ, Chow A, Zheng X, et al. Simple clinical and laboratory
predictors of chikungunya versus dengue infections in adults. PLoS Negl
Trop Dis. 2012;6:e1786.

55. Inamadar AC, Palit A, Sampagavi VV, et al. Cutaneous manifestations

of chikungunya fever: observations made during a recent outbreak in
south India. Int J Dermatol. 2008;47:154159.

76. Gerardin P, Barau G, Michault A, et al. Multidisciplinary prospective

study of mother-to-child chikungunya virus infections on the island
of La Reunion. PLoS Med. 2008;5:e60.

56. Bandyopadhyay D, Ghosh SK. Mucocutaneous features of chikungunya

fever: a study from an outbreak in West Bengal India. Int J Dermatol.
2008;47:11481152.

77. Valamparampil JJ, Chirakkarot S, Letha S, et al. Clinical profile of

chikungunya in infants. Indian J Pediatr. 2009;76:151155.

57. Mishra K, Rajawat V. Chikungunya-induced genital ulcers. Indian J

Dermatol Venereol Leprol. 2008;74:383384.
58. Mahendradas P, Ranganna SK, Shetty R, et al. Ocular manifestations
associated with chikungunya. Ophthalmology. 2008;115:287291.
59. Sissoko D, Malvy D, Ezzedine K, et al. Postepidemic chikungunya
disease on Reunion Island: course of rheumatic manifestations and
associated factors over a 15-month period. PLoS Negl Trop Dis.
2009;3:e389.

78. Pellot AS, Alessandri JL, Robin S, et al. Severe forms of chikungunya
virus infection in a pediatric intensive care unit on Reunion Island.
Med Trop (Mars). 2012;72:Spec No:8893.
79. Le Bomin A, Hebert JC, Marty P, et al. Confirmed chikungunya in
children in Mayotte. Description of 50 patients hospitalized from
February to June 2006. Med Trop (Mars). 2008;68:491495.
80. Robin S, Ramful D, Le Seach F, et al. Neurologic manifestations of
pediatric chikungunya infection. J Child Neurol. 2008;23:10281035.

60. Lynch N, Ellis Pegler R. Persistent arthritis following chikungunya virus

infection. N Z Med J. 2010;123:7981.

81. Lewthwaite P, Vasanthapuram R, Osborne JC, et al. Chikungunya virus

and central nervous system infections in children India. Emerg Infect Dis.
2009;15:329331.

61. Schilte C, Staikowsky F, Couderc T, et al. Chikungunya virusassociated

long-term arthralgia: a 36-month prospective longitudinal study.
PLoS Negl Trop Dis. 2013;7:e2137.

82. Hochedez P, Canestri A, Guihot A, et al. Management of travelers with

fever and exanthema, notably dengue and chikungunya infections.
Am J Trop Med Hyg. 2008;78:710713.

62. Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an

emerging rheumatism among travelers returned from Indian Ocean
islands. Report of 47 cases. Medicine (Baltimore). 2007;86:123137.

83. Lakshmi V, Neeraja M, Subbalaxmi MV, et al. Clinical features and

molecular diagnosis of chikungunya fever from South India. Clin Infect
Dis. 2008;46:14361446.

63. Brighton SW, Simson IW. A destructive arthropathy following

chikungunya virus arthritisa possible association. Clin Rheumatol.
1984;3:253258.

84. Pan American Health Organization/Centers for Disease Control and

Prevention (PAHO/CDC). Preparedness and response for chikungunya
virus. Introduction in the Americas 2011. Available at: http://www.paho.
org/hq/index.php?option=com_content&view=article&id=
3545&Itemid=40377&lang=e. Accessed April 1, 2015.

64. Malvy D, Ezzedine K, Mamani-Matsuda M, et al. Destructive arthritis in a

patient with chikungunya virus infection with persistent specific IgM
antibodies. BMC Infect Dis. 2009;9:200.
65. Miner JJ, Aw Yeang HX, Fox JM, et al. Brief report: chikungunya viral
arthritis in the United States: a mimic of seronegative rheumatoid arthritis.
Arthritis Rheumatol. 2015;67:12141220.
66. Javelle E, Ribera A, Degasne I, et al. Specific management of
postchikungunya rheumatic disorders: a retrospective study of 159 cases
in Reunion Island from 20062012. PLoS Negl Trop Dis. 2015;
9:e0003603.
67. Chopra A, Anuradha V, Lagoo-Joshi V, et al. Chikungunya virus
aches and pains: an emerging challenge. Arthritis Rheum. 2008;58:
29212922.
68. Manimunda SP, Vijayachari P, Uppoor R, 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;104:392399.
69. Josseran L, Paquet C, Zehgnoun A, et al. Chikungunya disease outbreak
Reunion Island. Emerg Infect Dis. 2006;12:19941995.

85. Grivard P1, Le Roux K, Laurent P, et al. Molecular and serological

diagnosis of chikungunya virus infection. Pathol Biol (Paris). 2007;55:
490494.
86. Litzba N, Schuffenecker I, Zeller H, et al. Evaluation of the first
commercial chikungunya virus indirect immunofluorescence test.
J Virol Methods. 2008;149:175179.
87. Briolant S, Garin D, Scaramozzino N, et al. In vitro inhibition of
chikungunya and Semliki Forest viruses replication by antiviral
compounds: synergistic effect of interferon-alpha and ribavirin
combination. Antiviral Res. 2004;61:111117.
88. de Lamballerie X, Ninove L, Charrel RN. Antiviral treatment of
chikungunya virus infection. Infect Disord Drug Targets. 2009;9:
101104.
89. Brighton SW. Chloroquine phosphate treatment of chronic chikungunya
arthritis. An open pilot study. S Afr Med J. 1984;66:217218.

70. Rajapakse S, Rodrigo C, Rajapakse A. Atypical manifestations of

chikungunya infection. Trans R Soc Trop Med Hyg. 2010;104:8996.

90. Chopra A, Saluja M, Venugopalan A. Effectiveness of chloroquine

and inflammatory cytokine response in patients with early persistent
musculoskeletal pain and arthritis following chikungunya virus infection.
Arthritis Rheumatol. 2014;66:319326.

71. Lemant J, Boisson V, Winer A, et al. Serious acute chikungunya virus

infection requiring intensive care during the Reunion Island outbreak in
20052006. Crit Care Med. 2008;36:25362541.

91. Zaid A1, Rulli NE, Rolph MS, et al. Disease exacerbation by etanercept
in a mouse model of alphaviral arthritis and myositis. Arthritis Rheum.
2011;63:488491.

72. Wielanek AC, Monredon JD, Amrani ME, et al. Guillain-Barr syndrome
complicating a chikungunya virus infection. Neurology. 2007;69:
21052107.

92. Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, et al. Persistent chronic
inflammation and infection by chikungunya arthritogenic alphavirus in
spite of a robust host immune response. J Immunol. 2010;184:59145927.

73. Singh SS, Manimunda SP, Sugunan AP, et al. Four cases of acute flaccid
paralysis associated with chikungunya virus infection. Epidemiol Infect.
2008;136:12771280.

93. Ganu MA, Ganu AS. Post-chikungunya chronic arthritisour experience

with DMARDs over two year follow up. J Assoc Physicians India.
2011;59:8386.

74. Ezzedine K, Cazanave C, Pistone T, et al. Dual infection by chikungunya

virus and other imported infectious agent in a traveler returning from
India. Travel Med Infect Dis. 2008;6:152154.

94. Ribra A1, Degasne I, Jaffar Bandjee MC, et al. Chronic rheumatic
manifestations following chikungunya virus infection: clinical description
and therapeutic considerations. Med Trop (Mars). 2012;72spec no:8385.

210

www.jclinrheum.com

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

JCR: Journal of Clinical Rheumatology Volume 22, Number 4, June 2016

Chikungunya and the Rheumatologist

95. Weaver SC, Osorio JE, Livengood JA, et al. Chikungunya virus and
prospects for a vaccine [review]. Expert Rev Vaccines. 2012;11:
10871101.

98. Couderc T, Khandoudi N, Grandadam M, et al. Prophylaxis and

therapy for chikungunya virus infection. J Infect Dis. 2009;200:
516523.

96. Edelman R, Tacket CO, Wasserman SS, et al. Phase II safety and
immunogenicity study of live chikungunya virus vaccine TSI-GSD-218.
Am J Trop Med Hyg. 2000;62:681.

99. Fric J, Bertin-Maghit S, Wang CI, et al. Use of human monoclonal

antibodies to treat chikungunya virus infection. J Infect Dis. 2013;207:
319322.

97. Akahata W, Yang ZY, Andersen H, et al. A virus-like particle vaccine for
epidemic chikungunya virus protects nonhuman primates against
infection. Nat Med. 2010;16:334.

100. Pal P, Dowd KA, Brien JD, et al. Development of a highly protective
combination monoclonal antibody therapy against chikungunya virus.
PLoS Pathog. 2013;9:e1003312.

2016 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.jclinrheum.com

211