Chikungunya fever

21/06/14 09:24

Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
Chikungunya fever
Author
Mary Elizabeth Wilson, MD

Section Editor
Martin S Hirsch, MD

Deputy Editor
Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2014. | This topic last updated: Jun 11, 2014.
INTRODUCTION Chikungunya is an arthropod-borne virus (arbovirus) endemic to West Africa that causes acute
febrile polyarthralgia and arthritis. The name chikungunya is derived from a local language of Tanzania meaning "that
which bends up" or "stooped walk" because of the incapacitating arthralgia caused by the disease.
Multiple outbreaks beyond West Africa have been described. Since 2004, chikungunya has spread broadly, causing
massive outbreaks with explosive onset in the Indian Ocean region, India, and other parts of Asia [1,2]. Chikungunya
had traditionally been perceived as a tropical disease until an outbreak in Italy in 2007. In addition, thousands of
cases have been identified in travelers returning from outbreak areas [3]. The distribution of mosquito vectors
capable of transmitting chikungunya virus is wide; in the future, transmission could occur in regions with no prior
case reports [4].
EPIDEMIOLOGY The United States Centers for Disease Control (CDC) maintains a map with reported current or
previous local transmission of chikungunya virus.
Endemic areas Chikungunya virus is endemic in parts of west Africa where it appears to be maintained in a cycle
involving humans, Aedes mosquitoes, primates, and perhaps other animals [5,6]. Serosurveys of humans in parts of
West Africa have identified antibodies to chikungunya virus in 35 to 50 percent of the population in the absence of
recognized outbreaks.
Spread and resurgence Chikungunya virus spreads by means of travel of infected individuals between regions
where competent mosquitoes exist for perpetuation of local transmission. Imported cases have been described in
many Asian and European countries as well as in the Americas and Australia [7-14]. Rapid spread in the last few
years may also be related to a viral mutation that enhances replication efficiency in the Aedes albopictus mosquito.
(See 'Transmission' below and 'Mutation of virus and vector replication' below.)
After chikungunya virus was identified during an outbreak in East Africa in Tanzania in the early 1950s, the virus was
noted to be the cause of multiple outbreaks in many countries of central, southern, and western Africa. Outside
Africa, the first documented chikungunya fever outbreak was in Thailand in 1958. This was followed by outbreaks in
multiple other Asian countries, including India, Sri Lanka, Malaysia, Indonesia, Cambodia, Vietnam, Myanmar, the
Philippines, and Pakistan.
After a period of relatively little chikungunya activity, large outbreaks were observed in Africa in the late 1990s. In the
Democratic Republic of the Congo, for example, an urban outbreak involved an estimated 50,000 people in 1999 to
2000. Epidemics also occurred in Indonesia in 2001 to 2003 after decades without obvious chikungunya fever cases.
Indian Ocean and Asia Rapid spread of chikungunya virus has been observed in outbreaks involving the Indian
Ocean islands, where attack rates have been extremely high in previously unexposed populations. A massive
outbreak in Lamu (an island off the coast of Kenya) affected thousands in 2004; a seroprevalence study suggested
that the widespread epidemic may have affected 75 percent of the island's 18,000 inhabitants [15]. The epidemic on
Reunion Island in 2005 to 2006 involved approximately 266,000 individuals (34 percent of the island's population); a
higher attack rate was observed among elderly residents [16]. In the Comoro Islands, a seroprevalence study found
63 percent positive for chikungunya virus antibodies [17].
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In India, nearly 1.4 million cases of chikungunya fever were reported in 2006, and outbreaks have continued to occur.
The appearance and spread of chikungunya virus in India was observed after a hiatus of almost 32 years [18,19].
Chikungunya virus also reappeared in Malaysia in 2006 [20], in Thailand in 2008, in Singapore in 2008, and caused
an outbreak in Guangdong Province, China, in 2010 [21].
Europe Although chikungunya fever has traditionally been considered a disease of tropical and subtropical
regions, in the summer of 2007 chikungunya virus caused an outbreak in northeastern Italy [22]. The index case was
a traveler from India who became ill while visiting Italy, and phylogenetic analysis of the virus demonstrated similarity
with chikungunya strains found in the Indian Ocean outbreaks.
Between July and September 2007, 205 cases of chikungunya fever were identified in Italy by epidemiologic and
clinical criteria; 175 cases were confirmed by laboratory testing. The clinical attack rate in the two affected Italian
villages was 5.4 and 2.5 percent but increased with age (1.6 percent for residents <40 years old versus 8.8 percent
for those 80 years of age and older) [22]. Cases of chikungunya fever related to local transmission ceased in Italy
when temperatures dropped, and human cases were not reported in 2008. Local transmission occurred in France in
2010 [23].
Because the Indian Ocean islands, India, and Malaysia are popular tourist destinations among European travelers,
many imported cases of chikungunya fever appeared in Europe at the time of the outbreaks in India and the Indian
Ocean islands [24].
Americas In December 2013, chikungunya fever was reported in the Caribbean Island of St Martin [25]. Since
then, local transmission has been confirmed in 17 countries or territories in the Caribbean or South America
(Anguilla, Antigua and Barbuda, the British Virgin Islands, Dominica, the Dominican Republic, French Guiana,
Guadeloupe, Guyana, Haiti, Martinique, Puerto Rico, Saint Barthelemy, Saint Kitts and Nevis, Saint Lucia, Saint
Martin, Saint Vincent and the Grenadines, and Sint Maarten) [25-28]. In addition, imported cases to Aruba and the
United States have been reported [26-31]. This is the first time that local transmission of chikungunya has been
reported in the Americas [32]. As of the end of May 2014, more than 100,000 suspected cases and 4406 laboratoryconfirmed cases had been reported [28].
The United States Centers for Disease Control maintains a page summarizing the status of chikungunya
transmission in the Caribbean.
TRANSMISSION In endemic areas of Africa, chikungunya virus transmission occurs in a cycle involving humans,
several species of Aedes mosquitoes that inhabit forests and villages, and animals (nonhuman primates and perhaps
other animals). In Asia and elsewhere, however, major outbreaks are sustained by mosquito transmission among
susceptible humans. The virus can spread via travel of infected individuals between regions where competent
mosquitoes exist for perpetuation of local transmission. (See 'Epidemiology' above.)
Mosquito vectors The major chikungunya virus mosquito vectors are Aedes aegypti and Aedes albopictus.
These vectors are also capable of transmitting dengue virus, which, like chikungunya virus, is increasing in
geographic range and intensity of transmission. (See "Mosquito vectors of infectious diseases" and "Epidemiology of
dengue virus infections".)
Aedes aegypti Ae. aegypti is well adapted to urban settings and is widely distributed in urban areas of the
tropics and subtropics. It prefers the human host as a source of blood meals and breeds readily in flowerpots and in
trash, such as discarded cups. A single Ae. aegypti mosquito may be able to infect more than one human, since this
species feeds on another host if its blood meal is interrupted.
Aedes albopictus Ae. albopictus (the so-called Asian tiger mosquito) is competent to transmit a number of
arboviruses in the laboratory (including yellow fever, West Nile, Japanese encephalitis, and eastern equine
encephalitis viruses). It bites a range of animal species so has been considered a relatively inefficient vector, since
blood meals taken from nonsusceptible hosts do not contribute to virus transmission [33]. However, some
populations of Ae. albopictus may be more anthropophilic (eg, preferring human blood) than others; in some settings,
humans may be the most abundant host [33].
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Ae. albopictus has become widely dispersed beyond Asia; it is now established in many parts of the Americas,
Europe, Africa, and the Pacific Islands [34]. Modes of mosquito dissemination include transport of mosquito larvae
and eggs in used tires by container ships, and air traffic with subsequent establishment in new areas with suitable
environmental and climatic conditions [35,36]. Outbreaks of chikungunya fever in Italy and Reunion have resulted
from virus transmission by Ae. albopictus [22,33]. Subsequently simultaneous outbreaks of chikungunya fever and
dengue infections have been documented in Central Africa (Gabon) in association with the introduction of the Aedes
albopictus vector. Dengue-chikungunya coinfections have been documented in humans and in a wild-caught
mosquito [37].
Mosquito competence Mosquito susceptibility to infection by chikungunya virus and mosquito competence
for virus transmission can vary [38]. Among Ae. aegypti and Ae. albopictus strains in Florida evaluated for
susceptibility to infection by and competence for transmission of a chikungunya virus from the Reunion outbreak, all
mosquitoes were susceptible to infection and capable of transmitting the virus [39]. Thus, local mosquitoes possess
the capacity to serve as vectors for transmission of chikungunya virus in Florida.
Similarly, Ae. albopictus collected in southern France demonstrated high susceptibility to infection with chikungunya
virus (77.1 percent), which was comparable to the susceptibility of mosquitoes collected from Reunion [40]. Given
the wide distribution of mosquito vectors capable of transmitting chikungunya virus, in the future transmission could
occur in regions with no prior case reports [4].
Seasonal synchrony In order for a viremic traveler to initiate a local outbreak in a non-endemic area, there
must be seasonal synchrony between the geographic source of ongoing viral transmission and the geographic
destination vulnerable to introduction of infection (due to infestation with competent mosquito vectors) [41]. For
example, transmission of chikungunya virus in Italy during the summer of 2007 was successful because of presence
of virus in an individual traveling within the northern hemisphere between India and Italy; the period of active
transmission in India coincided with Italy's hottest months. Spread from the southern to northern hemisphere is less
likely because the warm seasons and vector activity for these regions may not be synchronous.
Extrinsic incubation period The extrinsic incubation period is the period between a mosquito blood meal
from a viremic host and the transmission of virus to a new host. During this period, the virus must replicate and reach
the mosquito salivary glands so that it will be transmitted to a new host when the mosquito takes the next blood
meal. The extrinsic incubation period varies depending on the virus, the mosquito vector, and environmental
conditions including temperature and humidity. In general, the warmer the temperature, the shorter the extrinsic
incubation period and the sooner the mosquito can transmit virus to a new host. In cool temperatures and in many
temperate areas, a mosquito may die before the extrinsic incubation period is complete.
The mutation in the chikungunya virus strain that caused the massive outbreak on Reunion (described below) may
also be capable of shortening the extrinsic incubation period, allowing more mosquitoes to survive long enough to
transmit virus [42]. (See 'Mutation of virus and vector replication' below.)
Nosocomial and vertical transmission Additional modes of transmission include nosocomial and vertical
transmission. Nosocomial transmission has been described in France, where a nurse was infected by exposure to
blood while caring for a patient infected in Reunion [7,9]. Transmission via transfusion of blood products and/or organ
transplantation could also occur, since chikungunya viremia (may exceed 109 RNA copies/mL plasma) is likely prior
to onset of symptoms [9,43]. Chikungunya virus infects the human cornea and could be transmitted via corneal
grafts. Infected corneas have been documented in individuals in the absence of systemic symptoms of chikungunya
infection [44].
Vertical transmission of chikungunya has been described in Reunion; among 39 women in the outbreak with viremia
at the time of delivery, the rate of vertical transmission was 48.7 percent [45]. Symptoms among neonates were
observed within three to seven days and included fever, poor feeding, and rash; 89 percent had thrombocytopenia.
Among 19 infected neonates, 10 had severe disease, primarily encephalopathy. Caesarean delivery was not
protective against vertical transmission.
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VIROLOGY Chikungunya is a single-stranded RNA virus of the genus Alphavirus (Togaviridae family). It was first
isolated from mosquitoes and humans during an outbreak in Tanganyika (Tanzania) in 1952 to 1953 [46]. Thus far,
three lineages distinguishable by genotypic and antigenic characteristics have been identified: the clusters of Central
and East Africa, West Africa, and Asia.
Other alphaviruses that cause illnesses associated with fever and arthralgia or arthritis include O'nyong-nyong (East
and Central Africa), Barmah and Ross River viruses (Australia and the Pacific), Semliki virus (Africa), Mayaro virus
(South America), and Sindbis group viruses (widespread excluding the Americas) [24,47]. (See "Specific viruses that
cause arthritis".)
The pathogenesis of the severe and persistent joint symptoms that characterize chikungunya virus infections is
uncertain. Some data suggest that macrophage-derived products such as tumor necrosis factor-alpha, interferongamma, and macrophage chemoattractant protein-1 may play important roles in the joint tissue damage [48].
Mutation of virus and vector replication The replication efficiency of chikungunya virus within the Ae. albopictus
mosquito may be enhanced in the presence of a mutation in the viral gene encoding the envelope protein of the virus
(mutation A226V). This mutation was observed in >90 percent of viral sequences in the latter period of the Reunion
outbreak, although it was not observed in the initial outbreak strains, suggesting an enhanced survival benefit for this
mutant (A226V) [49]. The mutation was also found in chikungunya virus isolates from the outbreak in Italy [50].
The presence of this mutation has been associated with enhanced Ae. albopictus susceptibility to infection and more
rapid viral dissemination into the mosquito salivary glands [42]. As a result, a lower level of human viremia is required
for transmission of this mutant virus to a biting mosquito, facilitating the cycle of infection.
CLINICAL MANIFESTATIONS
Acute infection Clinical signs and symptoms begin abruptly with fever and malaise following an incubation period
of two to four days (range 1 to 14) [51].
Fever may be high grade (40C); the usual duration of fever is three to five days (range 1 to 10 days). Polyarthralgia
begins two to five days after onset of fever and commonly involves multiple joints (often 10 or more joint groups)
[7,19,52,53]. Joints affected include hands (50 to 76 percent), wrists (29 to 81 percent), and ankles (41 to 68
percent). Arthralgia is symmetrical in 64 to 73 percent and involves distal joints more than proximal joints.
Involvement of the axial skeleton was noted in 34 to 52 percent of cases. Pain may be intense and disabling, leading
to immobilization.
Skin manifestations have been reported in 40 to 75 percent of patients [19,53]. The most common skin manifestation
is macular or maculopapular rash (usually appearing three days or later after onset of illness and lasting three to
seven days). The rash often starts on the limbs and trunk, can involve the face, and may be patchy or diffuse. Islands
of normal skin may be seen along with the diffuse rash. Pruritus has been reported in 25 to 50 percent of patients in
some series. Bullous skin lesions have also been described, most often in children. Hemorrhagic manifestations are
uncommon.
Additional manifestations may include headache, myalgia, and gastrointestinal symptoms.
On physical examination, periarticular edema or swelling has been observed in 32 to 95 percent of cases. In one
series, large joint effusions were noted in 15 percent of cases. Peripheral lymphadenopathy (most often cervical)
may be present (9 to 41 percent of cases) [8,54]. Conjunctivitis may be observed [55].
The most common laboratory abnormalities are lymphopenia and thrombocytopenia. Liver enzymes may be
elevated.
There is no evidence of congenital infection in infants who were exposed in utero [56].
Persistent symptoms Following acute illness (usually lasting 7 to 10 days), some patients may experience
persistent rheumatologic signs and symptoms including arthritis/arthralgia, edematous polyarthritis of fingers and

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toes, morning pain and stiffness, and severe tenosynovitis (especially of wrists, hands, and ankles) [57]. Carpal
tunnel syndromes may result from hypertrophic tenosynovitis. In addition, patients may report joint or bone pain at
sites of previous injury. Occasionally, unusual joints (such as sternoclavicular or temperomandibular joints) are
involved. New onset Raynaud phenomena in the second or third month following infection have been described in up
to 20 percent of cases [52]. Cryoglobulinemia has also been found in patients with persistent symptoms attributed to
chikungunya infection, >90 percent in one series [58].
The duration of persistent symptoms is variable. Among 47 patients with acute chikungunya fever followed in
Marseilles, France, 82 percent had persistent joint symptoms. At one, three, and six months following acute illness,
symptoms persisted in 88, 86, and 48 percent of patients, respectively; at 15 months, 4 percent remained
symptomatic [52]. In contrast, among 88 patients in Reunion evaluated a mean of 18 months after confirmation of
acute chikungunya infection, 63 percent reported persistent polyarthralgia [54]. Morning stiffness was reported by 75
percent of individuals, and almost half reported that the pain had a negative impact on daily activities. Another study
of 180 patients from Reunion with viremic chikungunya infection found that at 36 months 60 percent still had
arthralgias [59].One study in South Africa reported arthralgia three years after the acute illness in 12 percent of
patients [60].
Severe complications In older reports, chikungunya fever has been described as a self-limited illness, although
severe complications and death have been reported in the more recent outbreaks. It is unclear whether these
differences reflect a modulation in virus virulence, improved epidemiologic observation, or both. Severe
complications and death occur more often among patients older than 65 years and in those with underlying chronic
medical problems.
Severe complications include respiratory failure, cardiovascular decompensation, myocarditis, acute hepatitis, renal
failure, and neurologic involvement. Meningoencephalitis is the most common neurologic complication; other
manifestations include acute flaccid paralysis and Guillain Barr syndrome [61-63]. Ocular manifestations
(iridocyclitis, retinitis, episcleritis, macular choroiditis) and sensorineural hearing loss have also been described
[55,64,65]. In Reunion, the estimated incidence of severe disease (eg, hospitalized patients with complications, such
as respiratory failure, meningoencephalitis, acute hepatitis, or kidney failure) was 17 per 100,000 population [16,66].
Deaths associated with chikungunya virus infection were reported during outbreaks in Mauritius, Reunion, and India
[66-69]. In Reunion there were 228 deaths; the mean age was 78 years [66]. During the chikungunya epidemic in
Ahmedabad, India, in 2006, about 60,000 cases were described; the number of deaths during the four months of
peak epidemic activity exceeded the average death rate during those months in the previous four years by almost
3000 [69].
Subclinical infection Some individuals have serologic evidence for exposure to chikungunya virus infection in
the absence of clinical symptoms. As noted above, in West Africa seropositivity has been noted in 35 to 50 percent
of the individuals in the absence of recognized outbreaks. During the Reunion outbreak, a survey found that about
3.2 percent of military policemen were seropositive in the absence of clinical symptoms [70]. A Thai study noted a
ratio of clinical-to-subclinical chikungunya infection of about 1.8:1 [71].
Differential diagnosis Chikungunya and dengue virus infections have some common clinical symptoms and
areas of geographic distribution; distinguishing them may be difficult in the setting of acute febrile illness with rash.
However, polyarthralgia occurs in virtually all cases of chikungunya fever but is not typical of dengue fever. In a
comparison of patients with confirmed dengue or chikungunya infection in Singapore, at the time of presentation,
significantly more chikungunya patients than dengue patients had myalgia or arthralgia [72]. A platelet count <118 x
109/L was more likely to be found in those with dengue infections; low platelet count was a key laboratory finding
distinguishing dengue from chikungunya infection.
Other infections in the differential diagnosis include other viral infections (primary HIV infection, measles, rubella,
Ross River virus), malaria, rickettsial infections, relapsing fever, leptospirosis, meningococcal infections, Epstein-Barr
virus (EBV), and enteric fever (typhoid and paratyphoid fevers). In a study of 62 returned travelers with fever and
rash seen in Paris between January 2006 and September 2007, the most common diagnoses were chikungunya (35
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percent), dengue (26 percent), and African tick bite fever (10 percent) [73]. Leukopenia, neutropenia, and
thrombocytopenia were significantly more common in patients diagnosed with dengue than chikungunya. Others
have reported similar findings [72].
If the clinical course is atypical or fever persists longer than five to seven days, the possibility of dual infection should
be considered [74]. Chikungunya virus outbreaks have occurred simultaneously with outbreaks of dengue or yellow
fever [75], and coinfection with chikungunya virus and other pathogens has been described (eg, chikungunya and
dengue [76], chikungunya and yellow fever [74], chikungunya and amebiasis [77]).
DIAGNOSIS Diagnostic techniques for identification of chikungunya virus include serology, viral culture, and
molecular techniques [9,19,47]. Serology is the primary tool for diagnosis in the clinical setting. IgM anti-chikungunya
virus antibodies (detected by direct enzyme-linked immunosorbent assay [ELISA]) are present starting about five
days (range 1 to 12 days) following onset of symptoms and persist for several weeks to three months. IgG antibodies
begin to appear about two weeks following onset of symptoms and persist for years.
In endemic areas, chikungunya infection can be suspected based on characteristic clinical findings in outbreaks; in
endemic areas where good laboratory facilities are unavailable, many infections may remain undiagnosed.
Viral culture and molecular techniques are important research tools. Chikungunya virus can be isolated from blood
during the first week of illness using mosquito cells, mammalian cells (Vero), or in mice. Sensitivity of viral culture is
high in early infection but drops five days after onset of illness. Chikungunya virus RNA can also be detected by
reverse transcription polymerase chain reaction (RT-PCR) during the first five days following onset of symptoms with
excellent sensitivity and specificity [9]. Virus isolation allows identification of the viral strain and can be important for
epidemiologic and research purposes, but RT-PCR is faster than culture with greater sensitivity and specificity.
TREATMENT AND PREVENTION Treatment of chikungunya infection consists of supportive care including
antiinflammatory agents that relieve symptoms in many patients and analgesic agents [52]. No antiviral agents have
been shown to be effective in human infection, although ribavirin and interferon-alpha appear to have in vitro activity
against virus replication [78]. Chloroquine sulfate has been suggested as a possible treatment because of its
antiinflammatory properties but has not been demonstrated to be effective [79]. For seriously ill patients, there are
insufficient data for use of corticosteroids or antiviral therapy. The documentation of long-term viral persistence in
nonhuman primates raises questions about the roles immune dysregulation and persistent virus in chronic symptoms
[80].
Thus far there is no licensed vaccine for prevention of chikungunya infection; active research is under way to develop
a vaccine using variety of approaches [81-83]. A virus-like particle vaccine has undergone a National Institutes of
Health (NIH) phase I trial. Active work is also underway to develop monoclonal antibodies for treatment [84].
Prevention consists of minimizing mosquito exposure [85]. Patients receiving care in an area inhabited by
mosquitoes competent to transmit chikungunya virus should be treated in screened, mosquito-free areas or under a
bednet to avoid spread. (See "Prevention of arthropod and insect bites: Repellents and other measures".)
SUMMARY AND RECOMMENDATIONS
Chikungunya is an arthropod-borne virus (arbovirus) endemic to West Africa that causes acute febrile
polyarthralgia and arthritis. (See 'Introduction' above.)
Chikungunya virus appears to spread across wide geographic areas via travel of infected individuals between
regions where competent mosquitoes exist for perpetuation of local transmission. Multiple outbreaks beyond
West Africa have been described; since 2004, chikungunya virus has spread broadly, causing massive
outbreaks with explosive onset in the Indian Ocean region, India, other parts of Asia, Europe, and, most
recently, the Americas. (See 'Epidemiology' above.)
Clinical manifestations of acute infection include high fever and bilateral polyarthralgia with intense pain. The
most common skin manifestation is macular or maculopapular rash (usually appearing three days or later after

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onset of illness and lasting three to seven days). Additional manifestations may include headache, myalgia, and
gastrointestinal symptoms. (See 'Acute infection' above.)
Many patients experience persistent rheumatologic symptoms following acute illness. These may include
polyarthralgia, morning stiffness, tenosynovitis, and Raynaud phenomena. Severe complications (including
meningoencephalitis, cardiopulmonary decompensation, acute renal failure, and death) have been described
with greater frequency among patients older than 65 years and those with underlying chronic medical
problems. (See 'Persistent symptoms' above and 'Severe complications' above.)
Serology is the primary tool for diagnosis in the clinical setting. IgM anti-chikungunya virus antibodies are
present starting about five days (range 1 to 12 days) following onset of symptoms and persist for several weeks
to three months. IgG antibodies start to appear about two weeks following onset of symptoms and persist for
years. (See 'Diagnosis' above.)
Treatment of chikungunya infection consists of supportive care including antiinflammatory and analgesic
agents. No antiviral agents have been shown to be effective in human infection. Prevention consists of
minimizing mosquito exposure. Patients receiving care in an area inhabited by mosquitoes competent to
transmit chikungunya should be treated in screened, mosquito-free areas or under a bednet to avoid spread.
(See 'Treatment and prevention' above.)
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