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Chikungunya fever is a self-remitting febrile viral illness that has been associated with frequent outbreaks in tropical countries of Africa and Southeast Asia. The illness has only recently become a concern in Western countries and temperate zones around the world. The recent re-emergence and travel-related spread of Chikungunya infection to Europe and the United States has drawn global attention. In fact, international travel stands out as one of the major risk factors for the rapid global spread of the disease.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]
The term “Chikungunya” often refers to both the virus (CHIKV) and the illness or fever (CHIKF) caused by this virus. It was derived from the African dialect Swahili or Makonde and translates as “to be bent over.” In Congo, it is referred to as “buka-buka,” which means “broken-broken.” These terms refer to the “stooped-over posture” exhibited by individuals with the disease as a consequence of severe chronic incapacitating arthralgias.
The roots of this viral illness date back to 1953, when it was first described during an outbreak in a Swahili village in the Newala district of Tanzania, Africa.[14, 15] Chikungunya virus is transmitted to humans through day-biting mosquitoes that belong to the Aedes genus (see the image below).
See 11 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify and manage infectious travel diseases.
The exact pathophysiology of Chikungunya virus remains to be investigated. To date, most of the research in this field has been from the Indian subcontinent and other Asian countries.
Chikungunya virus infection has a clinical presentation that overlaps with that of Ross River virus infection (fever, rash, polyarthritis) and dengue fever virus transmitted by the same mosquitoes. Evaluation of the T-cell– and B-cell–mediated immunity has shed light on some possible mechanisms.
Using a murine model, Lum et al have shown that anti–Chikungunya virus antibodies were elicited early in the course of the illness and were directed against the C-terminus of the viral E2 glycoprotein. They showed that both natural and Chikungunya virus infection–induced specific antibodies were essential for controlling Chikungunya virus infections.
Waquier et al conducted a large ex vivo multiplex study of T-cell immunity and 50 cytokine, chemokine, and growth factor plasma profiles in 69 acutely infected patients from the Gabonese outbreak in 2007. They concluded that Chikungunya virus infection elicited strong innate immunity with an abundant production of proinflammatory markers and cytokines, including high levels of alpha interferon, interleukin (IL)–4, IL10, and gamma interferon. By flow cytometric analysis, the authors also demonstrated that humans show a CD8+ lymphocytic response in the early stages and a CD4+ predominant response in the later stages. Most importantly, the authors described a CD95-based apoptosis of CD4+ lymphocytes that could partially explain the lymphopenia in these patients. Hence, severe or chronic infections could be attributed to an absence or deregulation of one of these pathways.
The exact mechanism of entry of the virus into mammalian cells is under investigation.[18, 19] Bernard et al evaluated this mechanism and found that Chikungunya virus enters mammalian epithelial cells via a clathrin-independent, Esp-15–dependent, dynamin 2–dependent route and requires an endocytic pathway in combination with other unknown pathways. The authors speculate that Chikungunya virus is capable of undergoing genetic drifts and could acquire alternate entry mechanisms.
Several murine models with Chikungunya virus–related joint and neurological diseases are being investigated. Other state-of-the-art in vivo imaging techniques using bioluminescence imaging with luciferase-tagged pathogens and intravital 2-photon imaging systems are being evaluated for study of Chikungunya infection’s chronic phase.[21, 22, 23, 24] Further research in this field would undoubtedly provide a better understanding of the in vivo interactions between Chikungunya virus and immune cells and shed light on the immunopathogenesis.
Chikungunya virus is an alpha virus that belongs to the Togaviridae family. It is a single-stranded RNA virus and is approximately 11.8 kb long with a capsid and a phospholipid envelope. Phylogenetic analysis has revealed 3 distinct groups based on partial sequences of NS4 and E1 genes: (1) the West African, (2) the East-Central-South African (ECSA), and (3) the Asian.[7, 8]
Chikungunya virus is transmitted to humans through day-biting mosquitoes that belong to the Aedes genus. Being an arbovirus, the virus is maintained in the environment between humans or other animals and mosquitoes. Humans serve as major reservoirs during epidemics.
During inter-epidemic quiescence in Africa, the virus is thought to be maintained in an epizootic cycle that involves vertebrates such as monkeys, rodents, and birds. In Africa, the virus is maintained in a sylvatic cycle among wild primates, monkeys and, wild Aedes mosquitoes (Aedes furcifer, Aedes taylori, Aedes luteocephalus, Aedes africanus, Aedes neoafricanus). A sylvatic cycle has not yet been identified outside the African continent.
In Asia, the virus is maintained in an urban cycle involving Aedes aegypti mosquitoes (see image below) and humans. The method of viral maintenance in the environment during the quiescent inter-epidemic periods in Asia remains unknown. Unlike its counterpart, the dengue virus, a transovarian transmission has not yet been reported, supporting the historical theory that the virus first originated in Africa and later spread to other countries in Asia. Historically, Chikungunya outbreaks are known to demonstrate a secular, cyclical, and seasonal trend.[25, 26, 27]
Epidemics are characterized by explosive outbreaks between years-long periods of quiescence. The exact reason for this is unknown. Several socioeconomic factors, susceptibility of humans and mosquitoes to the virus, and ability of transmission all seem to play a role.
Evolution of Chikungunya virus
Phylogenetic analysis has revealed that the Chikungunya virus genome has remained stable over the years since its first discovery in 1952. Comparison of two Asian Chikungunya virus strains that were isolated 10 years apart showed 99.4% identity. Most of the early strains isolated from the Reunion Island Chikungunya virus outbreak were similar to the ECSA cluster.[5, 28, 29] However, the strains isolated from the 2006-2007 outbreak revealed an alanine to valine amino acid mutation at position 226 in the E1 glycoprotein. The presence of alanine (A226) denotes cholesterol-dependent growth and replication of Chikungunya virus in certain Aedes species.
This particular mutation raised considerable interest in the research field, as it resulted in cholesterol-independent growth and replication of Chikungunya virus and was exclusively seen in Chikungunya virus isolated from Aedes albopictus mosquitoes. This mutation was also associated with enhanced fitness in Chikungunya virus, enabling it to infect A albopictus mosquitoes and other species that normally lack cholesterol. This ability of the Chikungunya virus to adapt to a new species has significant implications with respect to the range of transmission and spread across the globe.[30, 31, 32, 33, 34]
The above findings led experts to speculate that Chikungunya virus would no longer be restricted to the tropical countries but could spread to temperate regions, as A albopictus predominates in temperate zones where A aegypti is scarce (the Americas, Europe, China, Japan).[35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]
Numerous Chikungunya epidemics have been reported in several countries in Southern and South East Asia. Distinct strains of Chikungunya virus within varying transmission cycles have been reported from different locations. The African variant has managed to persist over the years with frequent outbreaks due to a sylvatic cycle maintained between monkeys and wild mosquitoes. Conversely, the Asian variant causes epidemics that are maintained by an urban cycle, characterized by long inter-epidemic quiescence for more than 10 years or so.
The first Asian epidemic was reported in Bangkok, Thailand, in 1958, continued until 1964, and reappeared after a hiatus in the mid-1970s and declined again in 1976. Major outbreaks were also reported from northwestern and southern parts of India, Sri Lanka, Myanmar, and Thailand in the early 1960s. The cases then declined before sporadic outbreaks were later reported in the Philippines and Indonesia in 1980s and Malaysia in the 1990s.[7, 9, 11]
The next major outbreak occurred in 2001 on islands in the Indian Ocean (Mauritius, Mayotte, Madagascar, Reunion Island). The most severe Chikungunya fever outbreak was reported in 2006 on Reunion Island, where one-third of the population was infected, resulting in 237 deaths. Around the same time, an historical outbreak on the Indian subcontinent involved 1.42 million people, with high morbidity rates.
By 2007, the disease was no longer considered a tropical illness, as it had spread to several nontropical and temperate areas, including Singapore.
According to figures from 2013-2014 from the Centers for Disease Control and Prevention (CDC), European Center for Disease Prevention and Control (ECDC), and the Pan American Health Organization (PAHO), several imported cases of travel-related Chikungunya fever have been reported in the United States, Caribbean islands, Britain, France, Germany, Sweden, Portugal, Canary Islands, and the archipelagos off the coast of Western Africa.[36, 37, 38, 39, 40, 41]
Many travel-related cases of Chikungunya infection have been imported into the United States since 2006. As of December 2014, a total of 1,938 travel-associated cases from 47 states and 2 US territories (Puerto Rico, Virgin Islands) have been reported.
The first case of local transmission to a person who had not traveled outside the United States was reported in July 2014, which was the first documented case of mosquitoes in the United States spreading the illness to a nontraveler. As of December 2014, a total of 11 locally transmitted cases have been reported in the United States, all in Florida.
In addition, 3402 locally mosquito-transmitted cases in Puerto Rico and 86 cases in the Virgin Islands have been reported.[46, 37, 38] However, a recent study by the Puerto Rico Department of Health (PRDH) and the CDC shows that cases are underreported in Puerto Rico. From June 20 to August 19, 2014, The PRDH and CDC collected passive surveillance data in 250 participants, 70 (28%) of whom tested positive for past or current chikungunya virus infection. Only two of 25 participants (8%) with chikungunya infection who sought care had been reported to health authorities.
These cases illustrate the magnitude of the global spread of Chikungunya infection. They also emphasize the need to maintain efficient surveillance networks and implementation of adequate prevention measures, both at the personal and community level, to contain the infection and to prevent outbreaks.
Although Chikungunya fever is a self-remitting illness, rare cases of complications have been reported in India during major outbreaks among patients with comorbidities (cardiovascular, respiratory, neurological), neonates, elderly patients, immunocompromised patients. In a report from the Reunion Island outbreak in 2005, 610 patients with comorbidities had atypical presentations, 65 of whom died. Some of the complications included hepatitis, meningoencephalitis, bullous dermatosis, and pneumonia.
The overall mortality in this report was 10.6% and was higher among elderly individuals. The most common risk factors associated with a high mortality and severe infection were cardiovascular (226 patients), respiratory (150 patients), and neurological (147 patients) conditions.[48, 49, 50]
Chikungunya virus is not known to be neurovirulent or neuroinvasive, unlike other alpha viruses. However, rare cases of encephalitis (predominantly demyelinating), myelitis, entrapment neuropathy, seizures, abnormal cerebrospinal fluid (CSF) chemistries, flaccid paralysis, neurological sequelae, and severe peripheral neuropathy and Guillain Barré–type presentations have been reported from several centers in India.[51, 52, 53] During the epidemic in the Reunion Islands, 4 newborns had severe attacks of meningoencephalitis, 3 with disseminated intravascular coagulation (DIC) and 1 with intracerebral hemorrhage from severe thrombocytopenia.
Coinfection of Chikungunya fever with dengue has been reported from Yemen.[42, 54] Unlike dengue fever (see Table 1), hemorrhagic manifestations are uncommon with Chikungunya fever and are generally mild (epistaxis, gingival bleeding, subconjunctival hemorrhage, petechial or purpuric rash) if present. Other rare complications include sudden sensorineural hearing loss, granulomatous and nongranulomatous anterior uveitis, optic neuritis, retrobulbar neuritis, dendritic lesions, hypokalemic periodic paralysis, and multiorgan failure. The prognosis of eye disease was good, with most patients recovering their vision. In general, the neurological outcome was good, with most patients recovering from the initial episode.
Complications were more commonly seen in infants, adults with comorbidities, and elderly patients.[55, 56, 57] Intrauterine infection in pregnant women with vertical transmission has also been reported.[58, 59]
Das et al have described the capacity of Chikungunya virus to infect the neurons and glial cells, indicating the neuroinvasive and neurovirulent potential of this virus. However, the neurotropism of Chikungunya virus remains controversial and merits further investigation.
Persistent severe arthralgias could lead to long-term disability and loss of work days.[60, 61, 62, 63] Thus, the burden on the economy in terms of loss of productivity and income is estimated to be significant.
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