|Classification and external resources|
Rash from Chikungunya on the right foot
Chikungunya (in the Makonde language "that which bends up") virus (CHIKV) is an arthropod-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes. There have been recent breakouts of CHIKV associated with severe illness.
CHIKV infection causes an illness with a similar mode of transmission as dengue fever, with an acute febrile phase lasting two to five days, followed by a longer period of joint pains in the extremities. The pain associated with CHIKV infection of the joints may persist for weeks or months, or in some cases years. Prevention is via mosquito control and preventing bite by infected mosquitoes. There is no specific treatment with medications used to help with symptoms.
Signs and symptoms
The incubation period of chikungunya disease ranges from one to twelve days, usually two to three. Its symptoms include a fever up to 40 °C (104 °F), a petechial or maculopapular rash of the trunk and occasionally the limbs, and arthralgia or arthritis affecting multiple joints. Other nonspecific symptoms can include headache, nausea, vomitting, conjunctivitis, slight photophobia and partial loss of taste. Ocular inflammation from Chikungunya may present as iridocyclitis, and have retinal lesions as well. Pedal oedema (swelling of legs) is observed in many patients, the cause of which remains obscure as it is not related to any cardiovascular, renal or hepatic abnormalities.
Typically, the fever lasts for two days and then ends abruptly. However, other symptoms—namely joint pain, intense headache, insomnia and an extreme degree of prostration—last for a variable period; usually for about five to seven days. Patients have complained of joint pains for much longer time periods; some as long as two years, depending on their age. Recovery from the disease varies by age. Younger patients recover within 5 to 15 days; middle-aged patients recover in 1 to 2.5 months. Recovery is longer for the elderly. The severity of the disease as well as its duration is less in younger patients and pregnant women. In pregnant women, no untoward effects are noticed after the infection.
Observations during recent epidemics have suggested chikungunya may cause long-term symptoms following acute infection. Following the La Reunion outbreak in 2006, greater than 50% of subjects over 45 reported long term musculoskeletal pain with up to 60% of patients reporting prolonged arthralgia 3 years following initial infection. A study of imported cases in France reported that 59% of patients still suffered from arthralgia two years after acute infection. Following a local epidemic of chikungunya in Italy, 66% of patients reported myalgia, arthralgia, or asthenia at one year post acute infection. Long-term symptoms are not an entirely new observation; long-term arthritis was observed following an outbreak in 1979. Common predictors of prolonged symptoms are increased age and prior rheumatalogical disease. The cause of these chronic symptoms is currently not fully known. Markers of autoimmune or rheumatoid disease have not been found in patients reporting chronic symptoms. However, some evidence from human patients and animal models suggest that chikungunya may be able to establish chronic infections within the host. Viral antigen was detected in a muscle biopsy of a patient suffering a recurrent episode of disease three months after initial onset. Additionally, viral antigen and RNA were found in synovial macrophages of a patient during a relapse of musculoskeletal disease 18 months post initial infection. Several animal models have also suggested that chikungunya virus may establish persistent infections. In a mouse model viral RNA was detected specifically in joint-associated tissue for at least 16 weeks post inoculation and was associated with chronic synovitis. Similarly, another study reported detection of a viral reporter gene in joint tissue of mice for weeks post inoculation. In a non-human primate model, chikungunya virus was found to persist in the spleen for at least 6 weeks.
|Cryoelectron microscopy reconstruction of Chikungunya virus. From EMDB entry |
|Group:||Group IV ((+)ssRNA)|
Chikungunya virus is an alphavirus with a positive sense single-stranded RNA genome of approximately 11.6kb. It is a member of the Semliki Forest Virus complex and is closely related to Ross River Virus, O’Nyong Nyong virus and Semliki Forest Virus. In the United States it is classified as a Category C priority pathogen and work requires Biosafety Level III precautions.
Human epithelial, endothelial, primary fibroblasts and monocyte-derived macrophages are permissive for chikungunya virus in vitro and viral replication is highly cytopathic but susceptible to type I and II interferon. In vivo, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells and myofibers.
Type 1 interferon
Upon infection with chikungunya, the host's fibroblasts will produce type 1 (alpha and beta) interferon. Mice that lack the interferon alpha receptor die in 2–3 days upon being exposed to 102 chikungunya PFU, while wild type mice survive even when exposed to as much as 102 PFU of the virus. At the same time, mice that are partially type 1 deficient (IFN α/β +/−) are mildly affected and experience symptoms such as muscle weakness and lethargy. Partidos et al. 2011 saw similar results with the live attenuated strain CHIKV181/25. However, rather than dying, the type 1 interferon deficient (IFN α/β −/−) mice were temporarily disabled and the partially type 1 interferon deficient mice did not have any problems.
Several studies have attempted to find the upstream components of the type 1 interferon pathway involved in the host's response to chikungunya infection. So far, no one knows the chikungunya specific pathogen associated molecular pattern. Nonetheless, IPS-1—also known as Cardif, MAVS, and VISA—has been found to be an important factor. In 2011, White et al. found that interfering with IPS-1 decreased the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of IFN-β. Other studies have found that IRF3 and IRF7 are important in an age-dependent manner. Adult mice that lack both of these regulatory factors die upon infection with chikungunya. Neonates, on the other hand, succumb to the virus if they are deficient in one of these factors.
Chikungunya counters the Type I interferon response by producing NS2, a non-structural protein that degrades Rpb and turns off the host cell's ability to transcribe DNA. NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated.
Common laboratory tests for chikungunya include RT-PCR, virus isolation, and serological tests.
- Virus isolation provides the most definitive diagnosis, but takes one to two weeks for completion and must be carried out in biosafety level 3 laboratories. The technique involves exposing specific cell lines to samples from whole blood and identifying chikungunya virus-specific responses.
- RT-PCR using nested primer pairs is used to amplify several chikungunya-specific genes from whole blood. Results can be determined in one to two days.
- Serological diagnosis requires a larger amount of blood than the other methods, and uses an ELISA assay to measure chikungunya-specific IgM levels. Results require two to three days, and false positives can occur with infection via other related viruses, such as o'nyong'nyong virus and Semliki Forest virus.
The most effective means of prevention are protection against contact with the disease-carrying mosquitoes and mosquito control. These include using insect repellents with substances such as DEET (N,N-diethyl-meta-toluamide; also known as N,N'-diethyl-3-methylbenzamide or NNDB), icaridin (also known as picaridin and KBR3023), PMD (p-menthane-3,8-diol, a substance derived from the lemon eucalyptus tree), or IR3535. Wearing bite-proof long sleeves and trousers (pants) also offers protection.
In addition, garments can be treated with pyrethroids, a class of insecticides that often has repellent properties. Vaporized pyrethroids (for example in mosquito coils) are also insect repellents. Securing screens on windows and doors will help to keep mosquitoes out of the house. In the case of the day-active Aedes aegypti and Aedes albopictus, however, this will have only a limited effect, since many contacts between the mosquitoes and humans occur outside.
There are currently no approved vaccines available. A Phase II vaccine trial, used a live, attenuated virus, developing viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year. However, 8% of people reported transient joint pain and attenuation was found to be due to only two mutations in the E2 glycoprotein. Alternative vaccine strategies have been developed and shown efficacy in mouse models but have so far not reached clinical trials.
In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease but there is tentative evidence that it might help the chronic arthritis. Steroids do not appear useful either.
Chikungunya virus is an alphavirus closely related to the o'nyong'nyong virus, the Ross River virus in Australia, and the viruses that cause eastern equine encephalitis and western equine encephalitis.
Three genotypes of this virus have been described: West African, East/Central/South African and Asian genotypes.
Chikungunya is generally spread through bites from Aedes aegypti mosquitoes, but recent research by the Pasteur Institute in Paris has suggested chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by Asian tiger mosquito (Aedes albopictus).
Concurrent studies by arbovirologists at the University of Texas Medical Branch in Galveston, Texas, confirmed definitively that enhanced chikungunya virus infection of A. albopictus was caused by a point mutation in one of the viral envelope genes (E1). Enhanced transmission of chikungunya virus by A. albopictus could mean an increased risk for chikungunya outbreaks in other areas where the Asian tiger mosquito is present. A recent epidemic in Italy was likely perpetuated by A. albopictus.
On 28 May 2009 in Changwat Trang of Thailand where the virus is endemic, the provincial hospital decided to deliver by Caesarean section a male baby from his chikungunya-infected mother, Khwanruethai Sutmueang, 28, a Trang native, to prevent mother-fetus virus transmission. However, after delivering the baby, the physicians discovered the baby was already infected with the virus, and put him into intensive care because the infection had left the baby unable to breathe by himself or to drink milk. The physicians presumed the virus might be able to be transmitted from a mother to her fetus, but without laboratory confirmation.
In December 2013, chikungunya was confirmed on the Caribbean island of St. Martin with 66 confirmed cases and suspected cases of around 181. This is the first time in the Western Hemisphere that the disease has spread to humans from a population of infected mosquitoes. Among other islands, nearby Saint-Barthélemy and farther away Martinique have many suspected cases, while local transmission has been confirmed on Guadeloupe. By January, 2014, the Public Health Agency of Canada reported that cases were confirmed on all of those islands and the British Virgin Islands as well.
The word chikungunya is thought to derive from a description in the Makonde language, meaning "that which bends up", of the contorted posture of patients afflicted with the severe joint pain and arthritic symptoms associated with this disease. The disease was first described by Marion Robinson and W.H.R. Lumsden in 1955, following an outbreak in 1952 on the Makonde Plateau, along the border between Mozambique and Tanganyika (the mainland part of modern day Tanzania).
According to the initial 1955 report about the epidemiology of the disease, the term chikungunya is derived from the Makonde root verb kungunyala, meaning to dry up or become contorted. In concurrent research, Robinson glossed the Makonde term more specifically as "that which bends up". Subsequent authors apparently overlooked the references to the Makonde language and assumed the term derived from Swahili, the lingua franca of the region. The erroneous attribution of the term as a Swahili word has been repeated in numerous print sources. Many other erroneous spellings and forms of the term are in common use including "chicken guinea", "chicken gunaya", and "chickengunya".
Since its discovery in Tanganyika, Africa, in 1952, chikungunya virus outbreaks have occurred occasionally in Africa, South Asia, and Southeast Asia, but recent outbreaks have spread the disease over a wider range.
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