Chikungunya

Chikungunya (in the Makonde language "that which bends up") virus (CHIKV) is an insect-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 symptoms similar to dengue fever, with an acute febrile phase of the illness lasting only two to five days, followed by a prolonged arthralgic disease that affects the joints of the extremities. The pain associated with CHIKV infection of the joints persists for weeks or months, or in some cases years.

Signs and symptoms
The incubation period of chikungunya disease is from two to five days. Its symptoms include a fever up to 40 °C, 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, conjunctivitis, and slight photophobia. 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.

Diagnosis
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.

Causes
Chikungunya virus is indigenous to tropical Africa and Asia, where it is transmitted to humans by the bite of infected mosquitoes, usually of the genus Aedes. Chikungunya virus belongs to alphavirus genus of the Togaviridae family. It is an "Arbovirus" (Ar-arthropod, bo-borne).

CHIK fever epidemics are sustained by human-mosquito-human transmission. The main virus reservoirs are monkeys, but other species can also be affected, including humans.

Pathophysiology
Human epithelial and endothelial cells, primarily fibroblasts and monocyte-derived macrophages, are susceptible to infection. Lymphoid and monocytoid cells, primary lymphocytes and monocytes and monocyte-derived dendritic cells are not susceptible to infection. Viral entry occurs through pH-dependent endocytosis. Infection is cytopathic and associated with the induction of apoptosis in the infected cell.

Infection is highly sensitive to the antiviral activity of type I and II interferon.

Prevention
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 vector and the host occur outside.

Treatment
There are no specific treatments for chikungunya, and no vaccine is currently available. A Phase II vaccine trial, sponsored by the US Government and published in the American Journal of Tropical Medicine and Hygiene in 2000, used a live, attenuated virus, developing viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year.

A serological test for chikungunya is available from the University of Malaya in Kuala Lumpur, icul.

Chloroquine is gaining ground as a possible treatment for the symptoms associated with chikungunya, and as an anti-inflammatory agent to combat the arthritis associated with the virus. A University of Malaya study found that for arthritis-like symptoms not relieved by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), chloroquine phosphate (250 mg/day) has given promising results. Unpublished studies in cell culture and monkeys show no effect of chloroquine treatment on reduction of chikungunya disease. The fact sheet on chikungunya advises against using aspirin, ibuprofen, naproxen and other NSAIDs that are recommended for arthritic pain and fever.

Vaccine development
A virus-like particle-based vaccine has protected monkeys from chikungunya virus infection, and passive immunization from these monkeys protected immunodeficient mice against exposure to a dose of virus that would otherwise be lethal, demonstrating the humoral response was highly protective.

A DNA vaccine candidate is also being tested. The vaccine cassette was designed based on CHIKV capsid and envelope specific consensus sequences with several modifications, including codon optimization, RNA optimization, the addition of a Kozak sequence, and a substituted immunoglobulin E leader sequence. These constructs induced humoral and cellular immune responses in mice.

Passive immunity
Antibodies isolated from patients recovering from chikungunya fever have been shown to protect mice from infection.

Prognosis
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.

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.

Epidemiology
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.

In Africa, chikungunya is spread via a sylvatic cycle in which the virus largely resides in other primates in between human outbreaks.

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.

Evolution
This virus was first identified in Tanzania in the 1953 appears to have evolved from an alphavirus ~1713 AD (95% credible interval: 1573 - 1843) in Africa. The East/Central/South African (ECSA) and Asian strains diverged within the last 150 years (95% HPD: 1879 to 1927). The extant ECSA strains - which include the first isolate of this virus - evolved between 1924 and 1943. The Asian group split into two clades: an Indian lineage which has probably become extinct and a Southeast Asian lineage. The Southeast Asian lineage spread from Thailand to Indonesia; and then to the Philippines and more recently Malaysia. The recent Indian Ocean basin outbreak that began in 2004 appears to have originated from the ECSA group back in 2002 (95% credible interval: December 2001 to December 2003).

The estimated overall mutation rate is 4.33 × 10−4 nucleotide substitutions per site per year - a rate similar to those forun in other viruses with RNA genomes.

History
The word chikungunya is thought to derive from a description in the local Makonde dialect, 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.

The first recorded outbreak of this disease may have been in 1779. This is in agreement with the molecular genetics evidence that suggests it evolved around the year 1700.

Use as a biological weapon
Chikungunya was one of more than a dozen agents the United States researched as potential biological weapons before the nation suspended its biological weapons program.