Chikungunya (CHIKV) “That Which Bends Up”

By Jeremy Aguinaldo
August 27, 2014

458400_10101112204919271_1498007093_oJerry Aguinaldo is a fourth-term medical student and active member of the Public Health Students Association (PHSA). He received his MPH from the University of South Florida, focusing on global health. As a public health professional, Jerry is interested in infectious diseases on the global scale.

Case series:
Within a year, six women, ages 20 to 50, came into a teaching hospital in Dhaka City, Bangladesh and presented symptoms of severe incapacitating arthralgia or arthritis with morning stiffness. Their history included high grade fever with a duration of three to five days with or without maculopapular rash. All patients showed signs of multiple peripheral joints arthritis. They were treated with nonsteroidal anti-inflammatory drugs (NSAIDS). Two of them suffered residual joint pain for two to three months after recovering from the infection (Rashedul, et al., 2014).

Intro:
Chikungunya (CHIKV) is an arbovirus transmitted by mosquitoes, particularly the Aedes species, with A. aegypti and A. albopictus being the main vectors. The virus is a single stranded RNA alpha virus in the Togaviridae family. CHIKV was first isolated from sick individuals in Tanzania in 1952. The name “Chikungunya” is derived from Makonde, a language spoken in south Tanzania, which translates to “that which bends up,” referring to the posture from those infected patients afflicted with severe joint pain (Robinson, 1955).

The prognosis is generally good, yet some patients experience chronic arthritis. In 2008, it was listed as a US National Institute of Allergy and Infectious Diseases (NIAID)

The Caribbean region is currently facing an epidemic of CHIKV that started on St. Martin. This is the first time that CHIKV circulation has been active in the Caribbean region.

 

Epidemiology:
There were reports of sporadic and epidemic cases in West Africa in the 1960s. Major outbreaks usually appear every 7 to 20 years. CHIKV is endemic to Africa, India and Southeast Asia and is transmitted to humans currently by Aedes mosquitoes. There are three known genotypes that had been isolated based on the sequences of the Envelope protein (E1): Asian, East/Central African, and West African. The genome of the current strain circulating in the Caribbean was sequenced and found to have the Asian genotype, which suggest the probable origin for the current outbreak. Though not considered fatal disease, about 200 deaths had been associated with CHIKV on Reunion Island from 2005 to 2006 and there was a severe outbreak in Southern India from 2005 to 2007 (Thiboutot, et al., 2010).

In December 2013, it was confirmed that CHIKV was being locally transmitted by mosquitoes in the Americas for the first time in St. Martin with 66 confirmed cases and 181 suspected cases. Because the vector A. albopictus is already established in the Caribbean and this region is a travel hot spot for European as well as American travelers, the outbreak in St. Martin presents a threat of the emergence of this disease in European countries (Omarjee, et al., 2014).

On May 1, the Caribbean Public Health Agency (CARPHA) declared a Caribbean-wide epidemic of the virus. Since 2006, over 200 cases have been reported in the United States. However, those cases were from people who had traveled to other countries and contracted the disease. On July 17, 2014, the first case of CHIKV acquired in the United States was reported in Florida by a patient who had not recently traveled outside the country. This was the first time the virus was passed by mosquitoes to a person on the U.S. mainland (First Chikungunya case acquired in the United States reported in Florida, 2014).

 

Pathogenesis:
Symptoms appear four to seven days after getting bitten by a mosquito. Alpha virus typically kill infected tissue culture cells within 24 to 48 hours and cell death had been shown to occur through apoptosis. Alpha virus are also extremely efficient at shutting down the host cell synthesis. The virus attacks fibroblasts, which affects the muscles, joints, and skin connective tissue (Spector, Hodinka, & Young, 2000).

After disseminating through the bloodstream, it gains access into the brain, liver, and lymphoid tissues. The nociceptive nerve endings found within the joints and muscle connective tissues can cause pain. Case definitions for CHIKV include: Fever higher than 38.5 degrees C of sudden onset, articular pain in extremities, and absence of other aetological causes. 95% of infected adults are symptomatic after infection and most become disabled for weeks to months due to decreased dexterity, loss of mobility, and delayed reaction (Schwartz & Albert, 2010).

The chronic stage is characterized by polyarthralgia that can last from weeks to years. About 50% of newborns delivered while mothers were infected with CHIKV contracted the disease, leading to congenital illness and death. Due to similarities in clinical symptoms with dengue, limited awareness, and a lack of proper diagnostic tools, CHIKV is probably often underdiagnosed/misdiagnosed as dengue (Ramful, et al.).

 

Diagnosis:
According to the CDC, the virus should be handled under biosafety level (BSL) 3 conditions. Diagnosis of chikungunya is performed by testing plasma or serum to detect the specific virus via culture in the first three days of illness, or detecting CHIKV immunoglobulin (IgM) and neutralizing antibodies. Viral RNA can usually be identified during the first 8 days of illness. To rule out CHIKV, convalescent-phase samples should be obtained from patients whose acute-phase test negative (Chikungunya virus: Diagnostic Testing, n.d.).

 

Control:
Aedes aegypti bites primarily during the day and is most active for about two hours after sunrise and a few hours before sunset, but can also bite at night in areas that are well lit. Only females bite to obtain blood in order to lay eggs. The best method in preventing the risk of CHIKV infection mainly involves minimizing the risk of mosquito bites. Recommendations include checking the surroundings weekly for any water-filled containers. Empty containers must be stored, covered, turned over, or placed under a roof that does not allow them to fill with water from the rain. Bird baths should be cleaned and scrubbed and overflowed pet-watering dishes, potted plants, and flower pots should be dumped weekly. Hidden bodies of water such as wells, septic tanks, clogged drains, manholes, and other reservoirs that can contain water should be checked continuously. Any detection of unusual number of mosquitoes should contact the health authorities.

Those at risk where Aedes mosquitoes are most active should wear long sleeve shirts, long pants, socks and shoes. Mosquito repellants should be applied as directed on the product label. Mosquito netting over infant carriers, cribs and strollers should be used and windows and door screens should be installed or repaired to keep out mosquitoes (Chikungunya virus: Prevention, n.d.).

 

Treatment:
Common treatment are based on clinical manifestations for symptomatic relief with nonsalicylate analgesics and nonsteroidal anti-inflammatory drugs most commonly used. Methotrexate (MTX) was originally developed as a chemotherapeutic treatment for rheumatoid arthritis (RA) and useful for its anti-inflammatory effects at low doses (Parashar & Cherian).

Chloroquine was found to be effective in treating chronic CHIKV-induced arthralgia with the possible mechanism attributed most likely to its anti-inflammatory properties that are adapted for the treatment of some autoimmune illnesses (Brighton, 1984). Other experimental treatments include Ribavirin, 6-Azauridine, and Harringtonine (Leyssen, De Clercq, & Neyts).

Research has also demonstrated the use inhibitors based on RNA-Mediated interference (Dash, Tiwari, Santhosh, Parida, & Lakshmana Rao, 2008). RNA interference (RNAi) is a posttranscriptional process triggered by the introduction of double-stranded RNA (dsRNA) which leads to gene silencing in a sequence-specific manner.

Viperin (Virus inhibitory protein, endoplasmic reticulum-associated,interferon-inducible), also known as RSAD2 (radical SAM domain-containing 2), is a multifunctional protein in viral processes. Viperin demonstrated control in CHIKV replication by inducing monocytes, a major target cell of CHIKV in blood. Results showed some promise with CHIKV Ig showing prophylactic and therapeutic potential (Teng, Foo, & Simamarta, 2012).

A phase 1 dose-escalation trial was performed using a virus-like particle (VLP) chikungunya virus vaccine. The chikungunya VLP vaccine was shown to be immunogenic and safe in the study with 25 health adults. Antibody levels increase with each dose. The study showed much promise into vaccine development (Chang, et al., 2014).

 

References

Brighton, S. W. (1984). Chloroquine phosphate treatment of chronic Chikungunya arthritis. An open pilot study. South African Medical Journal, 66(6), 217-218.

Chang, L., Dowd, K. A., Mendoza, F. H., Saunders, J. G., Sitar, S., Plummer, S., & et. al. (2014). Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial. The Lancet, doi:10.1016/S0140-6736(14)61185-5.

Chikungunya virus: Diagnostic Testing. (n.d.). Retrieved from CDC: http://www.cdc.gov/chikungunya/hc/diagnostic.html

Chikungunya virus: Prevention. (n.d.). Retrieved from CDC: http://www.cdc.gov/chikungunya/prevention/index.html

Dash, P. K., Tiwari, M., Santhosh, S. R., Parida, M., & Lakshmana Rao, P. V. (2008). RNA intereference mediated inhibition of Chikungunya virus replication in mammalian cells. Biochemical and Biophysical Research Communications, 376(4), 718-722.

First Chikungunya case acquired in the United States reported in Florida. (2014, July 17). Retrieved from CDC: http://www.cdc.gov/media/releases/2014/p0717-chikungunya.html

Leyssen, P., De Clercq, E., & Neyts, J. (n.d.). The anti-yellow fever virus avtivity of ribavirin is independent of error-prone replication. Molecular Pharacology, 69(4), 1461-1467.

Omarjee, R., Prat, C. M., Flusin, O., Boucau, S., Tenebray, B., Merle, O., . . . Leparc-Goffart, I. (2014). Importance of case definition to monitor ongoing outbreak of chikungunya virus on a background of actively circulating dengue virus, St. Martin, December 2013 to January 2014. European Surveillance, 19(13).

Parashar, D., & Cherian, S. (n.d.). Antiviral Perspectives for Chikungunya Virus. BioMed Research International, 2014(Article ID 631642).

Ramful, D., Carbonnier, M., Pasquet, M., Bouhmani, B., Ghazouani, J., & et al. (n.d.). Mother-to-child transmission of Chikungunya virus infection. Pediatric Infectious Disease Journal, 26, 811-815.

Rashedul, H., Rahman, M., Moniruzzaman, Rahim, A., Barua, S., Biswas, R., . . . Chowdhury, J. (2014). Chikungunya- an emerging infection in Bangladesh: a case series. Journal of Medical Case Reports, 8(67). Retrieved from http://www.jmedicalcasereports.com/contents/8/1/67

Robinson, M. C. (1955, January). An epidemic of virus disease in Southern Province, Tanganyika territory, in 1952–1953. Transactions of the Royal Society of Tropical Medicine and Hygiene, 49(1), 28-32.

Schwartz, O., & Albert, M. (2010). Biology and pathogenesis of chikungunya virus. Nature Reviews: Microbiology, 8, 491-500.

Spector, S., Hodinka, R., & Young, S. (2000). Alphavirus. In Clinical Virology Manual: 3rd Editon (p. 362). American Society for Microbiology.

Teng, T. S., Foo, S. S., & Simamarta, D. (2012). Viperin restricts Chikungunya virus replication and pathology. The Journal of Clinical Investigation, 122(12), 4447-4460.

Thiboutot, M. M., Kannan, S., Kawalekar, O. U., Shedlock, D., Khan, A., Sarangan, G., . . . Muthumani, K. (2010). Chikungunya: A Potentially Emerging Epidemic? PLOS Neglected Tropical Diseases, 4(4).

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