Chikungunya

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Chikungunya virus (CHIKV) is an arthropod-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes.^[1]

CHIKV is transmitted similarly to dengue fever and causes an illness with an acute febrile phase lasting two to five days, followed by a longer period of joint pains in the extremities; this pain may persist for years in some cases.^[2][3] The best means of prevention is overall mosquito control and in addition, the avoidance of bites by any infected mosquitoes. There is no specific treatment currently available but medications can be used to reduce symptoms.

The name chikungunya is derived from the Makonde word meaning “that which bends up” in reference to the stooped posture developed as a result of the arthritic symptoms of the disease. The disease was first described by Marion Robinson^[4] and W.H.R. Lumsden^[5] in 1955, following an outbreak on the Makonde Plateau, along the border between Tanganyika and Mozambique, in 1952. Chikungunya is closely related to O’nyong’nyong virus^[6].

Chikungunya virus (CHIKV) belongs to the alphavirus genus of the Togaviridae family and is transmitted by mosquito bites. Both innate and adaptive immunity are involved in the pathogenesis of CHIKV infection.

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.^[7] In the United States it is classified as a Category C priority pathogen^[8] and work requires Biosafety Level 3 precautions.^[9]

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.^[10] In vivo, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells and myofibers.^[11][12]

Chikunguyna must be differentiated from other diseases that present with flu like symptoms such as fever, headache, fatigue, joint aches or arthralgias, myalgias. Diseases with similar symptoms include dengue, influenza, measles, rubella, malaria, and yellow fever.

Chikungunya was first described in Tanzania, Africa in 1952. Chikungunya outbreaks have occurred in countries in Africa, Asia, Europe, and the Indian and Pacific Oceans. In late 2013, the first local transmission of chikungunya virus in the Americas was identified in Caribbean countries and territories. Local transmission means that mosquitoes in the area have been infected with the virus and are spreading it to people.

People who travel to the Caribbean, Africa, Asia, islands in the Indian Ocean and Western Pacific are at risk as the virus is present in many of these areas. People at risk for more severe disease include newborns infected around the time of birth, older adults (≥65 years), and people with medical conditions such as high blood pressure, diabetes, or heart disease.

Complications are rare and include uveitis, retinitis, myocarditis, hepatitis, nephritis, bullous skin lesions, hemorrhage, meningoencephalitis, myelitis, Guillain-Barré syndrome, and cranial nerve palsies. Persons at risk for severe disease include neonates exposed intrapartum, older adults (e.g., > 65 years), and persons with underlying medical conditions (e.g., hypertension, diabetes, or cardiovascular disease). Most patients recover uneventfully, but variable proportions of patients may have persistent arthralgias (joint pains) for months to years.

Chikungunya which follows a bite of an infected mosquito Aedes aegypti or Aedes albopictus carrying chikungunya virus, can either present as an asymptomatic or as a symptomatic disease. The most common symptoms of the symptomatic disease include fever, arthralgia or polyarthritis, and maculopapular rash.

Chikungunya usually presents with clinical signs such as fever, skin rashes, and joint swelling with effusions that can be detected during a physical examination.

There are no pathognomonic laboratory findings for Chikungunya virus infection. Laboratory abnormalities include mild thrombocytopenia (>100,000/mm³), neutropenia, lymphopenia, and elevated liver function tests. Erythrocyte sedimentation rate and C-reactive protein are usually elevated.^[13]

There is no specific antiviral therapy for chikungunya virus. The treatment of the disease is based on decreasing the symptoms and maintain proper hydration. Paracetamol is the drug of choice and treatment should be instituted in all suspect cases without waiting for serological or viral confirmation. All suspected cases should be kept under mosquito nets during the febrile period.

In the absence of an effective vaccine to prevent chikungunya virus infection, the only available tool to prevent the infection is by reducing the human-vector contact.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

The name chikungunya is derived from the Makonde word meaning “that which bends up” in reference to the stooped posture developed as a result of the arthritic symptoms of the disease. The disease was first described by Marion Robinson^[1] and W.H.R. Lumsden^[2] in 1955, following an outbreak on the Makonde Plateau along the border between Tanganyika and Mozambique in 1952. Chikungunya is closely related to O’nyong’nyong virus^[3].

According to Lumsden’s initial report in 1955 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 that 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”.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2], Alonso Alvarado, M.D. [3], Vendhan Ramanujam M.B.B.S [4]

Chikungunya virus (CHIKV) belongs to the alphavirus genus of the Togaviridae family and is transmitted by mosquito bites. Both innate and adaptive immunity are involved in the pathogenesis of CHIKV infection.

Chikungunya virus is primarily transmitted to humans through the bites of infected mosquitoes, predominantly Aedes aegypti and Aedes albopictus. Humans are the primary host of Chikungunya virus during epidemic periods. Blood-borne transmission is possible; cases have been documented among laboratory personnel handling infected blood and a health care worker drawing blood from an infected patient. Rare in utero transmission has been documented mostly during the second trimester. Intrapartum transmission has also been documented when the mother was viremic around the time of delivery. Studies have not found Chikungunya virus in breast milk. The risk of a person transmitting the virus to a biting mosquito or through blood is highest when the patient is viremic during the first week of illness.

Following transmission through bites by infected mosquito (Aedes aegypti or Aedes albopictus), Chikungunya virus (CHIKV) replicates in the skin and fibroblasts, enters the bloodstream, and disseminates to the liver, muscle, joints, lymphoid tissues, and brain. After an incubation period of two to four days, affected individuals typically experience an abrupt onset of symptoms including high fever, rigors, headache, photophobia, incapacitating arthralgia, and rash characterized by petechiae and/or maculopapular lesions. Unlike other members of arthritogenic alphavirus, Chikungunya virus may also cause symptoms of meningoencephalitis and hemorrhagic disease. Cellular tropism in infected humans correlates with the results from tissue culture experiments which showed replication of CHIKV in various cell lines including epithelial cells, endothelial cells, fibroblasts, muscle satellite cells, and monocyte-derived macrophages.^[2][3]

In parallel with the development of acute symptoms, the upsurge of viral load triggers the activation of the innate immune response, hallmarked by the robust release of type I interferons and other proinflammatory cytokines and chemokines, which may be crucial to the control of CHIKV replication. Production of type I interferons (IFNs) is initiated by the detection of pathogen-associated molecular patterns such as surface glycoproteins, single-stranded or double-stranded RNA, and unmethylated CpG-containing DNA. Toll-like receptor 3 (TLR3), TLR7, TLR8, retinoic acid-inducible gene I-like receptors (RLRs), melanoma differentiation-associated protein 5 (MDA5), and other pattern recognition receptors (PRRs) have been suggested to engage the signalling cascade that leads to the activation of type I IFNs, which in turn triggers the transcription of interferon-stimulated genes that confer resistance to cells against CHIKV replication.^[4][5] Transient lymphopenia during acute infection may also be explained by the effects of type I interferons rather than direct cytotoxicity of CHIKV, since B lymphocytes and T lymphocytes are not susceptible to CHIKV infection.^[6][7]

In addition to the innate arm of the immune response, T cells and antibody-mediated responses may also be involved in the rapid viral clearance that occurs approximately a week after infection. Relapsing rheumatic symptoms including polyarthritis and tenosynovitis have been reported in infected patients and may be related to the induction of autoimmunity caused by molecular mimicry between viral and host antigens.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

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.^[1] In the United States it is classified as a Category C priority pathogen^[2] and work requires Biosafety Level 3 precautions.^[3] 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.^[4] In vivo, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells and myofibers.^[5][6]

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.^[7] In the United States it is classified as a Category C priority pathogen^[8] and work requires Biosafety Level 3 precautions.^[9]

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.^[10] In vivo, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells and myofibers.^[5][11][12]

Upon infection with chikungunya, the host’s fibroblasts produce type 1 (alpha and beta) interferon.^[13] Mice that lack the interferon alpha receptor die in 2–3 days after exposure to 10² chikungunya PFU, while wild type mice survive even when exposed to as much as 10⁶ PFU of the virus.^[13] At the same time, mice that are partially type 1 interferon deficient (IFN α/β +/−) are mildly affected and experience symptoms such as muscle weakness and lethargy.^[14] 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.^[15]

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.^[16] Nonetheless, IPS-1 (IFN-β promoter stimulator 1)—also known as Cardiff, MAVS (mitochondrial antiviral signaling protein), and VISA (virus-induced signaling adapter)—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.^[16] 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.^[17] Neonates, on the other hand, succumb to the virus if they are deficient in one of these factors.^[18]

Chikungunya counters the type 1 interferon response by producing NS2, a non-structural protein that degrades Rpb and turns off the host cell’s ability to transcribe DNA.^[19] NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated.^[20]

• 
  Transmission electron micrograph (TEM) depicts numerous Chikungunya virus particles. From Public Health Image Library (PHIL). ^[21]
• 
  At a magnification of 1000X, twice that of PHIL 10557, this scanning electron micrograph (SEM) revealed some of the minute exoskeletal details found at the proboscis tip of an unidentified mosquito found deceased in the suburbs of Decatur, Georgia From Public Health Image Library (PHIL). ^[21]
• 
  At a magnification of 1000X, twice that of PHIL 10557, this scanning electron micrograph (SEM) revealed some of the minute exoskeletal details found at the proboscis tip of an unidentified mosquito found deceased in the suburbs of Decatur, Georgia. The proboscis is the organ used by this, as well as other like insects, to feed upon the blood of a warm-blooded host, including human beings. From Public Health Image Library (PHIL). ^[21]
• 
  Magnified 1500X, this scanning electron micrograph (SEM) revealed some of the minute exoskeletal details found at the proboscis tip of an unidentified mosquito found deceased in the suburbs of Decatur, Georgia. The proboscis is the organ used by this, as well as other like insects, to feed upon the blood of a warm-blooded host, including human beings. From Public Health Image Library (PHIL). ^[21]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2], Alonso Alvarado, M.D. [3]

Chikunguyna must be differentiated from other diseases that present with flu like symptoms such as fever, headache, fatigue, joint aches or arthralgias, myalgias. Diseases with similar symptoms include dengue fever, influenza, measles, rubella, malaria, and yellow fever.

• The differential diagnosis of chikungunya virus infection varies based on the place of residence, the travel history, and the history of exposures.
• Dengue and chikungunya viruses are transmitted by the same mosquitoes (Aedes aegypti and Aedes albopictus) and have similar clinical features.
• The two viruses can circulate in the same area and can cause occasional co-infections in the same patient.
• Chikungunya virus infection is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia, while dengue virus infection is more likely to cause neutropenia, thrombocytopenia, hemorrhage, shock, and death.
• It is important to rule out dengue virus infection because proper clinical management of dengue can improve the outcome.
• In addition to dengue, other considerations include leptospirosis, malaria, rickettsia, group A streptococcus, rubella, measles, parvovirus, enteroviruses, adenovirus, other alphavirus infections (e.g., Mayaro, Ross River, Barmah Forest, O’nyong’nyong, and Sindbis viruses), post-infection arthritis, and rheumatologic conditions.

Shown below is a table summarizing the typical findings of the differential diagnoses of chikungunya.

• Chikungunya should be distinguished from dengue fever, which has the potential for much poorer clinical outcomes, including death. The two diseases can occur together in the same patient.
• Shock or severe hemorrhage is very rarely observed in Chikungunya.
• In Chikungunya the onset of the disease is more acute and the duration of fever is much shorter.
• A maculopapular rash is more frequent in Chikungunya, while petechia may occur in dengue fever.
• In Chikungunya the pain is much more pronounced and localized to the joints and tendons in comparison to dengue fever in which the pain is generalized.

• CDC Chikungunya virus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2], Alonso Alvarado, M.D. [3]

Chikungunya was first described in Tanzania, Africa in 1952. Chikungunya outbreaks have occurred in countries in Africa, Asia, Europe, and the Indian and Pacific Oceans. In late 2013, the first local transmission of chikungunya virus in America was identified in the countries and territories. Local transmission means that the mosquitoes in the area have been infected with the virus and are spreading it to people.

In December 2013, the World Health Organization (WHO) reported local transmission of chikungunya in Saint Martin. Local transmission means that mosquitoes in the area have been infected with chikungunya and are spreading it to people. This was the first time that local transmission of chikungunya has been reported in the Americas.

In 2014, 28 cases of chikungunya have been reported by the CDC ^[1] up to June 2. Florida is the state with the most reported cases (16 patients). Virgina had 3 reported cases while Connecticut had 2 reported cases, and only one other case was reported in other states (Arkansas, California, Maryland, Nevada, New York, Puerto Rico and US Virgin Islands).

Local transmission of chikungunya is now being reported in other countries in the Caribbean. As of June 4, 2014, the following Caribbean countries have reported cases of chikungunya: Anguilla, Antigua, British Virgin Islands, Dominica, Dominican Republic, French Guiana, Guadeloupe, Guyana, Haiti, Martinique, Puerto Rico, Saint Barthelemy, Saint Kitts, Saint Lucia, Saint Martin (French), Saint Vincent and the Grenadines, Sint Maarten (Dutch).

Chikungunya is generally not fatal. However, in 2005-2006, 200 deaths were associated with chikungunya on Réunion island and a widespread outbreak in India, primarily in Tamil Nadu, Karnataka, Kerala, and Andhra Pradesh.

After flood and heavy rains in Rajasthan, India in August 2006, thousands of cases were detected in Rajsamand, Bhilwara, Udaipur, and Chittorgarh districts and also in adjoining regions of Gujarat and Madhya Pradesh, and in Sri Lanka. In the southern Indian state of Kerala, 125 deaths were attributed to Chikungunya with the majority of the casualties reported in the district of Alapuzha, primarily in Cherthala.

In December 2006, an outbreak of 3,500 confirmed cases occurred in Maldives, and over 60,000 cases in Sri Lanka, with over 80 deaths. In October 2006 more than a dozen cases of Chikungunya were reported in Pakistan.

An outbreak of the disease during June 2007 in Pathanamthitta, Kottayam and Alappuzha districts of South Kerala, India claimed more than 50 lives. It is confirmed officially that there are 7000 confirmed Chikungunya patients in these areas. Unofficial reports suggest that more than one hundred thousand are suffering from symptoms of chikungunya. The European Network for Diagnostics of “Imported” Viral Diseases [4] claims that new phylogenetic variants of the virus which are fatal have been identified on Réunion. [5].

In August/September 2007 some 160 people were infected in Italy’s northern Ravenna region, resulting in one fatality.

Countries and territories where chikungunya cases have been reported Africa Asia Americas Europe Oceania / Pacific Islands Benin Burundi Cameroon Central African Republic Comoros Democratic Republic of the Congo Equatorial Guinea Gabon Guinea Kenya Madagascar Malawi Mauritius Mayotte Nigeria Republic of Congo Reunion Senegal Seychelles Sierra Leone South Africa Sudan Tanzania Uganda Zimbabwe Bangladesh Bhutan Cambodia China India Indonesia Laos Malaysia Maldives Myanmar (Burma) Pakistan Philippines Singapore Sri Lanka Taiwan Thailand Timor Vietnam Yemen Anguilla Antigua and Barbuda British Virgin Islands Dominica Dominican Republic French Guiana Guadeloupe Guyana Haiti Martinique Puerto Rico Saint Barthelemy Saint Kitts and Nevis Saint Martin Sint Maarten Saint Lucia Saint Vincent and the Grenadines Italy France Federal States of Micronesia New Caledonia Papua New Guinea

• CDC Chikungunya virus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

People who travel to the Caribbean, Africa, Asia, islands in the Indian Ocean and Western Pacific are at risk as the virus is present in many of these areas. People at risk for more severe disease include newborns infected around the time of birth, older adults (≥65 years), and people with medical conditions such as high blood pressure, diabetes, or heart disease.

Travelers who visit the following Caribbean countries are at risk of getting Chikungunya. ^[1]

• Anguilla
• Antigua
• British Virgin Islands
• Dominica
• Dominican Republic
• French Guiana
• Guadeloupe
• Guyana
• Haiti
• Martinique
• Puerto Rico
• Saint Barthelemy
• Saint Kitts
• Saint Lucia
• Saint Martin (French)
• Saint Vincent and the Grenadines
• Sint Maarten (Dutch)

• In addition, travelers to Africa, Asia, and islands in the Indian Ocean and Western Pacific are also at risk, as the virus is present in many of these areas.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2], Alonso Alvarado, M.D. [3]

Complications are rare and include uveitis, retinitis, myocarditis, hepatitis, nephritis, bullous skin lesions, hemorrhage, meningoencephalitis, myelitis, Guillain-Barré syndrome, and cranial nerve palsies. Persons at risk for severe disease include neonates exposed intrapartum, older adults (e.g., > 65 years), and persons with underlying medical conditions (e.g., hypertension, diabetes, or cardiovascular disease). Most patients recover uneventfully, but variable proportions of patients may have persistent arthralgias (joint pains) for months to years.

In a 14-month prospective observational study among travelers from areas with outbreaks, nearly all confirmed cases had fever, rash, and arthritis within 10 days of the disease onset, and the majority had rheumatism persisting longer than 2 weeks, characterized by finger and toe polyarthritis with morning stiffness, subacute tenosynovitis of wrists, hands, and ankles, or exacerbation of mechanic pain in previously injured joints and bones.^[1]

• Complications are rare and include uveitis, retinitis, myocarditis, hepatitis, nephritis, bullous skin lesions, hemorrhage, meningoencephalitis, myelitis, Guillain-Barré syndrome, and cranial nerve palsies.

• Some patients may experience relapse of rheumatic symptoms (eg, polyarthralgia, polyarthritis, or tenosynovitis) in the months following acute illness. It has been suggested that musculoskeletal complications are immune-mediated, and the presence of autoantibodies has been reported in infected patients with rheumatic symptoms.^[2]

• Neurologic complications including encephalitis, febrile seizures, and encephalopathies are common causes of hospitalization for pediatric patients with Chikungunya virus infection.^[3]

Persons at risk for severe disease include neonates exposed intrapartum, older adults (e.g., > 65 years), and persons with underlying medical conditions (e.g., hypertension, diabetes, or cardiovascular disease).

• Most patients recover uneventfully.
• Mortality is rare and risk factors for death include older age.

• CDC Chikungunya virus