Chikungunya virus (CHIKV) is an enzootic virus found in tropical and subtropical regions of Africa, south and south east Asia, and Indian Ocean Islands. The name chikungunya is used to describe the virus as well as the disease caused by it and is derived from Makonde or Swahili word Kun quanla in reference to the stooped posture developed as a result of arthritic symptoms of the disease. The disease is characterized by fever, headache, myalgia, rash and joint pain, usually self-limiting in nature but can persist in some for years.

VIRUS

The CHIKV is a single-stranded, positive sense RNA virus. The virus is around 70 nm in size, with an icosahedral-like nucleocapsid surrounded by an envelop embedded with multiple copies of major glycoproteins E1 and E2. The molecular mass of these two proteins is about 50 kDa, anchored in the membrane by conventional membrane spanning anchors. These two polypeptides E2-E1 form a stable heterodimer which forms the spikes on the virus surface. The virus can be inactivated by acid pH, lipid solvents, detergents, bleach, phenol, 70% alcohol and formaldehyde.

CHIKV belongs to family Togaviridae, genus Alphavirus, which is composed of various serocomplexes that are grouped together on the basis of antigenic properties.

CHIKV belongs to the Semliki Forest Virus (SFV) antigenic complex along with other mosquito-borne alphaviruses like Ross River Virus, Mayarovirus, O’Nyong Nyong, Grtah, Be baru and SFV. All alphaviruses are antigenically related and have worldwide distribution.

CHIKV has three lineages with distinct antigenic and genotypic characteristics: (i) West African, (ii) East and Central African and (iii) Asian.

TRANSMISSION CYCLE

The maintenance and transmission cycle of CHIKV occurs differently in Africa and Asia.

In Africa, the virus is maintained in an enzootic sylvatic cycle involving non-human primates and small mammals, and forest dwelling Aedes mosquitoes like Ae. furcifer, Ae. luteocephalus, Ae. taylori or Ae. africanus. Outbreaks usually occur due to heavy rainfall leading to spillover of the virus from enzootic forest cycle. During epidemics, man–mosquito–man cycle occurs without animal reservoir. Increase in mosquito population in rural areas can also lead to outbreaks in non-immune population.

In Asia, CHIKV is maintained by man mosquito–man cycle resulting in urban epidemics. Ae. aegypti and Ae. albopictus are the two main vectors which play a role in human transmission (Fig. 1).

Fig1. Sylvatic and epidemic chikungunya virus transmission cycle

Mother to fetus and blood transfusion have been reported as rare modes of transmission.

History of outbreaks: The first known outbreak of CHIKV was reported from Makonde plateau near Tanzania border, during 1952–53 when the virus was first isolated from blood of a patient. Since then, the virus has spread to the east, central and west Africa and Asia and Europe. Several outbreaks have been reported from various parts of Africa.

The first confirmed outbreak in Asia occurred in Philippines in 1954 with subsequent outbreaks in 1958 and 1968. During 1970, outbreaks occurred frequently in south and south east Asia. Thereafter, the activity of the virus became quiescent with only sporadic cases.

Global Re-emergence: CHIKV re-emerged both in Asia and Africa after remaining quiescent for several decades. Previous to 1999–2000, human infection of CHIKV in Africa was occurring at a very low level. The re-emergence started in the year 1999–2000 in Democratic Republic of Congo (DRC), and then it spreads to other parts of Africa. In 2005, Comoros island was affected severely where near two-thirds of population were infected. The virus then spreads to the neighbouring islands and Asian countries such as Indian Ocean islands, La Reunion, Malaysia, Indonesia, and India. Reunion experienced massive outbreak whereby April 2006, more than two lakhs cases (an estimated 2,44,000 cases) were infected with an attack rate of 35% and resulted in 203 deaths, involving almost one-third of its population. During the years 2006–2008, some of the SE Asian countries like Singapore and Maldives recorded the entry of virus for the first time. Imported cases were reported in Europe and USA. In 2007, a localized outbreak was reported in Italy affecting 197 cases. In US, since 2006, a median of 26 cases were reported each year, mostly among adult travellers returning from area with ongoing CHIKV epidemics.

Re-emergence in India: In India, CHIK virus was first isolated in 1963 from Kolkata and the activity was observed till 1971. Thereafter the virus got almost disappeared and was thought to lose its pathogenic potential. Re emergence of CHIK virus occurred after more than three decades of quiescence during the end of 2005 when outbreak occurred in several coastal states of the country like Andhra Pradesh, Karnataka, Gujarat and Odisha. The virus then spreads to several other states during 2006–2007 sparing the northern part. The outbreak continued for >3 years resulting in millions of cases. The vast number of immunologically naïve population probably contributed to the persistence of the virus. After this outbreak, the virus has become endemic in several eastern and western coastal states, such as Kerala, Karnataka, Maharashtra, Gujarat, Rajasthan, Madhya Pradesh, West Bengal, Odisha, Andhra Pradesh, Tamil Nadu and Delhi (Fig. 2). In India, Asian genotype was circulating before re-emergence, whereas central/east African genotype was isolated during the latest epidemics. Strains with and without A226V mutation were reported from different parts of the country. Thus both Ae. aegypti and Ae. albopictus were considered as the main vector during the last decade outbreak.

Fig2. Chikungunya active part of India

Possible factors for re-emergence: The explosive outbreak in Indian Ocean islands have been attributed to the East African strain with mutation in envelop glycoprotein E1 A226V (Ala-Val). This mutation has been shown to increase the CHIKV infectivity of Ae. albopictus with more efficient dissemination to mosquito salivary gland and increase in transmissibility.

Decrease in herd immunity has also been considered as an important factor for re emergence. The rapid transmission of virus during the early period of outbreak has been attributed to concurrent infection of CHIK virus with microfilaria which is endemic in coastal states.

CLINICAL FEATURES

The average incubation period is 2–4 days, which ranges from 1 to 12 days. Chikungunya is characterized by the clinical triad of sudden onset of fever, rash and joint pain followed by other constitutional symptoms for a period of 1–7 days. Fever is usually high grade (>40°C), associated with chill and rigor, nausea and vomiting. Fever may disappear and return in 1–2 days and known as “saddle back fever”.

Arthralgia is present in almost all patients with fever which commonly affects more than one joint with symmetrical involvement and swelling. Finger, wrist, elbows, toes, ankle and knee are commonly affected. The acute features of CHIKV infection usually resolves within 1–2 weeks, however, arthralgia may persist for months to years.

Cutaneous manifestations are normally present during acute infection and present as redness on trunk, face and limb, followed by maculopapular rash which gradually fades away or desquamate.

Neurological manifestations due to CHIKV infection have been reported both in children and adults, more commonly in patients with underlying illnesses like stroke, epilepsy and diabetes mellitus. Acute encephalitis, febrile seizure, acute flaccid paralysis, meningitis and Guillain-Barré syndrome are the common presentation. Optic neuritis, hearing loss and hypokalemic paralysis have also been reported.

Mother to child transmission of CHIKV was recorded for the first time during the last outbreak in reunion. Encephalopathy was the most common manifestation among the children born to CHIKV infected mother.

Prior to 2005, chikungunya was not considered as a fatal disease. However, the last decade CHIKV outbreak documented 1 in 1000 death. Heart failure, multiorgan failure, hepatitis and encephalitis have been attributed as the common causes of death.

PATHOGENESIS

Both viral and host immune responses have been attributed for CHIKV disease pathogenesis. Increased expression of cytokines both in animal model and in human studies has been shown to be associated with disease process.

Replication of CHIKV in muscle and joint tissue in high concentration, leading to recruitment of inflammatory cells like monocytes, macrophage and NK cells has been reported in non-human primate and mice models as well as in muscle tissue of CHIKV infected patients.

Increased plasma level of proinflammatory cytokines along with high viral load has been found during acute CHIKV infection. IL-6 in particular is described as the biomarker of disease severity, symptom persistence and has also been associated with genesis of joint pain.

Susceptibility of skeletal muscle progenitor cells has been hypothesized as the possible factor responsible for chronic and recurrence of myalgia.

DIAGNOSIS

The diagnosis of chikungunya virus infection is made on the basis of clinical, laboratory and epidemiological criteria. Three categories of cases, possible cases, probable cases and confirmed cases, are described.

• Possible cases: Defined on the basis of only clinical criteria like acute onset of fever and arthritis/arthralgia.

• Probable cases: Defined on the basis of both clinical and epidemiological criteria.– Epidemiological criteria are defined as residing or travelled to an area with active CHIKV infection.

 • Confirmed cases: Confirmation of CHIKV infection by any of the following laboratory tests: Virus isolation, detection of viral RNA, specific IgM antibody or demonstration of fourfold rise in IgG antibody titer.

The virus kinetics is grossly similar to other arboviruses like dengue virus. The laboratory tests are essentially in the line of diagnosis of dengue viral infection; in terms of virus isolation in mice, mosquito cell line and intra thoracic inoculation in mosquito; serological tests and molecular tests like IgM antibody detection and RT-PCR or LAMP assay respectively. However, presently antigen detection tests are not available for CHIKV infection (neither in ELISA nor immunochromatographic test format) and IgM antibody detection by MAC-ELISA is the most commonly employed test for diagnosis of acute infection (Table 1).

Table1. Important points in common chikungunya diagnostic test

TREATMENT

Acute infection is often treated with non steroidal anti-inflammatory drug (NSAID) along with bedrest and fluid therapy.

Chloroquine:

• Chloroquine has been tried in chronic arthritis cases for its anti-inflammatory activity.

 • Treatment with chloroquine has been shown to provide relief in chronic arthritis cases.

• However, several clinical trials have reported no beneficial role of chloroquine in acute CHIKV infection.

Steroid: The combination of low dose systemic steroids with NSAID has been reported to improve the pain and quality of life in patients with acute chikungunya arthritis as compared to NSAID alone.

Ribavirin:

 • Ribavirin, a broad-spectrum antiviral, acts by inhibiting viral polymerase, IMP dehydrogenase. Moderately beneficial effect of ribavirin has been shown to reduce the arthralgia and swelling in patients with chronic chikungunya arthralgia.

• The antiviral effect of ribavirin has been shown against CHIKV in cell culture.

• The combination of ribavirin and interferon-a has shown synergistic antiviral effect suggesting their possible beneficial role in treatment of CHIKV infection.

siRNA and shRNA molecules have shown reduction in virus titer in various cell lines but still needs extensive studies in in vivo models before clinical trials.

VACCINE

The potential of explosive resurgence and ongoing CHIKV activity, lack of effective antiviral agents emphasize the need of vaccine to prevent CHIKV infection.

The possibility of developing an effective vaccine for chikungunya virus is evident from:

• Lifelong protective immunity induced by CHIKV infection.

• Relatively less antigenic variation.

Several vaccine strategies have been employed for the development of CHIK virus vaccine. However, no vaccine has so far been licensed for use.

Vaccine strategies are:

 • Inactivated vaccine

• Live attenuated vaccine

• Virus-like particle

• Chimeric vaccine

• DNA vaccine.

Inactivated vaccine: Whole virus formalin inactivated vaccine prepared in various host system like embryonated egg, suckling mouse and cell culture was the first chikungunya vaccine to have developed during the period of 1960–1970. The inactivated vaccine prepared from mice brain and African green monkey kidney cell induced neutralizing antibody against CHIKV with no observed adverse effect in human volunteers. No further studies were carried out using inactivated vaccine for a long period. A recent study in 2009 using Vero cell derived formalin inactivated vaccine has shown good immunogenicity potential to neutralize the virus.

Live attenuated vaccine: A live attenuated CHIKV vaccine candidate (strain181/clone25) was developed by the US Army Reed Institute of Infectious Disease (USAMRIID) by serial passage of the parent strain 15561 in MRC 5 cells. The vaccine has shown to be safe and immunogenic but the phase 2 trials have reported transient arthralgia in some of the vaccines. A recent study has reported the possibilities of genetic instability because of attenuation only at two points.

Virus-like particle: Vaccine candidate using VRC-CHKVLP059-00-VP has been developed. The vaccine has been shown to be immunogenic in non-human primate. In a phase I clinical trial in healthy adults aged 18–50 years, the vaccine has been reported to be safe, immunogenic and well tolerated. The persistence of neutralizing antibodies for near five months in all participants also appears to be promising towards providing long-term protection against the virus.

Chimeric vaccine: Several chimeric vaccines have been developed containing non structural protein of Venezuela equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), Sin Nombre virus (SNV), vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). Vaccines with VEEV, EEEV, SINV had the capability of infecting mosquito and thereby the possibility of transmission was the cause of concern.

To overcome this problem, chimeric vaccine was constructed containing internal ribosome entry sequence (IRES) of EMCV between CHIKV non-structural and structural genes. This vaccine was non-infectious for mosquito as it is unable to translate the IRES protein. However, the vaccine was found to be poorly immunogenic.

Vaccines containing EMCV IRES into the subgenomic promoter of CHIKV and vsvDG-CHIKV chimeric vaccine have been reported to be highly immunogenic along with reduced transmission capability in mosquitoes.

DNA vaccine: DNA vaccines using the capsid expressing DNA construct and envelop proteins have been developed. The latter vaccine has reported to produce neutralizing antibodies.

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