Chikungunya Virus

Virology 

Chikungunya virus is an enveloped, positive strand, RNA virus (52,54,80). The species CHIK belongs to Togaviridae family and Alpha virus genus which consists of 28 viruses, of around 70 nm in diameter (62,104), six of which can cause human joint disorders—namely chikungunya virus, o’nyong-nyong virus (central Africa), Ross River and Barmah Forest viruses (Australia and the Pacific), Sindbis virus (cosmopolitan), and Mayaro virus (South America, French Guyana). These alphaviruses share certain antigenic determinants. To date, ten complete chikungunya virus nucleotide sequences have been determined (100,014): two human isolates recovered during the 1952–1953 outbreak in Tanzania (59), one strain (#37997) originally isolated from Aedes furcifer during the Senegal outbreak in 1983 (142), six during the recent outbreak in Réunion, and one (formally designated LR2006-OPY1) from a traveler returning from an Indian Ocean island (43,62,96).

Schuffenecker and colleagues have reported the near complete nucleotide sequences of chikungunya virus strains isolated from six patients in Réunion and the Seychelles, and partial (E1) sequences of isolates from 127 patients in Réunion, The Seychelles, Mayotte, Madagascar, and Mauritius (5,133). The phylogenetic analyses based on partial E1 sequences from African and Asian isolates revealed the existence of three distinct CHIKV phylogroups: one containing all isolates from West Africa, one containing isolates from Asia, and one corresponding to Eastern, Central, and Southern African isolates (24,67,107). They have world wide distribution and all alpha viruses are antigenetically related. The alpha viruses are characterized by inactivation by Diethyl ether or Sodium deoxycholate, sensitive to desiccation and to temperatures above 58°C and can be inactivated by acid pH, heat, lipid solvent, detergents, bleach, phenol, 70% alcohol, and formaldehyde. The most possess hemagglutinating activities (1,52,80,104,155).

Epidemiology 

The Chikungunya (CHIK) fever is caused by CHKV and was first reported in 1952 from Makonde plateaus, along the borders between Tanzania and Mozambique (74,116). However, CHIKV was first isolated by Ross in 1953 during an epidemic in Newala district of Tanzania (118). Chikungunya is a Makonde word meaning ‘The one which bends up’ referring to the posture of the affected patients acquired due to excruciating pain in the joints (2,117). The virus alternatively affects vertebrates and arthropods1. The arthropods remain infecting all its life. It has been reported from Congo (100), Uganda (66), South Africa (151), Senegal (27), Central African republic (13), Cameroon, Portugal and Guinea. Philippines (49), Malaysia (61,63), Mayotte and Reunion Island (29) are commonly affected in Asia. Before this outbreak, the spread of Chikungunya had never been reported from outside the tropical region although the vector invades the planet (4,62,65,73,141). Phylogenetic studies have shown that a common lineage diverged into a West African branch and an East African-Asian branch; this second lineage subsequently produced two distinct genotypes. The virus causing the Indian Ocean outbreak seems to belong to the East-African lineage. Chikungunya is believed to have originated in Africa (5,54) probably a thousand years ago and maintained in ‘sylvatic cycle’ involving wild primates and forest dwelling mosquitoes such as aedes furcifer, ae luteocephalus, or ae. taylori. It was subsequently introduced in Asia where, it is transmitted from human to human mainly by Ae. aegypti and, to a lesser extent, by Ae. albopictus through an urban transmission cycle (38,47)

Since 1952 Tanzania outbreak, CHIKV has caused outbreaks in East Africa (Tanzania and Uganda), in Austral Africa (Zimbabwe and South Africa), in West Africa (Senegal), and in Central Africa (Central African Republic and Democratic Republic of the Congo). The most recent epidemic re-emergence in Africa was documented in 1999–2000 in Kinshasa (20). Since the first documented Asian outbreak in 1958 in Bangkok, Thailand, outbreaks have been documented in Cambodia, Vietnam, Laos, Myanmar, Malaysia, Philippines, and Indonesia (17,21). The outbreaks in Africa and Asia, were unpredictable, with an intervals of 7 to 20 years between two consecutive epidemics (54).

The current outbreak started in the beginning of 2005 (29,34,35), CHIKV has emerged in the islands of the South-western Indian Ocean. The outbreak was first reported in Comoros in the beginning of the 2005 (14, 97), Later in the same year, the virus had circulated to the other islands and countries i.e. Mayotte, Seychelles, Réunion (21), and Mauritius (42), Madagaskar and India (40,57). Since the end of 2005, the rainy season renewed the circulation and led to the intensification of epidemic (6,8,16,19,22).

The spread of chikungunya fever outbreaks from Indian Ocean, Africa to all other continents reflects a role of many factors including the rapid international transport, previous introduction of exotic mosquito species, inadequate mosquito control, and climatic conditions. Table 1 shows the role of various factors in the spread (20).

Transmission

The virus is transmitted by culicine mosquitoes (2,3). Ae. aegypti, Ae. albopictus and polynesiensis are commonly involved in the transmission although Culex has also been reported for the transmission in some cases (3). A recent Indian study reported transmission of CHIK virus by Anopheles Stephansi also. The common reservoirs for CHIKV are monkeys and other vertebrates. In current outbreak, suspected reservoirs are Macaque monkeys, Lemurs and bald mouse. In the epidemic period, men also act as reservoir.

Amongst the potential vectors, species of sub-genus Ae. diomorphus, Ae. Dalzieli, Ae Vittatus and Ae. Argentopunctatus, are thought to be involved in the transmission (88). The role of cattles and rodents has also been reported in the transmission of the virus (38,41).

CHIKV usually shows a periodicity with occurrence of disease in the community with the silence interval of 3-4 years (53). The periodicity is probably due to their cycle in monkeys. The monkeys are common reservoir for the virus and following one cycle of circulation, all monkeys might become exposed and therefore immunologically protected. Following a gap of 3-4 years, when another group of susceptible and non immune population becomes available for infection. Mother to child transmission has also been reported in recent studies.

Vector

The disease is spread by culicine mosquitoes in general and aedes in particular (52). However, anopheles may also be involved in rare cases (154). In the current outbreak, both Aedes and Anopheles have been found to be involved. It’s a diurnal vector with peak of the activities at the end of the day. The mosquito bites during the day.

The vector mosquito aedes (38), has a body divided into three parts: a pair of antennae, three pairs of legs which are white striated. One pair of wings and a pair of beams, long antennae, a long horn, a body covered with scales decorated with white or silver plated spots are other characteristics of the mosquito. Aedes measures 8 to 10 mm in length. The different species of the Aedes can not be identified by naked eye. A. albopictus is more active outdoors while A. aegypti feeds and rests indoor.

linical Manifestations 

The infection is of acute onset and variable clinical features are common findings (10,52,80). The symptoms develop after an incubation period of 4 to 7 days (range: 1-12 days). In most of the cases the disease is self limiting and the symptoms disappears within 5 to 7 days even without treatment. Rarely the symptoms may persist for a longer period and occasionally complications may develop. All age groups and both sexes are equally affected. In susceptible populations, Chikungunya fever can have attack rates as high as 40 to 85 per cent. Prodromal symptoms are rarely reported (51,62,144).

A clinical triad of ‘Fever, Rashes and Arthralgia’ is suggestive of Chikungunya fever. The clinical features vary from high fever (more than 40 degree Celsius, rapid in rise and sometimes associated with rigor), severe headache, chills and rigors, nausea and vomiting (93,104). The fever is of short duration and usually resolves in three to four days. In some patients, a biphasic pattern of fever has been described with a febrile episode of four to six days, followed by a fever free period of a few days followed by recurrence of fever (usually 101-102oF) that may last a few days, giving it the name of ‘Saddle back fever (52,80). During the initial few days, headache, throat discomfort, abdominal pain and constipation are also frequent. There is conjunctival suffusion, persistent conjunctivitis, and cervical or sometimes generalized lymphadenopathy, with maculopapular or petechial rash present usually on the extremities, neck trunk and ear lobes (58,123).

The occurrence of poly-arthralgia, along with myalgia (26), is a typical feature of the illness (130,146). The joint pain is frightening in severity, completely immobilizing many patients and preventing sleep in first few days of the illness. The joint becomes very painful to touch. Movement at the joints causes excruciating pain to the person forcing to make bend up position giving it the name ‘Chikungunya’. The pain interfere with sleeping in the night Different joints of the same patients may be involved at different times. Swollen tender joints and crippling arthritis is usually evident (62). The viral polyarthropathy frequently involves the small joints of the hand, wrist and ankles and may also involve the larger joints such as knee and shoulder. The arthralgia can be intense, affecting mainly the extremities (ankles, wrists, phalanges) but also the large joints. The joint pains resolve in one to three weeks. Arthralgia/ arthritis appear to affect 73–80% of patients with serologically confirmed chikungunya virus or o’nyong nyong virus infection, and can persist in about 33% of patients for 4 months, 15% for 20 months, and 10% for 3–5 years. Radiological findings are normal, and biological markers of inflammation are normal or moderately elevated (51,130). The rheumatological manifestations are some what less frequent in children. Pediatric subjects may also experience febrile seizures, vomiting, abdominal pain and constipation (62,104).

The skin involvement is present in about 40–50% of cases, and consists of a pruriginous maculopapular rash predominating on the thorax, facial oedema, or in children, a bullous rash with pronounced sloughing, and localized petechiae and gingivorrhagia (mainly in children). Haemorrhagic fever has been reported in chikungunya virus-infected patients in Thailand. Malaysian epidemic. The Maculo-pauplar rashes and gingival hemorrhages are uncommon signs although more frequent in children. Rashes occur mainly on trunks or extensor surfaces of the limbs and are itching in nature. Rashes are usually accompanied by secondary rise in the temperature (62).

The symptoms generally resolve within 7–10 days, except for joint stiffness and pain. Arthralgia and arthritis is erratic, relapsing, and incapacitating arthralgia is the hallmark of Chikungunya, although it rarely affects children. It may persist for several months (66).

The forms affecting adults in Réunion was not generally considered to be a life threatening disease. However, more than 250 deaths have been directly or indirectly attributed to the disease in the ongoing Réunion outbreak. A majority of these patients were elderly. The possible link between chikungunya virus infection and multi-organ failure is under investigation. The reasons why these severe clinical manifestations of chikungunya had not previously been described are unclear. The possible clinical repercussions of mutations found in chikungunya virus strains isolated in Réunion remain to be determined (61,104).

The reports of severe chikungunya virus are found in the literature. The neurological complications such as meningoencephalitis were reported in a few patients during the first Indian outbreak in 1973, and during the ongoing Indian outbreak. The neuro virulence and neuroinvasiveness of several other alphaviruses is well established, and chikungunya virus has been isolated from two children with clinical signs of encephalitis and meningitis (85,87).

The other body systems are infrequently affected by CHIKV although; mild tachycardia is noted at the time of rise in fever (150). The rare complications include Myelomeningoencephalitis, Guillian barre syndrome, fulminant hepatitis, myocarditis, pericarditis (18). The asymptomatic infections are also frequent and the resulting immunity is durable and second attack is not reported. The infection is severe in infants, elderly and immunocompromised people (62). The nephritic presentation (143), Burkit Lymphoma (143) and Hypokalemic Paralysis (111) due to this has also been recorded. Recently a severe form of the disease with CNS involvement and fulminant hepatitis have also been reported on the Indian Ocean island of Réunion (13).

The data on ocular manifestations of CHIKV infection reports that Nongranulomatous anterior uveitis, panuveitis, granulomatous anterior uveitis, optic neuritis, lagophthalmos and VIth nerve palsy, retrobulbar neuritis, retinitis with vitreitis, bilateral neuroretinitis, keratitis and CRAO are common complaints when ocular symptoms develop (51,76,81,82).

Chikungunya in Pregnancy and in Newborn Babies 

The mother to child transmission of CHIK virus has also been recorded in the current outbreak (110,128,148). Out of 151 women with chikungunya virus infection was (confirmed by RT-PCR or serology), 35 of these women were ill at delivery, 30 delivered an infected newborn baby. A total of 35 neonatal chikungunya virus infection had been notified in Réunion, of which 27 were severe. Neonatal chikungunya virus infection had never been reported before this outbreak. The possible risks of embryopathy, fetopathy, and late sequelae are unknown; Recently, the researchers have reported cases of maternofetal chikungunya virus transmission At the beginning of the Réunion epidemic the attack rate was proportional to age. However, in January, 2006, the attack rate in children approached that observed in adults. During week 11 of 2006, more than 18% of all children with suspected chikungunya virus infection had been hospitalized, compared with 40% of adults, pointing towards high severity of the disease amongst adults (93,95,110).

Laboratory Diagnosis 

The probable diagnosis of Chikungunya fever can be made on the basis of presence of the virus in community, and a clinical triad of fever, rashes and arthralgia is suggestive of the illness. The cases definition is given in Table 2 (91).

The virus produces neutralizing and haemagglutination inhibiting (HI) antibodies and that helps in making serological diagnosis. Haemagglutination inhibiting test is a simplest diagnostic test, but non specific to CHIK virus. Confirmation of the illness is done by detection of the antigen or antibody to the agent in the blood sample of patient. Reverse Transcriptase Polymerase Chain Reaction (RT PCR) is confirmatory for the identification of CHIKV (15,103). IgM capture ELISA is a sensitive serologic assay, and is necessary to distinguish the CHIK from Dengue (32,33).

The gold standard for the diagnosis of Chikungunya fever is viral culture, which is seldom used due to lack of adequate facilities. More frequently, serodiagnostic methods for the detection of IgM and IgG antibodies against Chikungunya virus in acute and convalescent sera are used. These include indirect immunofluorescent method (IIF), enzyme linked immunosorbent assay (ELISA), haemagglutination inhibition or neutralization techniques (23,39).

In a patient with acute febrile polyarthritis, with or without a rashes, the diagnosis depends upon whether the area is endemic or non endemic. In the endemic area, clinical diagnosis is sufficient (Table 1) and the laboratory test abnormalities are usually minor and non-specific: moderate lymphopenia, normal or slightly decreased platelet count (>100,000), marginal increase in liver enzymes, normal to slightly elevated C-reactive protein level (usually <50 mg/ml), and normal renal function tests. RT-PCR tests to ensure an early diagnosis may be helpful in patients with serious manifestations. While, when there is no obvious epidemic, or an imported case is suspected in a patient returning from an epidemic region, serological, tests confirm the diagnosis. IgM antibodies appear 4-7 days after symptom onset and IgG antibodies after about 15 days (62).

Biological Diagnosis of Chikungunya Virus Infection

Virus isolation is based on inoculation of mosquito cell cultures, mosquitoes, mammalian cell cultures, or mice. Two main diagnostic methods are available, namely RT-PCR and serology (IgM or IgG) (62).

RT-PCR is useful during the initial viraemic phase (day 0 to day 7), but classic serological methods are simpler (haemagglutination inhibition, complement binding, immunofluorescence, and ELISA) (117). IgM is detectable after an average of 2 days by ELISA immunofluorescent assay (1–12 days) and persists for several weeks to 3 months. IgG is detected in convalescent samples and persists for years. The sensitivity and specificity of these tests are poorly established, and so is the possibility of false-positive reactions resulting from cross-reactivity with dengue or other arboviruses such as O’nyong-nyong virus (68,103).

Serologically, chikungunya virus is most closely related to o’nyong-nyong virus and is a member of the Semliki Forest antigenic complex. Individual serological testing is not particularly useful, except when faced with atypical or severe forms, or in travelers returning from an epidemic zone (98). PCR, antigen detection, and viral culture are also used to detect chikungunya virus in mosquitoes during epidemiological studies, and also to assess vector competence (the capacity to be infected by and transmit the virus). The virus isolation procedures need to be done under bio safety level 3 (BSL-3) precautions although, such precautions may not be necessary in the countries where CHIKV is endemic.

There are recent molecular biological methods for the diagnosis of chikungunya infections from the serum. Researchers from India has recently standardized and validated a real-time polymerase chain reaction assay for this virus and found this to be a valuable tool for rapid, real-time detection as well as quantification of Chikungunya virus in acute-phase serum samples without requiring any sophisticated equipment; this method has potential usefulness for clinical diagnosis and surveillance of Chikungunya virus in developing countries (95,121).

Differential Diagnosis

Chikungunya and dengue are among the most difficult diseases to distinguish, especially because simultaneous co-infection can occur (86,91). In the only published study comparing the symptoms of chikungunya and dengue, chikungunya symptom onset was more abrupt, fever was shorter lived, and rash, conjunctival injection, and arthralgia were more frequent than in dengue. Similarly, there is no retro orbital pain, a characteristic of Dengue, in CHIKF. Severe joint pain, which may or may not be associated with swellings is characteristic of CHIK fever (62).

The other common viral illness similar to CHIK fever is infection by O’nyong-nyong virus. This infection can be differentiated on the basis of circulation of the O’nyong-nyong virus in the community at the time of clinical diagnosis and confirmation by the serological diagnosis. O’nyong-nyong virus is also different from CHIKV as it is transmitted by anopheline mosquitoes (62). Sometimes, similar clinical presentation is made by Sindbis virus infection (45). The confirmatory diagnosis of CHIKF from Dengue or O’nyong-nyong can be made by the laboratory investigations only.

The differential diagnosis includes infection with another arthritis-inducing virus (such as rubella, parvovirus B19, hepatitis B and C, HTLV1, and HIV) or with a rash-inducing virus (e.g., dengue, infectious mononucleosis, and cytomegalovirus). Chronic forms must be differentiated from non-viral joint diseases including Lyme disease and inflammatory joint disease (104). A history of travel to an endemic region is of considerable diagnostic value. The arthralgia with exanthema may be caused by a variety of viral and bacterial infections, or adverse drug reactions. A number of differential diagnoses must be considered in infants less than 3 months old, and lumbar puncture is often justified (after assessing the bleeding risk). Bullous rash seems frequent in children, and Chikungunya virus may be found by PCR in blister fluid.

Pathogenesis 

The virus is spread by the bite of aedes mosquito to the human beings, after inoculation by a mosquito bite, the virus binds to a receptor (possibly an integrin) at the surface of the target cell and enters the skeletal muscles, where it replicates before being released into the bloodstream. The viremic phase, which is often short-lived, coincides with the onset of the fever and other symptoms. No detailed studies are available on the pathogenesis of the CHIK fever. It is expected that once after inoculation, primary viral multiplication occurs in lymphoid and myeloid cells. The arthropod vectors acquire the virus by sucking blood during this period. The virus than spread to the targeted organs and immune system becomes start functioning at this stage leading to the activation of the both humoral and cellular immunity. This response of the body leads to the clinical features of the disease (52). The convincing evidence and studies are not available (83).

The outbreak was initiated by a strain related to East-African isolates, from which viral variants have evolved following a traceable microevolution history. Unique molecular features of the outbreak isolates were identified. Notably, in the region coding for the non-structural proteins, ten amino acid changes were found, four of which were located in alphavirus-conserved positions of nsP2 (which contains helicase, protease, and RNA triphosphatase activities) and of the polymerase nsP4. The sole isolate obtained from the cerebrospinal fluid showed unique changes in nsP1 (T301I), nsP2 (Y642N), and nsP3 (E460 deletion), not obtained from isolates from sera. The high evolutionary potential and suggest possible clues for understanding the atypical magnitude and virulence of this outbreak (83,99).

In arthritis, proinflammatory factors that may contribute to the development of synovitis include nitric oxide, which is released by infected macrophages, and interferon gamma, which is found in large amounts in joint fluid. Joint fluid recovered from affected joints exhibits inflammatory properties, with 1500-15,000 cells/mm3. Although viable virus is usually absent from the fluid, viral RNA may be detectable in synovial biopsies using PCR technology (97).

The virus strain in current outbreak has been studied for possible genome change along with change in behavior and morbidity in detail to understand the causes of emergence and rate of rapid spread A recently published study has reported some changes in the virus at E1-226V portion of the genome, which possibly have made it possible for the virus to release its cholesterol dependence (133). Now, this strain of CHIKV is probably able to survive without cholesterol in humans and mosquitoes, and could have survived and multiplied better in mosquito, explaining partially, to its rapid spread (3). The increased pathogenecity, higher complication rate and mortalities are newer characteristics associated with this current outbreak. It’s also a probability that the virus could have genetically changed over a period of time leading to increased pathogenecity and increased infection rate.

Similarly, another group of researchers on virus genome has noted that in current outbreak, a mutation at residue 226 of the membrane fusion glycoprotein E1 (E1-A226 V), which was absent from the strains isolated during the first months of the ongoing outbreak in Réunion, but was found in more than 90% of isolates after September, 2005. This change could be related to virus adaptation to the mosquito vector species and higher attack rate and morbidity than all previous outbreaks (60,68).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There is currently no antiviral drug of proven efficacy available for the management of CHIKV infection. However, since the beginning of the current outbreak, the research efforts have been intensified to find effective drug or receptors.

Eight compounds, Ribavirin, 6-azauridine, glycyrrhizin, iota-carrageenan, fucoidan, and dextran sulfate IFN-α 2a and IFN-α 2b were tested by the researchers for antiviral activity on CHIKV. Vero cells grown to confluence in 24-well plates were exposed to different concentrations of the antiviral compounds (four wells per compound concentration) in maintenance medium for 4 days at 37◦C, in parallel with the virus-infected cell cultures (13).

IFN-α2a and IFN-α2b, ribavirin, 6-azauridine, glycyrrhizin, and three sulfated polysaccharides (iotacarrageenan, fucoidan, and dextran sulfate had inhibited CHIKV replication at concentrations which were significantly lower than the cytotoxic concentrations in quiescent cell cultures.

Antiviral activity of interferons and some other drugs was estimated by the reduction of the cytopathic effect of each alphavirus on infected Vero cells and by virus titer reduction. With CHIKV, the selectivity indices of human recombinant interferon-α and iota-carrageenan were much higher than that of ribavirin, which has been previously investigated for its inhibitory effect on alphavirus infections

The selectivity indices were calculated as the ratio of the 50% cytotoxic concentration (CC50) for cell viability in monolayer cell cultures to the average EC50 (CC50/EC50), all compounds showed selectivity indices ≥3 against CHIKV. The two recombinant IFN-_ exhibited the highest selectivity in dices (>901), and ribavirin (204), considered in this study as a positive control, had a selectivity index of 24. The selectivity indices of 6-azauridine and iota-carrageenan (>133) were higher than that of ribavirin, while glycyrrhizin, dextran sulfate, and fucoidan showed selectivity indices of 3, 5, and >12.6, respectively (13).

Human recombinant IFN-α was more selective and effective than ribavirin in its inhibitory effect on CHIKV replication. Its selectivity index (CC50/EC50) was >800 in growing cells. Moreover, among all the compounds tested, IFN- α showed the highest potency against CHIKV. On the other hand, pegylated IFN- α proved to be effective for the treatment of virulent VEEV-infected BALB/c mice resulting in a greatly enhanced survival from either a subcutaneous or an aerosol infection (13).

The study of antiviral activity of the combination of IFN-α 2b and ribavirin on CHIKV showed this combination to be subsynergistic against the virus. Ribavirin proved to be an active at concentrations much lower than its cytotoxic concentration in exponentially growing cells in increasing the antiviral activity of IFN-α.

The researchers across the world are making the efforts to identify the possible genes or targets for the development of anti viral agents and vaccines. A study has reported that among the virus-encoded enzymes, nsP2 constitutes an attractive target for the development of antiviral drugs. It is a multifunctional protein of approximately 90 kDa with a helicase motif in the N-terminal portion of the protein while the papain-like protease activity resides in the C-terminal portion. The nsP2 proteinase is an essential enzyme whose proteolytic activity is critical for virus replication.

Vanlandingham et al (142) worked with three full-length infectious cDNA clones based on the alphavirus chikungunya (CHIKV) were developed and characterized in vitro and in vivo. The full-length clone retained the viral phenotypes of CHIKV in both cell culture and in mosquitoes and should be a valuable tool for the study of virus interactions in an epidemiologically significant natural vector, Aedes aegypti. Two additional infectious clones were constructed that express green fluorescent protein (EGFP) in the midgut, salivary glands, and nervous tissue of Aedes aegypti mosquitoes following oral infection. The dissemination rates of this new viral vector exceed those of previous systems, thus expanding the repertoire and potential for gene expression studies on this important vector species (142).

The success of retroviral proteases inhibition and the early promise being shown by inhibitors of the NS3 hepatitis C virus have demonstrated the feasibility and the interest of antiviral strategies based on protease inhibition. This study will probably pave the way for the future antiviral agent development. Recently, another group of researchers in France has produced and charecterized a panel of Monoclonal antibodies (MAbs) reactive to CHIKV E2 glycoprotein. These MAbs are expected to be useful for the rapid diagnosis of CHIKV and for other basic researches on CHIKV (11,48).

ANTIVIRAL THERAPY 

Because the disease is considered to be self limiting and benign in nature and the available literature before this outbreak did not report mortality due to this virus, there is no specific treatment available for CHIKV infection. The research on either drug or vaccine for CHIKV was never given a priority in the past. However, there are recorded cases of deaths by CHIKV in current outbreak and the research and other activities have increased significantly in last 3 years.

There is no specific antiviral therapy available for CHIKV and treatment is mostly symptomatic and supportive by analgesics and antipyretics; corticosteroids; hydroxychloroquine; bed rest and fluids and the management of the complications appropriately. Non-steroidal anti-inflammatory drugs have consistently been found effective in alleviating the symptoms. Acetaminophen is usually sufficient to control the fever and pain (62, 94, 104).

Analgesics and Antipyretics

This group forms the main line of management in Chikungunya virus infection. Any antipyretic, acetaminophen commonly, is used to control the fever. Caution is however required as liver failure has been reported in a very small number of patients with alcohol-abuse or malnutrition. Non steroidal anti-inflammatory drugs (NSAIDS) are used for the pain relief. However, salicylates are not recommended for this purpose due to the fear of effect on platelets and resulting bleeding (92,91,94,130).

Chloroquine

Hydroxychloroquine/chloroquine for the treatment of viral arthropathies has also been tried (12). A South African trial on the use of chloroquine ended without conclusive evidences. However, it is still being used as an empirical treatment. Hydroxychloroquine remains unproven (12), despite an open-label pilot study showing modest improvements in 5 of 10 patients, at the expense of substantial adverse effects (62,123,124).

Corticosteroids 

Glucocorticoid therapy has no role in the management of alphavirus arthritis at the acute phase (156,157). Although glucocorticoids have not been reported to worsen the viral infection, they do not seem more effective than non-steroidal anti-inflammatory drugs and their use is fraught with difficulty, most notably because of their adverse effect profile. However, glucocorticoid therapy deserves a place in the therapeutic weaponry for severe subacute or chronic manifestations (81,82,130).

The caution should be paid as indiscriminate use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDS), especially aspirin and antibiotics can contribute to thrombocytopenia, gastrointestinal bleeding, nausea, vomiting and gastritis. This may lead to dehydration, pre-renal acute renal failure, dyselectrolytemia, and sometimes hypoglycaemia. These can indirectly contribute to the mortality due to Chikungunya fever. Therefore, use of corticosteroids should be done with caution.

In summary, the published evidence does not support the use of corticosteroids, antibiotics or antiviral drugs in the management of Chikungunya fever and indiscriminate use of these agents can be hazardous.

Interferon and Ribavirin, etc

The newer drugs are in trial phase only. Co-treatment with interferon alpha and ribavirin is somewhat synergistic in inhibiting chikungunya virus replication in vitro; however, in vivo use has not been reported to date. Synergistic efficacy was reported between interferon-α and ribavirin on chikungunya virus in vitro.

Complication Management

General

Electrolyte imbalance, pre-renal acute renal failure, bleeding manifestations should be watched for carefully and managed accordingly. Rare cases may require hospitalization and appropriate management is done for the complications.

Ocular

There is no established treatment for ocular manifestations of chikungunya fever, because the underlying mechanism is likely to be immune mediated. The use steroids have been suggested by some authors (82).

ADJUNCTIVE THERAPY 

As described above, the appropriate management for the clinical signs and symptoms and complications may be carried out in the health care setting.

ENDPOINTS FOR MONITORING THERAPY 

The condition of the patient should be regularly monitored. The co-infection with other viral or bacterial illnesses may be appropriately evaluated. The antipyretics or analgesic doses may changed as per the patient response. If the condition does not improve in 24-48 hours, the drugs may be changed appropriately.

VACCINES 

There is no vaccine commercially available, effective against Chikungunya virus. Chikungunya virus infection seems to elicit long-lasting protective immunity. Experiments in animal models have shown cross-protection among chikungunya virus and other alphaviruses.

Some candidate vaccines have been tested in human beings. In the latest trials, conducted by the US Army Medical Research Institute, very satisfactory seroconversion rates (98% on day 28) and neutralizing antibody titres were obtained, persisting in 85% of cases at 1 year. The vaccinees were clinically evaluated intensively for one month, and had repeated blood draws for serological assays (50% plaque-reduction neutralization test) for one year. This was a phase II, randomized, double-blind, placebo-controlled, safety and immunogenicity study of a serially passaged, plaque-purified live chikungunya (CHIK) vaccine. This live vaccine was safe, produced well-tolerated side effects, and was highly immunogenic (131). However, the trials were discontinued due to priority change later. These American vaccine trials were interrupted in 2003, even though the candidate vaccine appeared safe in human beings, when other infectious disease research efforts were prioritized to counter potential terrorist use of biological agents. A vaccine developed by the US military and tested in the 1980s in 73 healthy volunteers induced a meaningful titer of protective antibodies in 67% of cases after two injections 1 month apart (119). Tolerance was satisfactory, with mild to moderate arthralgia in 9% of cases. This vaccine is among the starting points used in current research efforts to develop a vaccine in France and other countries.

In the 1970s, Chikungunya virus vaccines prepared by Tween 80 and ether inactivation of virus grown in green monkey kidney cell cultures was shown to be as immunogenic as comparable formalin-inactivated vaccines (34). Both types of vaccine stimulated hemagglutination- inhibiting, complement-fixing, and neutralizing antibody and afforded protection to mice against a live virus challenge. It was shown that after Tween-ether treatment of chikungunya virus the infectivity of the virus was lost and the hemagglutinin titer was increased (34).

The work on the vaccine diminished in recent years, as U.S. Government focused on diseases more likely to threaten U.S. troops. The most recently the French government has taken initiative to restart work on CHKV vaccine. The cooperation and help from scientist in USA and India is being sought by the French Government.

On September 6, 2006, the US Army Medical Research and Material Command signed a Material Transfer Agreement with the French National Institute of Health and Medical Research focusing on the records of previous clinical studies. A phase III trial of the US Army candidate vaccine is in preparation The candidate vaccine is a live vaccine (TSI-GSD-218) based on chikungunya virus strain 15561 isolated from a patient in Thailand and attenuated by serial passage in MRC-5 cells (17,19, 121).

PREVENTION OR INFECTION CONTROL MEASURES

The vaccination is not available. Therefore, the only mode of prevention is use of physical means of protection from mosquito bite, i.e. full sleeve clothing, mosquito nets and repellants etc. The use of repellent should be done with the advice of doctors, specially in case of pregnant mothers and children less than 12 years. Center for Disease Control and prevention (CDC) has advised a repellent containing 30% to 50% DEET (N, N-diethyl-m-tolumide) (19). The repellents with lower concentration need to be applied more frequently.

 A community level action to fight the vector must be implemented (50,62):

1. Reduction of mosquito breeding sites, specially stagnant water reserves (uncovered barrels, flower vases, or cisterns). Water containers should be emptied. If that is not possible then Temephos in 1 ppm strength should be applied on weekly basis.
2. Application of larvicidal treatment by Bacillus thurungeinsis israelensis.
3. The spray of the insecticides should seriously be considered for the whole area when any such report of spread of CHIKV occurs (2% Pyrethrum).

World Health Organization (WHO) has strongly recommended the use of Communication for Behavioral Impact (COMBI) approach for mobilization of both individuals and communities during the outbreaks.

Public Health Measures (50,62,91)

1. Monitoring and reporting of fever cases in the affected area should be done on regular basis to keep an eye on trends of infection.
2. Active surveillance and case search for CHIK fever by health workers in affected area can be done. This will help in identifying the area and starting control measures.
3. Vector surveillance and control measures in affected area.
4. Training of health services providers including health workers, Anganwadi workers, private practitioners in cases identification and control measures. IEC activities for general public and NGO through all possible means, i.e. Radio, TV, Newspapers and Local available resources.

Recommendations to Visitors Going to the CHIKV Affected Areas(21, 28)

The people form Chikungunya non endemic areas, who are about to visit endemic areas should follow some guidelines to avoid infection (60):

• Use of anti-mosquito devices and wearing long sleeves, especially during the hours of highest mosquito activity.
• Mosquito repellent based on a 30% DEET concentration is recommended. Before using repellents, pregnant women and children under the age of 12 years should consult a physician or pharmacist. For newborn children under three months, repellents are not recommended; instead, insecticide-treated bed nets and protective clothing should be used.
•  Pregnant women, immuno-deprived people and people suffering from a severe chronic illness should consult their physicians prior to the travel in order to assess their risk and get recommendations on personal preventive measures (70).
• The patients with Chikungunya fever should be advised to avoid being bitten by mosquitoes as the disease can be transmitted to others. Thus, the role of educating the community and public health officials and adequate vector control measures at the individual and community levels can not be over emphasized.

Recommendations for Those Who Return From the Area (13, 44,46)

Persons who have visited Chikungunya virus affected area, and who develop a high fever along with unexplained joint pain in the 12 days after their return are advised to seek medical attention. It is especially important for these persons to take preventive measures to reduce mosquito bites while symptomatic in order to avoid possible further mosquito transmission to others.

• To raise awareness among health-care providers regarding the outbreak or exposure to of Chikungunya, to stress the need to consider Chikungunya fever as a differential diagnosis and to implement universal protective precautions when collecting or handling Chikungunya fever suspected patient samples (84).
• To raise awareness of the public that on the importance of taking the above-described preventive measures to avoid mosquito bites when traveling to areas where Chikungunya virus transmission occurs.
• The governments and the policy makers should make efforts to strengthen vector surveillance as well as vector control programs during the mosquito season.
• Encourage all travelers returning from areas with a risk of transmission to report that they had visited such an area, even if they had no symptoms. Control measures were undertaken to take into account even the possible asymptomatic cases.
• The prevention of transmission in health care settings.

The only effective preventive measures currently available are individual protection against mosquito bites and vector control. Mosquito control is the best available method for preventing Chikungunya. Breeding sites must be removed, destroyed, frequently emptied, and cleaned or treated with insecticides. Large-scale prevention campaigns using DDT have been effective against A aegypti but not A albopictus. Control of A aegypti has rarely been achieved and never sustained. However, vector control is an endless, costly, and labor-intensive measure and is not always well accepted by local populations, whose cooperation is crucial. Bed nets should be used in hospitals and day-care facilities.

CONTROVERSIES, CAVEATS, AND COMMENTS

Chikungunya virus is a major public health concern besides a challenge for policy makers and scientists as very little scientific information is available about the Chikungunya virus, disease, pathogenesis, treatment and prevention.

A pertinent issue pointed out by experts that, despite infecting millions of the people for more than 50 years since its first report in 1952, CHIKV has been neglected and there is lack of knowledge about the biology of the virus. Furthermore, CHIKV has clearly been responsible for disabling and persistent arthralgia, even then it’s unresolved whether the symptoms are due to persistence of the virus or inappropriate immune response.

The factors mentioned above merit future research including the reason(s) for mysterious behavior of dramatic outbreaks interspersed by periods of prolonged absence; development of an effective vaccine; affordable, reliable and reproducible indigenously developed, rapid sero-diagnostic useful in the field setting; and a nationwide network of reliable, high quality of virology laboratories and developing a surveillance system for monitoring outbreaks of Chikungunya. A drastic change in the outlook of the community and public health authorities with regard to hygiene and mosquito control measures is essential to stand a chance in the war against the mosquitoes.

There are a few felt challenges in CHIKV infection.  First, the clinical manifestations are highly variable and may be more severe than previously reported. Second, economic development does not protect countries from vector-borne diseases (e.g., West Nile virus in the USA, and dengue fever in Rio or Singapore).  On the contrary, modern lifestyles may amplify an epidemic through travel, population aging, and production of solid waste that can shelter aedes mosquitoes. Third, the Chikungunya outbreaks highlight the importance of monitoring vector borne and zoonotic diseases. These outbreaks have provided an opportunity to improve our previously poor knowledge of the biology, epidemiology, dynamics, and immunology of chikungunya virus infection. Genome sequencing may lead to new therapeutic and preventive measures. Fourth, the world wide distribution of Aedes mosquitoes, gives a possibility that Chikungunya virus can spread to hitherto unaffected regions of the world affecting larger population, which is still unknown. Fifth, the clinical features and number of people affected by this outbreak suggests of this virus shedding its earlier benign form and becoming more pathogenic. There appears a wide gap in the knowledge about natural history of the disease. Data on activities during inter epidemic period, and possible extra human spread. Sixth, the international trade of tyres has been implicated in the spread of the aedes eggs and then the disease. Some national governments banned the trade and transport of the tyres to curve the spread. The incident highlights the need and importance of international cooperation in disease control. Finally, the research on vaccine and medicine needs necessary funds and prioritization.

It only makes sense that world community and public health experts are empowered with appropriate knowledge and control and prevention strategies to avoid an epidemic, otherwise long disappeared diseases like this would keep returning to affect humanity time and again.

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Table 1: Factors That Might Have Contributed to Epidemics of Chikungunya Fever (13,20,36,27)

Can be Summarized as Follows:

Biological and genetic	Ecological	Physical environment	Social, political, and economic
Non-immune human populations Genetic adaption in virus to A. albopictus during epidemic5	East Africa drought that promoted standing water and disease transmission6 Warm European summer with high abundance of vector3	Artificial vector-breeding sites (household water-stores, manholes, used tyres)	International and domestic travel Delayed identifi ation and control of initial outbreaks Previous introduction of exotic A. albopictus to Indian Ocean islands and Italy

Table 2: Case Definitions (62,91):

Suspected Case	Probable Case	Confirmed Case
An acute illness characterized by sudden onset of fever with several of the following symptoms: Joint pain, headache, backache, photo phobia, arthralgia, rashes.	Above features and; Positive serology either when single serum sample was taken during acute onset phase; or during the convalescence.	A confirmation can be done by any of the following method: 1. Four fold HI antibody difference in paired sera. 2. Detection of IgM antibodies against CHIKV. 3. Virus isolation from serum. 4. Detection of CHIKV nucleic acid in sera by RT-PCR.

 

 

 

 

 

 

 

 

 

 

 

 

 

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Morens DM.  Chikungunya at the Door -- DeJaVu All Over Again?  New Engl J Med 2014;371:885-887.

Ciampi de Andrade D., et al.  Chronic pain associated with Chikungunya Fever: long lasting burden of an acute illness.  BMC Infectious Diseases. 2010;10:31.

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Pialoux, G., Gauzere, B., Jaureguiberry, S. and Strobel, M. Chikugunya, an Epidemic Arbovirus. The LANCET Infectious Diseases 2007; Vol.7, Issue 5, 319-327.

Lewthwaite P et al. Chikungunya Virus and Central Nervous System Infections in Children, India.Emerg Infect Dis. 2009 Feb;15(2):329-31.

Staples JE, et al.  Chikungunya Fever: An Epidemiological Review of a Re-Emerging Infectious Disease. Clin Infect Dis 2009;49:942-948.

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