Chikungunya Viral Infections: An Emerging Problem

Chikungunya—pronounced chik‐n‐gunya, with the accent on the first syllable—is an alphavirus that causes disease in Africa and Asia. The name chikungunya is derived from the Makonde word meaning “that which bends up.” This is in reference to the stooped posture that develops from the arthritic symptoms of the disease. However, some authors overlooked this reference and assumed that the term was derived from Swahili (a native language of East Africa and now the official language of Tanzania). Chikungunya viral disease was first described in Tanzania in 1952 to 1953. 1–3 Since then, the outbreaks have been reported from Africa and many parts of Asia. 4–6 In 1958, the virus was first isolated in Asia from Bangkok, Thailand. 7 Asian countries that have reported chikungunya activity include Thailand, Cambodia, Vietnam, Laos, Indonesia, Malaysia, Myanmar, India, Sri Lanka, and the Philippines. 8–19 In recent months, large outbreaks of chikungunya viral infections have been reported from India and from some smaller islands in the Indian Ocean. Aedes aegypti and Aedes albopictus mosquitoes, which act as vectors for chikungunya viral infections, are widely distributed in several South and Southeast Asian countries. These same vectors transmit the dengue virus. 20,21 Large numbers of people travel between India, the Indian Ocean islands, and the neighboring countries, and it is to be expected that cases of chikungunya infection would spread to other countries in the region. These countries are also popular tourist destinations, and patients may present on their return with a “dengue‐like illness” due to a chikungunya viral infection. In fact, it is possible that clinicians are already seeing such patients but incorrectly assuming their symptoms as due to the dengue virus. Several imported cases of chikungunya infection have already been reported from different European countries. 22,23 In this short review, we describe aspects relating to the recent outbreaks of chikungunya infection in some South Asian countries, the detection of imported cases in several European countries, the chikungunya virus and its mosquito vector, and the clinical manifestations, diagnosis, and treatment of these infections. Recently, India and several islands in the Indian Ocean such as the French Reunion Islands, Mauritius, and Seychelles have been reporting large numbers of patients with chikungunya viral infection. 24–26 Estimates suggest that since December 2005, more than 200,000 cases have occurred in India. Andhra Pradesh was the first state to report a reemergence of this infection. 26 Of 362 serum samples collected in this state and tested at the National Institute of Virology, Pune, 139 had been positive for chikungunya antibodies, six for dengue antibodies, and 15 for both. 15 The Reunion Island epidemic began in March 2005, and by January 2006, an estimated 1,200 new cases were seen each week. 25 Some reports suggest that by May 2006, nearly 255,000 people (of 777,000 residents) in Reunion had been affected and that 77 deaths were associated with chikungunya infection. 27–29 In neighboring Mauritius, 3,500 cases were reported in 2005. 25 Initially, most of the patients had a history of travel to Reunion, but later cases occurred without a specific travel history. Since November 2005, an increasing number of cases have also been reported from Seychelles, Mayotte, Comoros, Madagascar, and Malaysia. Furthermore, since March 2005, 123 cases with a confirmed chikungunya infection have developed severe clinical signs (neurological signs or fulminant hepatitis) and needed treatment in an intensive care setting. Estimates from 2004 suggest that nearly 1.5 million people travel from Mauritius, Reunion, Seychelles, Mayotte, and Madagascar to mainland Europe each year. Thus, it is likely that large numbers of infected people may be importing the virus into Europe. Furthermore, A albopictus, the main mosquito vector in the Reunion epidemic, is already found in several European countries. 30 However, at present, the exact vectorial competence and efficacy of virus transmission of these vectors in Europe are not known. From April 1, 2005, to February 28, 2006, 307 imported cases of chikungunya have been identified in France. 22 Most imported cases were seen in patients living in the Provence‐Alpes‐Cote d’Azur region in Southeast France, which is home to a large Comorian community. None of the imported cases in France developed serious manifestations. In addition, imported cases have also been reported in Germany, UK, Belgium, Switzerland, Norway, China, and the Czech Republic. 23 In March 2006, a nurse in France, who had never traveled to the Indian Ocean, developed a laboratory‐confirmed chikungunya infection 3 days after caring for a patient with an imported infection. Laboratory transmission of chikungunya infection has been previously reported. 31,32 Reasons for the reemergence of chikungunya infections in India and islands in the Indian Ocean are unclear. Studies on virus isolates from the current outbreak suggest that specific viral gene mutations may in some way facilitate its large‐scale spread in the region. Alternatively, the lack of herd immunity in these regions may have contributed to its rapid spread across states and countries. The chikungunya virus, a positive strand, enveloped RNA virus, is a member of the Alphavirus genus and belongs to the Togaviridae family. 33 It is endemic in large parts of Africa, the Middle East, India, and South‐East Asia and is closely related to O’nyong‐nyong viruses. 34 Khan and colleagues have studied the complete nucleotide sequence of the S27 African prototype chikungunya virus. 35 They found its genome to be similar in structure to that of other alphaviruses, and the presence of an internal polyadenylation site within the 3′ nontranslated region. Genetic analysis of chikungunya viruses based on partial E1 envelope glycoprotein gene sequences from African and Asian isolates showed the presence of three distinct phylogroups. 36 The first contained all isolates from West Africa; the second comprised all Southern, Eastern, and Central African strains; and the third contained isolates from Asia. Historical evidence that the virus originated in Africa and was subsequently introduced into Asia was confirmed by phylogenetic tree analysis. 36 Schuffenecker and colleagues 37 investigated changes in the viral genome of chikungunya viruses isolated from the present outbreak, with a view to understanding its unusual virulence that has resulted in unexpected morbidity and mortality patterns. They suggest that the outbreak began with a strain related to the East African strains of the virus. All the recent Indian Ocean sequences examined were found to share certain areas, which were different from the previously determined sequences. Numerous mosquito species are involved in the maintenance of chikungunya viral infections in Africa. 38–40 For example, in Senegal, Aedes furcifer, Aedes taylori, Aedes luteocephalus, Aedes africanus, and Aedes neoafricanus were determined to be of major importance in maintaining chikungunya virus transmission cycles. In Asia, chikungunya virus is transmitted from human to human mainly by A aegypti and to a lesser extent by A albopictus through an urban transmission cycle. Aedes albopictus has been the species implicated in the recent major epidemic in Reunion. Outbreaks typically occur during the rainy season when vector densities tend to rise. Chikungunya infection is characterized by abrupt onset fever, severe arthralgia, rash, and other constitutional symptoms. 41 Headache, conjunctival injection, and slight photophobia may occur. Generalized myalgia with back and shoulder pain is common, and lymphadenopathy occurs frequently. 16 The incubation period is between 2 and 10 days (usually 2–3 d), and the illness lasts for between 1 and 7 days. The fever (39–40°C) is often accompanied by intermittent shaking chills. A “saddle‐back” fever pattern may occur (an acute phase lasting 2–3 d, remitting for 1–2 d, before developing fever again). Joint involvement is usually symmetrical, polyarticular, and migratory and predominantly affects small joints of the hands, wrists, ankles, and feet. 42 Larger joints are less frequently involved. Periarticular swelling, pain, redness, and limitation of movement may be seen. The pain on movement is worse in the morning, improved by mild exercise and exacerbated by strenuous exercise. Fluid accumulation in the joints is uncommon. Patients with milder articular manifestations are usually symptom free within a few weeks, but more severe cases may take months to resolve. 43 Skin manifestations are typical. Many present with flushing, affecting their face and trunk. A maculopapular or petechial rash primarily involving the trunk and limbs can occur with defervescence. The rash may also affect the face, palms, and soles and be accompanied by pruritus. Most patients will have a headache during the acute disease, although it is usually not very severe. Photophobia and retroorbital pain may also occur. Some have conjunctival injection, and others complain of a sore throat due to pharyngeal inflammation. During the recent outbreak in Reunion and in the first outbreak in India, neurological complications such as meningoencephalitis were seen in a small proportion. 27,44 Mother to child transmission of chikungunya virus has been seen in the recent Reunion Island outbreak. 45 Chikungunya infection tends to present differently in younger patients. The arthralgia and arthritis appear to be less prominent and last for a shorter time. The rash is also seen less frequently. Previous reports on chikungunya infection suggest that it is often a self‐limiting illness. Most patients recover completely over a period of a few weeks. However, 5% to 10% of patients experience chronic joint pain, stiffness, and swelling lasting a year or more. The present outbreak appears to be more severe than previous ones, as several patients have developed complications and some deaths have also been reported. Clinical manifestations of chikungunya infection may be clinically indistinguishable from those due to dengue. 46 In Asia, the chikungunya virus has been isolated from children having an illness very similar to Dengue Haemorrhagic Fever (DHF). Dual infections may also occur, where both dengue and chikungunya have been simultaneously isolated from the same patient. 47 Hemorrhagic manifestations in chikungunya have been described particularly among cases in South‐East Asia and the Indian subcontinent. 48–51 These are milder and less common when compared with dengue. Classically, shock does not occur. Chikungunya infection should be suspected clinically when the characteristic triad of fever, rash, and rheumatic manifestations is present. Leucopenia is typical, and there may be a relative monocytosis. Thrombocytopenia occurs frequently. The main differential is between dengue and O’nyong‐nyong fevers. It has been suggested that dengue is characterized by more myalgia than arthralgia. Laboratory tests are needed for definitive diagnosis. Virus isolation by inoculation of mosquitoes, mosquito or mammalian cell cultures, or suckling mice is possible. Most patients have viremia during the first 48 hours of illness, but this may persist for up to 4 days in some patients. In patients recovering from chikungunya infection, virus‐specific immunoglobulin M antibodies are readily detected by capture enzyme‐linked immunosorbent assay. These may persist for more than 6 months. Hemagglutination inhibition (HI) antibodies appear when viremia ceases and are generally positive by day 5 to day 7 of illness. Neutralization and HI antibodies tend to parallel each other. Polymerase chain reaction‐based techniques are also available for diagnosis. 52–55 No specific treatment is available for chikungunya viral infections. The illness is usually self‐limiting. However, the recent epidemic in several South Asian countries appears to be resulting in greater morbidity and even some deaths. It is important to exclude other dangerous diseases such as dengue. Rest helps the acute joint symptoms. Movement and mild exercise tend to improve morning stiffness and arthralgia, but severe exercise may worsen the arthralgia. Analgesics and anti‐inflammatory drugs are useful. However, care is needed when using these drugs as the chikungunya virus is capable of causing thrombocytopenia. More than 12% of patients develop chronic joint symptoms, which respond only partially to the nonsteroidal anti‐inflammatory drugs (NSAIDs). Chloroquine phosphate (250 mg/d) has been found to be useful in arthritis refractory to aspirin or NSAIDs. An open pilot study to assess its efficacy was done in 10 patients, with treatment given for 20 weeks. 56 Both joint symptoms and morning stiffness improved significantly. Seven of the ten patients considered their symptoms as improved. It is possible that hydroxychloroquine would be useful as treatment in this setting. Hydroxychloroquine has been extensively used in rheumatological practice and is less toxic to the eyes than chloroquine. No vaccine is currently available. A phase II, randomized, double‐blind, placebo‐controlled safety and immunogenicity study of live chikungunya virus vaccine SI‐GSD‐218 was conducted in 73 healthy adult volunteers and found to be safe and highly immunogenic. 57 However, funding for this project appears to have been discontinued. Travelers to affected areas should be advised to take anti‐mosquito measures. Aedes aegypti female mosquitoes have two periods of peak biting activity, which are a few hours after dawn and in the late afternoon around dusk. 58 It would be advisable for pregnant women, the elderly, and those with significant medical conditions not to travel to countries affected by the present chikungunya epidemic as meningoencephalitis has been described in neonates of women infected a few days before giving birth and in the elderly among the recent cases in the Indian Ocean. Health personnel in South Asia and South‐East Asia are likely to come across patients with chikungunya viral infections, especially following the recent large outbreaks in some countries of the region. It is an important differential in patients presenting with a dengue‐like illness, where dengue testing has proved negative. These countries are also popular tourist destinations, and patients may present on their return with a dengue‐like illness due to a chikungunya viral infection. Several imported cases of chikungunya have already been reported from countries in Europe. Knowledge of aspects of this disease should allow the condition to be suspected and treated appropriately. This rash appeared on day 2 of a febrile illness in a patient who presented with myalgia and arthralgia after visiting Mauritius. Chikungunya was confi rmed serologically. Richard Foster, Michael Richardson, Stephen Toovey, South Africa. The authors state that they have no conflicts of interest.