KEY POINTS

■ Chikungunya virus (CHIKV) is a single-stranded RNA arbovirus of the genus Alphavirus of the Togaviridae family that is transmitted 
primarily throughout Africa, Asia, and India by Aedes aegypti and Aedes albopictus mosquitoes. Once considered an emerging 
infectious disease in developing tropical countries, CHIKV has now spread to the industrialized world.


■ The hallmark manifestation of CHIKV is severe, painful arthralgia. Other common symptoms include fever, backache, headache, and myalgia.


■ Diagnosis is made by isolating the virus in a Vero cell culture; reverse transcriptase polymerase chain reaction; detection of IgG and IgM antibodies using an enzyme-linked immunosorbent assay or immunofluorescent assay; and with a plaque reduction neutralization test.


■ Treatment of chikungunya virus is supportive and consists of analgesia, rest, and hydration. NSAIDs, cold compresses, exercise and physiotherapy, and corticosteroids can be used to ease suffering resulting from sequelae of the disease.


■ CHIKV can be managed by educating patients about prevention strategies, decreasing the vector population, minimizing vector-patient contact, and reporting cases of CHIKV to the nearest public health authorities.


On June 21, 2007, a man from Kerala, India traveled to the Emilia-Romagna region of Italy to visit a relative. Two days later, he fell ill with viremia. In due course, indigenous mosquitoes began to make a blood meal of him. Shortly thereafter, between July and September of 2007, over 200 residents of nearby Castiglione di Cervia, Castiglione di Ravenna, and beyond developed fevers and severe joint pain. Health officials initiated an active epidemiological investigation and analyzed blood samples by polymerase chain reaction (PCR) and serology.1,2 Their assumptions proved correct: the epidemic was caused by chikungunya virus (CHIKV), which was being transmitted by the Aedes albopictus mosquito to unsuspecting Italians, many of whom had never traveled to exotic lands. PCR analysis of the CHIKV sequence showed an Ala226Val mutation in the E1 protein, which was also present in the Indian Ocean variant of the African genotype. This supported the theory that someone who was infected in India had introduced the epidemic to these Italian villages.2

This outbreak of CHIKV in Europe marked the first time an emerging disease had spread beyond the artificial borders of a developing tropical country and laid its claim on the industrialized world. Although the morbidity and mortality rates of CHIKV are nowhere near as severe as malaria or dengue fever, its effects upon a naïve population can still be medically and economically substantial for both the affected patients and the community unless a timely diagnosis is made and public health authorities are notified immediately. The key for any community is to quickly determine whether each case is isolated or is the harbinger of an epidemic requiring major public health management. Averting an epidemic requires a multidisciplinary initiative to educate, recognize, diagnose, and alert.3 This article aims to raise health care professionals' awareness of the manifestations, diagnosis, and management of chikungunya virus as well as its public health implications.


ETIOLOGY AND HISTORY


Chikungunya virus is a single-stranded RNA arbovirus of the genus Alphavirus of the Togaviridae family.4 Three lineages of the disease have been identified, each with distinct genotypic and antigenic characteristics; two derive from Africa and one from Asia.4 The name "chikungunya" comes from the Swahili or Makonde words meaning "that which bends up" or "to walk bent over," which describes the posture of patients with CHIKV who are affected by severe, painful arthralgia.1,4,5 CHIKV is transmitted primarily throughout Africa, Asia, and India by Aedes aegypti and Aedes albopictus mosquitoes (Figure 1 and Figure 2).4 Both mosquitoes are well-established species in the United States.3 During epidemic periods, humans become the reservoir for the CHIKV virus. During interepidemic periods, however, monkeys, rodents, birds, and other unidentified vertebrates are the reservoir.6


Historical timeline In 1824, epidemics of fever, rash, and arthritis were cited in India and elsewhere.1 In 1952, the clinical features of chikungunya virus were first described during an outbreak in villages on the Makonde Plateau in the southern province of Tanganyika, Africa.1 The virus was isolated 1 year later during an epidemic in Tanzania using human sera and mosquitoes.2,7 In 2001, CHIKV was first documented in Indonesia, and by 2007, more than 15,000 cases had occurred there.8 The year 2004 witnessed an outbreak of CHIKV in Kenya followed by another massive outbreak on the French island of La Réunion in 2005.2 By this point in time, an estimated 266,000 people had developed chikungunya virus (attack rate, 35%).1,9 By 2006, a CHIKV epidemic reached Sri Lanka, and through 2007, more than 37,000 Sri Lankans were affected by the disease.8 In 2006, more than 1.3 million cases of CHIKV were reported in India with attack rates as high as 45% in some areas.8 In 2007, more than 17,000 were infected in Gabon, Africa. Around the same time in 2007, CHIKV was first introduced to Europe during the aforementioned outbreak in Italy.8 However, the attack rate measured only 5.4% in Castiglione di Cervia and 2.5% in Castiglione di Ravenna, a much smaller figure than in other countries.2 


CLINICAL MANIFESTATION


The incubation period of chikungunya virus is 2 to 4 days with a range of 1 to 12 days.4,10 The period of viremia lasts fewer than 7 days.2 Maternal-fetal transmission is possible, especially if delivery occurs during the viremic phase.11 For example, during the La Réunion outbreak, 41 cases of materno-neonatal transmission of CHIKV were confirmed.9 Nevertheless, reports of first trimester miscarriages have been rare. No evidence exists that the virus can be transmitted via breast milk.11 The case-fatality rate of chikungunya virus is less than 0.5%, and these fatalities appear to be related to increased age.1,2,12 Morbidity, however, is potentially substantial. Patients with CHIKV reported a median of 35 days off work, and more than 60% experienced persistent arthralgia 18 months after the onset of acute illness.13,14 


The onset of CHIKV can be abrupt. Common manifestations include fever (92%), arthralgia (87%), backache (67%), headache (62%), and myalgia (46-62%).4 Fever may reach up to 104°F (40°C) and usually lasts 24 to 48 hours. Painful and debilitating polyarthralgia is characteristic of the disease.4 The most commonly affected joints include the metacarpophalangeal joints, knees, wrists, metatarsal joints, and ankles.13 The shoulders and spine are also affected.4 During the Italian outbreak, the majority of patients experienced, in order of frequency, fever, joint pain, fatigue, rash, headache, and myalgia.2 


Less common manifestations include maculopapular rash (50%), stomatitis (25%), oral ulcers (15%), photosensitive hyperpigmentation (20%), and exfoliative dermatitis (5%).4 In Italy, approximately 20% of patients with chikungunya virus manifested pruritus, vomiting, and diarrhea.1 A maculopapular rash may also occur in 32.5% to 76.5% of patients,2,9,13,15 classically occurring after the fever breaks and covering the trunk and limbs and sometimes the palms, soles, and face.10 


Rare manifestations of the disease include photophobia, retro-orbital pain, vomiting, diarrhea, seizures, meningoencephalitis, neuroretinitis, anterior granulomatous/nongranulomatous uveitis, optic neuritis, retrobulbar neuritis, myocarditis, and hepatitis.4,10 According to the World Health Organization, the following symptoms are rare in adults but more common in children: photophobia, retro-orbital pain, vomiting, diarrhea, meningeal syndrome, and acute encephalopathy.4Table 1 summarizes the clinical manifestations of CHIKV.


Hematological findings include leucopenia and thrombocytopenia. Typically, the thrombocytopenia is minor and clinically insignificant. Both the erythrocyte sedimentation rate and C-reactive protein level are often elevated. Affected patients may also have a positive rheumatoid factor test result. However, none of these laboratory tests are diagnostic for CHIKV.4


Differential diagnosis When CHIKV is suspected, a differential diagnosis of alphavirus infections such as Ross River virus, Barmah Forest virus, o'nyong-nyong virus, Sindbis virus, Mayaro virus, and Semliki Forest virus should be ruled out.15,16 Dengue, malaria, and leptospirosis must also be considered.4,17


DIAGNOSIS 


Chikungunya virus can be diagnosed by isolating the virus in a Vero cell culture; reverse transcriptase polymerase chain reaction (RT-PCR); detection of IgG and IgM antibodies using an enzyme-linked immunosorbent assay (ELISA) or immunofluorescent assay (IFA); and with a plaque reduction neutralization test.3


In the United States, specific testing for CHIKV is limited and can be completed only through the CDC, Wadsworth Center of the New York State Department of Health, or Focus Diagnostics (commercial).3 According to Gibney and colleagues, there are no data that compare the sensitivity and specificity of these various CHIKV assays.3 However, in one study, the virus was successfully isolated in only 23.4% of RT-PCR confirmed positive serum samples.18 In addition, during the first week of the infection, RT-PCR appeared to be very accurate.16,18 IgG and IgM testing carries greater accuracy from day 5 on.18 While levels of IgM antibodies are usually detectable in blood samples within 2 weeks of acute illness, the WHO suggests waiting 1 week after the onset of symptoms to perform the ELISA for IgM.4 


SEQUELAE


The most common sequelae of the disease are arthralgia, fatigue, and mood disorders. Arthralgia observed with chikungunya infections may persist and has been the topic of several studies. In one such study, 107 people in northern Transvaal (modern day South Africa) who were seropositive for CHIKV in 1975, 1976, and 1977 were queried 3-5 years after infection about arthralgia. The majority of participants (87.9%) reported complete recovery. Only 3.7% reported occasional joint stiffness and discomfort, 2.8% reported persistent residual joint stiffness without pain, and 5.6% still suffered from joint pain, stiffness, and frequent effusions.19 Another study of 88 people who suffered from CHIKV infection during the outbreak on Reunion Island (March 2005-April 2006) found persistent arthralgia to be much more common. While 32 patients (36.4%) recovered from the joint pains caused by CHIKV in a mean of 2.9 months (± 2.4 months), 56 patients (63.8%) reported persistent arthralgia up to a mean of 18 months after the onset of chikungunya fever. Those with persistent arthralgia reported it as being polyarticular, and over half had continuous joint pain.20 


In another study, researchers investigated the morbidity of chikungunya virus and looked into other areas of health the condition might affect other than arthralgia. A telephone interview of 1,094 people who had been tested as either seropositive or seronegative for chikungunya virus during the 2005-2006 La Réunion outbreak was conducted. Questions centered on current symptoms including musculoskeletal/rheumatic, fatigue, cerebral, sensorineural, digestive, and dermatological manifestations. It was found that after an average of 24 months after the onset of acute CHIKV, those who actually had the infection were twice as likely to have musculoskeletal pain. They were also more likely to complain of light cerebral disorders including attention difficulties, memory trouble, mood disturbance, and depression. Infection was also associated with sensorineural impairment 24 months later. The researchers found that 33% of rheumatic symptoms, 10% of neurological complaints, and 7.5% of sensorineural complaints were caused by chikungunya virus. Overall, 43% to 75% of those infected still suffered from the sequelae of chikungunya virus an average of 24 months later.21 


TREATMENT 


The treatment of chikungunya virus is supportive and consists of analgesia, rest, and hydration. No data are available to indicate the efficacy of antiviral agents. Those recovering from CHIKV who experience joint manifestations may benefit from mild exercise and the application of cold compresses. Patients should be educated on the importance of seeking medical care if they experience any of the following symptoms: fever lasting more than 5 days, pain refractory to treatment, postural dizziness, cold extremities, decreased urine output, bleeding, or persistent vomiting.4 


Certain interventions may help ease suffering associated with the sequelae of chikungunya virus. Patients with osteoarticular problems may obtain relief by using NSAIDs, cold compresses, exercise and physiotherapy, and corticosteroids. Corticosteroids may also be used to treat uveitis and retinitis. Chronic dermatological issues such as hyperpigmentation and papular eruptions may be treated with zinc-oxide cream or calamine lotion. Those with psychosomatic manifestations should receive psychosocial evaluation, support, and reassurance. Corticosteroids should be considered in a certain set of these sequelae because the manifestations may be caused by an immunologic response.4


No vaccine is available to treat CHIKV. However, a DNA vaccine is being developed that contains CHIKV capsid and envelope consensus sequences. When tested in mice, the vaccine was shown to elicit both T-cell and humoral immune responses.22 Another group of researchers constructed a virus-like particle (VLP) vaccine that was shown to produce neutralizing activity in rhesus macaques. Upon CHIKV challenge of vaccinated monkeys, the immunized monkeys were protected against viremia.23 


PREVENTION AND MONITORING


In order to minimize the transmission of CHIKV and prevent outbreaks, infected individuals and their family members should be educated about prevention strategies. As outlined by WHO, guidelines for minimizing transmission include risk communication to the household members, decreasing the vector population, minimizing vector-patient contact, and reporting cases of CHIKV to the nearest public health authority.4 Risk communication to household members should involve educating the patient and family members on the transmission of the virus and the role of the mosquito as the vector. Patients should also be educated on the importance of avoiding contact with mosquitoes and be told how to reduce the nearby mosquito population.4 


In order to minimize the vector population, stagnant water in the house and yard should be eliminated, as it can serve as a breeding ground. Because mosquitoes can take refuge in tall grass and weeds during the hottest part of the day, grass should be cut short and weeds should be managed. Some cities provide fogging and waste management to decrease the mosquito population.4 To minimize vector-patient contact, people in infected communities should remain inside a house that has screens on all windows and doors. Patients should sleep under a bed net, as should uninfected infants, to avoid transmission. Everyone in the house should wear long-sleeved shirts and pants to minimize skin exposure to mosquitoes. Insecticides should be used throughout the house as well.4 Lastly, chikungunya virus should be reported to the public health authorities.4 While chikungunya virus is not a notifiable disease in the United States, the CDC urges clinicians to report suspected cases to local and state health officials as well as to the CDC.24


DISCUSSION


From 1995-2009, 109 cases of CHIKV were confirmed in the United States, and no known cases have arose from local transmission.3 Nevertheless, the threat of local transmission is more than theoretical considering that the Aedes mosquito has a foothold, to a larger (in bold) or lesser extent, in the following states: Alabama, Arizona, District of Columbia, Florida, Georgia, Illinois, Indiana, Kansas, Louisiana, Maryland, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, South Carolina, Tennessee, Texas, and Virginia.25 Mosquito density is greatest in the Gulf Coast states. However, episodic infestations with Aedes albopictus have been discovered in Chicago and as far north as Minnesota.26 


Physician assistants should become efficient at recognizing, diagnosing, and reporting cases of CHIKV for two reasons. The first is to adequately diagnose and manage the care of patients stricken with the disease in a competent and reassuring fashion. Second, PAs must learn to recognize CHIKV early in order to alert local public health authorities as soon as possible, especially since the patient may be a harbinger of a CHIKV outbreak. While the WHO advises health care providers to consider chikungunya virus when a patient presents with the triad of fever, rash, and joint manifestations,4 the CDC advises considering CHIKV in returning travelers presenting with fever and arthralgia or arthritis as well.24 JAAPA

The authors are affliated with the University of Toledo in Ohio. Alicia 
Weitzel is a PA student, Paul Rega is assistant professor, Departments of Public Health and Preventive Medicine, and Christopher Bork is professor, Department of Public Health and Preventive Medicine. The authors have indicated no relationships to disclose relating to the content of this article.


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