How to cite this article: Barrera-Cruz A, Díaz-Ramos RD, Viniegra-Osorio A, Grajales-Muñiz C, Dávila-Torres J. Technical guidelines for the prevention and treatment of chikungunya fever. Rev Med Inst Mex Seguro Soc. 2015 Jan-Feb;53(1):102-19.
Received: August 19th 2014
Accepted: November 10th 2014
Antonio Barrera-Cruz,a Rita Delia Díaz-Ramos,b Arturo Viniegra-Osorio,c Concepción Grajales-Muñiz,d Javier Dávila-Torrese
aCoordinación de Programas Médicos, Coordinación Técnica de Excelencia Clínica
bJefatura del Área de Proyectos y Programas Clínicos, Coordinación Técnica de Excelencia Clínica
cCoordinación Técnica de Excelencia Clínica
dJefatura de la División de Vigilancia Epidemiológica de Enfermedades Trasmisibles, Coordinación de Vigilancia Epidemiológica
eDirección de Prestaciones Médicas
Instituto Mexicano del Seguro Social, Distrito Federal, México
Communication with: Antonio Barrera-Cruz
Chikungunya fever is an emerging disease caused by an alphavirus belonging to the Togaviridae family, transmitted by the bite of Aedes genus species: Aedesaegypti and Aedesalbopictus. In 2013, PAHO/WHO received confirmation of the first cases of indigenous transmission of chikungunya in the Americas. This disease may be acute, subacute and chronic, affecting all age groups. Following an incubation period from three to seven days, the patient usually begins with a high fever (greater than 39 °C), arthralgia, back pain, headache, nausea, vomiting, arthritis, rash, and conjunctivitis (acute phase: 3-10 days). Most patients recover fully, but in some cases, joint involvement may persist chronically and cause discapacity and affect life quality. Serious complications are rare, however, attention must be focused on vulnerable populations (the elderly, children and pregnant women). So far, there is no specific antiviral treatment or effective vaccine, so it is giving priority symptomatic and supportive treatment for the acute phase and make an early diagnosis of atypical and severe forms, and to implement effective prevention and control measures. Given the eco-epidemiological conditions and distribution of vectors in the region of the Americas, the spread of the virus to other countries is likely, so that health professionals should be aware of and identify risk factors and major clinical manifestations, allow timely prevention and safe and effective treatment of this disease.
Keywords: Chikungunya virus; Hyperthermia; Fever
Chikungunya fever is an acute febrile disease caused by the chikungunya virus (CHIKV), transmitted by the bite of Aedes mosquitoes, which affects all age groups and both sexes. It represents an endemic disease in South East Asia, Africa, and Oceania, while it is an emerging disease in the Americas.1,2
The name chikungunya derives from the Makonde African language, belonging to an ethnic group living in southeast Tanzania and northern Mozambique. It means "he who bends", which describes the bent-over appearance of people who have this typical and painful arthralgia.1-3
The disease was first documented in the form of an outbreak in Tanzania in 1953. CHIKV belongs to the family Togaviridae of the genus Alphavirus, and it is transmitted to humans and other primates by the bite of infected mosquitoes belonging to the species Aedes, particularly Aedes aegypti and Aedes albopictus (Figure 1), the same species involved in the transmission of dengue virus. Recent investigations conducted by the Pasteur Institute in Paris suggest that the virus has undergone a mutation that has made it liable to be transmitted by the Aedes albopictus (Asian tiger mosquito), a more aggressive mosquito that is active throughout the day and has a longer average life.1,2,17-19
Aedes aegypti is confined to tropical and subtropical areas, while Aedes albopictus is present in temperate and even cold-temperate regions. In recent decades Aedes albopictus has left Asia and has established itself in parts of Africa, Europe, and the Americas.2-4,17-19
Figure 1 Aedes aegypti and Aedes albopictus. From: Guía de manejo clínico para la infección por el virus chikungunya (CHIKV). Santo Domingo, Dominican Republic, May 2014
Compared with Aedes aegypti, Aedes albopictus thrives in a wider variety of standing water that serves as breeding grounds (coconut husks, cocoa pods, holes in trees, puddles in rocks) plus artificial reservoirs (vehicle tires or dishes under flowerpots). This diversity of habitats explains the abundance of Aedes albopictus in rural and peri-urban areas and shady city parks. Aedes aegypti is more closely associated with housing and has indoor breeding areas, for example in vases, water containers, and water tanks in bathrooms as well as the same artificial outdoor habitats as Aedes albopictus.
CHIKV was first detected in Tanzania in 1952. The disease occurs in Africa, Asia, and the Indian subcontinent. Human infections in Africa have been relatively sparse for several years, but in 1999-2000 there was a large outbreak in the Democratic Republic of Congo, and in 2007 there was an outbreak in Gabon. CHIKV epidemics have shown a cyclical presentation with inter-epidemic periods ranging from 4 to 30 years. Since 2004, CHIKV has expanded its worldwide geographic distribution, which has caused sustained epidemics of unprecedented scale in Asia and Africa (Figure 2).2,3,12
Figure 2 Areas at risk of chikungunya. Source: WHO, 2012
Since 2004, there have been intense and widespread outbreaks in Africa, the islands of the Indian Ocean, and the Pacific region, including Australia and Southeast Asia (India, Indonesia, Myanmar, Maldives, Sri Lanka, and Thailand). In February 2005 a major outbreak began in the Indian Ocean islands, which was linked with many imported cases in Europe. In 2006 and 2007 there was a large outbreak in India that also affected other countries in Southeast Asia.
Since 2005, India, Indonesia, Maldives, Myanmar, and Thailand have reported more than 1.9 million cases. In 2007 the first transmission of the disease in Europe was reported, an outbreak located in the northeast of Italy, in the region of Emilia-Romagna, with 197 registered cases, which confirmed that outbreaks transmitted by Aedes albopictus are possible also in Europe (Figure 3).
Figure 3 Countries with cases of chikungunya (2014). Source: WHO, 2014
In 2013 the Pan American Health Organization (PAHO) reported the confirmation of two cases of indigenous transmission of CHIKV in the island of Saint Martin in the Caribbean. Local transmission has since been confirmed on the Dutch side of the island (St. Maarten), Anguilla, Dominica, French Guiana, Guadeloupe, British Virgin Islands, Martinique, and Saint Barthelemy.17-19
So far, chikungunya fever has been detected in almost 40 countries in Asia, Africa, Europe, and the Americas.1,2,19
Epidemiological situation in the Americas
According to PAHO, as of the 26th week of 2014 a total of 259,723 cases of suspected chikungunya fever have been reported in the Americas, of which 4721 have been confirmed and 21 of those patients died. 22 countries have suspected cases, of which the most affected is Saint Martin, with a rate of 11,832 per 100,000 population, followed by Martinique with 9038, Guadeloupe with 8954, Dominica with 4442, and Dominican Republic with 1305. There are also reports of imported cases in eight countries in the region. The fatality rate of this disease is estimated at 0.45%, with an incidence rate of 76.3 per 100,000 inhabitants.2-4,7
In Mexico, according to PAHO and the World Health Organization (WHO), the number of reported cases of indigenous transmission of CHIKV, through epidemiological week 41 (updated October 10, 2014), is zero suspected and confirmed cases.
Note that so far only six imported cases or foreign citizens who have arrived in the country during the period of communicability and/or clinical stage of the disease have been reported in our country. No indigenous cases have been documented, i.e. cases originating in Mexico in people who have not left the country at least two weeks before symptoms.
Epidemiological scenarios for virus transmission are:
There are two main vectors for CHIKV: Aedes aegypti and Aedes albopictus. Both mosquito species are widely distributed in the tropics, and Aedes albopictus is also present in more temperate latitudes. Given the wide distribution of these vectors in the Americas, the entire region is susceptible to the invasion and spread of the virus. These mosquitoes usually bite during the day, although their activity may be greatest in the early morning and evening. Both species bite outdoors, but Aedes aegypti can also bite in indoor environments.2,8
Humans are the main reservoir of CHIKV during epidemic periods. In interepidemic periods it has been mentioned that various vertebrates could act as potential reservoirs, including non-human primates, rodents, birds, and small mammals.
Mosquitoes acquire the virus from a viremic host. After an average extrinsic incubation period of 10 days, the mosquito is capable of transmitting the virus to a susceptible host, such as a human being. In humans bitten by an infected mosquito, symptoms usually appear after an intrinsic incubation period of three to seven days (range 1-12 days) (Figure 4).2,8
Figure 4 Extrinsic and intrinsic incubation periods of chikungunya virus
Susceptibility and immunity
All individuals not previously infected with CHIKV (immunologically virgin individuals) are at risk of becoming infected and developing the disease. Subsequently, those exposed to CHIKV develop lasting immunity that protects against reinfection.2,11
This guideline should be applied by all providers of health services in the Instituto Mexicano del Seguro Social (IMSS) in first, second, and third levels of care.
During an epidemic it is not necessary to subject all patients to the confirmatory tests listed above. The epidemiological link can be enough.2-4,7
CHIKV can cause acute, subacute, and chronic disease. The disease can affect women and men of all ages. However, clinical presentation varies with age, and complications and serious cases are more common in children under one year, in adults over 65 with chronic diseases (diabetes, hypertension, etc.), and in pregnant women. The disease rarely causes death, but joint pain can last for months or even years for some people.
Bites from infected mosquitos in humans produce manifestations of the disease in 95% of cases (Table I). Individuals with acute CHIKV infection with clinical or asymptomatic manifestations can contribute to the spread of the disease if the vectors that transmit the virus are present and active in the same area.
|Table I Major characteristics of the chikungunya virus|
|Means of transmission||Main mechanism:
Aedes aegypti or Aedes albopictus mosquito bites: widely distributed in the country. These are the same vectors that transmit dengue.
• Transplacental transmission from viremic mother to newborn during childbirth. Can cause infection in up to 50% of newborns, who may present severe forms of the disease
• Evidence is lacking, but miscarriages may occur in the first trimester. Newborn does not acquire immunity through mother.
• Exposure in laboratory Note: There is no evidence of the virus in breast milk
|Reservoir||Humans are the main reservoir of the CHIKV during viremic phase (first 5 days of onset of symptoms).|
|Incubation period||Mosquitoes acquire the virus from a viremic host and for 10 days can pass it on to a susceptible person, who will begin to have symptoms after an intrinsic incubation period of 3-7 days (range: 1-12 days)|
|Ecosystem features that favor transmission||Tropical weather favoring mosquito breeding, especially during the rainy season which multiplies the breeding grounds. Other factors related to human activity, urbanization, and poor access to constant water sources forcing families to store water in containers and other objects, poorly covered or left outdoors.|
|Susceptibility/immunity||It is a new disease so the entire population of the country - children, women, and men - are susceptible to infection. Then the people exposed to the virus develop prolonged immunity which protects them against reinfection.|
|Source: Guía de manejo clínico para la infección por el virus chikunguña (CHIKV). Santo Domingo, Dominican Republic, May 2014|
Scenario 1. Typical acute manifestations
After CHIKV infection, a silent incubation period of two to four days takes place (range 1 to 12 days). After this short period, the acute period of the disease occurs abruptly (Table II), which coincides with the maximum viremia:2,11,18,20,21
|Table II Frequency of symptoms of acute infection with CHIKV|
|Symptom or sign||Frequency|
|Source: Taken from PAHO/WHO/CDC. Preparedness and response for chikungunya virus introduction in the Americas|
Scenario 2. Subacute and chronic manifestations
After the acute episode of 7-10 days, a high percentage of patients begin the chronic phase of the disease.2,11,13,20,21 This is manifested by:
Figure 5 Articular manifestations of CHIKV
Scenario 3. Atypical manifestations
Atypical cases can be presented (about 0.3% of cases) with specific clinical manifestations:2-4,11
Scenario 4. Manifestations in the newborn
In most CHIKV infections that occur during pregnancy, the virus is not transmitted to the fetus. The highest risk of transmission is when the woman is infected in the intrapartum period, at which point vertical transmission can reach 49%. Cesarean section does not seem to prevent this transmission.2,11,13,24,25
Children are usually born asymptomatic and then develop:
Scenario 5. Severe clinical manifestations of the disease
The main complications that are associated described the chikungunya are:2,13
Most of these manifestations are seen in patients over 65 years and in this group lethality may be moderate to severe. High risk groups include:
The diagnosis is first established on the basis of clinical signs and epidemiology of the disease.2-4,8 To diagnose chikungunya three main types of tests (Table III) are used:
|Table III Laboratory tests for chikungunya|
|Test||Time after illness|
|Viral culture||First 3 days|
|RT-PCR||Between days 1 and 8|
|Analysis of IgM antibodies||Between day 4 and 2 months|
|IgG or neutralizing antibody test
showing increase in titers
|Two samples separated by 14 days, from day 7|
|Source: CDC. Information for clinicians: http:/ www.cdc.gov/chikunguña/pdfs/CHIKV_Clinicians.pdf|
The highest concentrations of IgM are recorded between three and five weeks after disease onset and persist for about two months. Samples are usually from blood or serum, but in neurological cases cerebrospinal fluid (CSF) can be obtained.
The virus can be isolated in the blood in the first days of the infection. The choice of appropriate laboratory test is based on the origin of the sample (human or mosquitoes collected in field) and the time of sample collection relative to the onset of symptoms (in the case of samples of human origin).
Virus isolation may be done with mosquitoes collected in the field or with serum samples from the acute phase (≤ 5 days). Serum obtained from whole blood collected during the first week of the disease and transported to the laboratory cold (between 2 ° and -8 °C or dry ice) as quickly as possible (≤ 48 hours), can be inoculated in a susceptible cell line or suckling mice. Chikungunya produces typical cytopathic effects (CPE) within three days after inoculation in a variety of cell lines including Vero, BHK-21 and HeLa cells. Virus isolation can be done in T-25 culture flasks or shell vials. It should be confirmed either by immunofluorescence (IF) using antiserum specific to CHIKV, or by RT-PCR from the culture supernatant or mouse brain suspension. Viral isolation should only be performed in laboratories with Biosafety Level 3 (BSL-3) to reduce the risk of viral transmission.
There have been various diagnostic RT-PCR tests for detecting CHIKV RNA. Real-time testing with closed system must be used because these have greater sensitivity and reduced risk of contamination.
Different protocols (primers and probes) exist for detecting CHIKV by RT-PCR (both conventional and in real time). Given the sensitivity, the protocols used by the Center for Disease Control and Prevention (CDC) and the Pasteur Institute (sequences available at http://wwwnc.cdc.gov/eid/article/13/5/pdfs/07-0015.pdf and http://wwwnc.cdc.gov/eid/article/14/3/pdfs/07-0906.pdf) are recommended. These protocols should be standardized and validated for local diagnostic use.
The determination of IgM may be performed by different commercially available techniques (ELISA or IFA). However, it should be noted that the best sensitivity is given by those using the whole virus as antigen compared with those using recombinant proteins (or peptides). It is recommended to implement the in-house technique ELISA IgM/IgG, using the purified viral antigen according to the protocols described by the CDC, since commercially available kits have not been sufficiently evaluated. The use of rapid testing is not recommended.
Given that chikungunya is emerging in the Americas (in addition to its infectious potential), viral isolation should be attempted in conditions of BSL-3 biosafety.
Time of collection:
To collect serum:
Sending sample to reference laboratory
The Laboratorio de Arbovirus y Virus Hemorrágicos at the Instituto de Diagnóstico y Referencia (InDRE) is the national reference laboratory and policy director for the diagnosis of chikungunya in Mexico.8
For sending samples to InDRE, the following specifications must be considered:
The basic triple packaging system is the use of a primary container, which contains the biological sample (serum). The primary receptacle (e.g. cryotubes) must be hermetically sealed to prevent sample spillage and must be fully labeled with patient name or sample number. It must also be surrounded with absorbent material such as gauze or paper towel, and placed in a secondary, hermetic, spill-proof and shock-proof container. If multiple primary containers are placed in a secondary container, it is necessary to use a rack and absorbent material to prevent leakage. Note that within the secondary container (cooler) there must be sufficient cooling to maintain a temperature of 2-8 °C. Secondary containers must be marked with the orientation of the container, and in its turn the secondary container must be contained in an outer shipping package (cardboard box or cooler) to protect the contents from external environmental elements and which must be labeled with information of the sender, recipient, and targeting signal. The documentation included in the triple packaging must be affixed to the inside of the package.
Other types of samples for laboratory examination
The indigenous cases must be reported to WHO, in collaboration with an epidemiologist, according to the International Health Regulations (IHR).
Differential diagnosis must take into account epidemiological characteristics, such as place of residence, history of travel, and exposure. Clinically it is difficult to differentiate from dengue; however, in chikungunya infection the pain is much more intense and localized on the joints and tendons, and in some cases could be disabling. Importantly, the two diseases are transmitted by the same vector, have similar clinical manifestations, and can even occur at the same time in the same patient.2,3,8,11
It is essential to distinguish chikungunya from dengue, which can have a more torpid evolution and can even cause death.
In chikungunya fever, shock, or severe bleeding are seldom observed; the onset is more acute and the duration of fever is much less. Maculopapular rash is also more common in dengue. Although with both diseases patients may experience myalgia and arthralgia, the joint pain is more intense and localized in chikungunya fever (Table IV).2,8,22,23
|Table IV Clinical comparison between chikungunya disease and dengue|
|Fever (< 39oC)||+++||++|
|Source: taken from the Guía de manejo clínico para la infección por el virus chikunguña (CHIKV). Santo Domingo, Dominican Republic, May 2014.|
Other diseases to be considered in the differential diagnosis are:
Treatment of chikungunya fever is primarily symptomatic; there is no specific antiviral drug treatment. Symptomatic treatment is recommended after excluding more serious diseases such as malaria, dengue, and bacterial infections.
Treatment consists mainly of relieving symptoms, including joint pain, with antipyretics and optimum liquid analgesics. Caution should be exercised in the use of steroids given the risk of reactivating rheumatological manifestations after their retirement. One should avoid using aspirin for risk for developing Reye’s syndrome in children under 12 years.2-4,11
Treatment of typical cases of disease caused by CHIKV in acute phase
In patients with subacute and chronic disease, although recovery is the expected result, the period of convalescence may be prolonged (sometimes up to a year or more) and persistent joint pain may require analgesic treatment, including prolonged anti-inflammatory therapy.
Treatment for subacute phase
Treatment for chronic phase
The symptomatic response to treatment is slow and has a high tendency to recurrence and chronicity at the level of articulation. It has been suggested that chloroquine, which is able to reduce viral replication, could be effective in prophylaxis and treatment of the early stage of the disease, but its use in the chronic phase has not been proven effective. The disabling peripheral arthritis, which tends to persist for months, if refractory to other agents, may occasionally respond to short-term corticosteroids. In patients with refractory joint symptoms one can evaluate alternative therapies such as methotrexate. In addition to pharmacotherapy, cases with prolonged joint pain and stiffness can benefit from a progressive program of physiotherapy. Movement and moderate exercise tend to improve morning stiffness and pain, but intense exercise may exacerbate symptoms.11,14-16
Patient care in health services by levels of complexity
a) In the first level of care it is recommended to:
The benchmarks are:
b) In the second level of care it is recommended to:
c) In the third level of care it is recommended to:
The main purpose of surveillance is to detect cases of chikungunya disease in a timely manner. Early detection allows for suitable response and characterization of the outbreak and identification of viral strains in circulation.2,5
Strengthen existing sites for sentinel surveillance of febrile syndrome, so they can detect cases of chikungunya. Tests for chikungunya should be done in the national reference laboratory in a percentage of patients with fever and joint pain, or fever and arthritis of unknown etiology (e.g. negative tests for malaria or dengue). To ensure that appropriate laboratory tests are carried out and monitoring capacity is maintained, laboratories must join the established network of laboratories for testing and eventual distribution of supplies.
Once an indigenous case of chikungunya disease is detected, a thorough epidemiological investigation should be done in order to:
Individuals can reduce their risk of infection by using personal repellents on skin or clothing. DEET (N, N-diethyl-meta-toluamide) and picaridin (aka KBR3023) are effective repellents widely available in the Americas. Young children and others who sleep or rest during the day should use mosquito nets to prevent infection transmitted by Aedes aegypti and Aedes albopictus, as both mosquitoes bite during the day.2,3,5
It is particularly important during an outbreak that individuals potentially infected with chikungunya rest under the protection of a mosquito net treated with insecticide (TI) to avoid mosquito bites and the subsequent spread of infection. The use of mosquito nets TI has the added benefit of killing the mosquitoes that make contact with the net, which can reduce the vector-human contact for other inhabitants of the house.
Prevention in the home
The use of screens in windows and doors reduces the input vectors to housing, and mosquito-proof water storage containers reduce oviposition sites and local production. Inside a house, use of mosquito nets TI and curtains TI also reduces vector-human contact.
The number of adult mosquitoes in the home can be reduced using pyrethroid aerosol sprays and other commercially available products designed for the home, such as mosquito coils and electric vaporizers. The aerosol spray can be applied throughout the house, but it should focus on areas where adult mosquitoes rest (dark and cooler areas) including bedrooms, closets, clothes baskets, and so on. In making recommendations to the public, it is important to emphasize the proper use of these products to reduce unnecessary exposure to pesticides.2,5,8
Recommendations for patient isolation
To avoid infecting others in the home, the community, or the hospital, it is important to keep the patient with acute chikungunya disease from being bitten by Aedes aegypti or Aedes albopictus mosquitoes during viremia, which is usually the first week of the disease. As these mosquitoes bite during the day, from dawn to dusk, and even after dark if there is artificial light, it is highly recommended to protect oneself with nets TI or to stay in a place protected with screens.2,8,11,21
In addition, doctors or health workers who visit patients infected by chikungunya should avoid mosquito bites by using insect repellent and wearing long sleeves and pants.
Prevention and control rely heavily on reducing the number of deposits of natural and artificial water that can serve as breeding ground for mosquitoes.
During outbreaks, insecticides can be applied either by spraying to kill mosquitoes in flight, or on the surfaces of tanks or around them, where mosquitoes land; insecticides can also be used to treat water tanks to remove immature larvae.
For protection during outbreaks it is recommended:
With the increase of cases of chikungunya in the Caribbean region and the risk of introduction of the virus into the country by major population movements and vectors in large parts of the country, the following is recommended:
To identify suspected cases of chikungunya virus it is recommended to:
With the occurrence of outbreaks
In Mexico, 1st priority is determined as the Yucatan peninsula (Figure 6) because of risk of local transmission in the Caribbean.
Figure 6 The Yucatan Peninsula is determined as 1st priority. Source: Centro Nacional de Programas Preventivos y Control de Enfermedades (CENAPRECE)
Actions and functions with suspected cases by administrative technical level
Care and epidemiological surveillance activities carried out by these units (local health centers/hospital units) for the surveillance of chikungunya fever are:
Currently, chikungunya fever virus is an emerging disease in the Americas. Because the risk of introduction of chikungunya to the region is high, because of importation from travel, the presence of competent vectors (the same vectors as dengue), and the susceptibility of the population, advance preparation is essential.
The disease occurs three to seven days after the bite of an infected mosquito, and it can last as long in the acute phase. The symptoms that occur during this period include: fever above 39 °C, severe joint pain, headache, back pain, myalgia, nausea, maculopapular rash, conjunctivitis, and even arthritis. Risk groups include children, the elderly, and pregnant women. So far, there is no preventive vaccine or antiviral treatment specific to the disease, so the recommended prevention measures are to avoid mosquito contact and bites, to use insect repellents, to not stay out in the open without protection, to prevent mosquitoes entering the home (put screens on doors and windows), and to keep the yard free of tires, cans, bottles, or any object in which water might stagnate and mosquitos appear.
Notably, the timely detection of cases and proper and prompt response with the active participation of all stakeholders will be needed to minimize the risk of importation and sustained transmission of chikungunya in our country.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.
Algorithm 1 Notification of a suspected outbreak by chikungunya
Algorithm 2 Diagnosis for the chikungunya virus