Open Journal Systems

CLINICAL INSTRUMENTS

Received: August 19^th 2014
Accepted: November 10^th 2014

Technical guidelines for the prevention and treatment of chikungunya fever

Antonio Barrera-Cruz,^a Rita Delia Díaz-Ramos,^b Arturo Viniegra-Osorio,^c Concepción Grajales-Muñiz,^d Javier Dávila-Torres^e

^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
Email: antonio.barrera@imss.gob.mx

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

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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

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.

Epidemiology

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

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).

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:

• Pre-epidemic scenario: the absence of virus circulation in the presence of risk factors that allow virus transmission and receptivity. Presence of cases of isolated non-viremic foreigners. 
• Epidemic scenario: presence of native and active viral transmission with more than one case in people who have not left Mexico.
• Endemic-epidemic scenario: presence of native viral transmission and detection of continued and active viral circulation with more than one case in people who have not left Mexico.

 

Transmission dynamics

Vectors

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

Reservoirs

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.

Incubation period

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

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

Objective(s)

General

1. Establish measures for prevention, detection, and timely response to CHIKV outbreaks through surveillance, case detection, research, and implementation of relevant public health actions.

Specific

1. Identify the different clinical manifestations of CHIKV, by clinical phases, classification, and expected frequency, according to the epidemiological behavior of the disease.
2. Define the criteria and means for the diagnosis of CHIKV fever and atypical cases, differential diagnosis with other prevalent diseases, and its treatment by clinical phases.
3. Prepare health services for the care of chikungunya fever cases in the different levels of care.
4. Guide the decisions of health personnel for appropriate referral of atypical or severe cases to second and third levels of care.
5. Promote and develop strategies and institutional coordination mechanisms for the implementation of actions for health promotion, prevention, and immediate response to the possible presentation of cases or outbreaks of chikungunya fever.

Scope of application

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.

Operational case definitions

1. Suspected case: any person with fever > 38.5 °C and acute onset arthritis or severe arthralgia not explained by other medical conditions, living or visiting areas with transmission of chikungunya virus during the two weeks before onset of symptoms, or who has contact with a confirmed case, or who has an epidemiological link to the areas of transmission.
2. Confirmed case: any suspected case with a positive result for chikungunya virus from one of the following specific laboratory tests:
• Viral isolation
• Detection of ribonucleic acid (RNA) by real time RT-PCR in serum samples taken within the first five days of onset of fever.
• Detection of IgM antibodies in serum sample after the sixth day of onset of fever.
• Detection of IgG antibodies in paired serum samples. An increase of at least four times in the titer of antibodies specific to CHIKV should be found. Two samples are required with a difference of at least one week between the first and second.
3. Eliminated case: any case in which there is no proven evidence of the presence of any virological or serological marker for CHIKV by proven laboratory techniques.

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

Case type

1. No cases: absence of both imported and indigenous cases.
2. Imported cases: cases from other countries that enter the country during the period of communicability and/or clinical stage of the disease.
3. Indigenous cases: cases originating in Mexico in people who have not left the country for at least two weeks before presenting symptoms.

Clinical scenarios

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.

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}

1. Sudden onset of high fever (> 39 °C). This lasts between 3 and 10 days. It may be continuous or intermittent.
2. The fever is accompanied by symmetrical joint pain of varying intensity, which occurs more frequently in hands and feet, but can also affect more proximal joints. One might also observe swelling, often associated with tenosynovitis. In some cases pain is so intense that it produces functional disability.
3. Erythema usually occurs between two and five days after the onset of fever in about half of patients. It is typically maculopapular and includes trunk and extremities; it can affect the palms, soles of feet, and face. The rash can also appear as a diffuse erythema that blanches with pressure. In young children, vesiculobullous lesions are the most common skin manifestations.
4. Ophthalmological manifestations include: anterior and posterior uveitis, and retinal vasculitis with benign course with resolution between 6 and 8 weeks.
5. No significant hematologic pathognomonic findings are observed in CHIKV infection. Abnormal laboratory findings may include mild thrombocytopenia (> 100,000/mm³), leukopenia, lymphopenia, and elevated liver function tests. Erythrocyte sedimentation rate and C-reactive protein are usually high.
6. Less common manifestations include: myopericarditis, meningoencephalitis, and massive toxic hepatitis.
7. Other symptoms include: headache, back pain, myalgia, nausea, vomiting, and conjunctivitis. There have been multiple, bilateral supraclavicular lymphadenopathies less than 0.5 cm.

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:

1. Polyarthritis/polyarthralgia of persistent or intermittent course, and subacute hypertrophic tenosynovitis of wrists and ankles, accompanied by morning stiffness and fatigue. These symptoms are more common two or three months after the onset of the disease, and persist even three years after disease onset.
2. The arthritis has a symmetrical and distal polyarticular pattern, with or without migration pattern involving hands, wrists, and ankles. It less often affects the elbows, knees (Figure 5), shoulders, hips, and temporomandibular.




Figure 5 Articular manifestations of CHIKV



3. Enthesopathy, heel pain, and chondrosternal pain occur less frequently.
4. Another manifestation described is digital tenosynovitis of the wrists and ankles, which may be severe, contributing to the development of carpal tunnel syndrome.
5. Some patients may also develop transient peripheral vascular disorders such as Raynaud's syndrome.
6. Depressive symptoms, general fatigue, and weakness are other symptoms that characterize this scenario.
7. There are generally no significant changes in laboratory tests or X-rays of the affected areas. However, some patients develop arthropathy/destructive arthritis, similar to rheumatoid or psoriatic arthritis. The prevalence of rheumatoid factor positivity in the chronic phase of the disease varies between 25 and 43%, and positivity for anti-citrullinated antibodies is lower.

Scenario 3. Atypical manifestations

Atypical cases can be presented (about 0.3% of cases) with specific clinical manifestations:^2-4,11

1. Neurological: meningoencephalitis, encephalopathy, seizures, Guillain-Barre syndrome, cerebellar syndrome, paresis, paralysis, neuropathy.
2. Optical: optic neuritis, iridocyclitis, episcleritis, retinitis, uveitis.
3. Cardiovascular: myocarditis, pericarditis, heart failure, arrhythmias, hemodynamic instability.
4. Dermatologic: photosensitive hyperpigmentation, intertriginous ulcers similar to canker sores, vesiculobullous dermatosis.
5. Other: blood dyscrasias, pneumonia, respiratory failure, hepatitis, pancreatitis, syndrome of inappropriate of antidiuretic hormone secretion (SIADH), hypoadrenalism.

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:

1. Fever, loss of appetite, pain, peripheral edema.
2. Various skin manifestations (maculopapular rash, vesicles, or bullae).
3. Those who become infected in the intrapartum period can also develop neurological disease (meningoencephalitis, white matter lesions, cerebral edema, and intracranial hemorrhage), bleeding symptoms, and myocardial disease.
4. Laboratory findings include elevated liver function tests, thrombocytopenia, lymphopenia, and reduced prothrombin levels. Infants who suffer neurological disease generally develop long-term disabilities.

Scenario 5. Severe clinical manifestations of the disease

The main complications that are associated described the chikungunya are:^2,13

1. Respiratory failure.
2. Cardiovascular decompensation.
3. Meningoencephalitis.
4. Other problems of the central nervous system.
5. Acute hepatitis.
6. Severe skin manifestations (desquamation and bullous lesions).

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:

• Infants (from viremic mothers with or without symptoms) during delivery or in the last four days before delivery.
• Children under one year.
• Adults over 65 years.
• Persons with comorbidities: diabetes, hypertension, cardiovascular disease, or chronic renal failure, as well as people living with HIV/AIDS, tuberculosis, cancer, or hematologic diseases.

Clinical and laboratory diagnosis

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:

1. Serology.
2. Virus isolation.
3. Reverse transcriptase polymerase chain reaction (RT-PCR).

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.

Additional notes

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.   

• The second sample for serological determination must be taken one to two weeks after the first sample. Confirmation will be given by seroconversion (IgM/IgG) or fourfold increase or more in the neutralizing antibody titer in paired samples.
• According to eco-epidemiological conditions, each country should consider the need to include within the detection algorithms other arboviruses that can complement differential diagnosis (e.g. Mayaro).

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. 

Collecting samples for serology, viral isolation, and molecular diagnosis

Serum samples

Time of collection:

• Acute phase: within the first five days of the onset of fever, detection of viral RNA shall be done by RT-qPCR.
• Convalescent phase: within 6-12 days of the onset of fever, determination of IgM antibodies shall be done.

To collect serum:

1. Collect aseptically 4-5 ml venous blood in a tube or vial. Allow blood to clot at room temperature, centrifuge at 2000 rpm to separate serum.
2. Collect serum in a clean, dry vial.
3. All clinical samples must be accompanied by clinical and epidemiological information.

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

1. Send (if possible) with dry ice; at the least, ensure the cold chain with cooling gels.
2. Send during the first 48 hours.
3. Always send clinical and epidemiological profile completely filled out.

Criteria for acceptance and rejection of samples

Acceptance criteria

For sending samples to InDRE, the following specifications must be considered:

1. They should be included in a primary container (1.5 ml Eppendorf vials or 2.0 ml cryovials), duly identified, and secondary and tertiary containers (InDRE shipments). (One must take into account that for the differential diagnosis of arbovirus and bacteria, if applicable, a higher volume than that indicated will be needed, and it is recommended in such cases to obtain at least two tubes of 5 ml of whole blood for about 4-5 ml serum). 
2. The operational definition of a suspected case must be met.
3. They must be accompanied with the unique form for sending samples, and a copy of the epidemiological study.

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.

Definitive rejection criteria

1. Sample is of insufficient amount (less than 2.0 ml).
2. Failure of cold chain.
3. Tube container without information. Shipping to InDRE should be only in Eppendorf tubes or cryovials. No samples will be received in a glass tube or vacutainer.
4. Lacking epidemiological study or unique sample submission form.
5. Forms incompletely filled out.
6. Delay in the time set for sending samples to the state laboratory (15 days from sampling to reception at the LESP or InDRE).

Other types of samples for laboratory examination

1. CSF in case of meningoencephalitis.
2. Synovial fluid in case of arthritis with effusion.
3. Autopsy material (serum or tissue available).

Transport of samples

• Transport samples to the laboratory (which oscillate between 2 and 8 °C in portable refrigerator) as quickly as possible.
• Do not freeze whole blood, as hemolysis may interfere with the results of serological tests.
• If more than 24 hours delay is anticipated for sending samples to the laboratory, the serum must be separated and kept refrigerated.  
• Serum samples for virus isolation and molecular diagnosis should be stored frozen (at -20 °C for short-term storage or -70 °C for long-term storage).²

Results that confirm recent chikungunya infection

1. Isolation of chikungunya, including confirmatory identification (either by immunofluorescence, RT-PCR, or sequencing).
2. Chikungunya RNA detection by RT-PCR in real time.
3. Identification of a positive result of IgM in a patient with acute symptoms of chikungunya, followed by the demonstration of CHIKV specific antibody by plaque reduction neutralization test (PRNT) with virus from the Semliki Forest virus (SFV) serogroup.   
4. Demonstration of seroconversion or fourfold increase in PRNT, HI, or ELISA titers (again using other viruses from SFV serogroup) among the samples obtained in acute and recovering phases.²

The indigenous cases must be reported to WHO, in collaboration with an epidemiologist, according to the International Health Regulations (IHR).

Differential diagnosis

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

Other diseases to be considered in the differential diagnosis are:

1. Leptospirosis.
2. Malaria.
3. Rash diseases of childhood.
4. Primary infection by HIV.
5. Infectious mononucleosis.
6. Juvenile idiopathic arthritis.
7. Post-infectious arthritis.

Treatment

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

• Identify warning signs and benchmarks.
• Bed rest.
• Normal diet for age plus plenty of liquids:
• Adults: plenty of fluids orally (at least five glasses of 250 ml or more per day, for an average adult of 70 kg).
• Girls and boys: plenty of fluids orally (milk, fruit juices, with caution in diabetics), oral serum (oral rehydration salts, ORS). Caution should be exercised with the exclusive use of water for rehydration, as it can cause electrolyte imbalance. The amount prescribed should be marked in glasses (250 ml), ounces, or liters.
• Treat fever: paracetamol is indicated. Adults 500-1000 mg to 4 grams per day, every 6 hours, and children under 5 years 10-15 mg/kg/dose every 6 hours.
• To treat pain and inflammation: if joint pain persists after the seventh day of disease onset, nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated, according to age and weight: diclofenac, ibuprofen or naproxen, after eliminating history of allergy.
• To treat rash and itching: lotions are indicated based on zinc oxide, and refreshing and moisturizing lotions with aloe vera, menthol, and camphor as well as commonly used antihistamines (such as diphenhydramine or loratadine, among others).
• Assess hydration status (diuresis, skinfold signs, enophthalmos or sunken eyes, dry mucous membranes) and recommend ORS if necessary.
• Recommend rest.
• Inform the patient about warning signs, home care, and prevention of transmission (use of mosquito nets, repellents, and protective clothing).
• DO NOT use topical or systemic corticosteroids.
• The use of aspirin is NOT recommended because of the risk of bleeding in a small number of patients and the risk of developing Reye's syndrome in children under 12 years of age.

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

• Encourage bed rest.
• Inform the patient about the duration of the disease.
• Indicate the use of NSAIDs.
• Recommend the use of antihistamines to relieve itching.
• Indicate the use of skin moisturizers.
• Suggest that the patient avoid using steroids (topical and systemic), aspirin, antibiotics, and self-medication.

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:

• Conduct outpatient management for typical cases without warning signs.
• Inform the public about warning signs, prevention, and care in the home and community.
• Assess the patient's hydration status and manage adequate rehydration therapy as needed.
• Evaluate hemodynamic status. Stabilize and immediately refer patients with slow capillary filling, decreased pulse, hypotension, oliguria, altered senses, or hemorrhagic manifestations.
• Treat symptoms (paracetamol).
• Consider referral of patients at higher risk of complications (people over 60, with chronic illnesses, pregnant women, and young children).
• Identify warning signs and benchmarks.

The benchmarks are:

• Diagnostic doubt with a specifically treatable disease.
• Fever that persists for more than five days.
• Persistent pain.
• Postural dizziness, cold extremities.
• Decreased production of urine.
• Any subcutaneous hemorrhage or through any hole.
• Persistent vomiting.
• Pregnancy.
• People over 60 years of age and newborns.
• Anyone with neurological signs or symptoms, including irritability, drowsiness, severe headache, or photophobia.

b) In the second level of care it is recommended to:

• Evaluate the patient to determine the presence of kidney failure, neurological signs and symptoms, liver failure, heart disease, thrombocytopenia, and malaria.
• Evaluate hemodynamic status and assess the presence of dehydration; administer appropriate supportive treatment and rehydration therapy as appropriate.
• Consider lumbar puncture in suspicion of meningitis.
• Take blood samples for serological tests for chikungunya and other diseases considered in the differential diagnosis (e.g. dengue).
• Review the history of present illness and assess if the patient has warning signs compatible with severe dengue. If so, administer appropriate supportive treatment in a unit that can monitor vital signs every hour during the critical phase.
• Refer to third level patients with any of the following conditions: pregnancy, oliguria/anuria, refractory hypotension, clinically significant bleeding, altered senses, meningoencephalitis, persistent fever over one week, and signs of decompensation of underlying diseases.

c) In the third level of care it is recommended to:

• Ensure that all the procedures mentioned above have been completed and that there is a comprehensive medical team to assist in the management of patients with serious or atypical disease.
• Take blood samples for serology and/or RT-PCR (see laboratory section for more specific facts on tests for CHIK).
• Consider other rheumatic diseases (e.g. rheumatoid arthritis, gout, rheumatic fever) or infectious diseases (e.g. viral or bacterial meningoencephalitis).
• Treat serious complications (for example, the use of transfusions for bleeding disorders or dialysis for acute renal failure).
• Evaluate and recommend disability rehabilitation therapies.
• Given the intensity of pain and potential long-term pain produced by CHIKV disease, treatments must be available for pain and psychological assistance, and one must consider the development of protocols, equipment, and facilities for chronic pain management.
• Consider autopsy with pathologist intervention for any patients who have died.

Surveillance methods

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

Preparation phase

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.

Response phase

Once an indigenous case of chikungunya disease is detected, a thorough epidemiological investigation should be done in order to:

• Track the spread of the virus.
• Monitor the possible introduction of the virus into surrounding areas.
• Describe the epidemiology and key clinical signs.
• Evaluate the clinical severity and impact on society (e.g. days lost from work, school closings, etc.).
• Identify risk factors for infection or serious illness.
• Identify lineages of chikungunya in circulation.

Prevention and control

Personal protection

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:

1. Wear clothes that minimize skin exposure to vectors.
2. Apply repellents to the skin or to clothing in strict accordance with the instructions for use of the product. Repellents should contain DEET, IR3535 (ethyl ester of 3-[N-butyl-N-acetyl]-aminopropionic) or icaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester).
3. People traveling to risk areas should take basic precautions, such as using repellent, long pants, and long-sleeved shirts, or installing screens on windows.

Recommendations from WHO/PAHO

1. Due to the high Aedes aegypti infestation and presence of Aedes albopictus in the region, it is recommended that prevention and control be aimed at reducing vector density, seeking the acceptance and cooperation of local people in deciding these measures.
2. Have a program of effective and operational control for dengue to provide the basis for adequate preparation against chikungunya virus.
3. Intensify recommendations for the epidemiological surveillance and control for dengue management as part of the integral management strategy.
4. Incorporate into the integrated vector management (IVM) scheme a program of independent quality control which must have participation and inter-sectoral collaboration at all levels of government and health, education, environment, social development, and tourism agencies, as well as seeking the participation of the whole community.⁷

Recommendations in Mexico

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:

1. Maintain and strengthen epidemiological surveillance for early detection of cases, in order to avoid the occurrence of outbreaks and deaths.
2. Strengthen epidemiological and entomological surveillance with ongoing activities in dengue risk areas inhabited by transmitting vectors of chikungunya virus.
3. Train health staff in surveillance procedures for the chikungunya virus, specifically in the detection and monitoring of cases, clinical care, and promotion, prevention, and control.
4. Emphasize the importance of mandatory reporting of the disease and compliance with specific monitoring procedures established in the Norma Oficial Mexicana NOM-017-SSA2-2012 for Epidemiological Surveillance.¹⁰
5. Implement the diagnosis of chikungunya virus in each federal LESP entity.^7,8

To identify suspected cases of chikungunya virus it is recommended to:

1. Verify that clinical and epidemiological assessment meets the operational definition of cases.
2. Conduct immediate notification of cases at all technical and administrative levels within the first 24 hours of awareness by health services.
3. Have a record of all suspected and confirmed cases.
4. Make appropriate and timely epidemiological case studies.
5. Perform active search in risk areas.
6. Take samples exclusively in cases that meet operational definition who also have a history of travel and exposure to the virus in countries where its circulation has been reported.
7. Serum sample should be taken within the first five days from the onset of symptoms (RT-PCR in real time) for virological surveillance and, if this is impossible, serum sample should be taken between the sixth and tenth day (serology) in accordance with the provisions of the guidelines for the diagnosis of dengue virus.
8. Perform laboratory tests for chikungunya at InDRE.
9. Follow up cases until final classification.
10. In all suspected cases it is necessary to immediately strengthen prevention and control.

With the occurrence of outbreaks

1. Immediately notify higher administrative levels.
2. Fill out and submit the outbreak study form within the first 48 hours of being aware of it, and constantly monitor its evolution until final resolution.
3. Keep all technical and administrative levels updated on the epidemiological situation of the disease.
4. Strengthen inter-agency and inter-sectoral coordination for vector control measures to reduce vector density, with community participation as recommended by PAHO.
5. Strengthen health promotion actions with emphasis on self-care.
6. Disseminate this information to all health units in the state to target detection and proper management of possible cases, to the Comité Estatal para la Vigilancia Epidemiológica (CEVE), and to state or regional offices of health sector institutions.
7. Follow up on the recommendations of this epidemiological warning through Comités para la Vigilancia Epidemiológica and state or regional offices of the institutions of the Sistema Nacional de Salud.

Risk areas

In Mexico, 1st priority is determined as the Yucatan peninsula (Figure 6) because of risk of local transmission in the Caribbean.

• Ports of entry for international travelers.
• Priority to industrial and tourist centers.
• Big cities with high frequency of international flights.

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:

1. Provide medical care to cases.
2. Verify that the patient meets the operational definition of a case to establish initial diagnosis.
3. Immediately report cases of chikungunya fever to jurisdiction/district level.
4. Promptly report all suspected cases through the "Weekly report of new disease cases" (SUIVE-1).
5. Conduct investigation of the case by completing the ETV epidemiological study on all patients who meet the operational definition.
6. Keep track of the cases identified in the unit.
7. Send copy of fully completed epidemiological study to the health jurisdiction/delegation for proper capture.
8. Continuously update information available according to clinical, epidemiological, or laboratory information.
9. Ensure the quality of sampling on the first contact with health services, according to the following criteria:
   
   a) Sampling (for serum) exclusively in cases that meet operational definition. Those who are in the first five days of symptom onset shall be analyzed by RT-PCR molecular tests in real time, and from the sixth to the twelfth day they shall be analyzed by serology (IgM ELISA).
   b) In the absence of outbreaks or periods of low transmission, 100% of suspected cases of chikungunya fever should be sampled, in order to opportunely identify the occurrence of cases.
   c) One the existence of outbreaks is demonstrated, 30% of suspected cases of chikungunya fever should be sampled.
   
   
10. Send the samples to the Health District, LESP, or municipality as appropriate, accompanied by a copy of the epidemiological study.
11. In primary care units, instructions should be given to the patient or patient’s caregiver about the worsening signs and symptoms of chikungunya fever as well as the conduct to be followed and which second or third level units they will be referred to if needed.
12. The cases with negative results for chikungunya fever should get differential diagnosis with dengue.
13. Follow up the case until its final classification.
14. Immediate notification of outbreaks (occurrence of two or more related cases in a defined geographical area) by the most expeditious means to the highest level, successively up to the national level and accompanied by the appropriate forms duly filled-out.
15. Participate in outbreak investigation and provide information necessary for analysis and filling out the corresponding outbreak study form.
16. Report deaths suspected by chikungunya fever to the next level up within the first 24 hours. The notification must include the signs and symptoms that confirm the operational definition of chikungunya fever.
17. Attending staff of the medical unit should obtain a (complete, visible, legible) copy of the medical file and send it to the relevant health jurisdiction, which in turn should send a copy to the Dirección General de Epidemiología (of the Secretaría de Salud) in a period not exceeding five days after the detection of the death.
18. Strengthen inter-agency and inter-sectoral coordination for vector control measures aimed at reducing vector density affecting environmental factors through sanitation activities with community participation.
19. Strengthen anticipatory actions to promote health.

Conclusions

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.

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