REVIEW ARTICLES

Received: November 19^th 2014

Accepted: December 18^th 2015

Technical Guidelines for the prevention, diagnosis and treatment of Zika virus infection

Antonio Barrera-Cruz,^a Rita Delia Díaz-Ramos,^a Ana Belem López-Morales,^a Concepción Grajales-Muñiz,^b Arturo Viniegra-Osorio,^a Jaime Antonio Zaldívar-Cervera,^c José de Jesús Arriaga Dávila^d

^aCoordinación Técnica de Excelencia Clínica

^bDivisión de Vigilancia Epidemiológica de Enfermedades Transmisibles, Coordinación de Vigilancia Epidemiológica

^cCoordinación de Unidades Médicas de Alta Especialidad

^dDirección de Prestaciones Médicas

Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Antonio Barrera-Cruz

Teléfonos: (55) 5553 3589; 5726 1700, extensión 14044

Email: antonio.barrera@imss.gob.mx

Infection Zika virus is an emerging disease in the Americas region, which is caused by Zika virus (ZIKV), an arbovirus of the flavivirus genus. The ZIKV is transmitted by the bite of Aedes mosquitoes, both in urban and jungle area. After the mosquito bite, the disease symptoms usually appear after an incubation period of three to twelve days. The infection may be asymptomatic or presented with fever and not purulent conjunctivitis, headache, myalgia, arthralgia, asthenia, maculopapular rash, edema in lower limbs and, less frequently, retro-orbital pain, anorexia, vomiting, diarrhea or pain abdominal. Symptoms last for 4-7 days and are self-limiting. Neurological and autoimmune complications are rare. Since 2014 it has been detected native circulation of Zika virus in the Americas. So far, there is no specific antiviral treatment or effective vaccine, so it´s giving priority symptomatic and supportive treatment for the acute phase and make an early diagnosis of atypical and severe forms.

Zika virus infection (ZIKV) is an emerging disease caused by the virus of the same name, similar to the viruses that cause dengue, yellow fever, Japanese encephalitis, chikungunya fever, St. Louis encephalitis, or West Nile fever. ZIKV is transmitted by the bite of Aedes mosquitoes, both in an urban area (A. aegypti), and the jungle.¹

The species Aedes aegypti is confined to tropical and subtropical areas, while the species Aedes albopictus is present in temperate, and even temperate-cold regions. In recent decades Ae. albopictus has left Asia and established itself in parts of Africa, Europe, and the Americas.²

Compared to Ae. aegypti, the species Ae. albopictus thrives in a wider variety of pools of water that serve as breeding grounds, such as coconut shells, cocoa pods, holes in trees, puddles on rocks, plus artificial reservoirs such as vehicle tires or dishes under flowerpots. This diversity of habitats explains the abundance of Ae. albopictus in rural and peri-urban areas as well as in shady city parks. The Ae. aegypti species is more closely associated with houses and has hatcheries indoors, for example in vases, water containers, and water tanks in bathrooms, plus the same artificial outdoor habitats as Ae. albopictus.^1,2

Global epidemiological context of Zika virus

The virus was isolated for the first time on April 18^th, 1947 in the forests of Zika, in Entebbe, Uganda, in a Rhesus monkey during a study about the transmission of jungle yellow fever. In early 1948, as a result of entomological and virological surveillance, ZIKV was also isolated from Aedes africans mosquitoes caught in the same forest. Serological analysis confirmed infection in humans in Uganda and Tanzania in 1952, but it was in 1968 that the virus was isolated in samples from people in Nigeria. From 1951 to 1981 cases were reported in Tanzania, Egypt, Central African Republic, Sierra Leone, and Gabon, as well as Asian countries like India, Malaysia, Philippines, Thailand, Vietnam, and Indonesia. Subsequently the virus was identified in Senegal and Ivory Coast. Remarkably, genetic analyses have shown that there are two major lineages in the virus: African and Asian.^3-6

In 2007, the first major outbreak of ZIKV infection took place on the island of Yap (Micronesia) in the Pacific Ocean, with 185 suspected cases reported, of which 49 (26%) were confirmed, and 59 (32%) were considered likely. The outbreak lasted for 13 weeks (April to July). They were identified in nine of the ten communities on the island. The attack rate was 14.6 per 1000 inhabitants and a seroprevalence of 75% of the general population (prevalence overestimated, although certainly very high, due to cross-reactivity between antibodies directed against other arboviruses). 61% of cases were female patients and the median age was 36.^7,8

In late October 2013, an outbreak began in French Polynesia, also in the Pacific, in which 10,000 cases were identified. Of this total, approximately 70 were serious, with neurological complications (Guillain- Barré syndrome, meningoencephalitis) or autoimmune complications (thrombocytopenic purpura, leukopenia) in a context of simultaneous circulation of dengue virus. The related vectors were Aedes aegypti and Aedes polynesiensis. ZIKV detection has been reported in mosquitoes, primates, and humans in 14 countries across three continents (Africa, Asia, Oceania).^9,10  

In 2014, cases were reported in New Caledonia (belonging to New Zealand) and Cook Islands, both in the Oceania region. In the past seven years cases have been reported sporadically in travelers (Thailand, Cambodia, Indonesia, and New Caledonia).^11-13

On May 7^th, 2015, the Pan American Health Organization (PAHO) issued an epidemiological alert to member states to establish and maintain the capacity to detect and confirm cases of Zika virus infection, to treat patients, and to implement strategies to reduce the presence of the vector.^8,14

The true incidence of ZIKV infection is unknown, because the clinical manifestations are similar to infection with dengue virus, and reliable and simple diagnostic laboratory tests are lacking.

Epidemiological situation in America

Given the occurrence of outbreaks of ZIKV infection in Polynesia, starting in November 2013, the Chilean Ministerio de Salud started monitoring the behavior of the virus in the South Pacific Islands, which in February 2014 allowed public health authorities in Chile to confirm a case of indigenous transmission of ZIKV infection in Easter Island (Chile).^15-18

Since February 2015, national authorities in Brazil have confirmed ZIKV circulation in 14 states: Alagoas, Bahía, Ceará, Maranhão, Mato Grosso, Pará, Paraíba, Paraná, Pernambuco, Piauí, Rio de Janeiro, Rio Grande do Norte, Roraima, and São Paulo. This is the first time that cases of ZIKV infection were reported in Continental America.¹⁹ From February 2014 to January 17^th, 2016 18 countries and territories have confirmed indigenous circulation of ZIKV between 2015 and 2016: Brazil, Barbados, Colombia, Ecuador, El Salvador, Guatemala, Guyana, French Guyana, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Puerto Rico, San Martin, Surinam, and Venezuela. Between November 2015 and January 2016, the local transmission of the virus was detected in 14 new countries and territories.¹⁶

Recent outbreaks of ZIKV fever in different regions of the world demonstrate the potential of this arbovirus to spread through territories in which there is a vector for this virus (Aedes sp.) (Figure 1).²⁰   

Figure 1 Geographical distribution of countries with evidence of past or current Zika virus transmission (as of October 2015). Sources: Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases, Division of Vector-Borne Diseases

Situation in Mexico and transmission risk

In Mexico, according to the Sistema Nacional de Vigilancia Epidemiológica (SINAVE / DGE / SS), through January 8, 2016 three imported cases of ZIKV have been identified (Nuevo Leon, Queretaro, and Tamaulipas) and 15 indigenous cases (10 in Chiapas, 1 in Jalisco, and 4 in Nuevo Leon). ZIKV is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. The evidence of the emergence of ZIKV infection cases outside their original areas with outbreaks in various world regions demonstrates the potential of this arbovirus to spread through the territories in which there are potential vectors, as in much of the country where the presence of Aedes aegypti is documented, so it is possible to infer the potential risk of the virus to spread to other countries in the Americas, including Mexico.^20,21 

Transmission dynamics

Vectors

The main vector for ZIKV is Aedes aegypti. However, it should be noted that the species Aedes aegypti and Ae. albopictus are widely distributed in the tropics and Ae. 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.^1,2 These mosquitoes tend to bite all day, although their activity may be highest at the beginning of the morning and late afternoon. Both species bite outdoors, but Ae. aegypti also can indoors. There are descriptions of sexual and perinatal transmission of the virus, and transmission through unscreened blood transfusions is also possible, which has been identified in asymptomatic blood donors during an outbreak in progress.^22-24

Features of the virus

It is an arbovirus of the genus flavivirus (family Flaviviridae), phylogenetically close to viruses such as dengue, chikungunya fever, yellow fever, Japanese encephalitis, or West Nile virus.

ZIKV is transmitted by the bite of Aedes mosquitoes (Aedes aegypti), both in urban areas and the jungle. ZIKV susceptibility is general. The immunity conferred by infection seems protective long-term.²⁵

Reservoirs

The reservoir of the disease is presumably monkeys, keeping the disease in a monkey-mosquito cycle in the wild. Monkeys and humans are probably the main reservoirs of the virus, and anthroponotic transmission (human-vector-human) occurs during outbreaks.

Incubation period

After the mosquito bite, symptoms of the disease usually appear after an incubation period of 3 to 12 days. Symptoms last from four to seven days and are self-limiting.

The infection may be asymptomatic, or present with mild or moderate clinical manifestations, and even neurological disorders.

Goals

General

• Publicize the prevention, detection, and timely response to ZIKV outbreaks through surveillance, case detection, investigation, and implementation of relevant public health actions.

Specific

• Identify the different clinical manifestations of ZIKV, their classification, and expected frequency, according to the epidemiological behavior of the disease.
• Establish specific criteria and means for diagnosing ZIKV fever, differential diagnosis with other prevalent diseases, and its treatment
• Guide the decisions of health personnel to appropriately refer serious or atypical cases to second and third levels of care.
• Establish specific recommendations for the affected population, for them to understand their disease and develop self-care measures.

Area of ​​application

This guide should be applied by all providers of health services at the Instituto Mexicano del Seguro Social in the first, second, and third level of care.

Definition of the disease

It is the disease caused by ZIKV, arbovirus of the genus flavivirus (family Flaviviridae), phylogenetically close to viruses such as dengue, yellow fever, Japanese encephalitis, or West Nile virus. Febrile illness, zoonotic, emergent, caused by ZIKV, acute course, usually benign and self-limiting, with potential risk of neurological complications. Its symptoms are non-specific and therefore can be confused with other febrile syndromes.

Operational case definitions

For the purposes of epidemiological surveillance, operational case definitions have been developed in order to unify the criteria for the identification, reporting, and classification of ZIKV cases. The definitions are characterized by high sensitivity; i.e. most cases can be detected through the most common signs and symptoms of the disease and screening tests.

Diagnostic specificity is given by laboratory studies, so it is essential to have the right virological, serological, and imaging results for the proper monitoring of the case until its final classification.

Suspected case of Zika virus infection

Any person with fever and rash and two or more of the following signs and symptoms: conjunctivitis (non-purulent), arthralgia, myalgia, headache, retroocular pain, vomiting, or neurological manifestations, resident or visiting areas with Zika virus transmission during the two weeks before onset of symptoms, or in contact with a confirmed case or having any epidemiological link to transmission areas.¹⁴

Confirmed case of Zika virus infection

Any suspected case with a positive result for Zika virus by laboratory tests endorsed by the InDRE.

During an epidemic it is not necessary to subject all patients to the confirmatory tests listed above. The epidemiological link may be sufficient. Importantly, indigenous transmission means mosquito populations living in a given area are infected with the virus and begin to transmit to people who are in the same area. In the presence of indigenous transmission, patients have no history of travel to endemic areas. Those who have contracted the disease in countries where ZIKV circulates are considered "imported" cases, i.e., they were bitten by infected mosquitoes during trips to places where this virus is present.¹⁴

Clinical manifestations

The infection may be asymptomatic, or present with moderate signs. Approximately 1 in 5 people infected with ZIKV becomes symptomatic. In symptomatic patients with moderate illness, symptoms are established acutely, and include fever, non-purulent conjunctivitis, headache, myalgia and arthralgia, asthenia, maculopapular rash, edema in the lower limbs, and, less frequently, retroorbital pain, anorexia, vomiting, diarrhea, or abdominal pain. Symptoms last from four to seven days and are self-limiting. Neurological and autoimmune complications are very frequent.^14,15 However, so far there is evidence of probable ecological association between increased microcephaly and neurological and autoimmune syndromes with prior Zika virus infection. So the possible causal nature of the association cannot be ruled out with the available evidence.

Increased microcephaly and other congenital anomalies

In October 2015, the Centro Nacional de Enlace of Brazil reported the detection of an unusual increase in infants with microcephaly in public and private health services in the state of Pernambuco in northeastern Brazil. Up to Epidemiological Week 1 of 2016, 3530 cases of microcephaly were recorded, including 46 deaths, in 20 Brazilian states and the Federal District. Between 2010 and 2014, nationwide, an annual average of 163 cases of microcephaly were recorded.¹⁶

Evidence of vertical transmission of the Zika virus  

On January 13^th, 2016, the Ministerio de Salud of Brazil reported the detection of Zika virus genome, using RT-PCR technique, in 4 cases of congenital malformation in the state of Rio Grande do Norte. The cases correspond to two miscarriages and two term newborns (37 and 42 weeks gestation, respectively) that died in the first 24 hours of life. Tissue samples from both newborns were also positive for Zika virus using immunohistochemistry. This evidence adds to the finding reported in the Epidemiological Alert of December 1^st, 2015 with respect to the detection of the Zika virus genome, using RT-PCR technique, in amniotic fluid of two pregnant women in Paraíba, whose fetuses had microcephaly according to the ultrasound test that had been done.¹⁶ 

Laboratory diagnostics

The diagnosis is established, first, based on the clinical signs and epidemiology of the disease, and confirmed by laboratory techniques, with techniques for detecting viral RNA (PCR) in acute patients and with IgG / IgM detection in patients with more than 5-6 days of disease progression, although cross-reactions with other flavivirus are possible.

In the first 5 days after the establishment of clinical signs (acute phase, viremic period) viral RNA can be detected from serum and using molecular techniques (real-time RT-PCR). Detection of dengue by PCR should be negative as the main differential diagnosis. A generic test against flavivirus could also be used, followed by genetic sequencing to establish the specific etiology. 

Serological tests (ELISA or neutralization) to detect specific IgM or IgG against ZIKV can be positive from day 5-6 after establishment of clinical signs. It is necessary to demonstrate increased antibody titer in paired samples with an interval of one to two weeks. The confirmation of positive results with PRNT (plaque reduction neutralization test) is recommended, showing at least a four-fold increase in the titer of neutralizing antibodies against ZIKV. Sometimes there may be cross-reactivity with other flaviviruses, especially dengue and, to a lesser extent, with yellow fever and West Nile virus. This can make one see a four-fold increase or more of the titer of neutralizing antibodies against dengue in a patient with ZIKV infection, especially if they previously had dengue infection. Because of this cross-reactivity between flaviviruses, serology results should be interpreted with care.^15,18

Tests

• Antigen detection: in specialized laboratories using PCR and viral isolation. This processes serum samples from patients in acute phase. 1 to 5 days from the onset of symptoms.
• Antibody detection: in specialized laboratories for IgM identification. This processes serum samples from patients in the acute phase, 6 days and onwards from the onset of symptoms.

Differential diagnosis

The differential diagnosis should take into account the epidemiological characteristics such as place of residence, history of travel, and exposure. In particular, the differential diagnosis should include: dengue and chikungunya fever (CHIK), so it is necessary to consider the following information: both diseases are borne by the same vector, have similar clinical manifestations, and can even occur at the same time in one patient.^26,27

Compared with dengue, ZIKV infection causes mild clinical manifestations, the onset of fever is sharper and of shorter duration. Moreover, dengue can have a more torpid evolution, even causing death.

In chikungunya virus infection (CHIKV), the joint pain is more intense and localized in the joints and tendons, and can in some cases be incapacitating. Shock or severe bleeding is rarely observed; the onset is more acute and the duration of fever is much shorter, and maculopapular rash is more common than in dengue (Table I).

Features of dengue and chikungunya

Dengue fever is a febrile disease transmitted by the bloodsucking female Aedes aegypti mosquito; the disease is self-limiting, incapacitating, and has risk of fatal complications, which may present benignly as dengue fever (DF), and seriously as dengue hemorrhagic fever (DHF).

There are four serotypes of dengue (DEN1, DEN2, DEN3, DEN4), the World Health Organization (WHO) estimates that these constitute a threat for 40% of the world population living in 112 tropical and subtropical countries. It is estimated that currently there are 50 million cases worldwide, of which about 400,000 are serious cases and 25,000 die from this disease.²⁸

Note that CHIKV can cause acute, subacute, and chronic disease. Bites of infected mosquitoes in people produce manifestations of the disease in 95% of cases. Individuals with acute CHIKV infection may present clinical manifestations or be asymptomatic, and can contribute to the spread of the disease if the vectors that transmit the virus are present and active in the same area.

After CHIKV infection, there is a silent incubation period of 2-4 days (range: 1-12 days). After this short period, the acute period of the disease takes place abruptly, coinciding with the maximum viremia. It manifests with high fever (typically above 39 °C), followed in a few hours by myalgia, arthralgia, and widespread, severe, and disabling arthritis, accompanied by headache, back pain, and maculopapular rash, predominantly on the thorax.^29,30

CHIKV can affect women and men of all ages. However, it is held that the clinical presentation varies with age, with more frequent complications and severe forms in children under 1 year, adults over 65 with chronic diseases (diabetes, hypertension, etc.) and in pregnant women. The abnormal laboratory findings may include mild thrombocytopenia (> 100 000/mm³), leukopenia, and elevated liver function tests. Among the subacute and chronic manifestations of CHIKV, there is distal polyarthritis and subacute hypertrophic tenosynovitis of the wrists and ankles. These symptoms are most common two or three months after the onset of the disease.

The chronic disease is characterized by persistent symptoms for more than three months. Notably, arthritis from CHIKV infection has a symmetric and distal polyarticular pattern, affecting the hands, wrists, and ankles; it less often affects the elbows, knees, shoulders, hips, and temporomandibular joints.

With regard to diagnosis with CHIKV, three main types of tests are used: 1. Serology 2. Viral isolation and 3. Reverse transcriptase polymerase chain reaction (RT-PCR).³¹

Samples taken during the first week of the onset of symptoms should be tested by serological methods (ELISA for the detection of immunoglobulin M [IgM] and G [IgG]) and virological (RT-PCR and isolation)). The highest concentrations of IgM are recorded between 3 and 5 weeks after disease onset and persist about 2 months.

Samples are usually from blood or serum, but in neurological cases with features of meningoencephalitis, cerebrospinal fluid (CSF) can also be obtained.

Samples collected during the first week after the onset of symptoms should be analyzed with serological and virological methods (RT-PCR). The virus can be isolated in the blood in the first days of 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).^29-32

Treatment

Treating ZIKV infection is mainly symptomatic. So far, there is no specific antiviral drug treatment, so it is recommended to start symptomatic treatment after ruling out diseases such as dengue, chikungunya, measles, and bacterial infections. 

Treatment consists mainly of relieving symptoms, including joint pain, antipyretics, optimal analgesics, and fluids. Avoid aspirin for risk of Reye syndrome.¹⁵

The main management recommendations include:

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

It should be noted that the best prevention of ZIKV infection is to prevent the proliferation of the vector that transmits it, following the same recommendations for dengue and chikungunya, which are to prevent accumulation of water in tires, pots, sinks, vases, and puddles, among others.

Monitoring methods

The main purpose of monitoring is to promptly detect cases of ZIKV. Early detection and timely notification will allow for adequate outbreak response and characterization and identification of circulating viral strains.^15,18

In countries with no indigenous cases of Zika virus infection it is recommended to:

• Test to detect ZIKV in a percentage of patients with fever and joint pain, or fever and arthritis of unknown etiology (e.g., in patients with negative tests for malaria, dengue, chikungunya, and febrile rash diseases). One should take into account the possible cross-reactivity with dengue in serological tests, particularly if there has been previous dengue infection. Early detection will allow the identification of circulating viral strains, the proper characterization of the outbreak, and implementation of a proportionate response.

In countries with indigenous cases of Zika virus infection, it is recommended to:

• Monitor the geographical spread of the virus to detect its introduction into new areas.
• Evaluate the clinical severity and impact on public health.
• Identify risk factors associated with ZIKV infection where there is capacity.
• Identify circulating ZIKV lineages.

These efforts provide the basis for developing and maintaining effective control measures. Once the introduction of the virus is documented, continuous surveillance should be maintained to monitor epidemiological and entomological changes that may affect the transmission of ZIKV. Any change detected by monitoring should be promptly communicated to the national prevention and control authorities to ensure the timely adoption of appropriate measures.

Prevention and Control

General prevention measures

It is important to minimize the contact of the vector with patients infected with dengue, chikungunya, or ZIKV. This measure helps prevent the spread of the virus and thus of the disease. It is necessary to educate the patient, other household members, and the community about the risk of transmission and measures to reduce the vector population and contact between the vector and people.^14,15

The following measures are repeated below to minimize vector contact with patients:

• The patient must rest in a place protected with mosquito nets, impregnated with insecticide or not.
• The patient as well as other household members should wear clothing that covers the extremities.
• Repellents containing icaridin, also known as picaridin (Autan) or DEET [N, N-diethyl-m-toluamide] (OFF) can be applied to exposed skin or clothing and should be used in strict accordance with the instructions on the product label.
• Use wire screens on doors and windows.

Prevention in the home

The use of screens in windows and doors reduces vectors entering the home, and mosquito-proof water storage containers reduce oviposition sites and local production. Within the home, the use of insecticide-treated (IT) bednets and IT curtains also reduces vector-human contact. 

The number of adult mosquitoes in the home can be reduced using commercially available pyrethroid aerosol sprays and other products designed for the home, such as mosquito coils and electric vaporizers. Aerosol spray can be applied throughout the house, but should focus on areas where adult mosquitoes rest (dark and cool areas) including bedrooms, closets, laundry baskets, etc. When making recommendations to the public, emphasis should be placed on the appropriate use of these products to reduce unnecessary exposure to pesticides 

For protection during outbreaks it is recommended to:

• Wear clothes that minimize skin exposure to vectors.
• Apply repellents to the skin or clothing, in strict compliance with the instructions for product use. Repellents should contain DEET (N, N-diethyl-3-methylbenzamide) (OFF) or icaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-­methylpropylester) also known as picaridin (Autan).
• People traveling to risk areas should take basic precautions, such as using repellent, long pants and long-sleeved shirts, and guards on windows that limit vector entrance (tulle or mosquito netting).

WHO / PAHO Recommendations

Based on the epidemiological situation in America from this condition, the Pan American Health Organization (PAHO) issued the Epidemiological Alert for ZIKV infection, whose main recommendations for surveillance include:^14-16

• Conduct epidemiological monitoring of ZIKV infection based on existing surveillance for chikungunya and dengue fever.
• Monitoring should be directed to:
• Detect the introduction of ZIKV to an area.
• Monitor the spread of ZIKV infection once introduced into a region.
• Monitor the appearance of neurological and autoimmune complications.
• In countries without ZIKV transmission:
• Strengthen event-based surveillance to detect early cases.
• Identify and investigate the emergence of clusters of febrile rash illness of unknown cause (in which dengue infection, chikungunya fever, measles, rubella, and parvovirus B19 have been ruled out).
• Test to detect ZIKV.

This should take into account possible cross-reactivity with dengue virus infection using serological tests.

Monitoring for the moment will be based exclusively on molecular methods (real time RT-PCR), allowing early detection and promoting the implementation of control measures that include integrated vector management, identification of circulating viral strains, and adequate characterization of outbreaks.

Patient isolation

To prevent transmission to others, the patient infected with ZIKV should avoid contact with Aedes mosquitoes, at least during the first week of illness (viremic phase). The use of nets that may or may not be impregnated with insecticide is recommended, or staying in a place protected with screens. The health personnel attending ZIKV-infected patients should be protected from bites by using mosquito repellents and wearing long sleeves and pants.  

Monitoring of neurological and autoimmune complications

Countries, particularly those in situations of possible ZIKV circulation, are encouraged to implement or intensify surveillance for neurological syndromes in all age groups. This monitoring can be established in the form of syndromic surveillance or hospital-based case monitoring. In choosing case monitoring, one must define the clinical presentations that will be subject to monitoring. It is suggested to include Guillain-Barré syndrome, Fisher syndrome, encephalitis, meningitis, and meningoencephalitis.  

The Guillain-Barré syndrome (GBS) in its typical form is an acute polyradiculoneuropathy that produces a bilateral and symmetrical lower sensorimotor development disorder, associated with generalized osteo-tendinous areflexia. In many cases there is a previous history of infection that causes the immune response in the nerves. Between 3.5 and 12% of patients die from complications during the acute phase. It is estimated that the annual incidence of GBS ranges between 0.4 and 4.0 cases per 100,000 population per year. In North America and in Europe GBS is most common in adults and increases steadily with age. Several studies indicate that men tend to be more affected than women. 

Fisher syndrome (or Miller Fisher) is characterized by impairment of eye movements, abnormal coordination, and loss of tendon reflexes. While the clinical triad (ataxia, ophthalmoplegia, and areflexia) is easily recognizable, in some cases it can coexist with GBS so some authors consider it a variant of GBS.

Monitoring of congenital anomalies

The purpose of monitoring should be aimed at the detection of an unusual increase in congenital abnormalities, and when an outbreak is detected, monitoring should focus on tracking the trend. For countries without an established monitoring system for congenital anomalies, the implementation of a system of detection of cases in health care facilities or hospitals is recommended. It is suggested to start by including only microcephaly, and then gradually extending to other congenital anomalies, based on the capacity and resources of the health system in the country.

As part of establishing the monitoring protocol it is essential to include a clear and operational definition of a case, as well as frequency and transmission flow data (e.g., from local to regional, then national, weekly or monthly).

Microcephaly is defined as a head circumference 2 standard deviations (SD) below the mean for age and sex, or approximately less than the third percentile. It is important to note that there are no absolute values ​​to define microcephaly, given that it varies by sex and gestational age. It is important to ensure issues related to confidentiality, referral, and reverse referral of cases where appropriate.

Event-based surveillance is a useful tool for detecting conditions or unusual events. For this reason, health professionals involved in prenatal and neonatal care should be encouraged to report all unusual events. It is recommended that infants who meet the criteria for microcephaly be evaluated by medical teams qualified to know the extent of neurological impairment and other possible abnormalities. Additional studies (laboratory and radiological) will be made according to local care protocols that include the diagnosis of other causes of microcephaly, especially those requiring treatment (e.g. congenital syphilis, cytomegalovirus, or toxoplasmosis). After clinical evaluation of the newborn, a plan of care and clinical follow-up must be developed for these newborns with microcephaly.¹⁶

Recommendations in Mexico

Given the dispersion of ZIKV in the world, including the occurrence of cases this year in Brazil and Colombia, and the risk of virus introduction to our country given high population movements and the existence of vectors in large parts of the national territory, it is necessary to maintain adequate surveillance for early detection of cases to guide prevention and control actions.

Therefore, the following is recommended:

• Keep health personnel updated on the epidemiological situation of ZIKV infection and the importance of timely detection and reporting of cases, measures of care, and prevention and control.
• In the identification of suspected cases of ZIKV infection: 
• Check that the clinical-epidemiological diagnosis meets the operational case definition.
• Give symptomatic or supportive treatment.
• Immediately report cases to all technical and administrative levels within the first 24 hours of its knowledge to health services.
• Register all suspected and confirmed cases.
• Make appropriate and timely epidemiological case studies.
• Take blood samples within the first five days of onset of the condition to obtain serum and keep the sample in strict cold chain at all times.
• With suspected cases, conduct active search in risk areas.
• Monitor the case until its final classification within the first two weeks of detection.

Suspected cases of ZIKV infection are the detonators of prevention and control.

• Upon the occurrence of outbreaks:
  • Immediately report the occurrence of outbreaks.
  • Fill out and submit the outbreak study form within the first 48 hours of knowledge about it, and monitor its evolution constantly until its final resolution.
• Strengthen health promotion actions with emphasis on measures for vector control and personal self-care.
• Together with program leaders on epidemiological surveillance committees, evaluate prevention and control activities to ensure maintaining low vector densities.
• Disseminate this information to all health units of states to guide detection and proper management of possible cases, to the State and Jurisdictional Comités de Vigilancia Epidemiológica and state or regional offices of the health sector institutions.
• Follow up on recommendations of epidemiological notices through the Comités de Vigilancia Epidemiológica and state or regional offices of the institutions of the Sistema Nacional de Salud.

Recommendations from the Department of Epidemiology

Travelers who go to Colombia and Brazil are at risk of ZIKV infection. If you have a fever, conjunctivitis, arthralgia and / or myalgia or edema of the legs and / or feet during your stay or 12 days after of your return to Mexico:³³

• Do not self-medicate, seek medical attention immediately.
• Drink plenty of fluids and oral serum or oral electrolytes to prevent dehydration.
• Mention to attending medical staff the history of travel to these regions.

While staying in one of these countries it is recommended:³³

• Currently there is no vaccine or medicine to prevent ZIKV infection.
• Travelers can protect themselves by preventing mosquito bites using the following recommendations:
  • Cover exposed skin by wearing long-sleeved shirts, long pants, and hats.
  • Use insect repellent. 
  • Always follow the repellent instructions and reapply as directed.
  • If you are also using sunscreen, apply sunscreen first and then apply insect repellent.
  • Avoid applying repellent to the hands, eyes, and mouth.
  • Try to sleep in closed rooms with filtered air or air conditioning.
  • Use a mosquito net if the area where you are sleeping is exposed to the outside.
  • Have on hand the phone number and address of the consulate or embassy of Mexico to contact if necessary.

Key points

Globally, viral vector-borne diseases are considered as having the most impact on public health. WHO currently lists the arboviruses as a priority health problem, and in 1998 they were considered the tenth leading cause of death from infectious diseases worldwide.

PAHO / WHO recommend its member states to establish and maintain the capacity to detect and confirm cases of Zika virus infection, treat patients, and implement an effective communication strategy with the public to reduce the presence of the mosquito that transmits this disease, especially in areas where the vector is present. 

ZIKV infection is a disease caused by Zika virus (ZIKAV), an arbovirus of the genus flavivirus (family Flaviviridae), phylogenetically close to viruses such as dengue, yellow fever, Japanese encephalitis, or West Nile virus. ZIKV is transmitted by the bite of Aedes mosquitoes, both in urban areas (A. aegypti) and the jungle. In Mexico, one imported case has been identified with a history of travel to Colombia. There is no identified local transmission. 

• After the mosquito bite, disease symptoms usually appear after an incubation period of three to twelve days. The infection may be asymptomatic, or present with mild to moderate clinical manifestations.
• In symptomatic cases, with moderate disease, symptoms are established acutely, and include fever, non-purulent conjunctivitis, headache, myalgia and arthralgia, asthenia, maculopapular rash, edema in the lower limbs, and, less frequently, retroorbital pain, anorexia, vomiting, diarrhea, or abdominal pain. Symptoms last from four to seven days and are self-limiting. Neurological and autoimmune complications are rare.
• In the first 5 days after the establishment of clinical signs (acute phase, viremic period) it can be detected with viral RNA from serum using molecular techniques (real time RT-PCR). Detection by PCR for dengue should be negative as the main differential diagnosis. A generic test against flavivirus could also be used, followed by genetic sequencing to establish the specific etiology.
• With clinical signs suggestive of infection and where dengue is ruled out, test for other flaviviruses, including ZIKV.
• There is no specific antiviral treatment for ZIKV infection. Symptomatic treatment is recommended after ruling out more serious diseases such as malaria, dengue fever, or bacterial infections.
• Maintain actions to promote elimination of potential breeding sites within households, as well as land fogging and fumigation.
• Because the Aedes aegypti mosquito is the transmitter of the diseases of dengue, chikungunya virus, and Zika, it is necessary that the population be aware of keeping their homes clean, avoiding keeping water in containers outside (pots, bottles, containers that can collect water) to prevent them from becoming breeding grounds for mosquitoes.
• Tanks or water cisterns for domestic use should be covered so that mosquitoes do not get in; avoid accumulating trash and throw it in sealed plastic bags; unclog drains that leave standing water, and use nets and screens on windows and doors.
• For people who are going to areas with circulation of dengue, chikungunya and Zika: before traveling, they should use repellents, mosquito nets, insecticides and appropriate clothing. During the stay: use measures of protection against bites, avoid mosquito-infested sites, and upon return visit a clinic in the presence of symptoms.
• Monitoring Zika virus fever must be developed based on existing surveillance for dengue and chikungunya, taking into account differences in the clinical presentation.

Conclusions

Currently, ZIKV infection is an emerging disease in the region of the Americas, because the risk of ZIKV being introduced into the region is high due to importation by travel, the presence of competent vectors (the same vectors as dengue) and the susceptibility of the population, so it is essential to implement effective actions prevention, to make timely detection of cases, and to coordinate an appropriate and rapid response, with the active participation of all stakeholders to provide effective and safe care and to minimize the risk of ZIKV importation and sustained transmission in the region.

Given the expansion of Zika virus transmission in the region of the Americas, PAHO / WHO recommend to its member states to establish and maintain the capacity to detect, report, and confirm cases of Zika virus infection, to prepare health services for a possible additional burden at all levels of care, and to implement an effective public communication strategy to reduce the presence of mosquitoes especially in areas where the vector is present.

So far, there is no specific antiviral treatment or effective vaccine, so it is priority to give symptomatic and supportive treatment for the acute phase and make timely identification of atypical and severe forms.

It should be noted that for the creation of these guidelines, documents prepared by PAHO / WHO and CDC (Centers for Disease Control and Prevention of Disease) were taken as a source of information, as well as documented experiences in attention to cases in other countries in the region, including Brazil, Colombia, and Chile.

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Annex 1 Algorithm for detecting Zika virus (ZIKV)³²

Notes:

1. According to the epidemiological profile of the country and accounting for the clinical characteristics of the infection, one should consider the inclusion of other Arboviruses as part of the differential algorithm for Zika virus.

2. This algorithm is not exhaustive, and dengue infection must be ruled out according to clinical management guidelines and the specific laboratory algorithm.

3. These recommendations are provisional and subject to further modifications according to advancing knowledge about the disease and the etiologic agent.