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Zika Virus Infection

1 Contact Hour
This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Friday, December 3, 2021
Course Description
Learn about the Zika epidemic as it relates to the recent outbreaks in the Americas and its connection to microcephalic cases. Primarily transmitted through infected aedes mosquitoes, understand the virology of Zika, related complications, treatment and prevention methods used to control the outbreak. Accurately assess symptoms and diagnose patients exhibiting Zika characteristics.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Pamela Downey (MSN, ARNP)

Outcomes

90% of participants will learn Zika prevention strategies, assessment and management of individuals who have Zika virus infection.

Objectives

  1. Describe the modes of transmission of the Zika virus and factors which are hypothesized to be causing its rapid spread.
  2. Describe potential complications of the Zika virus infection.
  3. Discuss the clinical assessment and management of the Zika virus infection.
  4. Describe local, state and national reporting procedures for Zika virus infection.
  5. Describe personal and environmental measures being implemented to control the spread of Zika virus infection.

Introduction

The impression given by the news media is that Zika belongs solely to poverty-stricken third-world countries. Travel-imported cases in the United States have been covered by the state only and only regarding numbers. Essentially, this coverage has led the United States citizenry to believe that the illness is benign except in the case of pregnancy. Young women who are pregnant seem to be the most at risk while men have nothing to worry about. The news agencies have covered the Centers for Disease Control and Prevention guidelines regarding travel restrictions for pregnant women. Little to no coverage has focused on other complications, which can affect all ages, races and sexes.

The Zika virus (ZIKV) is a member of the Flaviviridae virus family and the Flavivirus genus.

In humans, ZIKV causes a mild illness known as Zika virus infection, Zika fever, Zika or Zika disease. Since the 1950s, it had been known to occur within a narrow equatorial belt from Africa to Asia. In 2007, the virus spread eastward across the Pacific Ocean to Micronesia, French Polynesia, then to Easter Island. In 2015 it spread to South and Central America where the Zika outbreak has reached pandemic levels and then spread to the Caribbean and Puerto Rico. Travel-related cases have been reported worldwide in countries including the United States, Great Britain, Ireland and France to name just a few.

Zika virus infection is similar to a mild form of dengue fever. Treatment is supportive in nature and currently cannot be prevented by medications or vaccines.

Zika virus infection is related to yellow fever and West Nile disease, which are caused by other arthropod-borne flaviviruses. Possible complications from Zika virus infection include Guillain-Barré syndrome and microcephaly.

In January 2016, the United States Centers for Disease Control and Prevention (CDC) issued travel guidance on affected countries, including the use of enhanced precautions, considering postponing travel and guidelines for pregnant women. Other governments or health agencies soon issued similar travel warnings, while Colombia, Ecuador, El Salvador and Jamaica advised women to postpone getting pregnant until more was known about the risks.

Pathogenesis

Mosquito-borne flaviviruses are thought to initially replicate in dendritic cells near the site of inoculation followed by spread to the lymph nodes and bloodstream, although information regarding the pathogenesis of ZIKV is scarce. Although flaviviral replication is thought to occur in cellular cytoplasm, one study suggested that ZIKV antigens could be found in infected cell nuclei. As of today, infectious ZIKV has been detected in human blood as early as the day of illness onset. Viral nucleic acid has been detected as late as 11 days after illness onset.

Transmission

Through Mosquito Bites

The Zika virus is transmitted by daytime-active mosquitoes and has been isolated from a number of species in the genus Aedes. Zika virus is a mosquito-borne flavivirus primarily transmitted by Aedes aegypti mosquitoes. Aedes albopictus mosquitoes also might transmit the virus. A. aegypti and A. albopictus mosquitoes are found throughout much of the Region of the Americas, including parts of the United States, and also transmit dengue, chikungunya, yellow fever and West Nile viruses.

Studies show that the extrinsic incubation period for ZIKV in mosquitoes is about 10 days. Nonhuman (monkeys) and human primates are likely the main reservoirs of the virus, and anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks.

The Zika virus is transmitted to humans primarily via the bite of an infected Aedes species mosquito. Aedes mosquitoes become infected when they bite an already infected individual, draw blood and contract the Zika virus. The Zika virus then spreads when the infected mosquito then goes and bites another individual.

Aedes mosquitoes typically breed and lay eggs in or near domestic water-holding containers (i.e., buckets, bowls, animal dishes, flower pots, vases, etc.). They are aggressive daytime biters, prefer to bite humans and live indoors and outdoors near humans.

The potential societal risk of the Zika virus can be delimited by the distribution of the mosquito species that transmit it (its vectors). The global distribution of the most cited carrier of Zika virus, A. aegypti, is expanding due to global trade and travel (Figure 4). A. aegypti distribution is now the most extensive ever recorded – across all continents including North America and even the European periphery.

Global Aedes Aegypti Predicted Distribution (Figure 4)

Global Aedes Aegypti Predicted Distribution (Figure 4)

The map depicts the probability of occurrence:
blue = none
red = highest occurrence
Aedes aegypti

Aedes aegypti

Perinatal Transmission

Evidence of perinatal transmission of the Zika virus during pregnancy or childbirth is limited. Pregnant women can be infected with the Zika virus in any trimester. The incidence of Zika virus infection in pregnant women is currently unknown. Data on pregnant women infected with the Zika virus are limited. No evidence exists to suggest that pregnant women are more susceptible to Zika virus infection or experience more severe disease during pregnancy.1

It is possible that the Zika virus could be passed from a mother already infected with the Zika virus to the fetus during pregnancy. Perinatal transmission has been reported with other vector-borne viruses such as dengue and chikungunya. Studies are now being conducted on the possible perinatal transmission of the virus and its possible effects on the fetus.

So far, there are no documented reports of Zika virus transmission via breastfeeding. Zika virus RNA has been detected in breast milk, but Zika virus transmission through breastfeeding has not been documented. Because of the benefits of breastfeeding, mothers are encouraged to breastfeed even in areas where the Zika virus is found. Mothers in areas with Zika circulation should follow PAHO/WHO recommendations on breastfeeding (exclusive breastfeeding for the first 6 months, followed by continued breastfeeding with complementary foods up to 2 years and beyond).1

Possibly Through Infected Blood or Sexual Contact

ZIKV can be transmitted through blood but this is an infrequent mechanism. Zika virus RNA has been identified in asymptomatic blood donors during an ongoing outbreak. Standard precautions that are already in place for ensuring safe blood donations and transfusions should be followed.

ZIKV has been isolated in human semen.

Causes of Rapid Transmission of the Zika Virus

Mosquito Factors

  • Aedes mosquitoes, the main vector for ZIKV transmission, are widespread in all countries of the Americas Regions except Canada and continental Chile. Global warming is hypothesized as playing a role in the survival of mosquitoes, which thrive in warm and moist environments. Climate change associated with changes in precipitation patterns, humidity and temperature have helped to expand the range of places that are habitable to mosquitoes.
  • The number of mosquitoes biting humans infected with the Zika virus has multiplied.
  • The number of mosquitoes that are surviving long enough to infect other humans have multiplied.

Human Factors

  • Since this is a new virus to the Americas, the entire human population has not previously been exposed to Zika and therefore lacks immunity to the Zika virus.
  • Constant international travel is transporting diseases to new locales.
  • More and more people live in congested cities, making it easy for viruses to jump from individual to individual and for mosquitoes to find large concentrations of humans to bite.
  • Human-caused microperturbations in ecologic balance can cause innumerable slumbering infectious agents to emerge unexpectedly.

Complications

Given the increase in congenital anomalies, Guillain-Barré syndrome (GBS), and other neurological and autoimmune syndromes in areas where the Zika virus is circulating, the PAHO and WHO recommends its Member States:

  • Establish and maintain the capacity to detect and confirm Zika virus cases
  • Prepare healthcare facilities to respond to a possible increased demand for specialized care for neurological syndromes
  • Strengthen antenatal care
  • Continue with their efforts to reduce the presence of mosquito vectors through an effective vector control strategy and communication to the public

Guillain-Barré Syndrome (GBS)

GBS, in its typical form, is an acute polyradiculoneuropathy that produces a lower, bilateral and symmetrical sensorimotor development deficit, associated with generalized areflexia. In many cases, there is a 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. The annual incidence of GBS is estimated to be between 0.4 and 4.0 cases per 100,000 inhabitants per year. In North America and Europe, GBS is more common in adults and increases steadily with age. Several studies indicate that men tend to be more affected than women.

GBS occurs when an individual’s immune system attacks itself, particularly affecting the cells of the nervous system. This process can be initiated by infection with various viruses or bacteria. The main symptoms include muscular weakness and tingling (paresthesia) in the arms and legs. Severe complications can occur if the respiratory muscles are affected. The most seriously ill individuals need care in intensive care units.

Other Neurological Syndromes

Zika virus can cause other neurological syndromes (meningitis, meningoencephalitis and myelitis). The French Polynesian Health Authorities also reported an unusual increase in central nervous system abnormalities in fetuses and newborns registered during 2013 – 2014. This finding coincided with the Zika virus outbreak in the islands. None of the pregnant women described clinical signs of the Zika virus, but four women were found positive by IgM serology assays for flavivirus, suggesting a possible asymptomatic Zika virus infection.

  • 17 malformations were registered:
    • 12 – fetal cerebral malformations or polymalformative syndromes including brain lesions
    • 5 – brainstem dysfunction and absence of swallowing

The French Polynesian Health Authorities hypothesize that Zika virus infection may be associated with these abnormalities if mothers are infected during the first or second trimester of pregnancy.

World Health Organization (WHO) advises its Member States to implement or intensify surveillance of neurological and autoimmune complications in all age groups, particularly in situations of possible ZIKV circulation. This surveillance can be established as hospital-based, syndromic surveillance, or surveillance of cases. If case surveillance is implemented, a case definition should include GBS, Fisher syndrome, encephalitis, meningitis, and meningoencephalitis.

Fisher syndrome (or Miller Fisher syndrome) 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, sometimes it overlaps with GBS, so some authors consider it a variant of GBS, and it is associated with an autoimmune inflammation of nerves after an infection.

While in the Region of the Americas, such syndromes have not yet been reported, health services and practitioners should be alert to their possible occurrence to properly prepare health facilities for rapid detection and appropriate treatment of cases.

Microcephaly

Microcephaly is a neurological disorder in which the occipitofrontal circumference is smaller than that of other children of the same age, race and sex. Maternal-fetal transmission of the Zika virus has been documented throughout pregnancy. Zika virus infection has been confirmed in several infants with congenital microcephaly and in fetal losses among women infected during pregnancy. The spectrum of outcomes that may be associated with infection during pregnancy is not yet fully understood, nor are the factors that may increase fetal risk.

A large number of Brazilian newborns with microcephaly have been observed in parallel with the current Zika outbreak. It is not known how many of the microcephaly cases are associated with Zika virus infection. Studies are being conducted to investigate the association of Zika virus infection and microcephaly, including the role of other contributory factors (e.g., prior or concurrent infection with other organisms, nutrition and environment). The full spectrum of outcomes that might be associated with Zika virus infections during pregnancy is unknown and requires further investigation.2

Brazilian Health Authorities has confirmed that newborns of mothers who had a Zika virus infection during the first trimester of pregnancy are at an increased risk of microcephaly and/or other congenital anomalies.2

Zika virus infections have been confirmed in infants with microcephaly, although it is not known how many of the microcephaly cases are associated with Zika virus infection. Furthermore, Zika virus RNA has been detected in the pathologic specimens of fetal losses, although it is not known whether the Zika virus caused the fetal losses. Pregnant women can be infected with the Zika virus in any trimester.

The Brazil Ministry of Health continues to investigate the possible association between the Zika virus and a reported increase in the number of babies born with microcephaly. Due to concerns of microcephaly associated with maternal Zika virus infection, fetuses and infants of women infected with the Zika virus during pregnancy should be evaluated for possible congenital Zika virus infection and neurologic abnormalities.

Clinical Assessment and Management

Health History

The diagnosis of Zika virus infection should be suspected in individuals:

  • With characteristic clinical symptoms (fever, rash, headache, arthralgia, myalgia and conjunctivitis) and
  • Relevant epidemiologic exposure (residence in or travel to an area where the Aedes mosquito is present and where travel-related or local cases have been reported within two weeks prior to the onset of illness).

Signs and Symptoms

The incubation period (the time from exposure to onset of symptoms) of Zika virus infection is not clear but is typically 2 to 12 days after the mosquito vector bite. One out of four infected individuals (20 – 25%) develops symptoms of the disease.3 Among those who do, the symptoms/infection are usually mild and usually resolves within 2 to 7 days.

An estimated 80% of individuals infected with the Zika virus are asymptomatic.2 The Zika virus usually remains in the blood of an infected individual for a few days, but it can be found longer in some individuals.

Symptoms of infection with the Zika virus typically include3,4,5:

  • Acute onset of low-grade fever (37.8 to 38.5°C)
  • Maculopapular rash (may or may not be present)
maculopapular_rash

Maculopapular rash - wikipedia.org

  • Arthralgia (notably the small joints of hands and feet)
  • Conjunctivitis (nonpurulent)

Other commonly reported signs and symptoms include:

  • Mild headaches
  • Retro-orbital pain
  • Asthenia (weakness or debility)
  • Myalgia

More rarely observed signs and symptoms include:

  • Dizziness
  • Pruritus
  • Mucous membrane ulcerations
  • Anorexia
  • Nausea/vomiting
  • Diarrhea/constipation
  • Abdominal pain

Differential Diagnosis

The differential diagnosis of Zika virus infection includes5:

  • Other viral causes of arthritis:
    • Dengue fever5
      • Dengue virus and Zika virus infections present with similar clinical manifestations and are transmitted by the same mosquito vector. They differ clinically in that dengue infection usually presents with higher fever and more severe muscle pain, which may also be associated with hemorrhage. Coinfection with Zika, chikungunya and dengue viruses has been described. The diagnosis of dengue virus infection is established via serology.
    • Chikungunya6
      • Chikungunya virus and Zika virus infections present with similar signs and symptoms and are transmitted by the same mosquito vector. They differ clinically in that chikungunya usually presents with higher fever and more intense joint pain, affecting the hands, feet, knees and back. The infection can be disabling, causing patients to bend over such that they cannot walk or rendering individuals unable to perform simple manual tasks such as opening a water bottle. Coinfection with Zika, chikungunya and dengue viruses has been described. The diagnosis of chikungunya virus infection is established via serology.
    • Parvovirus
      • Parvovirus infection can present with acute and symmetric arthritis or arthralgia, most frequently involving the small joints of the hands, wrists, knees and feet. The rash may or may not be present. The diagnosis is established via serology.
    • Rubella
      • Clinical manifestations of rubella include low-grade fever and coryza. A macular rash begins on the face and spreads to the trunk. Arthritis may be present. The diagnosis is established via serology.
      • A number of other viruses may also cause arthritis, including enterovirus, adenovirus and alphaviruses.
    • Measles
      • Clinical manifestations of measles include fever, cough, sore throat, coryza, conjunctivitis and lymphadenitis. Koplik spots may precede a generalized rash. The diagnosis is established via serology.
    • Leptospirosis
      • Leptospirosis is characterized by fever, rigors, myalgia, conjunctival suffusion and headache. Less common signs and symptoms include cough, nausea, vomiting, diarrhea, abdominal pain and arthralgia. It may be distinguished from a Zika virus infection by the presence of jaundice. The diagnosis is established via serology.
    • Malaria
      • Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia and anemia. The diagnosis of malaria is established by the visualization of parasites on peripheral smear.
    • Rickettsial infection
      • Rickettsial infections with similar manifestations as Zika virus infection include African tick bite fever and relapsing fever. African tick bite fever is observed among travelers to Africa and is characterized by headache, fever, myalgia, solitary or multiple eschars with regional lymphadenopathy and generalized rash. The diagnosis is established via serology. Relapsing fever is characterized by fever, headache, neck stiffness, arthralgia, myalgia and nausea. Diagnostic tools include direct smear and polymerase chain reaction.

The preliminary diagnosis is based on the patient’s clinical features, places and dates of travel and activities. Laboratory diagnosis is generally accomplished by testing serum or plasma to detect the Zika virus, viral nucleic acid or virus-specific immunoglobulin M and neutralizing antibodies.

Laboratory/Diagnostic Tests

The diagnosis is definitively established via reverse-transcription polymerase chain reaction (RT-PCR) or serology. These tests are performed at the United States CDC Arboviral Diagnostic Laboratory and some state health departments or the PAHO/WHO.3

  • Reverse-Transcription Polymerase Chain Reaction (RT-PCR)
    • Within the first week (usually the first 3 – 5 days) after the onset of symptoms, the diagnosis of Zika virus infection may be established via RT-PCR tests on acute-phase serum for detection of Zika virus RNA.
    • Acute serum should be obtained to compare with convalescent serum obtained 2 – 3 weeks later.
    • RT-PCR testing for dengue virus and chikungunya virus should also be ordered.
  • Serologic Testing (Immunoglobulin M (IgM) and Confirmatory Neutralizing Antibody Titers)
    • Virus-specific IgM and confirmatory neutralizing antibody titers detect specific antibodies against ZIKV in the serum, which typically develops toward the end of the first week of illness.
    • Four days or more following the onset of symptoms, the diagnosis may be established by Zika virus serologic testing IgM and confirmatory neutralizing antibody titers.
    • Acute and convalescent sera should be obtained to detect an increased antibody titer in the paired samples with an interval of two to three weeks between both draws.
    • Serologic testing for dengue virus infection and chikungunya virus infection should also be ordered.
    • All serologic results should be interpreted with caution since there can be cross-reactivity with other flaviviruses, including dengue virus, West Nile virus and yellow fever.
  • Plaque-Reduction Neutralization Testing (PRNT)
    • Plaque-reduction neutralization testing can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections.

In 2016, Zika virus infection became a nationally notifiable condition. Healthcare providers are encouraged to report suspected cases to their state or local health departments to facilitate diagnosis and mitigate the risk of local transmission. State health departments are encouraged to report laboratory-confirmed cases to the CDC through ArboNET, the national surveillance system for arboviral disease.

Laboratory specimens may be sent directly to the CDC Arboviral Diagnostic Laboratory. Instructions are available online. Communication should be initiated with the laboratory via telephone (1-970-221-6400) prior to shipment of specimens.3

Test results are generally available 4 to 14 days after the receipt of the specimen. Reporting times for test results may be longer during summer months when arbovirus activity increases. Receipt of a hard copy of the results takes at least 2 weeks after testing is completed. All results will be sent to the appropriate state health department. All healthcare providers should notify their state health department of any direct submissions to the CDC.

Pregnant Women

Healthcare providers should question all pregnant women about recent travel. Pregnant women with a history of travel to an area with ongoing Zika virus transmission should be evaluated for Zika virus infection in accordance with CDC Interim Guidance protocols.7

Because of the similar geographic distribution and clinical presentation of Zika, dengue and chikungunya virus infection, pregnant women with symptoms consistent with Zika virus infection should also be evaluated for dengue and chikungunya virus infections, in accordance with existing guidelines. Referral to a maternal-fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended.

Laboratory testing of maternal serum for Zika virus infection including RT-PCR, IgM and neutralizing antibody testing is warranted for pregnant women7:

  • With a history of travel to an area with Zika virus transmission and
  • Who reports the presence of two or more symptoms consistent with Zika virus infection (acute onset of fever, maculopapular rash, arthralgia or conjunctivitis) during or within two weeks of travel or
  • Who have ultrasound findings of fetal microcephaly or intracranial calcifications

Laboratory testing for Zika virus infection is not indicated for pregnant women in the following categories7:

  • Pregnant women with no travel history to an area with Zika virus transmission
  • Pregnant women with a travel history to an area with Zika virus transmission but no clinical illness consistent with Zika virus infection and no ultrasound findings of fetal microcephaly or intracranial calcifications

It is possible that a pregnant woman with a relevant travel history and no clinical symptoms or positive ultrasound findings may have a fetus affected by the Zika virus infection in that asymptomatic Zika virus infection is common. The above interim guidance has been issued based on limited laboratory testing capacities, and it is possible these criteria may be revised.

Zika virus testing of maternal serum includes7:

  • RT-PCR testing for symptomatic pregnant women with onset of symptoms within the previous week.
  • IgM and neutralizing antibody testing should be performed on specimens collected 4 days or later after the onset of symptoms. Cross-reaction with related flaviviruses (e.g., dengue or yellow fever) is common with antibody testing. As such, it might be difficult to distinguish Zika virus infection from other flavivirus infections. Consultation with state or local health departments might be necessary to assist with the interpretation of results.

Laboratory evidence of maternal Zika virus infection includes7:

  • Zika virus RNA detected by RT-PCR in any clinical specimen.
  • Positive Zika virus IgM with confirmatory neutralizing antibody titers that are 4-fold or higher than dengue virus neutralizing antibody titers in serum. Testing is considered inconclusive if the Zika virus neutralizing antibody titers are less than 4-fold higher than dengue virus neutralizing antibody titers.

Fetuses and Infants

Zika virus infections have been documented through both intrauterine transmissions resulting in congenital Zika virus infection and intrapartum transmission from a viremic mother to her newborn.8

Zika virus RNA by RT-PCR testing of amniotic fluid can be performed for the detection of intrauterine Zika virus infection. However, the sensitivity and specificity of this approach for diagnosis of congenital infection are unknown. It is reasonable to offer amniocentesis to women at 15 weeks or greater gestational age with a history of travel to an area with Zika virus transmission and either positive/inconclusive laboratory testing for Zika virus infection or relevant ultrasound findings (fetal microcephaly or intracranial calcifications).

Amniocentesis is associated with an overall 0.1% risk of pregnancy loss when performed at less than 24 weeks of gestation.8 Amniocentesis performed at 15 weeks or later gestational age is associated with lower rates of complications than those performed at earlier gestational ages. Amniocentesis performed at 14 weeks or less of gestational age is not recommended. Healthcare providers should discuss the risks and benefits of amniocentesis with their patients. It is unknown whether a positive amniotic fluid RT-PCR result is predictive of a subsequent fetal abnormality, and, if so, what proportion of infants born after infection will have abnormalities. A positive RT-PCR result on amniotic fluid should be considered suggestive of intrauterine Zika virus infection and potentially useful to pregnant women and their healthcare providers.

Serial ultrasound examinations (every three to four weeks) are appropriate to monitor fetal growth and anatomy in pregnant women with laboratory evidence of Zika virus infection in serum or amniotic fluid.8 Data on fetal ultrasound findings in infected pregnant women is limited. One small study reported variable fetal ultrasound findings that may include lower-than-expected head circumference for time of gestation (e.g., more than two standard deviations below the mean), focal brain abnormalities in areas such as the cerebellum and intraocular and brain calcifications.

For live births, Zika virus laboratory testing is recommended for:

  • Infants with microcephaly or intracranial calcifications born to women who traveled to or resided in an area with Zika virus transmission while pregnant.
  • Infants born to mothers with positive or inconclusive test results for Zika virus infection.

Because the diagnosis of Zika virus infection is made through molecular and serologic testing, including RT-PCR for viral RNA and IgM and plaque reduction neutralization test (PRNT) for Zika virus antibodies, it is currently not known which type of testing most reliably establishes the diagnosis of congenital Zika virus infection. The CDC recommends both molecular and serologic testing of infants who are being evaluated for evidence of a congenital Zika virus infection.

The following Zika virus testing on infants per CDC interim guidelines includes8:

  • Test infant serum for Zika virus RNA per RT-PCR, Zika virus IgM and neutralizing antibodies, as well as, dengue virus IgM and neutralizing antibodies. The initial sample should be collected either from the umbilical cord or directly from the infant within 2 days of birth, if possible.
  • If cerebrospinal fluid (CSF) is obtained for other studies, test for Zika virus RNA by RT-PCR, Zika virus IgM and neutralizing antibodies, as well as, dengue virus IgM and neutralizing antibodies.
  • The mother’s serum should be tested for Zika virus IgM and neutralizing antibodies, as well as dengue virus IgM and neutralizing antibodies, if not already performed during pregnancy.
  • Testing of frozen and fixed placental tissue and cord tissue for Zika virus RNA by RT-PCR.
  • Testing of cord serum for Zika and dengue virus IgM and neutralizing antibodies.

The results of these assays can be falsely positive because of cross-reacting antibodies. Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections (e.g., dengue or yellow fever viruses).

Finally, histopathologic examination of the placenta and umbilical cord tissues with Zika virus immunohistochemical staining to detect Zika virus antigen on fixed tissue and Zika virus RT-PCR on fixed and frozen tissue can be considered.8

An infant is considered congenitally infected if Zika virus RNA or viral antigen is identified in any of the samples submitted, including testing of amniotic fluid and testing of the placenta or umbilical cord. In addition, Zika virus IgM antibodies with confirmatory neutralizing antibody titers that are 4-fold or higher than dengue virus neutralizing antibody titers in the infant serum or CSF constitute evidence of a congenital Zika virus infection. If Zika virus neutralizing antibody titers are less than 4-fold higher than dengue results, the results are considered inconclusive.

Fetal tissue testing is warranted for evaluation of fetal losses in women with a history of travel to an area of Zika virus transmission, together with either symptoms consistent with Zika virus infection during or within two weeks of travel or findings of fetal microcephaly. In such cases, Zika virus RT-PCR and immunohistochemical staining should be performed on fetal tissues, including the umbilical cord and placenta.

Treatment

As of 2016, no vaccine or antiviral medications are available to prevent or treat Zika virus infections. Effective vaccines exist for several flaviviruses. Vaccines for yellow fever virus, Japanese encephalitis and tick-borne encephalitis were introduced in the 1930s. The vaccine for dengue fever has just recently become available for use.

Work has begun towards developing a vaccine for the Zika virus, according to Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases. The researchers at the Vaccine Research Center have extensive experience from working with vaccines for other viruses such as West Nile virus, chikungunya virus and dengue fever.9 Nikos Vasilakis of the Center for Biodefense and Emerging Infectious Diseases has predicted that 10 to 12 years may be needed before an effective Zika virus vaccine becomes available.

The goals of clinical management, whether pregnant or not, are supportive in nature and include:

  • Rest
  • Drinking fluids to prevent dehydration
  • Administration of acetaminophen and analgesics to relieve fever and pain respectively

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen should be avoided until dengue infection has been ruled out to reduce the risk of hemorrhage.

In pregnant women with laboratory evidence of Zika virus infection in serum or amniotic fluid, serial ultrasound examinations (every three to four weeks) are appropriate to monitor fetal growth and anatomy.

Because of similar geographic distribution and symptoms, individuals with suspected Zika virus infections also should be evaluated and managed for possible dengue or chikungunya virus infection.

Individuals infected with the Zika, chikungunya or dengue viruses should avoid mosquito bites during the first week of infection to prevent other mosquitoes from becoming infected and reducing the risk of local transmission by passing the viruses on to other individuals.

Special Circumstances: Evaluation

For the purpose of evaluating an infant for possible congenital Zika virus infection, microcephaly is defined as occipitofrontal circumference less than the third percentile, based on standard growth charts (e.g., Fenton, Olsen, CDC or WHO growth curves) for sex, age and gestational age at birth. For a diagnosis of microcephaly to be made, the occipitofrontal circumference should be disproportionately small in comparison with the length of the infant and not explained by other etiologies (e.g., other congenital disorders). If an infant’s occipitofrontal circumference is equal to or greater than the third percentile but is notably disproportionate to the length of the infant or if the infant has deficits that are related to the central nervous system, additional evaluation for Zika virus infection should be considered.

For all infants with possible congenital Zika virus infection, evaluation should include10:

  • A comprehensive physical examination, including careful measurement of the occipitofrontal circumference, length, weight and assessment of gestational age.
  • Evaluation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly and rash or other skin lesions. Full-body photographs and any rash, skin lesions or dysmorphic features should be documented. If an abnormality is noted, consultation with an appropriate specialist is recommended.
  • A cranial ultrasound, unless prenatal ultrasound results from the third trimester demonstrated no abnormalities of the brain.
  • Evaluation of hearing by evoked otoacoustic emissions testing or auditory brainstem response testing, either before discharge from the hospital or within one month after birth. Infants with abnormal initial hearing screens should be referred to an audiologist for further evaluation.
  • Ophthalmologic evaluation, including examination of the retina, either before discharge from the hospital or within one month after birth. Infants with an abnormal initial eye evaluation should be referred to a pediatric ophthalmologist for further evaluation.
  • Other evaluations are specific to the infant’s clinical presentation.

For infants with microcephaly or intracranial calcifications detected prenatally or at birth whose mothers were possibly infected with the Zika virus during pregnancy, evaluation should include:

  • Testing the infant for Zika virus infection.
    • For infants with microcephaly or intracranial calcifications who have a positive or inconclusive test finding for Zika virus infection, healthcare providers should:
      • Assess the infant for possible long-term sequelae including a repeat hearing screen at age 6 months, even if the initial screening hearing test was normal, because of the potential for delayed hearing loss as has been described with other infections such as cytomegalovirus.
      • Order an ophthalmologic evaluation, including retinal examination, occurring during the first month of life, given reports of abnormal eye findings.
      • Report the case to the state, territorial or local health departments.
    • For infants with microcephaly or intracranial calcifications who have negative results on all Zika virus tests performed, healthcare providers should evaluate for other possible etiologies and treat as indicated. Evaluation should include:
      • Consultation with a clinical geneticist or dysmorphologist.
      • Consultation with a pediatric neurologist to determine appropriate brain imaging and additional evaluation (e.g., ultrasound, computerized tomography scan, magnetic resonance imaging and electroencephalogram).
      • Testing for other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection and herpes simplex virus infections. A pediatric infectious disease specialist should be consulted.
      • A complete blood count, platelet count and liver function and enzyme tests, including alanine aminotransferase, aspartate aminotransferase and bilirubin.
      • Consideration of genetic and other teratogenic causes based on additional congenital anomalies that are identified through clinical examination and imaging studies.
  • Testing the mother for Zika virus infection, if this testing had not already been performed during pregnancy.

Recommendations for long-term follow-up for infants with possible congenital Zika virus infection include10:

  • Conducting additional hearing screen at age 6 months, plus any appropriate follow-up of hearing abnormalities detected through a newborn hearing screening.
  • Carefully evaluating occipitofrontal circumference and developmental characteristics and milestones throughout the first year of life, with the use of appropriate consultations with medical specialists (e.g., pediatric neurology, developmental and behavioral pediatrics, physical and speech therapy).
  • Reporting the case to state, territorial or local health departments and monitoring for additional guidance as it is released.

For infants without microcephaly or intracranial calcifications detected prenatally or at birth whose mothers were possibly infected with the Zika virus during pregnancy, subsequent evaluation is dependent on results from maternal Zika virus testing.7

  • If the test results for the mother were negative for the Zika virus infection, the infant should receive routine care (e.g., newborn metabolic and hearing screens).
    • If the results of all of the infant’s tests are negative for evidence of Zika virus infection, then no further Zika virus testing and evaluation are recommended.
  • If the mother received positive or inconclusive results of tests for Zika virus infection, the infant should be tested for a possible congenital Zika virus infection.
    • If any of the infant’s samples test positive or inconclusive, then the infant should undergo further clinical evaluation.
    • The infant should be followed to assess for possible long-term sequelae which should include:
      • Cranial ultrasound to assess for subclinical findings, unless prenatal ultrasound results from the third trimester demonstrated no abnormalities of the brain
      • Ophthalmologic examination
      • Repeat hearing screen
      • Developmental monitoring and screening during the first year of life
    • The infant’s case should be reported to the state, territorial or local health departments.

Prognosis

Severe disease requiring hospitalization is rare. Case-fatality rates are low. In the Americas Region, ZIKV is new and up until now has had a minimal geographic and demographic distribution. There is only recent evidence that it can cause death. However, sporadic cases have been reported of more serious manifestations and complications in individuals with pre-existing diseases or conditions causing death.

Prevention

Mosquitoes and their breeding sites pose a significant risk factor for Zika virus infection. Prevention and control rely on reducing mosquitoes through source reduction (removal and modification of breeding sites) and reducing contact between mosquitoes and humans.

Individuals in areas of autochthonous transmission or when traveling to areas where mosquitoes carrying the Zika virus or other viruses are endemic should take measures to avoid mosquito bites. Measures include both personal preventative protections, as well as environmental control measures.

Personal protective measures include11:

  • Preventing mosquito bites:
    • Wear shirts with long sleeves, long pants (preferably light-colored) that cover as much of the body as possible and hats.
      • Since mosquitoes can bite through thin clothing, use permethrin or another Environmental Protection Agency (EPA) registered insecticide to treat clothing and gear (such as boots, pants, socks, tents, etc.) or purchase permethrin-treated clothing and gear for extra protection. Read product information to find out how long the protection will last.
        • Treated clothing remains protective after multiple washing but read the product information to learn how long the protection lasts.
        • If personally treating items, follow the product instructions carefully.
        • Do not use permethrin products directly on the skin, only on clothing and gear.
    • Use only an EPA registered insect repellant containing DEET, Picaridin (also known as KBR 3023, Bayrepel, Icaridin), Oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) and IR3535.
      • If traveling, consider bringing the insect repellent along.
      • Always follow the product label instructions.
      • Reapply insect repellent as directed.
      • Do not spray repellent on the skin under clothing.
      • If also using sunscreen, apply sunscreen first before applying insect repellent.
    • Stay in places with air conditioning or that use window and door screens to keep mosquitoes outside.
    • Stay indoors as much as possible with air conditioning, window/door screens or closed doors and/or mosquito nets as physical barriers to minimize contact with mosquitoes.
    • Sleep under a mosquito bed net if sleeping outside or in a room that is not well screened since mosquitoes can live indoors and will bite day or night. Buy a bed net at the local outdoor store or online before traveling overseas.
      • Choose a WHOPES-approved bed net (like Pramax®).
      • Permethrin-treated bed nets provide more protection than untreated nets.
        • Permethrin is an insecticide that kills mosquitoes and other insects.
          • Do not wash bed nets or expose them to sunlight since this will break down the insecticide more quickly.

Environmental control measures to eliminate or control mosquitoes include12:

  • Identification and elimination of potential mosquito larvae breeding sites including:
    • Avoiding allowing standing water to collect outdoors (such as in flowerpots, buckets, bottles, jars and other similar containers near houses).
    • Once a week, emptying and scrubbing, turning over, covering or throwing out items that hold water such as buckets, flowerpots, tires, toys or trash containers both inside and outside of the home, so that places where mosquitoes can breed are removed.
    • Covering domestic water tanks so that mosquitoes cannot enter.
    • Unblocking drains that allow stagnant or standing water.
    • Using screens and mosquito nets in windows and doors to reduce contact between mosquitoes and humans.
    • Avoiding accumulating garbage by putting it in closed plastic bags and keeping it in closed containers.
    • Health authorities advising that spraying of insecticides will be occurring during outbreaks.
    • Using larvicides insecticides recommended by the WHO Pesticide Evaluation Scheme to treat relatively large water containers.

Special attention and help should be given to those who may not be able to protect themselves adequately, such as infants/young children, the sick or the elderly.

  • If infants/young children12:
    • Do not use insect repellent on infants younger than 2 months of age.
    • Dress infants/young children in clothing that fully covers the arms, legs and head.
    • Cover crib, stroller and baby carrier with mosquito netting.
    • Do not apply insect repellent onto an infant’s/young child’s hands, eyes, mouth, and cut or irritated skin.
    • Adults: Spray insect repellent onto your own hands first and then apply to an infant’s/young child’s face.

The only way to prevent congenital Zika virus infection is to prevent maternal infection, either by avoiding areas where Zika virus transmission is ongoing or strictly following steps to avoid mosquito bites.

If an individual has a Zika virus infection, it is imperative that other individuals be protected from acquiring the virus. Since the Zika virus can be found in the infected individual’s blood during the first week of infection, if a mosquito bites the infected individual the mosquito can then pass the Zika virus onto another individual by simply biting them. Individuals with Zika virus infection may reduce the spread of infection to others by following the same personal protective measures mentioned above to protect themselves from being bitten further by other mosquitoes and then those mosquitoes biting other individuals and so on and so on. Individuals with symptoms of Zika, dengue or chikungunya should visit a healthcare center.

Anecdotal reports of apparent sexual transmission of the Zika virus have been described, although this appears to be an infrequent mechanism for virus transmission. Information regarding the persistence of the virus at different sites following infection is not yet available. Pending further study, it may be wise for men with symptoms of Zika virus infection who have female sexual partners of childbearing age to use barrier protection and defer unprotected sex for at least a few weeks following resolution of symptoms.

Travel Advisory

On Friday, January 15, 2016, the CDC issued interim travel guidance related to the Zika virus for 14 countries and territories in Central and South America and the Caribbean.13 The CDC issued a travel alert (Level 2-Practice Enhanced Precautions) for individuals traveling to regions and certain countries where Zika virus transmission is ongoing. These regions and countries include Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela, and the Commonwealth of Puerto Rico.

Because of the potential for birth defects, the CDC issued travel guidance for pregnant American women and women of childbearing age who may become pregnant, warning them to avoid visiting places where the virus is currently circulating.

Until more is known and out of an abundance of caution, the CDC recommends special precautions for pregnant women and women trying to become pregnant13:

  • Pregnant women in any trimester should consider postponing travel to the areas where Zika virus transmission is ongoing. Pregnant women who must travel to one of these areas should talk to their doctor or another healthcare provider prior to travel. If a pregnant woman travels to an area with Zika virus transmission, she should be advised to follow strict steps to avoid mosquito bites. Mosquitoes that spread the Zika virus bite both indoors and outdoors, mostly during the daytime. It is, therefore, important to ensure protection from mosquitoes throughout the entire day.
  • Women trying to become pregnant should consult with their healthcare provider prior to traveling to these areas and strictly follow steps to prevent mosquito bites during the trip.

The CDC has issued interim guidelines for healthcare providers in the United States for the evaluation of pregnant women during a Zika virus outbreak. These guidelines include recommendations for pregnant women considering travel to an area with Zika virus transmission and recommendations for screening, testing and management of the pregnant returning traveler.

Governments or health agencies of the United Kingdom, Ireland, New Zealand, Canada, and the European Union have also issued similar travel warnings. In Colombia, the Minister of Health and Social Protection, Alejandro Gaviria Uribe, recommended avoiding pregnancy for eight months, while the countries of Ecuador, El Salvador and Jamaica have issued similar warnings. Women in other countries in Latin America and the Caribbean that have been hit with Zika have been told to simply avoid getting pregnant - in some cases for two years.

International Responses

WHO is actively working with the countries of the Americas to develop or maintain their ability to detect and confirm cases of Zika virus infection, treat individuals affected by the disease and implement effective strategies to reduce the presence of the mosquito and minimize the likelihood of an outbreak.

WHO support involves:

  • Building the capacity of laboratories to detect the Zika virus in a timely fashion together with other collaborating centers and strategic partners.
  • Advising on risk communication to respond to the introduction of the Zika virus in the country.
  • Controlling the vector by working actively with the populace to eliminate mosquito populations.
  • Preparing recommendations for the clinical care and monitoring of individuals with Zika virus infection in collaboration with professional associations and experts from the countries.
  • Monitoring the geographic expansion of the Zika virus and the emergence of complications and serious cases through surveillance of events and country reporting through the International Health Regulations channel.
  • Supporting health ministry initiatives aimed at learning more about the characteristics of the Zika virus, its impact on health and the possible consequences of infection.

The WHO is supporting countries to control Zika virus infection through:

  • Defining and prioritizing research into Zika virus infection by convening experts and partners.
  • Enhancing surveillance of the Zika virus and potential complications.
  • Strengthening capacity in risk communication to help countries meet their commitments under the International Health Regulations.
  • Providing training on clinical management, diagnosis and vector control, including through a number of WHO Collaborating Centers.
  • Strengthening the capacity of laboratories to detect the virus.
  • Supporting health authorities to implement vector control strategies aimed at reducing Aedes mosquito populations such as providing larvicide to treat standing water sites that cannot be treated in other ways, such as cleaning, emptying and covering them.
  • Preparing recommendations for clinical care and follow-up of individuals with Zika virus infection in collaboration with experts and other health agencies.

Summary

Outbreaks of Zika virus infection, caused by an emerging mosquito-borne flavivirus, have occurred in Africa, Southeast Asia and the Pacific Islands. Currently, there is an ongoing Zika virus outbreak in the Americas. Zika virus is transmitted to humans via the bite of an infected Aedes mosquito. This type of mosquito usually bites during the daytime and breeds in standing water.

Clinical manifestations of Zika virus infection include acute onset of low-grade fever with maculopapular rash, arthralgia (notably of the small joints of the hands and feet) or conjunctivitis (nonpurulent). Clinical illness is consistent with Zika virus infection if two or more of these symptoms are present. Zika virus infection has also been associated with congenital microcephaly, fetal loss and Guillain-Barré syndrome.

Signs and symptoms typically occur 2 to 12 days after the mosquito vector bite. Zika virus infection is usually mild. Clinical manifestations usually resolve within two to seven days. Asymptomatic infection up to 80% is common. Symptomatic infection develops in 20 to 25% of individuals who become infected with the Zika virus.

The diagnosis of Zika virus infection should be suspected in individuals with typical clinical manifestations and relevant epidemiologic exposure (residence in or travel to an area where the Aedes mosquito is present and where travel-related or local cases have been reported or in unprotected sexual contact with an individual who meets these criteria).

The diagnosis of Zika virus infection is established via serum RT-PCR testing or serology. Within the first seven days following the onset of symptoms, the diagnosis may be established via serum RT-PCR for detection of Zika viral RNA. Four or more days after the onset of symptoms, the diagnosis may be established via Zika virus serologic testing.

Pregnant women with Zika virus exposure should undergo ultrasonography to evaluate for the presence of fetal microcephaly or intracranial calcifications. Laboratory testing for Zika virus infection is warranted for pregnant women with Zika virus exposure and either of the following:

  • Presence of two or more symptoms consistent with Zika virus infection (acute onset of fever, maculopapular rash, arthralgia or conjunctivitis) during or within two weeks of exposure.
  • Ultrasound findings of fetal microcephaly or intracranial calcifications (with or without maternal clinical illness consistent with Zika virus infection).

Serial ultrasonography (every three to four weeks) is appropriate (with focus on evaluation for microcephaly or intracranial calcifications) for pregnant women in either of the following categories:

  • Positive or inconclusive laboratory test results for Zika virus infection.
  • Zika virus exposure and two or more symptoms consistent with Zika virus infection (acute onset of fever, maculopapular rash, arthralgia or conjunctivitis) during or within two weeks of exposure, regardless of laboratory test results.

Indications for Zika virus laboratory testing of infants include:

  • Infants with microcephaly or intracranial calcifications born to women with Zika virus exposure while pregnant.
  • Infants born to mothers with positive or inconclusive laboratory test results for Zika virus infection.

An infant with microcephaly or intracranial calcifications born to a mother who was potentially infected with the Zika virus during pregnancy should undergo further clinical evaluation. In addition, an infant with positive or inconclusive test results for Zika virus infection should be assessed for possible long-term sequelae.

There is no specific treatment for Zika virus infection, and there is no vaccine for prevention. Management consists of symptomatic treatment. Preventive measures include personal protective measures to prevent mosquito bites and institution of measures to eliminate and control mosquito breeding sites.

Pregnant women should be particularly careful regarding adherence to mosquito protective measures and about traveling to areas where transmission of the Zika virus is high. In January 2016, the United States Centers for Disease Control and Prevention and the European Centre for Prevention and Control advised that pregnant women consider postponing travel to any area where Zika virus transmission is ongoing.

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References

  1. Brazil Zika outbreak: More babies born with birth defects BBC Web site. Published January 21, 2016. Visit Source.
  2. Rapid risk assessment: Mircrocephaly in Brazil potentially linked to the Zika virus epidemic. European Centre for Disease Prevention and Control. Published November 25, 2015. Retrieved 18 January 2016. Visit Source.
  3. CDC. Zika virus. For health care providers: diagnostic testing. Atlanta, GA: US Department of Health and Human Services, CDC; 2015.
  4. For Health Care Providers: Clinical Evaluation & Disease. Zika Virus. DVBD, NCEZID, Centers for Disease Control and Prevention. 19 January 2016.
  5. Maron, Dina Fine. First Dengue Fever Vaccine Gets Green Light in 3 Countries. Scientific American. Retrieved 28 January 2016.
  6. CDC. Chikungunya virus: clinical evaluation & disease. Atlanta, GA: US Department of Health and Human Services, CDC; 2015.
  7. American Academy of Pediatrics/American College of Obstetricians and Gynecologists. Guidelines for perinatal care. 7th ed. Elk Grove Village, IL: American Academy of Pediatrics/American College of Obstetricians and Gynecologists; 2012.
  8. Vogel, Gretchen (3 December 2015). Fast-spreading virus may cause severe birth defects. Science News. AAAS.
  9. Fauci, Anthony S.; Morens, David M. (14 January 2016). Zika Virus in the Americas – Yet Another Arbovirus Threat. New England Journal of Medicine 374 (2): 160113142101009.
  10. Developmental disabilities. Atlanta, GA: US Department of Health and Human Services; 2015.
  11. CDC. Travelers’ health. CDC issues interim travel guidance related to Zika virus for 14 countries and territories in Central and South America and the Caribbean. Atlanta, GA: US Department of Health and Human Services, CDC; 2016.
  12. CDC. Zika virus: prevention. Atlanta, GA: US Department of Health and Human Services, CDC; 2015.
  13. CDC. Travelers’ health: protection against mosquitoes, ticks, & other arthropods.