Zika Virus

Zika virus (ZIKV) belongs to the Flavivirus genus; like other flaviviruses, Zika virus is an icosahedral, enveloped, single-stranded RNA virus.[1, 2]  The lipid envelope is covered with dense projections that consist of a membrane and envelope glycoproteins.[2]  

In most cases, Zika virus infection causes a mild, self-limited illness. The incubation period is around 3-14 days.[1]  The spectrum of Zika virus disease overlaps with other arboviral infections, but rash (maculopapular and likely immune-mediated) typically predominates.[1]  Unlike other arboviral infections, Zika virus has potential for sexual transmission[1]  and has been associated with congenital brain abnormalities in pregnant women infected during the first trimester. 

Zika virus was first described in a captive sentinel febrile rhesus monkey in the Zika forest of Entebbe, Uganda in 1947. In 1948, the virus was recovered from the mosquito Aedes africanus in the Zika forest. The first human case was reported shortly thereafter in 1952.[1, 2]  Zika virus is widely distributed outside Africa. Outbreaks have been described in Micronesia and French Polynesia.[3, 4]  A large outbreak of Zika was declared in the Americas in 2015-2016 that later spread mostly via travel to US states. In February 2016, the World Health Organization (WHO) declared the spread of Zika virus a public health emergency.[5]  Since 2017, Zika cases have declined, and as of January 2021, no countries in the world report active Zika virus infection outbreaks.[6]

Zika virus infection is among the nationally notifiable diseases in the United States since 2016. Healthcare professionals should inform state and local health departments of suspected cases of ZIKV infection to facilitate diagnosis and to reduce the risk of local transmission. 

For the latest information concerning Zika virus, see also Medscape’s Zika Virus Resource Center.

The genome of the Zika virus has a length of 10.7 kb, divided into structural and non-structural segments. There are 3 structural proteins (core [C], pre-membrane [prM], and envelope [E]) and 7 non-structural (NS) proteins.[1]  The prM and E proteins facilitate viral attachment to the host cell membrane AXL receptor, a transmembrane receptor tyrosine kinase protein. This is followed by endocytic uptake and then uncoating of the nucleocapsid and release of viral RNA into the cytoplasm. The NS proteins form a replication complex that synthesizes positive-sense RNA from negative-sense RNA. A viral polyprotein is produced and modified by the endoplasmic reticulum. Immature virions collect both in the endoplasmic reticulum and in secretory vesicles before being released. The C protein along with other NS proteins cause cell cycle arrest, apoptosis and death.[1, 2]   

Sirohi et al described the structure of mature ZIKV based on cryoelectron microscopy. The virus resembles other known flavivirus structures with the exception of approximately 10 amino acids surrounding the Asn154 glycosylation site in each of the 180 envelope glycoproteins comprising the icosahedral shell, the carbohydrate moiety that may be the site where the virus attaches to the host cells.[7]

Zika virus has 2 Zika virus lineages (Asian and African) and 3 genotypes (West African, East African, and Asian) based on phylogenetic analysis.[1]  The Asian lineage spread from Asia to the Pactific Islands and the Americas. It is poorly understood if these lineages have any impact on clinical outcomes. It is speculated that Zika virus Asian lineage is associated with serious outbreaks and congenital malformations and that African lineage is intrinsically more virulent and is associated with acute infection and adverse pregnancy outcomes.[8]

Zika virus is well-adapted to grow in various hosts, ranging from arthropods to vertebrates. Zika virus has tropism for various tissues in the human body such as skin, blood, placenta cells, testes, retinal cells, neural stem cells and neuroprogenitor cells. Zika virus also infects monocytes, facilitating passage across blood-brain and placental barriers. Host cells invaded by Zika virus undergo cellular appoptosis, necrosis, and death. Thus, Zika virus affecting neuronal progenitor cells affects neuronal growth, causing fetal brain abnormalities and placental insufficiency resulting in fetal loss.[9]  

The first defense against Zika virus is produced by the innate immune system.[10] Activation of type I interferon (IFN) and IFN-stimulated genes (ISG) inhibits Zika virus replication. Zika virus is able to evade the immune response with the help of NS proteins inhibiting the signaling pathway responsible for activation of IFN and ISG.[10] Studies have demonstrated inhibition of stress granule formation and modulation of nonsense-mediated mRNA decay machinery by Zika virus, enhancing its viral replication. Further studies are needed to completely understand the mechanisms behind Zika virus's evasion of the immune response.[11]  

Research has demonstrated interaction between ZIKV and dengue virus immune response impacting immunogenicity and disease complications. Studies have demonstrated a lower seroprevalence of dengue virus in Zika virus infected mothers of children with congenital Zika syndrome and mothers with vertical transmission of Zika virus to the fetus. This is suggestive of potential cross-protection against Zika virus in those with previous history of dengue virus infection. The CD4+ and CD8+ T cell response from dengue virus infection has been demonstrated to suppress Zika virus replication, imparting protection against Zika virus infection. On the contrary, previous Zika virus infection has been shown to increase the risk for severe disease in those with dengue virus infection.[8]   

The global prevalence of Zika virus infection has not been widely reported owing to asymptomatic clinical course, clinical resemblance to other infection with other flaviviruses (dengue, chikungunya), and difficulty in confirming diagnosis.

Based on outbreak reports, entomologic surveys, and seroprevalence surveys, Zika virus infection had been reported in various hosts, including humans, primates, and mosquitoes, in a total of 87 countries and territories across Africa, the Americas, Southeast Asia, and the Western Pacific, as of July 2019.[12]

The prevalence of Zika virus infection in Uganda was 6.1% in 1952 among a population of 99 residents.[13] The prevalence of Zika virus infection was 7.1% in Java, Indonesia, from 1977-1978 among patients who were hospitalized for fever.[14]  A seroprevalence of around 20-22% was estimated based on study survey in Senegal, Mali and Gambia from 2007-2012.[1]

Since Zika virus was first isolated in 1947, the disease has spread outside Africa, mainly into Southeast Asia and the Americas. Until 2007, sporadic cases of Zika virus illness in humans were reported. In 2007, Yap Island in Micronesia reported an outbreak of Zika virus infection transmitted via Aedes hensilli that sickened approximately 73% of the population.[4] Since 2013-2015, epidemics of Zika virus infection have occurred in French Polynesia, New Caledonia, the Cook Islands, the Easter Islands, and other Pacific Islands.[15]  The outbreak in French Polynesia highlighted Guillian-Barre syndrome as a potential neurologic complication associated with Zika.

In May 2015, Brazil reported the first outbreak of Zika virus infection in the Americas, accounting for around 205,578 cases, in 2016. The Asian lineage associated with the outbreak had potentially circulated in Brazil since 2013. Aedes aegypti (major) and Aedes albopictus (minor) were recognized as vectors for the transmission of Zika virus. The infection spread rapidly to several other countries and became a pandemic. During the outbreak in Brazil, a notable 22% rise in hospitalizations occured between 2014 to 2015 due to Zika-associated Guillain-Barré syndrome (GBS); confirmed or suspected cases of congenital Zika syndrome were reported in more than 5,000 newborns.[16, 17]  Brazil reported a total of 6 deaths in 2015-2016. The incidence of new cases eventually decreased due to herd immunity. 

Before 2015, only 14 travel-associated cases of Zika virus disease were reported in the United States. In 2016, around 5,168 laboratory-confirmed non-congenital Zika virus infections were reported in the United States. Most (95%) cases were imported as a result of travel to areas with ongoing outbreaks, 4% were potentially acquired via local vector-borne transmission in Florida and Texas, and 1% of the cases were acquired through other routes (sexual transmission, laboratory-acquired and unknown source). Guillain-Barré syndrome was reported in 0.3% of cases, of which 3% required hospitalization. Zika-associated birth defects occured in 10% of babies born to women in the United States.[18, 19]

United States territories such as Puerto Rico and the US Virgin Islands have reported around 37,188 symptomatic Zika virus disease cases, the majority of which were related to autochthonous transmission of the virus. Around 5% of babies born to women in US territories had Zika-associated birth defects.[18]

Outside of Americas and US states and territories, Cape Verde reported the first African Zika epidemic in 2015-2016. Ethiopia reported evidence of Zika virus infection in 2018. Multiple countries in Southeast Asia such as India, Indonesia, Mynamar, and Thailand have reported Zika virus cases and associated complications.[12]  

Zika virus infections have been reported in Europe since 2013. The European CDC reported 71 cases of Zika virus infection in 2019, the majority  (92%) of which were travel associated with few locally transmitted as a result of sexual contact or vertical transmission. The first 3 cases of vector-borne local transmission of ZIKV infection via Ae albopictus were reported in France in October 2019.[20]

Laboratory-confirmed symptomatic Zika virus disease cases reported to ArboNET by states and territories - United States, 2017. Courtesy of the Centers for Disease Control and Prevention (CDC).

World map of areas with color-coded risk for Zika based on current or previously reported Zika cases, as of November 4, 2019. Courtesy of the Centers for Disease Control and Prevention (CDC).

Most cases of Zika virus infection are mild and self-limited. Owing to the mild nature of the disease, more than 80% of Zika virus infection cases likely go unnoticed.[1]  

Serious neurologic complications have been reported in rare cases, including Guillain-Barré syndrome.[1, 21]

In addition, adverse pregnancy outcomes and congenital Zika syndrome due to vertical transmission of Zika virus are of greatest concern with poor long-term prognosis.[14, 22]  

Zika virus infection has short-term adverse effects on fertility.

For further detail, see History.

Patients should be educated concerning travel risks associated with Zika virus and prevention of mosquito bites and mosquito-control measures. Travelers should refer to CDC site before arranging travel plans for up-to-date information on Zika virus transmission internationally and in US states and territories.

The CDC provides information for women who are pregnant or trying to get pregnant on implications of Zika virus infection during pregnancy and helpful travel, testing, and management information related to the topic.[23]

The World Health Organization (WHO) and CDC recommend that mothers with Zika virus infection still breastfeed their infants, including those born with microcephaly. Zika virus has been isolated from breast milk but the risk for transmission via breast milk has not been documented.[24]

For more details, see Prevention.

Zika virus can be transmitted by vector-borne and non-vector-borne routes. 

Vector-borne Transmission

Like many other flaviviruses, Zika virus is transmitted by an arthropod: the Aedes mosquito, including Aedes aegypti, Aedes africanus, Aedes luteocephalus, Aedes albopictus, Aedes vittatus, Aedes furcifer, Aedes hensilli, and Aedes apicoargenteus.[1, 2, 4, 25]  Zika virus has also been isolated from domestic mosquito Culex quinquefasciatus. Zika virus circulates among different human and animal species with the mosquito as the vector of transmssion. The sylvatic cycle transmits Zika virus between non-human primates, and the urban life cycle infects humans. Ae. aegypti, a major vector for human transmission, and Ae. albopictus, a minor vector with few reported outbreaks, are typically found in tropical and subtropical regions and have also been discovered in other non-tropical parts of the world. The CDC has released a map of potential ZIKV spread in the United States based on the estimated range of Aedes aegypti and Aedes albopictus mosquitoes. 

In United States, transmission is active in months of June to October while the mosquito vectors feeds on humans during daytime. Zika virus is transmitted from the salivary gland of the biting mosquito into the host's blood circulation and subsequently infects the skin cells and other organs.[26]

Non-vector-borne Transmission

Zika outbreaks unearthed various non-vector-borne transmission routes of Zika virus. 

Vertical transmission of Zika virus from mother to fetus is estimated to occur in 20-30% of infected pregnant women during all trimesters. Infection during the first trimester is considered most serious and is associated with congenital Zika syndrome. Zika virus has also been isolated in breastmilk; however, there is no clear evidence of transmission to babies during breastfeeding. Breastfeeding is encouraged in Zika virus-infected or possibly infected mothers as the benefits of breastfeeding outweigh the risks.[1, 27]  

Zika virus has been idenitified in the semen of 50-60% of men in the first month of infection, lasting up to 281 days in one case. Cases of sexual transmission of Zika virus from male-to-female partners has been reported in the United States and French Polynesia. Transmission from female-to-male and male-to-male partners has also been reported. The highest risk for sexual transmission from an infected partner is estimated to occur up to 32-44 days from the onset of symptoms.[1, 2, 28]

Zika virus can be detected in the serum for a short time during acute illness. The estimated prevelance of Zkia virus RNA in blood donors is around 1%. Blood tranfusion-related transmission of Zika virus remains a concern. Zika virus has been isolated in urine, saliva, and solid organs during transplantation; however, there is no clear evidence of transmission from these routes.[1, 2, 29]

In most cases, Zika virus (ZIKV) infection causes a mild, self-limited illness. The incubation period likely is 3-12 days.[1]  Owing to the mild nature of the disease, more than 80% of Zika virus infection cases likely go unnoticed.[1]  The spectrum of Zika virus disease overlaps with other that of arboviral infections, but rash (maculopapular and likely immune-mediated) typically predominates.[1]

The rash in Zika virus infection usually is a fine maculopapular rash that is diffusely distributed. It can involve the face, trunk, and extremities, including palms and soles. Occasionally, the rash may be pruritic. The rash, along with other symptoms, usually occurs within 2 weeks after travel to a Zika virus–affected area. Zika virus rash usually occurs within the first week of illness, with the illness itself lasting from several days to weeks. 

Rash in a patient with Zika virus infection. Courtesy of Carolina O Barbosa, MD, and Antonio C Bandeira, MD, Salvador, Brazil.

Rash in a patient with Zika virus infection. Courtesy of Carolina O Barbosa, MD, and Antonio C Bandeira, MD, Salvador, Brazil.

Rash in a patient with Zika virus infection. Courtesy of Carolina O Barbosa, MD, and Antonio C Bandeira, MD, Salvador, Brazil.

Rash in a patient with Zika virus infection. Courtesy of Carolina O Barbosa, MD, and Antonio C Bandeira, MD, Salvador, Brazil.

Aside from rash, the most common symptoms of Zika virus infection include fever, arthralgia (involving the small joints of the hands and feet), retroocular headache, and conjunctivitis.[2, 4, 21] Symptoms last from 2-7 days.[1]

In rare cases, Zika virus infection is complicated by Guillain-Barré syndrome.[1, 21] A case of probable Zika virus-related hypertensive iridocyclitis was reported in an otherwise healthy young physician.[13]

More commonly, patients recover quickly and fully. In a review of 49 confirmed and 59 probable cases of Zika virus infection occurring in a 2007 outbreak on Yap Island, Micronesia, no hospitalizations, hemorrhagic complications, or deaths were attributed to the infection.[4]

Microcephaly and Other Congenital Malformations

Although Zika virus infection generally is well-tolerated, great concern is emerging over congenital malformations due to transplacental transmission of Zika virus. Six months after an outbreak of Zika virus infection began in Brazil, the incidence of microcephaly increased twenty-fold. Whereas the historical prevalence of microcephaly was 2 cases per 10,000 live births, 1248 new suspected cases of microcephaly were reported in 2015,[14, 15] and, as of January 2016, the number of suspected microcephaly cases increased to 4810, of which 270 were confirmed and 462 rejected as false diagnoses of microcephaly.[15]

Infants born with congenital microcephaly and suspected vertical acquisition of Zika virus have been found to have various ophthalmologic abnormalities, including loss of foveal reflex, macular pigment mottling, chorioretinal macular atrophy, optic nerve head hypoplasia, and optic nerve double-ring sign.[14]

Of note, causality has not been definitively proven, and concerns exist over the accuracy of the historical incidence of microcephaly and potential increased diagnoses in the past year leading to a false perception of increased incidence.[15]

A study of 35 infants with microcephaly (defined as head circumference ≥2 standard deviations below the mean for sex and gestational age) born between August and October 2015 in various states throughout Brazil found that the mothers of all 35 had lived in or visited Zika virus–affected areas during pregnancy.[16] Twenty-seven of these infants had severe microcephaly, and test results were negative for other congenital infections in all cases. Zika virus RNA also has been detected in amniotic fluid and placental and fetal tissue in several cases of nervous-system malformations amid the Brazilian outbreak.[15]

The WHO recommends that newborns born to mothers with Zika virus infection undergo head circumference measurement between 1 and 7 days after birth. A head circumference of more than 2 standard deviations below the mean is considered microcephaly; a circumference of more than 3 standard deviations below the mean is classified as severe microcephaly, which should prompt neuroimaging.[30]

Serious complications have been reported in some cases of Zika virus infection, including Guillain-Barré syndrome.[1, 21] In addition, there is  great concern over congenital malformations due to transplacental transmission of Zika virus, including microcephaly and various ophthalmologic abnormalities.[14, 15]

In March 2016, a 15-year-old patient diagnosed with acute myelitis on the French Caribbean island of Guadeloupe was found to have high levels of Zika virus in her cerebrospinal fluid, urine, and blood, suggesting that Zika virus may be neurotropic. Thus, Zika virus infection should be considered among individuals with acute myelitis who live in or travel from areas endemic for Zika virus.[31]

For more details, see History.

Confirmation of Zika virus infection based on diagnostic testing is challenging due to test sensitivity, specificity, and the epidemiologic prevelance of Zika. 

Diagnostic testing of Zika virus (ZIKV) infection is based on molecular and serologic methods.[32] Nucleic acid amplification testing (NAAT) is standard diagnostic testing for confirmation of acute infection. A negative NAAT for Zika virus does not rule out infection due to transient viremia during active infection. FDA has issued emergency use authorization on Zika NAAT testing to be performed on serum, plasma, whole blood, cerebrospinal fluid, urine, or amniotic fluid. 

Serologic testing with immunoglobulin IgM can be performed as early as 7 days after symptom onset. A negative immunoglobulin IgM serologic test does not rule out infection due to lack of precise timing to detect presence of antibody response. Early or late antibody testing can result in a false negative result due to lack of antibody development or waning of antibody response post infection, respectively. IgM antibody can remain positive for up to 12 weeks or longer in patients with history of Zika virus infection making it difficult to interpret recent or acute infection. False-positive IgM test result can occur due to cross-reactivity with other flaviviruses (eg, yellow fever, dengue, Japenese encephalitis, West Nile). Zika virus IgM antibody assays can be used on serum, plasma, whole blood, or cerebrospinal fluid.

In presence of concern for cross-reactivity with other flaviviruses, plaque reduction neutralization tests (PRNTs) provide quantitative virus-specific antibody titers for dengue, Zika, and other flaviviruses. CDC uses a PRNT with a 90% cutoff value titer ≥10 in serum and ≥2 in cerebrospinal fluid (the typical starting dilutions) to define positive specimens. A neutralizing antibody titer ≥4- fold higher titers compared to other flavivirus titers is considered diagnostic. Differentiation from other flaviviruses and late diagnosis of Zika virus infection more than 3 months from illness is possible with PRNT. Diagnostic testing using PRNT >1 year past illness is challenging, as observed with 27% of persistent neutralizing antibody titers in patients in Florida with an inability to distinguish between dengue and Zika.

The last locally-acquired Zika nucleic acid amplification tests (NAAT)-confirmed case in the continental United States was in September 2017 and in the US territories was reported in May 2018. As the prevelance of Zika virus infection has declined, potential detection of false-positive test results is likely. 

The WHO recommends using the Brighton criteria to diagnose Guillain-Barré syndrome.[33]

Prompt diagnosis and laboratory confirmation of Zika virus infection is challenging.

Serologic Testing

Zika virus infection is diagnosed based on detection and isolation of Zika virus RNA from serum using nucleic acid amplification test (NAAT). The highest sensitivity of NAAT is during the initial week of illness, which is characterized by high viremia. After the initial week of illness, serologic testing for virus-specific immunoglobin M (IgM) and neutralizing antibodies against Zika virus infection can be performed using enzyme-linked immunosorbent assay (ELISA).[18]  Serum IgM antibody testing should be performed if NAAT results are negative, regardless of when the specimen was collected.

In patients within 7 days of symptom onset, a positive serum NAAT for Zika is suggestive of the presence of acute Zika virus infection. The NAAT should be repeated on newly extracted RNA from the same specimen to rule out false-positive test results.

In patients within 7 days of symptom onset, a negative serum NAAT and IgM antibody testing is suggestive of absence of Zika virus infection. 

In patients more than 7 days to 12 weeks from symptom onset, a negative IgM antibody testing is suggestive of absence of Zika virus infection.

In patients with indeterminate IgM antibody testing, repeat IgM testing or confirmatory PRNTs test should be performed. 

In patients with positive IgM antibody testing without positive NAAT, a confirmatory PRNTs test should be performed. 

A 4-fold higher titer based on PRNT results might not differentiate anti-Zika virus antibodies from cross-reacting antibodies in all persons with previous infection or vaccination against a related flavivirus.

If IgM testing is positive for Zika or dengue virus or returns equivocal results, the following PRNT interpretations apply:

• A PRNT titer ≥10 indicates evidence of infection with that specific flavivirus when the PRNT to the other flavivirus(es) tested is < 10.
• A PRNT titer < 10 to a specific flavivirus indicates an absence of infection with that virus.
• A positive PRNT result ( ≥10 to multiple flaviviruses) indicates evidence of recent flaviviral infection. 

The tables from CDC below provide interpretation of dengue and Zika virus diagnostic testing results in nonpregnant and pregnant patients with a clinically compatible illness and the risk for infection with both viruses. 

Diagnostic testing to interpret infection from Dengue and Zika virus. Courtesy of the Centers for Disease Control and Prevention (CDC).

Dengue and Zika virus diagnostic testing interpretation in nonpregnant and pregnant patients. Courtesy of the Centers for Disease Control and Prevention (CDC).

Dengue and Zika virus testing recommendations for nonpregnant persons with a clinically compatible illness and risk for infection with both viruses. Courtesy of the Centers for Disease Control and Prevention (CDC).

Testing for Zika Virus Infection in Pregnant Women

Pregnant women with symptoms and possible exposure to Zika virus should undergo molecular and serologic diagnostic testing for confirmation of Zika virus infection. A NAAT on serum and urine specimen and IgM antibody test on serum should be performed and collected within 12 weeks of symptom onset. The diagnostic testing algorithm below should be used to interpret diagnosis of Zika and distinguish from dengue virus infection.

Testing algorithm for pregnant women with a clinically compatible illness and risk for Zika and Dengue virus. Courtesy of the Centers for Disease Control and Prevention (CDC).

Testing for Congential Zika Virus Infection

Molecular and serologic diagnostic testing for Zika virus is recommended for confirmation of diagnosis. Other than Zika virus RNA testing in infant's serum and urine and IgM antibodies in serum, cerebrospinal fluid testing for NAAT and IgM antibody testing is recommended to increase diagnostic yield. 

Cord blood testing is not recommended due to false-positive and false-negative test results. 

Following clinical and diagnostic algorithm should be followed as recommended by CDC:

Recommendations for the evaluation of infants with possible congenital Zika virus infection based on infant clinical findings, maternal testing results, and infant testing results - United States, October 2017. Courtesy of the Centers for Disease Control and Prevention (CDC).

CDC has provided guidance on interpretation of NAAT and IgM antibody testing for diagnosis of congenital Zika virus infection. 

Interpretation of results of laboratory testing of infant’s blood, urine, and/or cerebrospinal fluid for evidence of congenital Zika virus infection. Courtesy of the Centers for Disease Control and Prevention (CDC).

Differentiation between dengue and Zika virus infection in infants can be performed by PRNT, if IgM test on infant's initial sample is nonnegative (nonnegative serology terminology varies by assay and might include “positive,” “equivocal,” “presumptive positive,” or “possible positive”) and NAAT is negative. PRNT does not distinguish between infant or maternal passive antibodies collected from infant during or immediately after birth. As maternal antibodies usually are not detected past 18 months, diagnostic testing past 18 months can help to diagnose congenital Zika virus infection.

In infants with nonnegative IgM and positive Zika neutralizing antibodies at birth, PRNT at age of ≥ 18 months can confirm or rule out congenital Zika virus infection: 

• A positive PRNT is suggestive of presumed congenital Zika virus infection. It is difficult to interpret timing of infection in infants traveling or residing in areas with Zika. 
• A negative PRNT is suggestive of absence of congenital Zika virus infection. 

For infants with clinical findings consistent with congenital Zika syndrome and maternal laboratory evidence of possible ZIKV infection during pregnancy, PRNT at age of ≥ 18 months can be considered if infant testing was negative (NAAT and IgM antibody) or not performed at birth.

Congenital Zika virus infection

A comprehensive workup is recommended in infants with clinical findings consistent with congenital Zika syndrome (CZS). CDC provides guidance on recommended evaluation for management of CZS. Standard evaluation includes comprehensive physical exam including growth parameters and developmental monitoring and screening; vision screening using tools as recommended by the American Academy of Pediatrics; and a newborn hearing screen at birth, preferably with automated auditory brainstem response (ABR). 

Further evaluation is recommended:

• Head ultrasound
• Comprehensive ophthalmologic exam performed by age 1 month by an ophthalmologist experienced in assessing and intervening in infants.
• Infants should be referred for automated ABR by age 1 month if the newborn hearing screen was passed using only otoacoustic emissions methodology
• Subspecialist consultation as seen in the following table to help with infant care

Consultations for infants with clinical findings consistent with congenital Zika syndrome - United States, October 2017. Courtesy of the Centers for Disease Control and Prevention (CDC).

Close monitoring and prompt testing is recommended for any complications associated with congenital Zika syndrome:

• Diaphragmatic paralysis should be considered in an infant who develops respiratory distress or failure or who fails to wean from a ventilator.
• Swallowing dysfunction, such as difficulty breathing with feeding, coughing or choking during feeding, or extended feeding times, requires assessment for dysphagia.
• Signs of increasing intracranial pressure (eg, increasing head circumference, irritability, or vomiting) should prompt neuroimaging to assess for postnatal hydrocephalus.

A multidisciplinary team and regular well-child visits should be performed with routine preventative care and immunizations. A diagnostic ABR no longer is recommended at age 4–6 months for infants who passed the initial hearing screen with automated ABR due to lack of data suggesting delayed-onset hearing loss in infants with CZS.

Infants without clinical findings of CZS who were born to a mother with laboratory evidence of Zika virus infection or travel to area with Zika virus should be closely monitored during subsequent well-chils visit. Any clinical findings consistent with CZS should prompt appropriate subspecialist referrals for evaluation and management.

Diagnosis of congenital Zika virus infection during pregnancy can be performed using prenatal ultrasound and amniocentesis. However, interpretation of these tests is unknown. CDC recommends shared decision-making between the patient and provider before pursuing prenatal screening testing. 

Ultrasound examination specifically for detection of abnormalities related to congenital Zika virus infection are unknown due to variable sensitivity, specificity, and positive and negative predictive values.[34]  Per CDC, prenatal ultrasound findings associated with congenital Zika virus infection include intracranial calcifications at the gray-white matter junction, ventriculomegaly, abnormalities of the corpus callosum, microcephaly, and limb anomalies. Correlation of prenatal ultrasound findings suggestive of congenital Zika virus infection with maternal laboratory evidence of Zika virus or maternal exposure to Zika virus during pregnancy should be taken into consideration during interpretation and reporting. There are no recommended timings to conduct ultrasound. Abnormal prenatal ultrasound has been detected in the second and third trimester of pregnancy based on limited case reports. Frequency of prenatal ultrasound should be performed based on clinical judegement, patient preference, and the risk for Zika. 

Detection of a fetal anomaly should be followed by amniocentesis for evaluation of intrauterine Zika virus infection. Zika virus RNA can be found transiently in amniotic fluid, thus absence of RNA via NAAT does not rule out congenital Zika virus infection. The sensitivity and specificity of amniocentesis for determination of congenital infection and prediction of fetal abnormality is unknown.[35]

Detection of a fetal anomaly should be followed by amniocentesis for evaluation of intrauterine Zika virus infection. Zika virus RNA can be found transiently in amniotic fluid, thus absence of RNA via NAAT does not rule out congenital Zika virus infection. The sensitivity and specificity of amniocentesis for determination of congenital infection and prediction of fetal abnormality is unknown.[35]

Zika virus (ZIKV) infection usually is mild and self-limited. There are no specific FDA-approved treatment options or vaccines for treatment and prevention of Zika virus infection.[18]

Supportive care with rest and adequate fluid hydration is advised. Symptoms such as fever and pain can be controlled with acetaminophen and pruritic rash with antihistamines. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with unconfirmed Zika virus infection should be avoided since the use of such drugs in dengue fever is associated with hemorrhagic risk and risk for Reye syndrome in the pediatric population.[35]

The WHO recommends optimal supportive care in patients with Guillain-Barré syndrome, including frequent neurologic examinations, testing of vital signs, and respiratory function monitoring to decrease the likelihood of complications (eg, blood clots, respiratory failure). Patients whose symptoms are escalating rapidly or who are unable to walk should receive intravenous immunoglobulin therapy or therapeutic plasma exchange.[33] Managament of pregnant women with Zika and infants with Congenital Zika syndrome requires specialist consultation and care. Further information is available in the guidelines section. 

There are no FDA-approved treatment options for Zika. Multiple antiviral drugs are under investigation for treatment of ZIKV infection.[1, 8, 36]  The anti-Zika drugs under investigation target various stages of viral life cycle with direct antiviral activity (nucleoside analogs, polymerase inhibitors, RNA-dependent RNA polymerase inhibitors such as sofosbuvir, galidesivir) or activity against host cell mechanisms (purine or pyrimidine synthesis inhibitors, entry inhibitors). Some of the anti-Zika drugs have shown promising efficacy in in-vivo and in-vitro studies. Few FDA-approved drugs for other non-Zika indications such as interferon (in-vitro antiviral activity), antimalarials like chloroquine and mefloquine (in-vitro anti-Zika activity and safe in all trimesters), anti-helminthics such as ivermectin (antiviral activity), and antibiotics like azithromycin (reduce infectivity) have potential anti-Zika activity but are still under investigation to establish efficacy and safety for use. Overall, there have been multiple challenges associated with development of anti-Zika drugs as these drugs should be able to cross blood-brain barrier and placental barrier in pregnant women and should be safe for consumption during pregnancy. Moreover, any approved anti-Zika drug should be reasonably-priced as the majority of the ZIKV circulation occurs in tropical and sub-tropical countries with limited-resources.[37]

ZIKV infection during pregnancy can result in congenital Zika syndrome associated with following features:

• Severe microcephaly 
• Subcortical calcifications
• Ocular findings: focal pigmentary mottling, chorioretinal atrophy, optic nerve hypoplasia or atrophy
• Congenital contractures, such as clubfoot or arthrogryposis
• Hypertonia restricting body movement soon after birth

Expert consultation with a maternal-fetal medicine and infectious diseases specialists is advised for management of Zika virus infection during pregnancy.

A multidisciplinary team approach is recommended while caring for infants with congenital Zika syndrome. Consultation with infectious diseases, clinical geneticist, neurology, ophthalmologist, early intervention, and developmental specialists, and family and supportive services is recommended. Other sub-speciality consultation with endocrinology, lactation specialist, nutritionist, gastroenterologist, speech or occupational therapist, orthopedist, physiatrist, physcial therapist, pulmonologist, otolaryngolosit can be considered on a case-by-case basis.

Patients infected with arboviruses such as Zika virus should be advised to limit activity during symptomatic illness in order to avoid exposure to mosquitoes and potential risk for human-to-arthropod transmission and subsequent local spread of disease.[35]

Avoidance of Travel to Areas of Active Zika Virus Transmission

The best method for preventing Zika virus infection is to avoid travel to areas with active Zika virus transmission. Travelers should refer to the CDC site before arranging travel plans for up-to-date information on ZIKV transmission internationally and in US states and territories.

Mosquito Control and Prevention of Mosquito Bites

Residents who live in endemic areas or travelers to endemic areas are advised to avoid mosquito bites. Different strategies to prevent mosquito bites include wearing full-sleeved shirts and long pants, sleeping under a mosquito bed net, using screens on windows and doors, treating clothing and gear with permethrin, or using permethrin-treated clothing and gear.[18]

Environmental Protection Agency (EPA)–registered mosquito-repelling agents such as DEET, picaridin, IR3535, oil of lemon eucalyptus (OLE), 2-undecanone, and para-menthane-diol (PMD) products can be used by all age groups including pregnant and breastfeeding individuals, except for OLE and PMD products, which are contraindicated in those younger than 3 years, for prevention of mosquito bites. Mosquito larval habitats can be controlled by appropriate handling of water-holding containers, including routinely discarding or covering stagnant water or using larvicidal agents. Certain other measures to control mosquitoes, including the use of genetically engineered Aedes aegypti mosquitoes as previously performed to prevent dengue infection by reducing the natural population of mosquitoes, is under investigation.

Caution should be exercised to prevent local transmission of Zika virus from infected patients to uninfected mosquitoes. Mosquito bites should be avoided during initial stages of Zika infection owing to high viremia. This reduces infection of mosquitoes and prevents local spread of viral illness. 

Caution should be exercised when traveling overseas to prevent mosquito bites. Travelers preferably should stay in a hotel or lodging with air conditionining or with screens on windows and doors and sleep under a mosquito bed net, preferably permethrin-treated.

In November 2017, the EPA registered a novel biopesticide (ZAP Males) in an attempt to control populations of Aedes albopictus (Asian tiger mosquitoes). In this approach, male mosquitoes of this species are infected with a strain of Wolbachia pipientis that prevents healthy offspring when the infected males mate with Aedes albopictus females. This has been approved in twenty US states, including California, Connecticut, Delaware, Illinois, Indiana, Kentucky, Massachusetts, Maine, Maryland, Missouri, New Hampshire, New Jersey, Nevada, New York, Ohio, Pennsylvania, Rhode Island, Tennessee, Vermont, Florida, Hawaii, Texas, and West Virginia, as well as the District of Columbia.[38]  Similarly, an experimental use permit for field testing and release of Wolbachia-infected Ae aegypti male mosquitoes was issued by the EPA in Florida, Texas, and California. The results of these field studies are not available yet.

Preventing Other Modes of Zika Virus Transmission

Until recently, the mosquito was the only known vector for Zika virus transmission. As the infection spreads, new possible routes of transmission facilitating human-to-human spread of the virus without an intermediate vector have been discovered. The CDC has issued interim guidelines advising sexual abstinence or regular use of condoms to prevent the spread of Zika virus to sexual partners, especially during pregnancy.[39]

On July 6, 2018, the FDA issued guidance to all blood centers in all states and US territories to screen donated whole blood and blood components with blood screening nucleic acid test approved by FDA. An FDA-approved pathogen-reduction device can considered to be used for plasma and apheresis platelet donations.[40]  

The CDC advises that women with Zika (symptomatic or asymptomatic) or travel to an area with Zika outbreak should wait at least 2 months from symptom onset or a positive test date or return before attempting to conceive and should use condoms or abstain from sex. In case of travel by a male partner or both partners, at least a 3-month wait time is advised.[41]  

A travel alert has been issued for pregnant women in any trimester to avoid or postpone travel to areas with ongoing Zika outbreak.[35]  Travel to areas with current or past transmission but no ongoing outbreak should be discussed with healthcare provider to asses risk. Appropriate precautions to prevent mosquito bites should be taken when traveling to all other areas with presence of Aedes mosquitoes. 

Zika Virus Vaccine Development

No vaccine is approved and available for the prevention of Zika virus infection. 

Multiple pre-clinical and clinical trials are ongoing across the world to develop a vaccine against ZIKV.[42]  Various vaccine candidates are under development such as DNA and RNA-based vaccines, inactivated whole virus and live attenuated vaccines, viral vector and protein antigen vaccines. Few clinical trials have progressed to phase 1 or 2. A summary of all vaccines currently under investigation is listed in table 1.  

Table 1. Zika virus vaccines currently in development (Open Table in a new window)

Abbreviations: NIAID: National Institute of Allergy and Infectious Diseases, WRAIR: Walter Reed Army Institute of Research, BIDMC: Beth Israel Deacones Medical Center, VRC: Vaccine Research Center

Evidence suggests that Zika infection prior to pregnancy would not pose a risk for birth defects to a future pregnancy. Based on previous studies, a person with a history of Zika virus infection is protected from a future Zika infection.

Prevention

Travel Advisories

Updates on areas with ongoing Zika virus transmission are available online. Mosquitoes that spread Zika virus usually do not live at elevations above 6,500 feet (2,000 meters). People who live in or visit areas above this elevation are at a very low risk of acquiring Zika virus from a mosquito unless they visit or travel through areas of lower elevation.[43]  

Prevention of Mosquito Bites

The CDC recommends that all residents of and visitors to areas where Zika virus is spreading take the following steps to prevent mosquito bites[43] :

• Cover exposed skin by wearing long-sleeved shirts and long pants.
• Use insect repellents that are registered with the Environmental Protection Agency (EPA) and contain DEET, picaridin, oil of lemon eucalyptus, para-menthane-diol, or IR3535. Always use as directed.
• Use permethrin-treated clothing and gear (boots, pants, socks, tents).
• Stay and sleep in screened-in or air-conditioned rooms.
• Sleep under a mosquito bed net if air conditioned or screened rooms are not available or if sleeping outdoors.
• Mosquito netting can be used to cover babies younger than 2 months in carriers, strollers, or cribs to protect them from mosquito bites.

Prevention of Sexual Transmission

The CDC recommends the following for the prevention of sexual transmission of Zika virus[44] :

• Pregnant women with male sex partners who live in or have traveled to an area with active Zika virus transmission should use barriers against infection during sex or abstain from sex for the duration of the pregnancy. 
• Couples planning to concieve in which a partner had confirmed Zika virus infection or clinical illness consistent with Zika virus disease or travels to an area with risk for Zika virus transmission should consider using barrier methods against infection or abstain from sex, as follows:

  • Men with Zika virus infection/travel, for at least 3 months after onset of illness (symptomatic) or last possible exposure (asymptomatic or travel)
  • Women with Zika virus infection/travel, for at least 2 months after onset of illness or last possible exposure (asymptomatic or travel)
  • Both partners with Zika virus infection/travel, for at least 3 months after onset of illness in male partner (symptomatic) or last possible exposure (asymptomatic or travel)
• Couples planning to conceive with 1 or both partners with ongoing exposure (live or frequently travel to an area with risk for Zika virus transmission) 

  • Discussion with healthcare provider on risks and possible health effects of Zika on baby and protection strategies from Zika virus. 

​Virus Transmission by Blood and Blood Components 

On May 12, 2021, the US Food and Drug Administration (FDA) stopped recommending that blood establishments test donated blood for Zika virus (ZIKV). The FDA withdrew its July 2018 guidance titled, “Revised Recommendations for Reducing the Risk of Zika,” after it determined that ZIKV is not a “relevant transfusion-transmitted infection” (RTTI) because it “no longer has sufficient incidence and/or prevalence to affect the potential donor population.”[45]

Licensed blood establishments that stop testing donated blood for ZIKV are required to report this change, the date testing ended, and “corresponding changes to the circular of information” to the FDA in the yearly report under 21 DFR 601.12(d).[45]

The CDC offers the following recommendations for Zika virus testing in non-pregnant patients[32] :

• Zika virus nucleic acid amplification test (NAAT) should be performed on serum collected ≤7 days after symptom onset.
• Zika virus IgM antibody testing should be performed on NAAT-negative serum specimens and serum collected >7 days after onset of symptoms. 
• For serum specimens collected < 7 days after onset of symptoms, the combination of a negative NAAT result and negative IgM antibody testing suggests the patient did not have a recent flavivirus infection. 
• For specimens collected from 7 days to 12 weeks after onset of symptoms, a negative IgM antibody result to Zika virus rules out recent infection with either virus, and testing for other etiologies should be considered.
• If Zika virus IgM antibody testing is positive without a positive NAAT,a plaque reduction neutralization test (PRNT) titer ≥10 against Zika virus with negative PRNTs against dengue and other flaviviruses is evidence of recent Zika virus infection. Negative PRNT titers against Zika virus in a serum specimen collected >7 days after illness onset rule out infection.

Preconception 

The CDC makes the following recommendations to individuals considering conception after exposure to the Zika virus[46] :

• Women with travel to an area with Zika outbreak or risk for Zika should wait at least 2-months after symptom onset or after return from travel before attempting conception.
• Men with travel to an area with Zika outbreak or risk for Zika should wait at least 3 months after symptom onset or after return from travel before attempting conception.
• Both partners with travel to an area with Zika outbreak or risk for Zika should wait at least 3 months after symptom onset of male partner or after return from travel before attempting conception.

Asymptomatic women and men who reside in an area with active Zika virus transmission and are planning to become pregnant should discuss the risks for active Zika virus transmission with their healthcare providers, and providers should discuss their patients’ reproductive life plans in the context of potential Zika virus exposure.

Testing for evidence of Zika virus infection should be performed in persons with possible exposure to Zika virus who have 1 or more of the following symptoms within 2 weeks of possible exposure:

• Acute onset of fever
• Rash
• Arthralgia
• Conjunctivitis

Routine testing is NOT recommended for asymptomatic women or men with exposure to Zika virus who are attempting conception.

Pregnant Women

The CDC recommends that all pregnant women consider postponing travel to areas with active Zika virus transmission and avoid sex with someone with recent travel to Zika risk area.[47]

If a pregnant woman is living or travelling to an area with Zika virus transmission, they should be advised to strictly follow recommended steps to avoid mosquito bites throughout the entire day and to avoid getting ZIKV through sex by using condoms during sexual activity (oral, vaginal, or anal) or avoiding sex during pregnancy.

Pregnant women and their partner with history of travel to an area with risk for Zika or Zika outbreak, should monitor for symptoms (acute onset of fever, rash, arthralgia, conjuctivitis) and avoid sexual transmission through abstinence or use of condoms. 

Zika testing is recommended in pregnant women under the following conditions:

• Pregnant women with travel to an area with risk for Zika or sex with partner with travel or residence in area with Zika should undergo testing if symptomatic or ultrasound suggest fetus abnormalities related to ZIKV infection.
• Pregnant women who reside or frequently (daily or weekly) travel to an area with risk for Zika should undergo testing if symptomatic at any time during pregnancy or if asymptomatic during first prenatal care visit and at 2 additional regular prenatal care visits during pregnancy. 

Routine Zika testing is NOT recommended in asymptomatic pregnant women with infrequent travel-associated exposure to an area with Zika.

Guidelines on Zika testing in pregnancy by the Centers for Disease Control and Prevention are as follows[48] :​

Asymptomatic pregnant women:

• For asymptomatic pregnant persons living in or with recent travel to the United States and its territories, routine Zika virus testing is NOT currently recommended.
• For asymptomatic pregnant women with recent travel to  an area with risk for Zika outside the United States and its territories, Zika virus testing is NOT routinely recommended, but NAAT testing may still be considered up to 12 weeks after travel.
• Zika virus serologic testing is NOT recommended for asymptomatic pregnant women.

Symptomatic pregnant women:

• For symptomatic pregnant women who had recent travel to areas with  a risk of Zika, specimens should be collected for Zika virus NAAT testing on a serum specimen, and Zika virus NAAT on a urine specimenas soon as possible after the onset of symptoms up to 12 weeks after symptom onset. 
• Zika virus IgM testing is NOT recommended for symptomatic pregnant women.
• For symptomatic pregnant women who have had sex with someone who lives in or recently traveled to areas with  a risk for Zika, a specimen for Zika NAAT should be collected as soon as possible after the onset of symptoms up to 12 weeks after symptom onset.

The CDC's Interim Guidance for the Evaluation and Management of Infants with Possible Congenital Zika Virus Infection contains the following major recommendations[49] :

• All infants born to mothers with possible exposure to Zika virus during pregnancy should receive a standard evaluation at birth and at each well-child visit. A standard evaluation should include a comprehensive physical exam (including growth parameters), age-appropriate vision screening and developmental screening and monitoring, and a standard newborn hearing screening at birth, preferably using auditory brainstem response (ABR) methodology.
• Zika virus testing is recommended for infants with clinical findings consistent with congenital Zika syndrome and possible maternal Zika virus exposure during pregnancy, regardless of maternal testing results. Infants should have a head ultrasound and a comprehensive ophthalmologic exam performed by age 1 month by an ophthalmologist experienced in assessment of and intervention in infants. Infants should be referred for automated ABR by age 1 month if the newborn hearing screen was passed using only otoacoustic emissions methodology. Appropriate consultation with a developmental specialist, family support services, neurology, infectious diseases, and clinical genetics should be performed. 
• Zika virus testing is recommended for infants without clinical findings consistent with congenital Zika syndrome and laboratory evidence of possible maternal Zika virus infection during pregnancy.
• Zika RNA nucleic acid amplification testing (NAAT) of serum and urine and Zika virus IgM testing of serum should be performed within a  few days after birth (preferred) up to first few weeks to months after birth. 
• Zika virus PCR and serologic testing is recommended during the first 2 weeks after symptom onset to diagnose postnatal Zika virus disease. Serologic testing is recommended 2-12 weeks after symptom onset.
• Testing CSF for Zika virus RNA and Zika virus IgM antibodies should be considered, especially if serum and urine testing are negative and another etiology has not been identified.

Previously recommended screenings (eg, thyroid screening, complete blood count [CBC], liver function tests [LFTs], hearing screening at 4-6 months, behavioral audiology at 9-months) are not recommended because data are lacking to show that these screenings might be needed.