In less than 2 years since entry into the Americas, we have witnessed the emergent spread of Zika virus into large subsets of immunologically naïve human populations and then encountered the devastating effects of microcephaly and brain anomalies that can arise from in utero infection with the virus. Diagnostic evaluation and management of affected infants continues to evolve as our understanding of Zika virus rapidly advances. The development of a safe and effective vaccine holds the potential to attenuate the spread of infection and limit the impact of congenital infection.
Key points
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Zika virus is a flavivirus related to dengue, yellow fever, and West Nile viruses, that is spread by Aedes mosquitoes, and has rapidly spread worldwide along the distribution of its vector.
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Zika virus was initially thought to cause asymptomatic or only mild, self-limiting symptoms, but more severe cases and the sequela of Guillain-Barré syndrome have now been recognized.
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In utero exposure has been observed to result in a congenital syndrome marked by microcephaly and a range of other brain anomalies.
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Affected infants require accurate diagnosis, close monitoring, and access to multidisciplinary care throughout childhood.
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Although vaccine development is an active area of research, there is currently no vaccine or treatment for Zika virus infection. Current preventive strategies rely on decreasing infected bites and use of barrier protection during pregnancy.
Introduction
The recent, explosive, pandemic spread of Zika virus (ZIKV) has resulted in a rapid and accelerated outpouring of collaborative research regarding this once understudied infection. ZIKV was first identified incidentally in 1947 by way of tree canopy surveillance among nonhuman primates in the Zika forest of Uganda. The virus was isolated from the Aedes mosquito shortly after, hinting at what was later confirmed to be the principal vector of transmission. Although serologic surveillance studies from West Africa and Southeast Asia suggested that infection occurred in humans, early epidemiologic and challenge studies pointed toward only mild and self-limiting febrile illness. The initial lack of specificity of symptoms may have allowed ongoing eastward geographic spread to be unrecognized, and little else was reported until the first large outbreak of ZIKV occurred on the island of Yap, Micronesia, in 2007, affecting the vast majority of the island’s population. Spread continued across the Pacific islands, with similar large outbreaks reported in French Polynesia in 2013, and the Chilean Easter Island in 2014. ZIKV was next detected in Brazil in May 2015, with more than 1.5 million cases reported by early 2016. Six months after arrival in Brazil, a sharp increase in the prevalence of infants born with microcephaly was observed, finally bringing the alarming public health implications of this infection into focus. The World Health Organization (WHO) declared a public health emergency of international concern as infection continued to spread to the rest of South and Central America and the Caribbean.
Mosquito-borne transmission of ZIKV has been reported in 48 countries and territories in the Americas to date since 2015. Given the location of the Aedes mosquito species globally, it is predicted that there will be continued spread and outbreaks in new countries. Although the mechanism of entry into the Western hemisphere can be only speculated, this pandemic reminds us of the interconnectedness of our global community. ZIKV is one of several mosquito-borne infections to have emerged as a pandemic threat over the past few decades, following behind the dengue, West Nile, and chikungunya viruses. Not only has this epidemic exemplified the ability of human international travel to accelerate the emergence and spread of potentially devastating infectious diseases, it also has illustrated our ability to swiftly disseminate data and make coordinated research efforts to improve our understanding of infectious agents. New insights are continually gleaned, but despite these labors, many questions remain unanswered, including a complete description of the clinical spectrum associated with ZIKV infection. Improved rapid diagnostics and the development of effective counterstrategies for containment and prevention of infection are urgently needed to improve the impact of ZIKV infection on children globally.
Introduction
The recent, explosive, pandemic spread of Zika virus (ZIKV) has resulted in a rapid and accelerated outpouring of collaborative research regarding this once understudied infection. ZIKV was first identified incidentally in 1947 by way of tree canopy surveillance among nonhuman primates in the Zika forest of Uganda. The virus was isolated from the Aedes mosquito shortly after, hinting at what was later confirmed to be the principal vector of transmission. Although serologic surveillance studies from West Africa and Southeast Asia suggested that infection occurred in humans, early epidemiologic and challenge studies pointed toward only mild and self-limiting febrile illness. The initial lack of specificity of symptoms may have allowed ongoing eastward geographic spread to be unrecognized, and little else was reported until the first large outbreak of ZIKV occurred on the island of Yap, Micronesia, in 2007, affecting the vast majority of the island’s population. Spread continued across the Pacific islands, with similar large outbreaks reported in French Polynesia in 2013, and the Chilean Easter Island in 2014. ZIKV was next detected in Brazil in May 2015, with more than 1.5 million cases reported by early 2016. Six months after arrival in Brazil, a sharp increase in the prevalence of infants born with microcephaly was observed, finally bringing the alarming public health implications of this infection into focus. The World Health Organization (WHO) declared a public health emergency of international concern as infection continued to spread to the rest of South and Central America and the Caribbean.
Mosquito-borne transmission of ZIKV has been reported in 48 countries and territories in the Americas to date since 2015. Given the location of the Aedes mosquito species globally, it is predicted that there will be continued spread and outbreaks in new countries. Although the mechanism of entry into the Western hemisphere can be only speculated, this pandemic reminds us of the interconnectedness of our global community. ZIKV is one of several mosquito-borne infections to have emerged as a pandemic threat over the past few decades, following behind the dengue, West Nile, and chikungunya viruses. Not only has this epidemic exemplified the ability of human international travel to accelerate the emergence and spread of potentially devastating infectious diseases, it also has illustrated our ability to swiftly disseminate data and make coordinated research efforts to improve our understanding of infectious agents. New insights are continually gleaned, but despite these labors, many questions remain unanswered, including a complete description of the clinical spectrum associated with ZIKV infection. Improved rapid diagnostics and the development of effective counterstrategies for containment and prevention of infection are urgently needed to improve the impact of ZIKV infection on children globally.
Zika virus in the United States
Local transmission in the United States began in the territory of Puerto Rico, with more than 34,000 locally acquired cases now reported. Local transmission was reported for the first time in the continental United States in July 2016 in Miami, Florida. In November 2016, Texas became the second state to report local transmission. At this time, there have been close to 5,000 travel-associated cases, involving every state other than Alaska, and 224 locally acquired mosquito-borne cases in the continental United States; approximately one-third of all reported cases in the United States have been in pregnant women. Preliminary estimates suggest that microcephaly and other brain anomalies have occurred in 6% of infants and fetuses born to women in the United States who had laboratory-confirmed evidence of ZIKV infection during pregnancy, increasing up to 15% in those women with first-trimester infection.
Epidemiology
ZIKV is an arbovirus, within the family Flaviviridae, sharing the flavivirus genus with the yellow fever, dengue, and West Nile virues. It is a single-stranded RNA virus with Asian and African lineages. Transmission is primarily via the bite of an infected Aedes aegypti mosquito, which is widely distributed throughout the tropics, but also can be transmitted by other Aedes species, such as Aedes albopictus, which has a broader distribution within North America. The Aedes mosquito has a short flight range and is well-adapted to live and breed near people and their homes, laying eggs in the stagnant water of puddles and containers. Although the bite of an infected mosquito is the principal route of infection, case studies have suggested transmission by exposure to body fluids; the virus can be detected in blood, semen, vaginal secretions, urine, cerebrospinal fluid, and saliva after resolution of symptoms ( Box 1 ).
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Mosquito-borne
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Sexual contact
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Vertical
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Blood transfusion
The incubation period of ZIKV disease varies from 3 to 14 days after exposure. Viremia is detected up to 10 days before symptoms develop, clearing as quickly as 2 days after symptom onset, although prolonged shedding also is known, with ZIKV RNA being detected in whole blood up to 81 days after illness. Prolonged viral detection of up to 15 weeks after illness has been reported in pregnant patients, and at least 67 days after birth in an infant. It is presumed that congenital infection occurs via transplacental transmission, and the persistence of ZIKV RNA in the serum of pregnant patients may reflect ongoing fetal infection.
Close surveillance has revealed that ZIKV is also sexually transmitted, with transmission from both infected male and infected female individuals reported, even when partners are asymptomatic. Prolonged shedding of up to 6 months has been documented in semen, where ZIKV RNA may be up to 100,000 times that of plasma levels. In at least 1 case, acquisition has occurred without a known risk factor, other than close contact.
As ZIKV can be transmitted by blood products, the US Food and Drug Administration has provided recommendations regarding universal screening of donated blood and other products. The United Network for Organ Sharing also has provided guidance on issues of ZIKV infection related to organ transplantion.
Zika virus and microcephaly
Even the earliest work on ZIKV in mice suggested a distinct neurotropism of the virus, but the association in humans was not made until 2015, when a 20-fold increase in the prevalence of microcephaly was noticed among newborns in Brazil. Health authorities from French Polynesia then retrospectively noted that the prevalence of central nervous system malformations in fetuses and newborns had increased to 50-fold above baseline during their own ZIKV 2013 outbreak. Numerous similar reports have since surfaced, and based on review of the body of accumulating evidence showing associations with in utero infection, the US Centers for Disease Control and Prevention (CDC) concluded ZIKV to be a cause of congenital microcephaly and other severe brain defects in April 2016. To date, 31 countries or territories have reported microcephaly and other central nervous system malformations potentially associated with ZIKV infection.
Identification of Infection in Affected Fetuses
The ZIKV genome was completely recovered from the brain of a severely affected fetus with microcephaly, agyria, hydrocephalus, and multifocal calcifications following maternal acquisition of infection during first-trimester travel to Brazil, resulting in termination of pregnancy at 32 weeks’ gestation. Several other well-documented cases have detected evidence of ZIKV infection by immunohistochemical staining, polymerase chain reaction (PCR), and culture within the brains of fetuses and infants with microcephaly. ZIKV has been identified in the amniotic fluid and placenta of fetuses who have died, indicating an ability to infect the fetus by crossing the placental barrier. Levels of ZIKV RNA were found to be up to 1200-fold higher in fetal/neonatal brain tissue than placental tissue, indicating active viral replication occurs in the brain.
Biologic Plausibility
Murine models support vertical transmission via placental infection and injury, followed by fetal brain infection leading to the development of microcephaly. In vitro studies of placental infection with ZIKV demonstrate spread of infection from the basal to parietal decidua, then to chorionic villi and amniochorionic membranes. Placental-specific macrophages (Hofbauer cells) may help to disseminate infection to the central nervous system. In neurospheres and brain organoids, ZIKV impairs growth of neural progenitor cells, and is associated with cell-cycle dysregulation and programmed cell death responses. In addition to direct cytotoxicity, the possibility of immune-mediated effects, such as disruption of neurovascular development or induction of autoimmune responses against gangliosides, has been raised. The exact mechanisms of teratogenicity and the role of contributing cofactors remain to be elucidated, but several parallels can be drawn to established congenital infections, such as cytomegalovirus and rubella, further fortifying the biologic plausibility of congenital ZIKV infection.
Timing of Infection
Infections early in pregnancy have been most commonly associated with microcephaly in the infant. Epidemiologic mapping from Brazil suggests that microcephaly best correlates with ZIKV incidence during week 17 of pregnancy (week 14 for severe microcephaly), but central nervous system anomalies have been reported in all trimesters. Microcephaly cases reported in Colombia in 2016 peaked approximately 24 weeks after the peak of the ZIKV disease, further supporting that the greatest risk of microcephaly correlates with infection during the first and early second trimesters. A case-control study among pregnant women from Rio de Janeiro, Brazil, found that 29% of women developing ZIKV infection at any time during pregnancy had abnormalities detectable by prenatal ultrasound; there were no abnormalities noted in the uninfected controls. A larger case-control study from the same area has recently shown similar findings, with 42% of infants born to mothers infected during pregnancy having abnormal clinical or neuroimaging, although adverse outcomes occurred even in infants exposed as late as 39 weeks’ gestation, indicating that effects may still occur during the latter part of pregnancy. Interestingly, microcephaly has not been reported with intrapartum transmission to date.
Congenital Zika syndrome
Although the full range of congenital manifestations remains to be determined, a typical pattern of clinical features and imaging findings of affected infants has clearly emerged, leading to the term congenital Zika syndrome ( Box 2 ). Some cases have closely resembled the fetal brain disruption sequence characterized by severe microcephaly, overlapping cranial sutures, prominent occipital bone, and redundant scalp skin, hypothesized to result from decrease in intracranial pressure secondary to fetal brain volume loss. Brain anomalies may occur without the presence of congenital microcephaly. Affected fetuses may have decreasing head circumferences documented in utero by ultrasound, but microcephaly also may develop after birth, indicating the need for ongoing evaluation in all potentially affected infants until more is known.
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Microcephaly a
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Craniofacial disproportion and cutis gyrata
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Hypertonicity and hyperreflexia
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Seizures
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Irritability
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Abnormal neuroradiology findings b
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Dysphagia and other feeding difficulties
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Ocular abnormalities c
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Sensorineural hearing loss
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Arthrogryposis
a There is no standard definition for microcephaly. The Centers for Disease Control and Prevention define congenital microcephaly for live-born births as head circumference less than the third percentile for age and sex.
b Reported abnormal neuroradiology findings include calcifications (mostly subcortical), ventriculomegaly, cortical thinning, abnormal gyral patterns, such as lissencephaly, hypoplasia/agenesis of the corpus callosum, decreased myelination, cerebellar hypoplasia, enlargement of the cisterna magna, and increased extra-axial fluid.
c Reported ocular abnormalities include focal pigment mottling of the retina and chorioretinal atropy, optic nerve abnormalities, coloboma, lens subluxation, hemorrhagic retinopathy, abnormal vasculature of the retina, maculopathy, microphthalmia, cataracts.
A number of ocular anomalies have been described, predominantly of the posterior eye (see Box 2 ). First-trimester infection and smaller head circumference correlate with abnormal eye findings. Ocular involvement may be bilateral in up to 70% of infants with eye disease. Sensory neural hearing loss was reported in up to 6% of affected infants with microcephaly. Arthrogryposis, a disorder of multiple congenital joint contractures, is likely a consequence of diminished fetal movements arising from underlying neurologic involvement. Review of 34 published reports identified 5 features that differentiate congenital Zika syndrome from other congenital infections, including severe microcephaly with partially collapsed skull, thin cerebral cortices with subcortical calcifications, macular scarring and focal pigmentary retinal mottling, congenial contractures, and marked early hypertonia. Differential causes of microcephaly include other congenital infections, such as cytomegalovirus, human immunodeficiency virus, varicella-zoster, and rubella infection. Rare genetic conditions, such as Aicardi-Goutières syndrome, also may share overlapping manifestations with the congenital Zika syndrome.
Other clinical manifestations of Zika disease
Outside of congenital infection, ZIKV infection in humans is mostly asymptomatic. Mild, self-limiting symptoms occur in approximately 20% of those infected. These symptoms, which overlap with the other common mosquito-borne infections of dengue virus and chikungunya virus, include pruritic maculopapular rash, fever, myalgias, arthralgias, headache, retroorbital pain, nonpurulent conjunctivitis, sore throat, petechiae, emesis, and diarrhea. Severe infection is rare, with only occasional fatalities reported. A strong association with ZIKV and Guillain-Barré syndrome exists. Prevalence can be 2 to 10 times or even higher above baseline in affected areas, which has allowed bilateral flaccid paralysis to serve as a sentinel marker of ZIKV during these recent outbreaks. Other neurologic complications, such as acute myelitis, meningoencephalitis, and even hearing loss also have been documented.
In children who acquire ZIKV infection postnatally, symptoms are the same as those reported in the general population. The effects of ZIKV infection in the immunocompromised host are not yet well described. Bacterial superinfection and allograft dysfunction were noted among the complications seen in a small group of solid organ transplant recipients from Brazil.
Diagnosis
Diagnostic tests to confirm suspected exposure include the molecular detection of ZIKV RNA by reverse transcriptase PCR and serology. Zika virus–specific immunoglobulin (Ig)M and neutralizing antibodies typically develop toward the end of the first week of illness, but may take up to 2 weeks. IgM levels generally continue to be detectable for 12 weeks after symptom onset. The specific approach to testing will vary depending on available resources, but testing should be considered in patients who present with typical clinical manifestations of ZIKV disease in the setting of an associated epidemiologic risk factor (such as residence in, or travel to, an area where mosquito-borne transmission of ZIKV has been reported or unprotected sexual contact with a person who has). The CDC recommends that pregnant women in the United States be assessed for possible ZIKV exposure at each prenatal care visit, and tested if there has been possible exposure. Similarly, the CDC recommends laboratory testing of infants born to mothers with known or possible ZIKV infection or infants found to have abnormal clinical or neuroimaging findings that could be compatible with congenital Zika syndrome in the setting of a maternal epidemiologic link. Samples should be collected directly from the infant, ideally within in the first 2 days of life, to help distinguish between congenital, peripartum, and postnatal timing of infection. Maternal testing should be considered simultaneously, if not previously carried out. Like recommendations for the general population, postnatal testing of children should be performed if a child presents with compatible symptoms of acute infection, but testing of asymptomatic children is not needed if there is no concern for congenital infection. There are several general caveats to interpretation ( Box 3 ), pointing to the urgent need for more precise and scalable diagnostic tests. In the meantime, laboratory diagnosis of congenital infection must be interpreted in the context of suspected timing of infection during pregnancy, serology results, and compatible clinical findings. Specific guidance on testing pregnant women and infants born to mothers with possible ZIKV infection during pregnancy should be checked periodically for revisions to these guidelines as updates become available.
| Test | Specimens a | Use | Comment |
|---|---|---|---|
| Molecular diagnostics | |||
| RT-PCR | Serum Urine CSF | Recent infection |
|
| Serology | |||
| IgM | Serum CSF | Recent infection |
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| PRNT | Serum | Confirms specificity of IgM |
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