CHAPTER 108: ZIKA VIRUS INFECTION AND ZIKA-ASSOCIATED CONGENITAL ABNORMALITIES

Zika is a mosquito-borne virus that is closely related to the dengue viruses and within the same taxonomic family as yellow fever virus. Although the majority of human Zika virus infections are asymptomatic or so mild that they may go unrecognized, ~20% of infections result in dengue-like illnesses with fever, myalgia, and rash. Long an obscure virus of little human consequence, Zika has since 2013 spread pandemically and directionally around the globe from Southeast Asia to the South Pacific Islands; in 2015–2016, it spread to South and Central America and the Caribbean (Figure 108-1), including the U.S. Commonwealth of Puerto Rico and the Territory of the U.S. Virgin Islands (USVI). From these epidemics, travel-related cases and exported cases were observed in 2016 in all 50 U.S. states and the District of Columbia as well as in many other nations. Many primary care and other providers thus face diagnosing Zika cases and counseling patients about both actual Zika risks and unfounded fears. During this recent pandemic spread, Zika has been temporally and geographically linked in some countries to fetal development of microcephaly and other birth defects. In adults, Zika infection has been linked to Guillain-Barré syndrome and possibly to apparently rare cases of acute meningoencephalitis and myelitis.

Discovered incidentally in 1947 during mosquito and primate surveillance in Uganda, Zika long remained an obscure enzootic arbovirus (i.e., an arthropod-borne virus) that initially was confined to Africa’s equatorial belt and then, at some indeterminate time in the past, spread to equatorial Asia. Zika has long circulated enzootically between wild primates and arboreal mosquitoes. Neither teratogenic nor neurologic complications of Zika were described until 2013.

Since 2013, however, Zika virus has spread around the globe, arriving back in the area of its presumed origin—West Africa—to cause an epidemic in Cabo Verde. The last 10,000-mile leg of that journey, from the islands of the South Pacific to West Africa, was made in about 2 years or less. It remains unclear how an obscure enzootic virus that long had been unable to adapt to human spread suddenly changed completely in its epidemiologic behavior and clinical expression to cause a deadly pandemic.

With the exception of dengue, no other arthropod-borne virus has ever expanded so far geographically, and no arbovirus, including dengue, has spread so far so quickly. The reasons for the sudden and explosive emergence of Zika virus are not known, since the virus existed in Africa and parts of Asia/Southeast Asia for decades without causing recognized outbreaks. Likely co-factors in this explosive spread include human movement (air, boat, and land travel of millions of people), population susceptibility, and high prevalences of the principal vector mosquito, Aedes aegypti, in increasingly crowded urban settings.

By September 2016, 48 countries in the Americas and the Caribbean were experiencing ongoing local Zika virus transmission, including an explosive epidemic in Puerto Rico. A simultaneous 2016 epidemic was occurring in the U.S. Territory of American Samoa, a Polynesian island in the southern Pacific Ocean. The epidemic in Puerto Rico has involved all areas of the island and is associated with multiple exportations of the virus to the continental United States. In July 2016, a geographically restricted Zika outbreak associated with autochthonous (local) mosquito-borne transmission appeared in a neighborhood immediately north of Miami, Florida; additional such outbreaks have been predicted by public health officials.

Zika is a positive-sense single-stranded RNA virus in the Flaviviridae family (i.e., a flavivirus), which includes not only many arboviruses but several non-arboviruses as well (e.g., hepatitis C virus). The arthropod-borne flaviviruses include 37 mosquito-borne viruses, such as yellow fever, dengue, West Nile, and Japanese encephalitis viruses, and 12 tick-borne viruses, such as tick-borne encephalitis and Omsk hemorrhagic fever viruses.

The surface glycoproteins of Zika and other flaviviruses contain virus-specific epitopes within their attachment and fusion domains as well as flavivirus complex or flavivirus group epitopes shared with other, and in some cases all other, flaviviruses. These facts have great importance for serologic diagnosis: in places where more than one flavivirus circulates or where flavivirus vaccines have been used, second- and higher-order flavivirus exposures that follow an initial flavivirus exposure prompt an anamnestic immune system memory response. The result is the circulation in the bloodstream of high-titered antibodies that are serologically reactive not only with past and currently infecting flaviviruses but also with flaviviruses to which an individual has never been exposed—a situation that makes serologic diagnosis difficult or impossible.

All RNA viruses, including Zika, mutate as they spread through populations of new hosts; therefore, it is not surprising that Zika strains have been diversifying during the current pandemic. The Americas strain genome, closely related to Pacific Zika strains from 2013–2014, appears to differ slightly from the genome of a strain causing a 2007 epidemic in Yap State (Federated States of Micronesia) and is even more different in genetic sequence from older Asian and African strains. Nevertheless, there is no evidence that the pandemic virus has evolved new phenotypic properties that facilitate spread. As phylogenetic and epidemiologic studies are completed, more information should become available. Fortunately, current research tests and diagnostic tests to detect virus, viral RNA, and antiviral antibody are capable of identifying all current Zika virus strains and human antibodies to them.

As expected with almost every RNA virus and with many DNA viruses, monoclonal antibodies as well as immune serums and hyperimmune antiserums to dengue virus can enhance in vitro infection of FcR-bearing cells by Zika virus. This phenomenon is referred to as antibody-dependent infection enhancement (ADE), which has been epidemiologically linked to dengue hemorrhagic fever. ADE is widely suspected of being involved in the occurrence of severe dengue diseases (dengue hemorrhagic fever and dengue shock syndrome) upon sequential infection with different dengue serotypes. ADE has even been suspected to occur in dengue infections that follow vaccination with experimental dengue vaccines. Thus it has been speculated that dengue immunity (which is common in much of the Americas, including Puerto Rico and the USVI) may make people more susceptible to Zika infection or even more susceptible to severe Zika disease, including (as some have speculated) birth defects in infants of infected pregnant women.

However, to date, there has been no evidence of more severe Zika disease or of altered Zika clinical presentations in dengue/flavivirus-immune persons. As a universal in vitro phenomenon among the flaviviruses, ADE does not necessarily indicate actual risk to those who are infected. Antibodies to other flaviviruses, such as Japanese encephalitis virus, do not appear to put people at risk of severe dengue disease, even though they mediate ADE in in vitro assays. Around the globe, millions of people who live in areas where multiple flaviviruses circulate and where flavivirus vaccines are administered do not show evidence of increased risk of clinical severity from sequential flavivirus infection/exposure. Questions concerning Zika risks in dengue-immune persons can be answered only by large-scale, prospective epidemiologic studies.

Like most arboviruses, Zika has long existed in enzootic sylvatic reservoirs and has only occasionally infected humans who entered such environments (e.g., hunters). Arbovirus reservoirs include one or more vector mosquitoes or ticks and one or more vertebrate hosts. In Africa, Zika appears to have long existed in an enzootic cycle that includes wild primates and Aedes africanus mosquitoes. Unlike the reservoirs of some other flaviviruses, such as West Nile, Zika reservoir cycles have not appeared to involve either birds or domestic mammals. Because of the need to maintain constant coadaptation to two (or more) genetically very different hosts—e.g., a mosquito and a primate—it might be expected that arboviruses would be trapped in narrow ecologic niches that should restrict their ability to switch to new hosts. However, phylogenetic studies suggest a significant capacity of these viruses, on the whole, to adapt to new ecologic niches via unappreciated mechanisms. The emergence of Zika virus strains newly adapted to ongoing human–A. aegypti–human transmission, after having arisen from earlier Zika strains that were adapted to primate–Aedes africanus–primate transmission, appears to be an example of this phenomenon.

In the current pandemic in the Western Hemisphere, Zika is believed to be transmitted largely by A. aegypti mosquitoes, which are also vectors of yellow fever and dengue viruses and of the unrelated chikungunya alphavirus. In recent times, however, Zika outbreaks have also been linked to transmission by two additional related mosquito vectors: Aedes hensilli and Aedes albopictus. Zika virus has been isolated from A. albopictus mosquitoes in the Americas, but the potential role of the latter alternative vector in Zika transmission remains to be determined. This issue is of special importance to the United States, since A. albopictus is much more widely distributed in continental states than is A. aegypti, being at least transiently prevalent, if not continuously prevalent, in 40 states and in parts of Canada. This distribution potentially increases the risk that returning Zika-infected travelers or other incoming infected individuals from Zika-affected areas could ignite small local outbreaks in U.S. cities and towns. However, it is believed that risks of local outbreaks in the continental United States are substantial only within certain areas of Florida, Texas, and Louisiana. In addition to the mosquito vectors already noted, Zika virus has been isolated from 16 other Aedes species and from 7 non-Aedes mosquito species, including two Culex species. There is no evidence to date that these other mosquitoes are involved in Zika transmission.

Understanding vector mosquito behavior is of critical importance to the control of disease due to Zika virus (and to dengue, yellow fever, and chikungunya viruses). Both A. aegypti and A. albopictus are peridomestic mosquitoes that oviposit (deposit eggs, or “breed”) in solid water-filled containers found in and around human dwellings and gathering places, including in rubber tires, flowerpots, and discarded cans and bottles. The horizontal and vertical flight ranges of these mosquitoes are limited. The transmission hazards posed by Zika and other flaviviruses are therefore neither general over wide geographic areas nor specifically related to general area-wide issues of sanitation, standing/stagnant water, or marshes. The flight range of mosquitoes is ~150 meters, and Zika hazards to individuals come from proximate environments in which people live, work, or enjoy recreation, and particularly within houses, on their porches, and in yards close to houses. Understanding vector mosquito bionomics is thus of great importance in designing control approaches and in advising patients about prevention of Zika infection.

Relatively little is known about Zika virus disease because, until recently, only a handful of human cases had ever been documented. However, by analogy with dengue and other closely related flaviviruses, it is believed that Zika infection begins with the probing “bite” of an infected mosquito. In probing unsuccessfully for a small blood vessel, a female mosquito may inject Zika-infected saliva into pericapillary tissues, infecting Langerhans and other dendritic cells, which then move along lymph channels to regional lymph nodes. Within the lymph node, virus multiplies largely in macrophages and monocytes. After an incubation period of several days (average, 5–7 days; possibly as long as 12 days in some cases), during which time lymphatic infection spreads, bouts of viremia carry free virus and virus-infected monocytes throughout the body, eliciting fever and clinical symptoms. Patients may be viremic for up to a week; during this interval, viral culture and Zika polymerase chain reaction (PCR) are usually positive, and the bite of an uninfected mosquito may lead to midgut infection of that mosquito. Around the fifth to seventh day of human infection, viremia begins to disappear, resulting in inability to transmit the virus further.

The transmission cycle is completed as follows: a mosquito that takes a blood meal from a viremic human acquires viral midgut infection and undergoes a variable 8- to 12-day extrinsic incubation period, during which time the virus spreads to the mosquito’s salivary glands. The mosquito may then take another blood meal and spread the virus onward by injecting saliva into pericapillary tissues of the next susceptible human she encounters. Although the great majority of human Zika infections result from human–mosquito–human transmission, human Zika infections have also resulted from sexual transmission—from male to female and, less commonly, from male to male and from female to male. Infection has also uncommonly resulted from blood transfusion and from laboratory accidents.

The precise level of risk of Zika sexual transmission from infected men has not yet been accurately determined. Investigators in Brazil have proposed that sexual transmission may contribute significantly to overall virus transmission; however, evidence to this effect is scant. Presumably because they represent an “immunologically privileged” site, the testes of infected men (including some who do not know they are infected) may harbor Zika virus or Zika virus RNA for many weeks. As shown by PCR detection of viral RNA, Zika virus has remained in the semen of infected men for at least 6 months after clearance of virus from the blood.

There is little evidence that prolonged testicular infection is harmful to infected men; however, such men may potentially transmit the virus to their sexual partners, including pregnant women or women trying to conceive. The risks of onward sexual transmission from such infected men are presumed to decrease to zero over time, but this presumption has not been confirmed or quantified. Such prolonged infections pose an additional level of risk to sexual partners and make comprehensive counseling concerning safe sexual practices important. The Centers for Disease Control and Prevention (CDC) has recommended that during periods of Zika exposure, male partners of pregnant women either abstain from sex or use condoms for the duration of the pregnancy. Detection of live Zika virus in urine and saliva has led to (unconfirmed) speculation about additional means of direct person-to-person transmission. Like almost any virus that causes acute infection associated with viremia, it is presumed that Zika can cross the placental barrier to expose fetuses (see below).

Early epidemiologic surveillance and human challenge studies characterized Zika as a mild or inapparent dengue-like disease (i.e., with fever, conjunctival injection, one or more episodes of macular or maculopapular rash, retro-orbital pain, muscle aches, arthralgias, lumbar backache, and prostration) (Figure 108-2). The ratio of inapparent to apparent infection, widely cited as being ~5:1, has varied from study to study; however, all studies find more inapparent (asymptomatic, or with mild symptoms that do not lead to recognition of Zika disease) than apparent cases. A distinctive rash may appear either early or later in the course of infection and is usually pink, finely maculopapular, and more prominent on the trunk than the extremities. However, similar to the rash of measles, it may first appear on the face before spreading to the trunk and extremities. Although there is significant variability between individuals, maculopapules are typically fine, confluent, and sometimes indistinct; may be hard to appreciate even by touching with the fingertips; and may be easily missed in darker-skinned persons. The Köbner phenomenon, in which lesions are most pronounced in areas of pressure or injury to the skin, is commonly seen. Fine branny flaking, but never desquamation in sheets or casts, may be seen a week or so after acute illness. Although most flavivirus infections that produce a rash can lead to rash-associated pruritus, particularly in association with skin flaking, there have been increasing reports of Zika patients with uncharacteristically severe pruritus during a stage in the course of illness when skin flaking is not occurring. A pinpoint petechial enanthem on the hard palate has also been reported.

Myalgias are most noticeable in large muscle groups, such as the quadriceps. Retro-orbital pain upon movement of the extra-ocular muscles may be marked. Fever is usual but does not normally exceed 40.0°C and may recur in a “saddleback” (or “camelback”) pattern around the fifth day. Asthenia and prostration lasting several days are common. Other common complaints include anorexia, gastrointestinal upset, peripheral edema, and unusual or metallic taste. Diagnosed cases of Zika in the United States should be reported immediately to state and local health departments.

It has become clear that in some South and Central American countries, particularly Brazil, Zika infection of pregnant women is associated with a range of birth defects, including microcephaly, cerebral calcifications, cerebellar atrophy, visual defects, arthrogryposis, limb reduction defects, and many other problems, as well as later-onset problems in infants who did not have obvious defects detected in utero or at birth. These later issues include ocular damage, delayed development, seizures, feeding problems, and persistent crying. The scope and incidence of these problems are being intensively studied, and many questions remain unanswered.

In early 2016 in northeastern Brazil, a temporal–geographic association between epidemic Zika and epidemic microcephaly caused widespread alarm and declaration of a “public health emergency of international concern” by the World Health Organization (WHO). Many of these babies with microcephaly/other birth defects as well as aborted fetuses have been found to have Zika infection or Zika RNA sequences—sometimes in neural tissue—indicating active infection. In the northeastern Brazilian state of Bahia, the incidence of microcephaly in fetuses of pregnant women infected during the first trimester is reported to be between 1% and 13%. Other countries in the Americas and elsewhere have reported proven or suspected cases of microcephaly/other fetal malformations that are potentially associated with Zika infection of pregnant women; however, to date, the apparent incidence rates are considerably lower than those seen in northeastern Brazil. Curiously, other areas of Brazil that have experienced Zika epidemics have reported far fewer cases of birth defects than has northeastern Brazil.

Similarly, most other countries of the region with significant Zika epidemics have reported, as of September 2016, far lower incidences of microcephaly/birth defects or lesser elevation of birth defect incidence rates. That only one South American country (and predominantly only one region within that country) has thus far had a far higher reported incidence of Zika-associated birth defects than all others remains unexplained. Possibilities that have been proposed include differences in the timing of the epidemics (portending later rises in birth defect incidences in countries with low incidences to date, as infected pregnant women begin to come to term), different incidence rates of infection in pregnant women, an undetected agent other than Zika serving as the true primary causal agent (considered unlikely by most experts), or the involvement of one or more unidentified cofactors in Zika-associated birth defects. Studies of Zika pathogenesis and natural history following fetal infection are in progress, as are studies in an experimental rhesus macaque model.

In classical conceptualizations of teratogenicity, the risk to the fetus is thought to be greatest during the time of maximal organ development—i.e., at ~6–14 weeks for the fetal brain—and before development of the fetal immune system, consistent with teratogenicity data for other viruses that identify the time of maximal risk as being within the first trimester. However, the pathogenesis and natural history of Zika microcephaly have not yet been established. Much lower reported frequencies of damage to specific fetal organs other than the brain and eye raise the possibility that Zika could be damaging the fetus not through teratogenic disruption of organ development, but through aggressive viral encephalitis not controlled by either the fetal immune system (which might recognize the virus as “self” because of first-trimester infection) or by maternal antiviral antibody that crosses the placenta. Accumulating in vitro and animal studies demonstrating the extraordinary neurotropism of Zika virus favor the direct neurotoxic effect as the cause of microcephaly and of the brain damage occurring later in the developmental process of the fetal brain, which is referred to as the “fetal brain disruption syndrome.”

Available data have not yet quantified the risks of Zika virus in pregnancy, although two relatively robust studies have estimated incidences of severe birth defects of all types in Zika-infected pregnant women at ~1–29%. As would be expected from experiences with other viral teratogens, especially rubella, studies are beginning to suggest, as of mid-2016, that the most severe birth defects, including profound microcephaly, tend to result from first-trimester or early second-trimester Zika infections.

Some studies have claimed that symptomatic disease (e.g., illness with rash) in pregnant women is more likely to lead to fetal infection than asymptomatic infection; however, many of those data have been generated by retrospective methods, and babies with apparent congenital Zika infection have been delivered by women who did not have recognized Zika infection. Clinical data and experimental primate data suggest that pregnant Zika-infected women may be viremic for longer periods than nonpregnant infected women or infected men; however, it is not known whether this difference is due to altered immunity in pregnancy or, as seems more likely, persistent infection of the fetus.

Neurologic complications associated with Zika epidemics continue to be reported at relatively low frequency, estimated at ~1 per 4000 Zika infections for Guillain-Barré syndrome. Other possibly immune-mediated complications have been reported as well, including rare cases of meningoencephalitis and acute myelitis, although causality has not yet been established. In addition to deaths from birth defects and neurologic complications, rare Zika deaths have been reported almost invariably in elderly individuals with unrelated underlying conditions. In two such cases, thrombocytopenia was documented.

In a “pure” Zika epidemic, the diagnosis can often be reliably made on clinical grounds. Unfortunately, however, dengue and chikungunya, which cause similar clinical pictures, and which are transmitted by the same mosquito species, have both been co-epidemic in the Americas; thus a specific clinical diagnosis, including that in travelers returning to or migrating to the United States or Europe from epidemic areas, may be problematic. Diagnostic recommendations for clinicians and laboratory workers recently have been made by the CDC. During acute illness, the diagnosis can be made either by Zika virus isolation or by detection of Zika virus RNA by PCR. These tests are often available only through reference laboratories, including state health departments or the CDC. Anti-Zika IgM develops during or at the end of clinical illness but is often nonspecific in cross-reacting with other flaviviruses; IgM tests are not widely available commercially. Although several new diagnostic tests have become available in the United States under Emergency Use Authorization, the same diagnostic problems of specimen timing and interpretation of results remain. Infection may be confirmed by viral isolation or PCR only during a narrow window of time (~7 days) which includes the acute illness, with an additional week of detection provided by testing urine.

Serologic diagnosis of Zika that has occurred in the recent or distant past can be problematic because of serologic cross-reaction with other flaviviruses or with flavivirus vaccines to which tested individuals have been exposed and immunized, respectively. Although the alphavirus chikungunya causes a similar clinical illness and is transmitted by the same vector, it does not serologically cross-react with Zika. Interpretation of the results of flavivirus serologic tests by experienced flavivirologists is desirable, as the many complexities involved may confuse clinicians and commercial laboratory personnel.

Small-joint polyarthralgia and large-joint persistent arthralgia favor a diagnosis of infection by an alphavirus such as chikungunya or, in Australia, Ross River virus. Other acute febrile illnesses that may enter into the differential diagnosis, depending on the patient’s history and the locale in which infection is presumed to have been acquired, include influenza, leptospirosis, and (in areas without adequate vaccination) measles and rubella. In the United States, laboratory diagnosis of Zika infection should be reported immediately to state and local health departments.

There is no specific treatment for Zika infection. The mainstays of patient management are bed rest and supportive care. When multiple arboviruses are co-circulating, a specific viral diagnosis can be important in anticipating and preventing/managing complications. For example, in dengue, aspirin should be avoided to lessen the possibility of hemorrhagic complications, and some patients may need to be monitored for rising hematocrit indicative of impending shock syndrome, so that life-saving treatment can be promptly instituted. With chikungunya infection, patients should be monitored and managed for acute arthralgias and for chronic arthritis. The CDC recommends that in some situations, and particularly for pregnant women, fever and pain should be treated only with acetaminophen.

The CDC has recommended that pregnant women postpone travel to places where Zika is circulating if possible and that if either pregnant women or women trying to become pregnant must travel, they consult with their health care provider beforehand and plan to take extensive precautions to avoid mosquito exposure. Such women should be promptly evaluated by their health care provider for known or suspected maternal Zika infection and should be followed throughout pregnancy. Guidelines for evaluation and testing of infants with congenital Zika infection, Zika-associated microcephaly, or fetal intracranial calcifications are available at https://www.cdc.gov/zika/hc-providers/index.html.

The CDC has continued to release frequent and updated information that supports management and counseling of women and of couples who have been or may become exposed to Zika virus. As recommendations have frequently changed in light of newly available information, it is desirable for practitioners to consult the CDC website (https://www.cdc.gov/zika/) regularly. Other recommendations have been made by the Pan American Health Association, the WHO, and other national and professional agencies. Recommendations address different types of exposures, including exposures of women and couples living in epidemic areas, exposures of women and couples who may travel to epidemic areas, and exposures of women living in the areas of the continental United States that are not experiencing Zika transmission but who may nevertheless be exposed to infected sexual partners. The most important goal of such counseling is to apply multiple available approaches to protect women from Zika infection while pregnant, including the interval of pregnancy between conception and pregnancy determination and during the 2–3 weeks before conception.

Because no vaccine or effective drug is currently available, prevention must depend upon community and governmental efforts (education and counseling, vector control, diagnosis of infection) and personal protection undertaken by individuals. The CDC’s Draft Interim Response Plan (available at http://www.cdc.gov/zika/public-health-partners) represents a framework for Zika control at the national, state, and local level. There remains an important role for practitioners in counseling and educating patients, who may be confused by the many complexities of Zika virus infection and by the continually evolving information reported in the media as the pandemic progresses and as hundreds of scientific studies are completed and reported.

Until such time as vaccines become available, the prevention of Zika infection relies upon personal protection and public health approaches. Personal protection involves avoidance of mosquitoes and mosquito breeding areas, use of insect repellants, wearing of clothing that covers exposed skin, and condom use for sexual exposures. Public health approaches include disease and vector surveillance, educational and awareness measures, and mosquito vector control. The main forms of vector control are source reduction (physical removal of mosquito breeding sites), larviciding (the killing of larvae by the addition of larvicidal chemicals to water in which mosquito ovaposition occurs), and adulticiding (the killing of adult mosquitoes with insecticides delivered by household space sprayers or outdoor truck or vehicle mounted sprayers or with aerial sprays dropped by low-flying aircraft). Because efficacy is imperfect when any of these approaches is used alone, it is highly desirable that all approaches be used simultaneously. To be effective, adulticides must be delivered in frequently repeated cycles: as a result of continual larval hatching, adult mosquito populations return to previous levels within 1–2 days after effective spray-killing.

More than a century ago, the U.S. Army under the direction of William Crawford Gorgas (later Army Surgeon General) completely eliminated A. aegypti from Havana and other Cuban ports and from the Panama Canal Zone without any of the modern control approaches available today. Similarly, in the early to mid-20^th century, A. aegypti mosquitoes were nearly eliminated from the Western Hemisphere with the same basic methods supplemented by DDT insecticide. Control of Zika and other flaviviruses borne by A. aegypti is possible with existing approaches; however, it would require considerable social and political will, financing, training of a large cadre of vector control personnel, and a willingness of the public to participate in source reduction and to let vector control personnel operate on their premises.

A number of existing vaccine platforms used for related flaviviruses are now being quickly adapted to Zika to speed up the normally lengthy vaccine development process. Vaccines in various stages of clinical trial are based on the following technology platforms: DNA vaccine technology; live attenuated chimeras comprising a dengue backbone into which genes coding for Zika external proteins have been inserted; Zika virus particle inactivation; vesicular stomatitis virus–vectored expression of Zika proteins; and mRNA vaccine technology. An effective Zika vaccine that could be licensed for general use is not, however, expected until 2018 at the earliest.

In the meantime, the best general preventive measures against Zika include personal protection afforded by use of insect repellants, covering of exposed skin with clothing, use of screens and air-conditioning, regular trash removal, and removal of yard/household debris conducive to the accumulation of the standing water that provides mosquito breeding sites. As information about Zika and associated microcephaly has been unfolding rapidly, it is expected that understanding of Zika disease and recommendations for clinicians will frequently change. Health care providers managing patients with Zika virus infection or those with concerns about Zika virus exposure should periodically consult updated information provided by the CDC, state and local health departments, professional societies, and the published medical and public health research literature.