The potential for a localized or regional outbreak of Zika virus disease in the United States is significant given the level of travel exposure, opportunities for Zika virus migration, and the prevalence of Aedes aegypti mosquitoes along the southern and southeastern rim of the country. This course will review the history of Zika virus migration and the important clinical and public health aspects of Zika virus disease, including the epidemiology, modes of transmission, clinical manifestations, approach to diagnosis, and strategies for prevention and control of Zika virus infection.
This course is designed for physicians, physician assistants, and nurses in all settings who may identify and act to prevent Zika virus disease.
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NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program. AACN Synergy CERP Category A.
In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.
This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.
The purpose of this course is to enhance the knowledge and skill of physicians, nurses, and other health professionals who may be called upon to address the concerns of international travelers, provide advice to women of childbearing age, or assess febrile rash illness in persons recently returned from endemic areas.
Upon completion of this course, you should be able to:
- Describe the historical background and dynamics of the emerging Zika virus epidemic in the Americas and its potential impact on public health.
- Discuss and advise patients as to the risks of Zika virus transmission via various routes.
- Recognize and manage a patient presenting with characteristic clinical and epidemiologic features of acute Zika virus disease.
- Discuss the salient features of microcephaly, including the incidence, causative factors, and clinical and pathologic findings unique to congenital Zika virus infection.
- Select the appropriate laboratory diagnostic tests for Zika virus in relation to a patient's clinical profile and the time elapsed since exposure or onset of symptoms.
- Using your knowledge of Zika virus disease, devise a management plan for persons with known or suspected infection.
- Using knowledge of Zika virus shedding by infected men and the risk of sexual transmission, counsel infected men and couples on the importance and recommended duration of safe sex practice.
- Using knowledge of vector transmission and the behavior of Aedes aegypti mosquitoes, devise an effective strategy for avoiding bites, limiting exposure, and eliminating mosquito-breeding habitat.
John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.
Carol Shenold, RN, ICP, graduated from St. Paul’s Nursing School, Dallas, Texas, achieving her diploma in nursing. Over the past thirty years she has worked in hospital nursing in various states in the areas of obstetrics, orthopedics, intensive care, surgery and general medicine.
Mrs. Shenold served as the Continuum of Care Manager for Vencor Oklahoma City, coordinating quality review, utilization review, Case Management, Infection Control, and Quality Management. During that time, the hospital achieved Accreditation with Commendation with the Joint Commission, with a score of 100.
Mrs. Shenold was previously the Infection Control Nurse for Deaconess Hospital, a 300-bed acute care facility in Oklahoma City. She is an active member of the Association for Professionals in Infection Control and Epidemiology (APIC). She worked for the Oklahoma Foundation for Medical Quality for six years.
Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Contributing faculty, Carol Shenold, RN, ICP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John V. Jurica, MD, MPH
Jane C. Norman, RN, MSN, CNE, PhD
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
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#98710: Zika Virus Disease
Zika virus (ZIKV) is the latest in a series of related human arboviral pathogens that has migrated out of Africa and Asia into the Americas over the past two decades [1,2,3]. Arboviruses are transmitted by blood-feeding arthropod vectors, principally mosquitoes and ticks, and are maintained in cycles of transmission between a competent vector and any susceptible vertebrate species in the environs. Like yellow fever, dengue, and chikungunya viruses, the vector for ZIKV is the Aedes mosquito, and epidemics within susceptible population groups are sustained by a mosquito-human-mosquito transmission cycle.
Until recently, ZIKV disease was rarely reported and of little known consequence; circulation of the virus was largely confined to a mosquito-nonhuman primate-mosquito transmission cycle in forested terrain across a portion of east Africa and the adjacent Asian Pacific . In 2007, the first outbreak of human ZIKV disease appeared on Yap Island in Micronesia. This was followed in 2013 by a large-scale epidemic in French Polynesia. Subsequent outbreaks were reported on other Pacific islands as ZIKV migrated in epidemic fashion across the Pacific and into the Americas. With the aid of a highly competent vector (the A. aegypti mosquito) having ready access to large, susceptible population groups, successive outbreaks of ZIKV disease have spread rapidly throughout South and Central America and the Caribbean, including Puerto Rico (Figure 1) .
Primary ZIKV infection is most often asymptomatic or causes a relatively mild, self-limited illness. However, infection during pregnancy is often complicated by transmission of virus to the developing fetus, resulting in arrested neurologic development, microcephaly, and related congenital anomalies. There is also growing evidence linking ZIKV infection with post-infectious Guillain-Barré syndrome. In February 2016, following the report of a marked increase in newborn infant microcephaly some months following a large ZIKV outbreak in Brazil, the World Health Organization (WHO) declared ZIKV disease a public health emergency of international concern . A short time later, the Centers for Disease Control and Prevention (CDC) elevated its response to level 1, the highest for the agency . Because of the link between exposure to ZIKV during pregnancy and microcephaly, pregnant women and those who may become pregnant are advised to avoid travel to regions of ongoing ZIKV transmission, and all travelers are urged to take enhanced precautions in areas where ZIKV is circulating.
As of December 2016, within the United States, cases of ZIKV disease have been primarily reported in returning travelers and in women having intimate sexual contact with men infected while traveling to regions with ongoing mosquito transmission. Because of ongoing ZIKV circulation in many nearby regions of the hemisphere, the number of ZIKV disease cases among travelers visiting or returning to the United States is expected to increase. ZIKV disease and ZIKV congenital infection have been added to the list of nationally notifiable conditions, and the CDC Arboviral Disease Branch provides periodic updates of confirmed ZIKV cases reported in the United States and its territories . As of December 7, 2016, a total of 4,575 cases have been reported; 1 case was laboratory-acquired, 4,389 were acquired in association with travel to endemic areas outside the country, and 185 cases were locally acquired, mainly in or around Miami in Florida . One locally acquired case has been confirmed in south Texas . Puerto Rico has been particularly affected, and data suggest that 25% of the population may be infected by the end of 2016 . The potential for a localized or regional outbreak of ZIKV disease in the United States is significant given the level of travel exposure, opportunities for ZIKV migration, and the prevalence of A. aegypti mosquitoes along the southern and southeastern rim of the country .
This course will review the history of ZIKV migration and the important clinical and public health aspects of ZIKV disease, including the epidemiology, modes of transmission, clinical manifestations, approach to diagnosis, and strategies for prevention and control of ZIKV infection. The purpose is to enhance the knowledge and skill of physicians, nurses, and other health professionals who may be called upon to address the concerns of international travelers, provide advice to women of childbearing age, or assess febrile rash illness in persons recently returned from endemic areas.
ZIKV is a single-stranded RNA virus closely related to dengue and belonging to the family of flaviviruses . Like other flaviviruses that infect humans, ZIKV is transmitted by the bite of an infected mosquito.
ZIKV was first identified in 1947, after being isolated from an ill rhesus monkey caged in the Zika Forest of Uganda as part of a sentinel surveillance program for yellow fever . One year later, the virus was isolated from A. africanus mosquitoes recovered from the same forest. In subsequent decades, documentation of human ZIKV infection was provided by population-based serologic studies of arbovirus infection in parts of Africa and Asia, combined with occasional case reports of human ZIKV isolation in association with febrile illness. By 1981, ambient human seropositivity for ZIKV had been reported from Nigeria, Uganda, other nearby African countries, and parts of Asia, including India, Malaysia, the Philippines, and Indonesia .
In April 2007, on Yap Island, Federated States of Micronesia in the western Pacific, physicians became aware of an outbreak of mild dengue-like illness characterized by rash, conjunctivitis, and arthralgia. The ensuing investigation was the first population-based epidemiologic study of a human ZIKV epidemic . The outbreak lasted four months; 49 confirmed and 57 suspected cases were identified. ZIKV RNA was detected in serum samples obtained from patients during the acute phase of illness. No dengue or other arbovirus RNA was detectable. A household survey and serologic study conducted on a select sample of the population revealed that 414 of 557 participants (74%) were positive for immunoglobulin M (IgM) antibody to ZIKV, indicating recent infection. Clinical illness attributable to ZIKV infection was reported in 19% of participants who were seropositive. Investigators estimated that 5,005 of 6,892 Yap residents (73%) 3 years of age or older were infected with ZIKV during the outbreak; moreover, approximately 80% of infections had been asymptomatic or too mild to prompt medical attention. The A. hensilii mosquito was judged to be the vector, though no virus or viral RNA could be detected in any pools of trapped mosquitoes .
In 2013–2014, an outbreak of ZIKV infection was reported from French Polynesia, a territory consisting of 67 islands arranged in five archipelagoes located in the South Pacific. Between October 2013 and February 2014, the regional sentinel surveillance network recorded 8,262 suspected cases of ZIKV disease . Of 746 samples sent for laboratory confirmation, 396 (53%) were confirmed by reverse transcription polymerase chain reaction (RT-PCR). An estimated 28,000 cases of ZIKV-like illness were seen during the course of the epidemic (about 11% of the population of French Polynesia). The A. aegypti mosquito was considered to be the principal vector. The clinical features were similar to those seen in the Yap outbreak, except that an unexpected cluster of Guillain-Barré syndrome cases and other neurologic complications were encountered during the course of the outbreak . Subsequent outbreaks in 2014–2015 were reported on other Pacific islands, including New Caledonia, Easter Island, Cook Islands, and Samoa.
In early spring 2015, ZIKV was identified as the cause of an outbreak of febrile rash illness in Bahia State, Brazil, the first indication that the virus had migrated to the Americas. In the months that followed, Brazil reported a progressive, widespread outbreak of ZIKV disease among adults and children in 29 Brazilian states, followed in turn by an unexpected and significant increase in the number of reported infants born with microcephaly . By December 2015, the number of suspected cases of ZIKV disease had reached 56,318. Brazilian authorities estimate that 500,000 to 1,500,000 persons were infected with ZIKV during the first 18 months of the outbreak. As of November 2016, outbreaks of ZIKV disease and evidence of continuing mosquito-borne transmission had been reported from 73 countries and territories, primarily in Latin America and the Caribbean .
New and important aspects of ZIKV disease and transmission have emerged from investigations of the current epidemic. It is now established that primary ZIKV infection during pregnancy is often transmitted to the developing fetus and leads to excess fetal loss, microcephaly, and related congenital abnormalities [13,14]. There is growing realization that ZIKV infection is linked to the observed increases in the incidence of post-infectious Guillain-Barré syndrome, now reported in several countries . Finally, sexual transmission of ZIKV by men with recent symptomatic infection has been documented, adding a further element of complexity to strategies for prevention in women who are pregnant or may become pregnant .
In epidemic settings and endemic areas, ZIKV infection is primarily vector-borne, transmitted by the bite of an infected Aedes mosquito. In addition, other modes of transmission are now known to be important in human ZIKV disease. These include sexual transmission from an infected male to female and male partners; transplacental transmission from mother to fetus during pregnancy, leading to congenital ZIKV disease; and perinatal transmission from a viremic mother to her newborn infant [16,17]. There is theoretical concern that blood transfusion and tissue/organ transplantation could also serve as vehicles of transmission. Therefore, the U.S. Food and Drug Administration has recommended universal screening of donated whole blood and components for ZIKV in the United States and its territories .
As noted, the A. aegypti mosquito is the principal vector of transmission for most human arbovirus infections, including yellow fever, dengue, chikungunya viruses and ZIKV [2,3]. A. aegypti is one of several species belonging to the Aedes genus (Stegomyia subgenus) of mosquitoes . Aedes species are distributed in various combinations throughout tropical and subtropical regions of the world, having adapted in different ways to prevailing climate and habitat. In remote rainforests of Africa, where ZIKV circulates in a mosquito-nonhuman primate-mosquito transmission cycle, the principle vector is A. africanus. In heavily populated and urban areas of Latin America and the Caribbean, the vector of transmission for outbreaks of human ZIKV disease is A. aegypti and, to a lesser extent, A. albopictus.
There is also variability among Aedes species with respect to vector competence (i.e., the intrinsic ability of a vector to transmit a disease agent) and vectorial capacity (i.e., the overall effectiveness of a vector to sustain and propagate a disease outbreak in a given location) [3,4]. A. aegypti and A. albopictus appear to have comparable vector competence for ZIKV transmission; however, A. aegypti exhibits greater vector capacity among human population groups, perhaps because of its behavior and adaptation to an urban environment .
In times past, A. aegypti thrived on nonhuman hosts and laid its eggs in water collected in tree holes and the axils of forest plant leaves; in recent decades, this mosquito has adapted to an urban habitat and shows a preference for the human host over other mammals . It flourishes in impoverished crowded areas with no piped water, inadequate trash disposal, and ineffective domicile barrier protection, such as afforded by screened doors and windows. A single female deposits its eggs at multiple sites, taking advantage of stagnant water found in cemetery vases, pet bowls, abandoned barrels, and automobile tires. Adult mosquitoes of both sexes feed on nectar and fruit, but females require blood protein in order to fully develop their eggs. Thus, only the female mosquito bites.
A. aegypti is an aggressive daytime biting mosquito, and feeding is most intense in the hours around dawn and dusk. The bite itself is barely perceptible. Female A. aegypti mosquitoes are stealth feeders, approaching victims from behind and biting on ankles and elbows—a "sneak attack" that avoids being noticed . This mosquito does not feed sufficiently with a single bite; it is a "sip feeder" that bites multiple humans in the course of a blood meal, thereby optimizing the vector capacity of a single mosquito carrying the virus. The female prefers shady areas for rest and is adept at hiding in closets and under beds, later to emerge for a nocturnal blood meal.
With the exception of mountainous regions above 3,500 feet, the range of A. aegypti and A. albopictus includes all of Latin America and the Caribbean and extends into parts of the contiguous United States. While the prevailing range of A. aegypti within the United States is limited to south Texas along the Mexican border, south Florida, and coastal areas of the gulf and southern Atlantic states, climate conditions are favorable for periodic expansion into adjacent states . The A. albopictus species is acclimated to a milder climate and has a broader range that extends from the eastern seaboard through the Southeast and a portion of the Midwest, and throughout the Southwest. Of public health concern is the following scenario: a local area of ZIKV circulation among A. aegypti mosquitoes and humans becomes established in the United States, from which A. albopictus emerges as a secondary vector with potential for a more widespread outbreak in other parts of the country.
Epidemiologic investigation and published case reports have demonstrated that a man with symptomatic ZIKV infection can transmit the virus to his partner through intimate sexual contact, including vaginal, anal, and likely oral sex [16,20,21]. Within the United States and other countries having no ZIKV circulation, cases of well-documented ZIKV disease have been reported in women whose only risk exposure was sexual contact with a symptomatic male partner who had recently traveled from an area with ongoing ZIKV transmission. An illustrative case report is that of a woman, 24 years of age, living in France, who on February 16, 2016, became ill with fever, arthralgia, myalgia, and a pruritic rash . Samples of urine and saliva collected on the third day of illness were positive for ZIKV RNA by RT-PCR, and the serum tested positive for acute phase ZIKV IgM antibody. There is no known ZIKV circulation in that part of Europe, and the patient had no history of travel to an endemic area. She did report having sexual contact (vaginal intercourse and oral sex) on several occasions in the week prior to onset of symptoms with a man who had just returned from a two-month stay in Brazil. He also had experienced a febrile rash illness with arthralgia during the four days prior to his departure for France on February 10. Urine and semen samples obtained 16 days after onset of his symptoms tested positive for ZIKV RNA by RT-PCR. ZIKV was isolated by culture from semen samples obtained on day 18 and on day 24 following onset of his illness .
The full spectrum of behaviors and circumstances by which ZIKV is transmitted sexually is not yet known. ZIKV has been detected in saliva, urine, semen, and breast milk following acute infection, but not in vaginal swab specimens collected from infected women . In one reported case, ZIKV RNA was detected in semen up to 62 days after onset of symptoms, and replication-competent ZIKV has been isolated from semen at least two weeks after onset of illness . The duration of infectious ZIKV in semen remains unknown. Studies are underway to determine the incidence, duration, and pattern of virus shedding in men with symptomatic and asymptomatic ZIKV infection. For now, the CDC recommends that men who have been diagnosed with ZIKV consider using condoms or abstaining from sex for six months following infection .
All reported cases of sexual transmission have involved vaginal or anal sex with men shortly before, during, or shortly after a symptomatic illness consistent with ZIKV disease . It is not known whether infected men who never develop symptoms can transmit ZIKV to their sex partners. Sexual transmission of ZIKV from infected women to their sex partners has not been reported. The consistent and correct use of latex condoms is known to reduce substantially the risk of acquiring sexually transmitted infections, including those caused by viruses.
In the course of acute infection during pregnancy, ZIKV can be transmitted across the placenta to the developing fetus. Evidence for intrauterine fetal infection includes demonstration of ZIKV in the placenta and products of conception following spontaneous abortion, identification of ZIKV RNA in amniotic fluid by RT-PCR, and virologic and serologic studies of infants born with microcephaly. The true incidence and natural history of this phenomenon, including the importance of such factors as gestational age, level and duration of viremia, and immune enhancement by pre-existing heterologous anti-flavivirus antibodies, is currently unknown .
Two cases of intrapartum transmission of ZIKV from a newly infected, viremic mother to her newborn infant have been reported . One infant was considered to be asymptomatic; the other child developed a rash and transient thrombocytopenia. Although ZIKV has been identified in breast milk, there have been no reports of transmission through breastfeeding.
In epidemic settings, the majority of primary ZIKV infections are asymptomatic, and those who do become ill usually experience a self-limited, mild febrile illness with rash, conjunctivitis, myalgia, and arthralgia lasting three to six days. The incubation period for ZIKV is not well defined; it is considered to be similar to that of other mosquito-borne flaviviruses—usually less than one week and in the range of 3 to 10 days.
The first detailed description of the illness caused by acute ZIKV infection is a self-reported case study in 1964 of a young (28 years of age) European research worker at the East Africa Virus Research Institute in Uganda :
"The illness began with a slight frontal headache in the evening, followed the next morning by an aching sensation in the back and thighs and the appearance of a maculopapular rash covering the face, neck, trunk, and upper arms. Throughout day 2, the rash, which was non-itching, spread gradually to involve all four extremities, including the palms of the hands and the soles of the feet. Toward midday the patient was febrile (99.4° F) and experiencing malaise accompanied by pain in the back and a frontal headache. By the evening of day 2, the temperature had returned to normal, the rash was beginning to fade from the back and neck, and the patient felt better apart from slight headache. On day 3, the patient felt no ill effects and the temperature remained normal. The rash persisted on the trunk and extremities, faded slowly throughout days 3 and 4, and disappeared completely on day 5. No other signs or symptoms were noted during the illness."
The patient had visited Zika Forest 21 days before the onset of illness and had been bitten by mosquitoes at a time when ZIKV was being isolated from mosquitoes collected in the forest. ZIKV was isolated from the patient's blood by mouse inoculation studies, and a rise in antibody to ZIKV was demonstrated. The clinical features of the infection—a mild, self-limited febrile illness with malaise, myalgias, headache, and exanthum—was likened to that seen with other arthropod-borne viruses such as West Nile and chikungunya .
A more complete description of the natural history of acute ZIKV infection is provided by clinical observations collected during the investigation of the four month-long epidemic on Yap Island in 2007 . Based on results of a seroepidemiologic survey, only about 18% of 5,005 islanders estimated to have been infected developed symptoms attributable to ZIKV. In the course of this investigation, information regarding symptoms and signs was obtained from 31 of 49 confirmed cases (63%) of ZIKV disease. The most common clinical characteristics were macular or papular rash (90%), fever (65%), arthritis or arthralgia (65%), non-purulent conjunctivitis (55%), myalgia (48%), and headache (45%) . Other symptoms included retro-orbital pain, edema, and vomiting. The median duration of rash was 6 days (range: 2 to 14) and arthralgia was 3.5 days (range: 1 to 14). There were no hospitalizations or deaths attributed to ZIKV illness in the course of this outbreak.
A similar pattern of illness was observed in a cohort study from Rio de Janeiro, wherein pregnant women who had experienced fever and rash illness within the previous five days were enrolled in a surveillance study designed to assess the cause of illness and to monitor subsequent maternal health and fetal development . During the period from September 2015 through February 2016, 72 of 88 women enrolled tested positive for acute ZIKV infection by RT-PCR on blood, urine, or both. All women had rash, as this was an inclusion criterion; the prevailing pattern was a descending macular or maculopapular exanthem accompanied by pruritus in 94% of patients. Arthralgia was reported in 65% of ZIKV-positive women, conjunctival injection was seen in 58%, and lymphadenopathy (generalized or regional) was present in 41%. Fever was documented in only one-third of patients and, when present, was low-grade and of short duration. Nausea and vomiting were reported in 21%, and respiratory findings were evident in 7% .
From these observations there emerges a distinctive, though nonspecific, clinical ZIKV syndrome: an acute onset descending maculopapular rash (often with pruritus), conjunctival injection, arthralgia, myalgia, and transient low-grade fever. Lymphadenopathy may be present, but respiratory symptoms and signs are conspicuously uncommon. ZIKV disease should be considered in patients with any combination of these symptoms who have traveled to areas with ongoing transmission in the two weeks preceding onset of illness. Rare manifestations of acute ZIKV infection, based on isolated case reports, include meningoencephalitis, myelitis, thrombocytopenic purpura, and ocular complications [4,26,27].
Because dengue and chikungunya viruses have the same vector of transmission and share a similar geographic distribution and clinical profile with ZIKV, patients with suspected ZIKV disease should be evaluated and managed for these possibilities as well. Other considerations in the differential diagnosis include malaria, rubella, measles, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections .
ZIKV is a neurotropic virus, which accounts for its association with post-infectious Guillain-Barré syndrome and with infant microcephaly and related neurologic abnormalities that follow intrauterine infection.
Guillain-Barré syndrome is an acute, progressive, immune-mediated motor axonal neuropathy characterized by flaccid paralysis. It is often triggered by infection. Most patients recover after many weeks or months but often require prolonged hospitalization, respiratory ventilation support, and management of other complications, all of which are costly and burdensome to any health system.
An unexpected increase in the number of patients presenting with Guillain-Barré syndrome has been observed in several countries experiencing large outbreaks and ongoing transmission of ZIKV. During the 2013–2014 ZIKV outbreak in French Polynesia, in the space of four months' time, 38 cases of Guillain-Barré syndrome were diagnosed among an estimated 28,000 persons who sought medical care for suspected ZIKV disease . Based on annual reported cases of Guillain-Barré syndrome for the prior four years, the number expected in a four-month period was three or less. Among the ZIKV-associated cases, 73% were male and the mean age was 46 years; 15 patients were admitted to the intensive care unit, and 9 required mechanical ventilation. There were no deaths. To date, this association between ZIKV outbreaks and clusters of Guillain-Barré syndrome has been reported in eight countries: French Polynesia, Brazil, El Salvador, the French territory of Martinique, Colombia, Suriname, the Bolivarian Republic of Venezuela, and Honduras .
Microcephaly is a rare pediatric disorder often associated with other congenital anomalies and developmental complications. Microcephaly may be classified as prenatal (congenital) or postnatal (developing sometime after birth); only the former has been linked with ZIKV infection. The growth of the fetal brain in utero approaches maximum volume after 21 weeks' gestation, a process that influences the size of the newborn infant skull. Microcephaly is the clinical (or radiographic) finding of a head size unexpectedly small for a given stage of development; it is usually defined as an occipitofrontal head circumference below the third percentile for gestational age and sex . Any injury that causes sequence disruption of normal fetal brain growth can lead to microcephaly. The common causative factors are genetic perturbations, maternal illness (e.g., infection), and exposure to teratogenic substances. The incidence of congenital microcephaly is estimated to be 2 to 10 cases per 10,000 live births .
The clinical course of children born with microcephaly is difficult to predict; when intrauterine infection is the cause, the severity and prognosis are determined in large part by gestational age of onset and the presence of additional neurologic deficits. Common childhood sequelae include developmental delay, hearing loss, vision defects, impaired intellectual ability, and seizures.
In November 2015, after alarming reports of an epidemic of microcephaly in northern Brazil, later attributed to maternofetal ZIKV infection, the Brazilian Ministry of Health set up a surveillance system for cases of microcephaly and other malformations possibly linked with ZIKV. As of June 4, 2016, 7,830 suspected cases had been reported, of which 40% were judged confirmed or probable cases of congenital ZIKV syndrome based on subsequent clinical and epidemiologic investigation . For this six-month period, the number of newborns with microcephaly associated with confirmed ZIKV infection represents a 40-fold increase in monthly reports of microcephaly in Brazil prior to 2015. In the course of this case-by-case investigation, clinicians also discovered that 1 in 5 children with definite or probable congenital ZIKV infection presented with head circumference in the normal range. Thus, the sensitivity of microcephaly alone to detect cases of congenital ZIKV was 83%, increasing to 87% when history of maternal rash was included .
The true rate, or risk, of adverse fetal outcomes following maternal ZIKV infection has not been determined. In the Rio de Janeiro prospective cohort study, 42 of 72 pregnant women with definite ZIKV infection, contracted between week 6 and week 36 of gestation, were agreeable to fetal monitoring by serial ultrasonography . Significant fetal abnormalities, including growth restriction, cerebral calcifications, microcephaly, and other brain malformations, were seen in 12 cases (29%). There were two fetal deaths after 30 weeks' gestation (4.8%) .
In comparison with other known causes of congenital infection (e.g., toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis), the microcephaly associated with ZIKV infection has a unique phenotype consistent with fetal brain disruption [4,29]. The severity of fetal brain injury and the characteristic clinical and pathologic features associated with congenital ZIKV are illustrated by the following case report. An expectant mother, 25 years of age, developed a febrile rash illness during the 13th week of gestation while living and working in northern Brazil. Ultrasonography performed at 14 and 20 weeks' gestation indicated normal fetal growth and anatomy. At 29 weeks, the patient reported reduced fetal movements and follow-up imaging showed early signs of fetal anomalies. Ultrasonography at 32 weeks' gestation confirmed intrauterine growth retardation, microcephaly, and numerous calcifications in various parts of the brain. Because of severe brain disease and a poor prognosis, the pregnancy was terminated by request at 32 weeks' gestation. Autopsy examination revealed microcephaly, widely open Sylvian fissures, small cerebellum and brain stem, almost complete agyria, and internal hydrocephalus of the lateral ventricles. Numerous calcifications of variable size were found in the cortex and subcortical white matter of the frontal, parietal, and occipital lobes. Microscopic examination of the brain showed extensive neuronal destructive change with multifocal filamentous neuronal calcifications, diffuse astrogliosis, and degeneration of the long descending tracts within the brain stem and spinal cord. Tissue samples were positive for ZIKV by RT-PCR assay and the complete genome of ZIKV was recovered from the fetal brain .
The distinctive characteristics of microcephaly associated with congenital ZIKV infection, evident on neuroimaging and by pathologic examination, are extensive intracranial calcifications, severe cortical atrophy and malformation, hypodensity of the white matter, cerebellar hypoplasia, and ventriculomegaly. Infection during pregnancy has also been linked to other adverse outcomes, including excess miscarriage and stillbirths, ocular defects, hearing loss, and impaired growth in infants.
In April 2016, after careful consideration of available data, epidemiologists at the CDC concluded that a causal relationship exists between prenatal ZIKV infection and microcephaly and other neurologic abnormalities [14,29]. Supporting evidence includes the timing of infection during prenatal development is consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in infants with confirmed congenital ZIKV infection; and identification of ZIKV in brain tissue of affected fetuses and infants.
The possibility of ZIKV disease should be considered in the patient with a compatible clinical syndrome (e.g., febrile rash illness with arthralgia and conjunctivitis) and epidemiologic risk factors, such as residence in or travel to an area of active ZIKV transmission within the previous two weeks, or sexual contact with a person known or suspected of recent ZIKV infection. Laboratory confirmation relies on molecular detection of the viral genome (via RT-PCR) in blood or body fluids and serologic assay for acute-phase ZIKV-specific IgM antibody.
The U.S. Food and Drug Administration has issued an emergency use authorization for two diagnostic tools for ZIKV: the Triplex Real-Time RT-PCR assay and the Zika MAC-ELISA for anti-ZIKV IgM . These have been distributed to qualified laboratories that are certified to perform high-complexity tests in the United States. Clinicians should contact local and state health departments to facilitate diagnostic testing. The CDC provides updated guidance for the selection and timing of ZIKV diagnostic testing at http://www.cdc.gov/zika/hc-providers/types-of-tests.html.
In the first week after onset of symptoms, ZIKV disease can often be diagnosed by performing RT-PCR on serum. However, RT-PCR for detection of viral nucleic acid in blood is dependent on timing of the sample in relation to the onset, duration, and level of viremia. The viremia that follows ZIKV infection begins a few days before onset of symptoms and lasts about five to seven days. By the time a patient presents with symptoms, the window of opportunity may be short or the degree of viremia below detectable levels. During acute infection, ZIKV is shed in the urine and detectable viral RNA persists well into the second week. For this reason, the CDC recommends that serum and urine samples be submitted for RT-PCR in patients presenting up to 14 days after onset of illness . A positive RT-PCR result on any sample confirms ZIKV infection, and no additional testing is indicated. A negative RT-PCR result does not exclude infection, and a serum sample should then be tested for anti-ZIKV IgM antibody.
Serologic testing is useful in patients who present more than one week after onset of symptoms. ZIKV-specific IgM antibodies develop toward the end of the first week of illness and remain detectable for 12 weeks; neutralizing antibodies (IgG) become detectable in the second week and persist for many years . Therefore, if serum and urine are negative by RT-PCR, serum IgM antibody testing for ZIKV should be performed. If the patient resides or has traveled in an endemic area where other flaviviruses are circulating, anti-dengue virus and anti-chikungunya virus IgM antibody testing should be requested as well.
The ZIKV IgM enzyme-linked immunosorbent assay (ELISA) is used for the qualitative detection of anti-ZIKV IgM antibodies in serum and cerebrospinal fluid; however, positive test results can be difficult to interpret because of cross-reactivity with related flaviviruses, which precludes identification of the specific infecting virus . This is especially problematic in persons residing in endemic areas or previously vaccinated against flaviviruses. When the IgM ELISA test result is presumed positive, equivocal, or inconclusive, the serum sample must be forwarded to the CDC (or a CDC-designated laboratory) for confirmation by plaque-reduction neutralization testing (PRNT). PRNT measures virus-specific neutralizing antibodies and is able to discriminate between cross-reacting antibodies in primary flavivirus infections .
If intrauterine ZIKV infection is suspected during the course of pregnancy and amniocentesis is performed, fluid should be tested by RT-PCR. When an infant is born with microcephaly or intracranial calcifications to a mother with potential ZIKV infection during pregnancy, the infant should be evaluated for congenital ZIKV infection. Interim guidelines for the evaluation and testing of infants with possible congenital ZIKV infection have been published by the CDC, and updated guidance is available at the CDC website . Serum samples for testing may be obtained from umbilical cord blood, but test results can be misleading; the current recommendation is to obtain a sample of blood, and cerebrospinal fluid if available, directly from the infant within two days of birth for RT-PCR and anti-ZIKV IgM testing. Frozen and fixed placenta tissue samples should also be tested by RT-PCR and submitted for ZIKV-specific immunohistochemical analysis at specialized reference laboratories . For infants with any positive or inconclusive test findings for ZIKV infection, healthcare providers should report the case to state, territorial, or local health department and assess the infant for long-term sequelae.
As noted, ZIKV disease and congenital ZIKV infection have been added to the list of nationally notifiable diseases. Healthcare providers are encouraged to report probable and confirmed ZIKV disease cases to the local or state health department in order to facilitate diagnosis and mitigate the risk for local transmission in areas where Aedes species mosquitoes are active. The WHO has developed an interim case definition for acute ZIKV disease . A suspected case is defined by the presence of rash and/or fever combined with at least one of the following: arthralgia, arthritis, or nonpurulent conjunctivitis. A probable case is a person with this syndrome and a positive IgM antibody test against ZIKV plus an epidemiologic link (i.e., contact with a confirmed case or residence/travel to an endemic area within the previous two weeks). A confirmed case requires laboratory confirmation of recent ZIKV infection by either molecular diagnostic testing (e.g., presence of ZIKV RNA in serum or other body fluids) or serologic test results specific for ZIKV and exclusive of other flaviviruses (e.g., positive anti-ZIKV IgM ELISA confirmed by PRNT).
The CDC is working with the Council of State and Territorial Epidemiologists (CSTE) to improve surveillance and promote effective prevention and control of ZIKV transmission within the United States. The CSTE has developed an interim position statement intended to standardize case definitions and establish criteria for the classification of ZIKV infection . When evaluating a patient with suspected, probable, or newly confirmed ZIKV infection, healthcare providers should consult this source or contact the local or state health department.
The CDC has established the U.S. Zika Virus Registry to gather information about the timing, absolute risk, and spectrum of outcomes associated with ZIKV infection during pregnancy. It is accessible at http://www.cdc.gov/zika/hc-providers/registry.html. The data collected through this registry will be used to update recommendations for clinical care, to plan for services for pregnant women and families affected by ZIKV, and to improve prevention of ZIKV infection during pregnancy . The CDC also offers consultation services as part of the registry, which may be accessed by calling (770) 488-7100 or emailing ZIKAMCH@cdc.gov.
There is no effective antiviral therapy for ZIKV infection; treatment is supportive and directed toward relief of symptoms. When the diagnosis is uncertain and dengue, or co-infection with dengue, is a possibility, the patient should be managed expectantly for each. In consideration of dengue, aspirin and nonsteroidal anti-inflammatory drugs should be avoided and the patient should be monitored for signs of progression to hemorrhagic fever or shock . In managing ZIKV disease, patient education and secondary prevention are important, especially in regard to sexual transmission and risk reduction in pregnancy. All pregnant women with molecular or serologic evidence of recent ZIKV infection should be evaluated and managed (monitored) for adverse pregnancy outcomes.
The CDC has published interim guidance for healthcare providers caring for pregnant women with possible ZIKV exposure and those with confirmed or suspected ZIKV infection . As noted, the CDC maintains a 24-hour consultation service for health officials and healthcare providers caring for pregnant women as a component of the Zika Virus Registry. The general recommendations for women residing in the United States and its territories are :
All pregnant women should be assessed for possible ZIKV exposure at each prenatal care visit.
Pregnant women are advised not to travel to an area with active ZIKV transmission.
Pregnant women who must travel to one of these areas should strictly follow steps to avoid mosquito bites and prevent sexual transmission during the trip.
Pregnant women with a sex partner who has traveled to or lives in an area with active ZIKV transmission should use condoms or other barrier methods to prevent infection or abstain from sex for the duration of the pregnancy.
Pregnant women who report symptoms or signs consistent with acute ZIKV disease should be tested for ZIKV infection. Serum and urine RT-PCR tests are recommended for those seeking care less than two weeks after onset of symptoms . A positive RT-PCR result confirms the diagnosis of recent maternal ZIKV infection. Patients with a negative RT-PCR test result should receive ZIKV IgM and dengue virus IgM antibody testing. Symptomatic pregnant women who seek care 2 to 12 weeks after symptom onset should first receive ZIKV and dengue virus antibody testing. If the ZIKV antibody test is positive or equivocal, reflex RT-PCR should be automatically performed on the serum sample to determine whether ZIKV RNA is present.
ZIKV testing is recommended for asymptomatic pregnant women who have traveled to areas with active ZIKV transmission or who have had potential sexual exposure (i.e., sexual contact without barrier/condom method with a person who lives in or has traveled to an area with ZIKV). RT-PCR testing of serum and urine is recommended for those presenting more than two weeks from the date of last possible exposure . RT-PCR testing is also indicated for pregnant women who present for care two or more weeks after exposure and have been found to be IgM positive. Serologic screening with the ZIKV IgM ELISA should be offered to asymptomatic pregnant women who, in the previous 2 to 12 weeks, have traveled to an area with ZIKV or have had sexual contact with a man confirmed to have ZIKV infection. In areas with active ZIKV transmission, asymptomatic pregnant women should undergo IgM testing as part of routine obstetric care in the first and second trimester.
Updated interim guidance provided by the CDC also includes recommendations for prenatal and postnatal management of the pregnant patient with confirmed or possible ZIKV, and for postnatal evaluation of the newborn infant (Table 1) .
CLINICAL MANAGEMENT OF A PREGNANT WOMAN WITH SUSPECTED ZIKA VIRUS INFECTION
|Interpretation of Laboratory Results||Prenatal Management||Postnatal Management|
|Recent Zika virus infection||Consider serial ultrasounds every three to four weeks to assess fetal anatomy and growth.a Decisions regarding amniocentesis should be individualized for each clinical circumstance.b||
|Recent flavivirus infection, specific virus cannot be identified|
|Presumptive recent Zika virus or flavivirus infectionc||Consider serial ultrasounds every three to four weeks to assess fetal anatomy and growth.a Amniocentesis might be considered; decisions should be individualized for each clinical circumstance.b||
|Recent dengue virus infection||Clinical management in accordance with existing guidelines.|
|No evidence of Zika virus or dengue virus infection||
Travelers who plan to visit areas of ongoing mosquito-borne transmission of ZIKV, chikungunya virus, and dengue virus should plan carefully and exercise caution. The CDC guidelines recommend limiting mosquito exposure and avoiding bites by taking the following steps :
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 diethyltoluamide (DEET), picaridin, IR3535, oil of lemon eucalyptus, or para-menthane-diol. Always use as directed. Pregnant and breastfeeding women can use all EPA-registered insect repellents, including DEET, according to the product label. Most repellents, including DEET, can be used on children older than 2 months of age. To apply, adults should spray insect repellent onto hands and then apply to a child's face. If it might be difficult to find recommended repellent at your destination, pack enough to last the entire trip.
Use permethrin-treated clothing and gear (e.g., boots, pants, socks, tents). These items may be purchased pretreated or treated when necessary. (Please note that permethrin is not effective in Puerto Rico.)
Stay and sleep in screened-in and air-conditioned rooms whenever possible.
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 infants younger than 2 months of age in carriers, strollers, or cribs to protect them from mosquito bites.
The CDC recommends that men who have traveled to or reside in an area with active ZIKV transmission and their pregnant partners should consistently and correctly use condoms during sex (i.e., vaginal intercourse, anal intercourse, and oral sex) or abstain from sex for the duration of the pregnancy . The purpose is to avoid even a minimal risk of sexual transmission, given the potential for adverse fetal effects when ZIKV is contracted during pregnancy. Pregnant women should discuss their male sex partner's history of travel to areas with active ZIKV transmission and any history of illness consistent with ZIKV disease with their healthcare provider.
Men with known (or presumed) ZIKV disease and their non-pregnant sex partners who want to reduce the risk for sexual transmission of ZIKV are advised to use condoms consistently and correctly during sex or to abstain from sex . The recommended duration of consistent condom use or abstinence depends on whether the man had confirmed infection or clinical illness consistent with ZIKV disease and whether he is residing in an area with ongoing transmission. In weighing the level of risk and a couple's concern about sexual transmission of ZIKV, several factors should be considered . The risk for acquiring mosquito-borne ZIKV infection depends on the duration and extent of exposure to infected mosquitoes and the steps taken to prevent mosquito bites. Viral transmission is of particular concern during pregnancy; therefore, a couple's resolve and strategy for prevention of unintended pregnancy should be taken into account, including use of the most effective contraceptive methods.
Because of the burden imposed by complications of ZIKV infection, especially in women of childbearing age, development of a ZIKV vaccine seems a compelling strategy for prevention. Vaccines have been developed against other arboviruses, including dengue and West Nile viruses, and a DNA vaccine has been shown to protect against ZIKV in a mouse model studied in Brazil . However, virologists anticipate it would likely take several years to bring a ZIKV vaccine to implementation, in part because the immunology of flavivirus infection poses potential barriers to a safe, predictable strategy, particularly in endemic areas where exposure to multiple flavivirus infections is common. Just as cross-reactivity of antibodies elicited by related flaviviruses confounds diagnosis, so may antibody cross-reactivity impact vaccine efficacy and safety . Among the issues to be considered is the phenomenon of immune enhancement, whereby immunologic memory acquired from earlier flavivirus infection (or vaccination) may, in response a new flavivirus infection, lead to an IgG antibody/Fc receptor/lymphocyte-mediated augmentation of infection with prolonged viremia, possibly increasing severity and risk for complications. As an example, one consideration could be whether a ZIKV immunization campaign in an area endemic for dengue virus infection places the population at greater risk for more serious illness from dengue virus infection (i.e., hemorrhagic fever and shock). While a ZIKV vaccine could hold greater promise for population groups outside endemic areas for other flaviviruses, its implementation (after years of development) would need to take into account the durable effect of mosquito control programs and the lingering scope of ZIKV circulation.
Strategies employed for prevention of the transmission of ZIKV and other mosquito-borne flaviviruses are directed toward elimination or control of mosquito vectors and interruption of human-mosquito contact. The initial target of these efforts is A. aegypti mosquito, the principle vector. Adult A. aegypti females feed on humans, rarely travel more than 100 yards from where they hatched, and live for about 10 days. They proliferate by making use of standing rain water or any of the many nearby stagnant sources associated with urban habitat, such as blocked gutters, bird baths, flower pots, abandoned food and beverage containers, and construction sites. Control activities are aimed at eliminating immature and adult mosquito habitats in and around homes, out buildings, work places, schools, and other venues where people gather.
Most governmental agencies use, and the CDC recommends, an integrated mosquito management approach that employs a combination of methods based on mosquito biology, life cycle, and behavior . An important feature of this approach is that all stakeholders become involved: health department and mosquito control specialists, government agencies, and community citizens and neighbors. The five key elements of this approach are :
Conduct mosquito surveillance: Monitor places where eggs are laid and young mosquitoes are found; track populations and the virus they are carrying; and determine which insecticide will be effective.
Remove places where mosquitoes lay eggs: Target public places, parks, roadside dumps, yards, and neighborhoods, including weekly removal of common sources of standing water.
Control young mosquitoes: Use EPA-registered larvicides to treat water-holding structures and containers.
Control adult mosquitoes: Use EPA adulticides available for public use to reduce the number of mosquitoes in an area, delivered by backpack sprayers, trucks, or airplanes.
Monitor control programs: Conduct additional studies to assess the effectiveness of efforts.
Two novel approaches that have shown considerable promise are the genetic control of A. aegypti mosquitoes and the development of mosquitoes that are resistant to arbovirus infection. The first field-trialed genetic control strategy is known as the Release of Insects carrying Dominant Lethal (RIDL) genes and involves the mass rearing of A. aegypti that have been genetically modified to express a repressible lethal gene . During their rearing in insectaries, the mosquitoes are provided with a dietary supplement not present in nature (tetracycline), and this supplement represses the lethal gene activation .
Only male mosquitoes are released, and these compete with wild males to mate with wild females. Offspring do not survive to the adult stage because they do not receive the dietary additive in the wild. Lines of RIDL males have been shown to have minimal fitness costs (i.e., they are competitive with wild males) and a field release in Bahia, Brazil, reportedly achieved a 95% reduction in local mosquito populations .
An alternative approach is the use of endosymbiotic bacteria to prevent arboviruses replicating within the mosquito. The Eliminate Dengue project has demonstrated that Wolbachia bacteria from Drosophila fruit flies can prevent dengue virus transmission in A. aegypti mosquitoes without significant fitness costs . Wolbachia has also been shown to inhibit the replication of additional arboviruses, such as chikungunya virus and yellow fever virus, strongly suggesting potential inhibitory effects against ZIKV .
Whereas RIDL is a self-limiting approach (i.e., the genetic modification is not perpetuated in wild populations), Wolbachia-based control strategies rely on this endosymbiont successfully invading wild mosquito populations through a reproductive phenotype known as cytoplasmic incompatibility. This phenotype results in the generation of inviable offspring when an uninfected female mates with a Wolbachia-infected male. By contrast, Wolbachia-infected females can produce viable progeny when they mate with both infected and uninfected males, resulting in a reproductive advantage over uninfected females. Wolbachia-infected A. aegypti mosquitoes were released and successfully invaded wild populations in Australia and releases are ongoing in dengue virus-endemic countries such as Indonesia, Vietnam, and Brazil .
What effect either RIDL or Wolbachia will have on arboviral transmission and epidemiology in the field remains uncertain. Mathematical models of dengue virus transmission incorporating the dynamics of viral infection in humans and mosquitoes predict that one strain of Wolbachia (wMel) would reduce the basic reproduction number of dengue virus transmission by 70% . Models of dengue virus transmission control with RIDL also project high efficacy in reducing disease burden. These projections suggest that such strategies could have a direct impact on transmission of arboviruses such as ZIKV in countries, such as Brazil, where A. aegypti is the principle vector .
An important benefit of these environmentally friendly, species-specific approaches is the reduced dependence they pose for insecticides—an increasingly important feature of future disease vector control. Moreover, suppressing the mosquito population, or rendering it arbovirus-resistant, holds great potential in the simultaneous control of Zika, dengue, chikungunya, and yellow fever viruses. One hundred fifty countries presently have A. aegypti and are vulnerable to future outbreaks. The costs of implementing these novel technologies in Brazil and across the tropics should be considered in the context of the multifaceted benefits they pose in controlling several emerging infectious diseases.
For patients who are not proficient in English, it is important to provide information regarding prevention strategies, testing recommendations, and signs and symptoms of ZIKV disease in their native language, if possible. The CDC provides patient education posters and handouts in a variety of languages, including Spanish, Portuguese, French, and Vietnamese . Copies of these materials may be accessed at http://www.cdc.gov/zika/fs-posters. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.
In less than two years, an epidemic of mosquito-borne ZIKV disease has swept through the Americas, leaving in its wake thousands of cases of microcephaly and higher rates of post-infectious Guillain-Barré syndrome. New modes of transmission have been identified to which pregnant women are most vulnerable, and maternofetal transmission during pregnancy is known to cause congenital infection and adverse fetal outcomes. The CDC has announced that evidence supports the existence of a causal relationship between prenatal ZIKV infection and microcephaly and other serious neurologic anomalies. Health agencies have established disease surveillance networks and provided guidance for healthcare providers, travelers, and expectant couples on the best means for avoiding mosquito contact and preventing sexual transmission. More information is needed on the absolute risk and spectrum of fetal outcomes following maternal ZIKV infection during pregnancy, the clinical course and prognosis of infants born with congenital ZIKV syndrome, and the most effective means for vector control and prevention of ZIKV infection.
2. Fauci AS, Morens DM. Zika virus in the Americas: yet another arbovirus threat. N Engl J Med. 2016;374(7):601-604.
3. Gubler DJ. The global emergence/resurgence of arboviral diseases as public health problems. Arch Med Res. 2002;33(4):330-342.
4. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374(16):1552-1563.
5. Hennessey M, Fischer M, Staples JE. Zika virus spreads to new areas: region of the Americas, May 2015–January 2016. MMWR. 2016;65(3):55-58.
6. World Health Organization. Zika Virus Outbreak Global Response Interim Report, May 2016. Available at http://www.who.int/emergencies/zika-virus/response/report/en/. Last accessed August 8, 2016.
7. Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible association between Zika virus infection and microcephaly—Brazil, 2015. MMWR. 2016;65(3):59-62.
8. Centers for Disease Control and Prevention. Areas with Zika Virus. Available at http://www.cdc.gov/zika/geo/index.html. Last accessed December 13, 2016.
9. Monaghan AJ, Morin CW, Steinhoff DF, et al. On the seasonal occurrence and abundance of the Zika virus vector mosquitoAedes aegypti in the contiguous United States. PLoS Curr. 2016;1.
10. Kuno G, Chang GJ, Tsuchiva KR, Karabatsos N, Cropp CB. Phylogeny of the genus Flavivirus. J Virol. 1998;72(1):73-83.
11. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360(24):2536-2543.
12. European Centre for Disease Prevention and Control. Rapid Risk Assessment: Zika Virus Infection Outbreak, French Polynesia. Available at http://ecdc.europa.eu/en/publications/Publications/Zika-virus-French-Polynesia-rapid-risk-assessment.pdf. Last accessed August 8, 2016.
13. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951-958.
14. Centers for Disease Control and Prevention. CDC Concludes Zika Causes Microcephaly and Other Birth Defects. Available at http://www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html. Last accessed August 8, 2016.
15. Broutet N, Krauer F, Riesen M, et al. Zika virus as a cause of neurologic disorders. N Engl J Med. 2016;374(16):1506-1509.
16. Hills SL, Russell K, Hennessey M, et al. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—continental United States, 2016. MMWR. 2016;65(8):215-216.
17. European Centre for Disease Prevention and Control. Rapid Risk Assessment: Zika Virus Epidemic in the Americas: Potential Association with Microcephaly and Guillain-Barré Syndrome. Available at http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdf. Last accessed August 8, 2016.
18. Chouin-Carneiro T, Vega-Rua A, Vazeille M, et al. Differential susceptibilities of Aedes aegypti and Aedes albopictus from the Americas to Zika virus. PLoS Negl Trop Dis. 2016;10(3):e0004543.
19. Paz S, Semenza JC. El Niño and climate change-contributing factors in the dispersal of Zika virus in the Americas? Lancet. 2016;387(10020):745.
20. Oster AM, Brooks JT, Stryker JE, et al. Interim guidance for prevention of sexual transmission of Zika virus—United States, 2016. MMWR. 2016;65(5):120-121.
21. D'Ortenzio E, Matheron S, de Lamballerie X. Evidence of sexual transmission of Zika virus. N Engl J Med. 2016;374(22):2195-2198.
22. Oster AM, Russell K, Stryker JE, et al. Update: interim guidance for prevention of sexual transmission of Zika virus—United States, 2016. MMWR. 2016;65(12):323-325.
25. Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro: preliminary report. Obstet Gynecol Surv. 2016;71(6):331-333.
26. Carteaux G, Maquart M, Bedet A, et al. Zika virus associated with meningoencephalitis. N Engl J Med. 2016;374(16):1595-1596.
27. Karimi O, Goorhuis A, Schinkel J, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet. 2016;387(10022):939-940.
28. França GVA, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet. 2016;[Epub ahead of print].
29. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects: reviewing the evidence for causality. N Engl J Med. 2016;374(20):1981-1987.
30. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951-958.
31. Centers for Disease Control and Prevention. Diagnostic Tests for Zika Virus. Available at http://www.cdc.gov/zika/hc-providers/types-of-tests.html. Last accessed August 8, 2016.
32. Rabe IB, Staples JE, Villanueva J, et al. Interim guidance for interpretation of Zika virus antibody test results. MMWR. 2016;65(21):543-546.
33. Staples JE, Dziuban EJ, Fischer M, et al. Interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection—United States, 2016. MMWR. 2016;65(3):63-67.
34. Council of State and Territorial Epidemiologists. Zika Virus Disease and Congenital Zika Virus Infection Interim Case Definition and Addition to the Nationally Notifiable Diseases List. Available at https://www.cste2.org/docs/Zika_Virus_Disease_and_Congenital_Zika_Virus_Infection_Interim.pdf. Last accessed August 8, 2016.
35. Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016. MMWR. 2016;65(29):739-744.
36. Centers for Disease Control and Prevention. Guidelines for Travelers Visiting Friends and Family in Areas with Chikungunya, Dengue, or Zika. Available at http://wwwnc.cdc.gov/travel/page/guidelines-vfr-chikungunya-dengue-zika. Last accessed August 8, 2016.
37. Centers for Disease Control and Prevention. Integrated Mosquito Management for Aedes aegypti and Aedes albopictus Mosquitoes. Available at http://www.cdc.gov/zika/vector. Last accessed August 8, 2016.
38. Centers for Disease Control and Prevention. Chikungunya Virus: Transmission. Available at http://www.cdc.gov/chikungunya/transmission/index.html. Last accessed August 8, 2016.
39. Brito C. Zika virus: a new chapter in the history of medicine. Acta Med Port. 2015;28(6):679-680.
40. Centers for Disease Control and Prevention. Chikungunya Virus: Clinical Evaluation and Disease. Available at http://www.cdc.gov/chikungunya/hc/clinicalevaluation.html. Last accessed August 8, 2016.
41. Yakob L, Walker T. Zika virus outbreak in the Americas: the need for novel mosquito methods. Lancet Glob Health. 2016;4(3):e148-e149.
42. World Health Organization. Zika Situation Report. Available at http://www.who.int/emergencies/zika-virus/situation-report/3-november-2016/en/. Last accessed November 7, 2016.
43. Centers for Disease Control and Prevention. Zika Virus Registry. Available at http://www.cdc.gov/zika/hc-providers/registry.html. Last accessed August 8, 2016.
44. Ferguson NM, Kien DT, Clapham H, et al. Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. Sci Transl Med. 2015;7(279):279ra37.
45. World Health Organization. Zika Virus Disease: Interim Case Definition. Available at http://www.who.int/csr/disease/zika/case-definition/en. Last accessed August 15, 2016.
46. Larocca RA, Abbbink P, Peron JP, et al. Vaccine protection against Zika virus from Brazil. Nature. 2016;536(7617):474-478.
47. Marins KAO, Dye JM, Bavan S. Considerations for the development of Zika virus vaccines. Vaccine. 2016;34:3711-3712.
48. U.S. Food and Drug Administration. FDA Advises Testing for Zika Virus in All Donated Blood and Blood Components in the US. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518218.htm. Last accessed September 2, 2016.
49. Centers for Disease Control and Prevention. All Countries and Territories with Active Zika Virus Transmission. Available at http://www.cdc.gov/zika/geo/active-countries.html. Last accessed November 7, 2016.
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