Zika Virus Disease

Course #98711 - $15 • 3 Hours/Credits


Study Points

  1. Describe the historical background and dynamics of the Zika virus epidemic in the Americas and its potential impact on public health.
  2. Discuss and advise patients as to the risks of Zika virus infection in relation to the various routes of transmission.
  3. Recognize and manage a patient presenting with characteristic clinical and epidemiologic features of acute Zika virus disease.
  4. Discuss the salient features of microcephaly, including the incidence, causative factors, and clinical and pathologic findings unique to congenital Zika virus infection.
  5. 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.
  6. Devise a management plan for persons with known or suspected infection, including care of the pregnant patient or intimate partner.
  7. Using knowledge of Zika virus shedding by infected men and the risk of sexual transmission, counsel patients and couples on the importance and recommended duration of safe sex practice.
  8. 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.

    1 . Zika virus (ZIKV)
    A) is a single-stranded RNA flavivirus closely related to dengue.
    B) was first isolated in 2007, from a rhesus monkey on Yap Island.
    C) is a DNA virus related to cytomegalovirus (CMV) and, like CMV, causes birth defects.
    D) circulation in Latin America primarily involves a mosquito-horse-mosquito transmission cycle.

    HISTORICAL BACKGROUND AND EPIDEMIOLOGY

    ZIKV is a single-stranded RNA virus closely related to dengue and belonging to the family of flaviviruses [10]. 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 [1]. 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 [4].

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    2 . All of the following statements regarding human ZIKV outbreaks are true, EXCEPT:
    A) The first large outbreak in South America began in early 2015 in Brazil.
    B) The first documented outbreak of human ZIKV disease occurred on Yap Island, Micronesia, in 2007.
    C) Aedes aegypti was first implicated as the primary vector in an outbreak in French Polynesia in 2013–2014.
    D) In the decade following discovery of ZIKV, human outbreaks were observed frequently in East Africa and nearby Asian Pacific.

    HISTORICAL BACKGROUND AND EPIDEMIOLOGY

    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 [1]. 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 [4].

    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 [11]. 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 [11].

    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 [12]. 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 [12]. 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 [6]. 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 [42].

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    3 . All of the following statements regarding Aedes mosquitoes and ZIKV transmissions are true, EXCEPT:
    A) Aedes aegypti females take a single blood meal "by sips" over multiple bites.
    B) The range of A. aegypti mosquitoes does not extend to any portion of the continental United States.
    C) A. aegypti has adapted well to urban habitat and prefers a blood meal from humans to that from other vertebrates.
    D) A. aegypti and A. albopictus are the vectors of transmission for ZIKV outbreaks in Latin America and the Caribbean.

    ZIKA VIRUS TRANSMISSION

    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 [10]. 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 [18].

    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 [19]. 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 [19]. 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 [9]. 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.

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    4 . Which of the following syndromes best describes acute ZIKV disease?
    A) Malaise, myalgia, abdominal cramps, and diarrhea
    B) Abrupt onset malaise, chills, fever, myalgia, and cough
    C) Sore throat, pain on swallowing, headache, myalgia, and fever
    D) Descending maculopapular rash, myalgia, arthralgia, mild fever, and conjunctival injection

    ZIKA VIRUS DISEASE

    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 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].

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    5 . Unusual manifestations or complications of ZIKV disease include all of the following, EXCEPT:
    A) Brain abscess
    B) Meningoencephalitis
    C) Guillain-Barré syndrome
    D) Intrauterine infection in pregnancy leading to adverse fetal outcomes

    ZIKA VIRUS DISEASE

    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 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 [5].

    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.

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    6 . Transplacental transmission of ZIKV to the developing fetus is associated with
    A) hearing loss.
    B) miscarriage or stillbirth.
    C) congenital microcephaly.
    D) All of the above

    ZIKA VIRUS DISEASE

    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 [30].

    The distinctive characteristics of microcephaly associated with congenital ZIKV infection, evident on neuroimaging and by pathologic examination, include 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.

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    7 . A man comes in for evaluation at the request of his wife, who is three months pregnant. He returned three days ago from a two-week business trip to Brazil. Four days before departure he developed a mild, transient illness consistent with a viral infection that lasted three days; he now feels well. His wife is concerned he may have had ZIKV. At this juncture, the best management course is to
    A) perform serum ZIKV RT-PCR testing; if negative, no further testing is necessary.
    B) recommend condom use for two weeks as a precaution and perform serum anti-ZIKV IgM antibody (ELISA) testing; if negative, no further testing is necessary.
    C) reassure him there is no need for laboratory diagnostic testing or any other precautions, as his risk was low, his symptoms are nonspecific, and he is now asymptomatic.
    D) perform serum and urine ZIKV RT-PCR testing and request anti-ZIKV IgM antibody (ELISA) testing if the results are negative, and advise strict condom use as a precaution to prevent sexual transmission until the diagnosis is clarified.

    DIAGNOSIS

    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 [31]. 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.

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    8 . Which of the following should be included in the general treatment of ZIKV infection?
    A) Aspirin and/or NSAIDs for myalgia
    B) Antiviral therapy with zanamivir or oseltamivir
    C) Patient education regarding sexual transmission and risk reduction in pregnancy
    D) All of the above

    CLINICAL MANAGEMENT ISSUES

    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 [32]. 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.

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    9 . In order to reduce the risk of sexual transmission, men with known (or presumed) ZIKV disease and their non-pregnant partners should
    A) only engage in oral sex.
    B) abstain from sex for three days following diagnosis.
    C) use condoms consistently and correctly during sex.
    D) initiate antiviral prophylaxis and continue for 10 days.

    PREVENTION

    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 [22]. 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 [22]. 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. The CDC interim guidance now recommends [52,55]:

    • Men with known infection or possible ZIKV exposure who are planning to conceive with their partner should wait at least three months after symptom onset or last possible exposure before engaging in unprotected sex.

    • For couples who are not trying to conceive, men should consider using condoms or abstaining from sex for at least three months after symptom onset or last exposure to minimize their risk for sexual transmission of ZIKV.

    • Men with ZIKV disease or possible ZIKV exposure whose partner is pregnant should consistently use condoms during sex or abstain from sex for the duration of the pregnancy.

    • If a couple has a female partner and only she travels to an area with risk of ZIKV disease, the couple should consider using condoms or not having sex for at least two months after the female partner returns (even if she is asymptomatic) or from the start of the female partner's symptoms or date of diagnosis.

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    10 . The Release of Insects carrying Dominant Lethal (RIDL) genes approach to vector control to prevent ZIKV transmission involves
    A) cytoplasmic incompatibility that results in the generation of inviable offspring.
    B) the use of endosymbiotic bacteria to prevent arboviruses from replicating within the A. aegypti mosquito.
    C) the mass rearing and release of A. aegypti mosquitoes that have been genetically modified to express a repressible lethal gene.
    D) the use of EPA-approved adulticides to reduce the number of mosquitoes in an area, delivered by backpack sprayers, trucks, or airplanes.

    VECTOR CONTROL

    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 [38]. 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 [39].

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