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ABSTRACT: A major outbreak of Zika virus disease occurred in several countries in 2015-2016.¹ This spurred the global community to develop preventive and supportive strategies against the spread of this infection. Recognizing the signs and symptoms of Zika infection, performing diagnostic tests based on current knowledge, successfully implementing preventive measures, and further evaluating the effects of Zika virus in pregnancy are of chief importance in response to the outbreak. The pharmacist's role in patient counseling and education and the pharmacy technician's role in symptom identification are essential for successfully managing the current outbreak and curbing further spread to the most vulnerable populations, including pregnant women.

Zika virus was first identified in 1947 in the Zika Forest, a research station in Entebbe, Uganda (East African Virus Research Institute, now the Uganda Virus Research Institute).^2,3 An outbreak in 2007 in the Yap Islands—where an estimated 75% of the population became infected in a 4-month period—initiated the spread of Zika virus in the Pacific region.⁴ In 2013, a major outbreak erupted in French Polynesia, and by the beginning of 2014, the first autochthonous transmission cases were reported in New Caledonia, followed by the Cook Islands.⁵ In 2014, imported cases in travelers to the Pacific area were reported in Norway, Germany, Australia, France, Canada, Italy, and Japan.⁵ In May 2015, the first cases of the Zika epidemic were reported in Brazil, and the outbreak has since spread through South America, Central America, and the Caribbean. In late July 2016, the Florida Department of Health announced what appeared to be the first cases of local, vector-borne (mosquito spread) Zika transmission in the continental United States (U.S.). Florida officials determined that Zika virus was being spread by mosquitoes in Wynwood, a 1-square-mile neighborhood in northern Miami.⁶ In the period from 2015 to August 2018, there were thousands of individuals in the U.S. infected with Zika virus. Altogether, there were 5,716 symptomatic cases, with the majority occurring in travelers returning from affected areas (5,430). Also, during that time period, 231 cases were presumed to be transmitted from local mosquitos (see Table 1).⁷

Surveillance from 2017 shows that rates have decreased. The total number dropped from 5,168 in 2016 to 452 in the U.S. and from 36,512 to 666 in the U.S. territories.⁸ There is however, still cause for great concern.

Concern over the global threat that Zika virus poses and the potential for birth defects and neurologic complications has gripped communities worldwide. The WHO outlines actions in its Zika Strategic Response Framework to be undertaken to control Zika virus disease. This document includes recommendations such as defining and prioritizing research, enhancing surveillance of Zika virus and potential complications, strengthening laboratory capacity for detection, and supporting health authorities' implementation of vector-control strategies aimed at reducing Aedes mosquito populations. Several other countries have made efforts to combat Zika transmission. Colombia, the Dominican Republic, Ecuador, El Salvador, and Jamaica echo the WHO in advising women to postpone pregnancy until more is known about the virus and its rare, but potentially serious, complications.⁵

The CDC has published a number of fact sheets that address Zika virus prevention, transmission, risks, and pregnancy considerations, among other topics. The CDC has also issued a level 2 travel warning, which includes the recommendation that pregnant women consider postponing travel to any area with ongoing Zika virus transmission.⁹ Areas at risk are listed in Table 2.¹⁰ Additionally, in response to the local transmission in northern Miami, specific guidance was issued for people who live in or traveled to the affected area any time after June 15, 2016. The guidance included advice for pregnant women and their partners and for couples planning a pregnancy.^6,9

Because of global concerns and the significance of understanding Zika virus and its effects in pregnancy, the pharmacist's role is becoming increasingly important, particularly with respect to prevention and counseling. Additionally, the role of the pharmacy technician is gaining in importance in terms of symptom identification.

TRANSMISSION

Zika virus is an arbovirus of the Flavivirus genus of the Flaviviridae family, which includes dengue, yellow fever, West Nile, Japanese encephalitis, and tickborne encephalitis viruses. Zika virus has been isolated from several species of Aedes mosquitoes, including Aedes africanus, Aedes aegypti, Aedes albopictus, Aedes luteocephalus, Aedes furcifer, and Aedes vittatus; however, only a few species have been implicated in the transmission of Zika virus to humans.¹¹ Although none of the aforementioned arboviruses continuously circulate in the continental U.S., local outbreaks have occurred—and will continue to—as a result of virus importation by infected, viremic travelers (except for West Nile, which is not imported, but endemic in the U.S.). Any viremic traveler visiting or returning to parts of the U.S. with established populations of Ae aegypti or Ae albopictus mosquitoes could initiate local virus transmission.¹²

Zika virus is spread in a variety of ways. These modes are commonly defined by the following categories: vector-borne transmission, blood-borne transmission, sexual transmission, and maternal transmission.³

Vector-Borne Transmission: As noted, Zika virus can be transmitted by mosquitoes. Ae aegypti is considered the main vector; however, Ae albopictus also plays a primary role in transmission. Ae albopictus is able to adapt to survive in a broader temperature range and at cooler temperatures than Ae aegypti, and it can be found in the U.S. as far north as New York and Chicago and in parts of southern Europe.¹³ Both Ae aegypti and Ae albopictus may also transmit dengue and chikungunya.¹⁴ Through globalization, both species have been transported throughout the tropics, subtropics, and parts of the temperate world.^5,12,14,15 Early laboratory-based studies showed the capacity of Ae aegypti to transmit the virus with an extrinsic incubation period of around 10 days after artificial feeding. Mosquitoes may be infective for up to 60 days after acquiring the virus.¹⁵

Blood-Borne Transmission: Transmission of Zika virus via blood transfusion has been suspected in a small number of cases, including two probable cases in Brazil. Zika virus was detected in the blood samples of approximately 3% of blood donors who were asymptomatic during the French Polynesian outbreak. This evidence suggests that there is at least the potential for Zika infection resulting from transmission via infected blood and blood products.^16-18 Moreover, in an examination of documented transfusion transmissions of other flaviviruses, such as West Nile, dengue, and yellow fever, all viruses have been proven to cause detectable viremia during asymptomatic and symptomatic infections.^19,20 In response to this potential method of Zika transmission, the WHO, CDC, and FDA are carefully monitoring blood-supply safety. FDA issued revised guidance recommending in July of 2018 that blood centers in all states and U.S. territories screen donated whole blood and blood components with a blood screening nucleic acid test licensed for use by FDA.²¹ As of August 2018, no transfusion-transmission cases have been documented in the US.²¹

Sexual Transmission: Zika infection may be sexually transmitted by males and females who have been infected. Sexual exposure includes vaginal sex, anal sex, oral sex, and other activities that might expose a partner to genital secretions. It is important to note that the transmitting partner does not have to be symptomatic to infect the other person. From 2015 to August 2018, there have been 52 instances of sexual transmission of Zika in the U.S., and additional reports from other countries; however, it has not yet been determined whether Zika virus is more readily transmitted by a female with Zika to a male, or vice versa, or exactly how long the virus remains in bodily fluids.^7,22-26

Because of the lack of serial semen specimens with detectable RNA, the precise duration and pattern of infectious Zika virus in semen remain unknown. However, viral RNA has been detected in semen approximately 60 days after infection. In one case, the virus was isolated from semen at least 2 weeks, and possibly up to 10 weeks, after symptom onset; in another case, it was 6 months after symptom onset.^27,28 The longest interval after symptomatic presentation that sexual transmission of Zika virus by a male may have occurred has been reported to be 32 to 41 days.²⁹

Regarding female transmission, there have been reports of Zika virus being transmitted from a symptomatically infected female to a male sex partner.³⁰ Zika virus RNA has been detected in vaginal fluids 3 days after symptom onset and in cervical mucus up to 11 days after symptom onset.³¹ As a result, sexual partners of infected females may be at risk for infection via exposure to vaginal secretions or menstrual blood.

Sexual transmission to a pregnant woman may have severe implications because the mother may transmit the virus to the developing fetus. It is not clear whether Zika virus that is transmitted sexually to an already-pregnant female has the same risk of birth defects as Zika that is transmitted via a mosquito bite.³²

Maternal Transmission: Mother-to-child transmission of Zika virus is not a new phenomenon; it has been reported in the past.³³ Current reports related to the most recent outbreak have confirmed this sequela of Zika transmission.⁵ Vertical transmission can occur during any point of pregnancy through the placental barrier and via perinatal transmission during delivery, resulting in infection of the infant.³⁴ Zika virus has been found in amniotic fluid, placenta, fetal tissues, and paired blood samples from newborn infants and their mothers. Although Zika RNA has been detected in breast milk and the potential exists for viral transmission from a Zika-infected mother to a nursing infant, there have been no reports of virus transmission via breastfeeding.^16,35 In utero transmission is the area of greatest concern and urgency because this mode has corresponded with the increase in the number of reported cases of microcephaly.

SIGNS AND SYMPTOMS

About one in five people exposed to Zika virus will develop symptomatic Zika infection. The incubation period (i.e., the time from exposure to symptoms) of Zika virus is unclear but is likely 2 to 14 days. The symptoms are similar to those in other arbovirus infections, such as dengue and chikungunya.³⁶

Zika infection is characterized by low-grade fever (37.8°C-38.5°C) and, frequently, a maculopapular pruritic rash. Other common symptoms include headache, asthenia, myalgia, arthralgia with possible swelling (notably in the small joints of the hands and feet), and conjunctivitis. Clinical illness is consistent with Zika infection if two or more symptoms are present. These symptoms are usually mild and last for several days to a week after a person is bitten by an infected mosquito.³⁷ However, many people who have been infected with the virus may not realize it because the symptoms often are not severe enough or have a long enough duration to require medical attention.³⁶   More recently, Zika virus infection has also been associated with more severe consequences including multi-organ failure, meningitis and encephalitis, and thrombocytopenia though such effects are not common.³⁸ In the most recent epidemic, there was an increase seen in the range of cells the virus can infect and persistence in multiple organs. Persistence of virus replication in the eye can lead to conjunctivitis, maculopathy and uveitis, which can lead to blindness.³⁸

Zika virus usually remains in the blood of an infected person for about a week, but it may persist for longer in some people. Case reports from non-pregnant adults showed that whole blood remained positive for Zika RNA for 60 to 100 days.³⁸ Once a person has been infected, he or she is likely to be protected from future infections.³⁶

DIAGNOSIS

The presentation of Zika virus is similar to that of dengue and chikungunya.^36,37 In one of the earliest documented Zika cases, the patient presented with maculopapular rash, a brief fever, and a mild headache.^39,40 Diagnosis was made by taking a sputum collection after resolution of the fever. Patients who present with documented signs and symptoms of Zika infection should be fully evaluated.

The diagnosis of Zika virus requires the clinician to review signs and symptoms, along with laboratory tests. The differential diagnosis must be taken into account, and an extensive travel and residential history should be obtained. Sexual contacts with whom the patient may have had unprotected sex, as well as contacts in general, must be thoroughly reviewed.

A definitive diagnosis of Zika infection is made by laboratory analysis. A polymerase chain reaction (PCR) test taken within the first week of symptom onset can detect viral RNA. ^36,41,42 Virus-specific immunoglobulin M (IgM) and neutralizing antibodies develop after symptoms have occurred for 1 week. Diagnosis can be difficult, as there is a cross-reaction with other flaviviruses, such as dengue. To distinguish between the different flaviviruses, plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies and to discriminate between cross-reacting antibodies in primary flavivirus infections.⁴³

The type of diagnostic tool used depends on how soon after the onset of symptoms the patient presents. Because reverse transcriptase PCR (RT-PCR) is effective only for a 3- to 7-day window (i.e., while the patient is viremic), RT-PCR urine and serum should be performed when a patient presents on days 1 to 6. A negative RT-PCR does not equate to absence of disease.⁴⁴ Patients who present between day 7 and day 14 after the onset of symptoms should undergo both urine RT-PCR and Zika virus serologic testing (Zika virus IgM and neutralizing antibody titers). Zika virus serologic testing is an appropriate diagnostic tool for patients who present 15 or more days after symptom onset.

The WHO has developed a system to standardize the reporting of Zika virus cases. There are three classifications: suspected, probable, and confirmed Zika virus (discussed below).^39,44

Suspected: Zika virus is suspected when a patient has a rash (maculopapular) and/or fever (37.8°C-38.5°C), along with at least one of the following symptoms (not explained by other medical conditions): arthralgia, arthritis, or conjunctivitis (nonpurulent/hyperemic).

Probable: A case is considered probable when there is IgM antibody against Zika virus (with no evidence of infection with other flaviviruses) and relevant epidemiologic exposure.

Confirmed: A case is confirmed when there is laboratory verification of Zika infection, either by detection of viral RNA or antigen in serum or other samples or by detection of Zika IgM antibody and Zika virus 90% PRNT (PRNT90) titer ≥20 and PRNT90 titer ratio ≥4 compared with other flaviviruses.^40,44

TREATMENT AND PREVENTION

The treatment of Zika virus involves primarily supportive care, such as rest, hydration, antipyretics, and analgesics for symptom management. Nonsteroidal anti-inflammatory drugs and aspirin should not be initiated until dengue has been ruled out because they may increase the risk of hemorrhage in these patients.⁴⁵ Acetaminophen is an acceptable option for patients.⁴⁶

Prevention consists of barriers to mosquito bites, efforts to control the virus-transmitting mosquitoes, and protected intercourse (for those who may have Zika virus). The CDC lists several recommendations for protecting against mosquito bites in efforts to avoid Zika exposure. Insect repellents for use in adults, including those pregnant or breastfeeding, include DEET, picaridin (known as KBR 3023 and icaridin outside the US), IR3535, oil of lemon eucalyptus (OLE), para-menthane-diol (PMD), and 2-undecanone.⁴⁷  This should be continued for three weeks after returning home to prevent infecting mosquitoes that could spread Zika to others.⁴⁸ Permethrin treated clothing is another option. Repellents on children younger than 2 months old is not recommended and oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) should not be used on children under 3 years old. Clothing that covers arms and legs as well as mosquito netting are suggestions.⁴⁷ Mosquito netting should be compact, white, rectangular, with 156 holes per square inch, long enough to tuck under the mattress, and permethrin-treated if possible. For travel, it is recommended to ensure that hotels have air conditioning or screens on windows and doors.

Patients who are at risk for Zika virus exposure should be advised to use barrier prophylactics, such as condoms, with their sexual partners. The CDC recommends that pregnant women practice abstinence or use condoms correctly and consistently to reduce the risk of sexual transmission.²³ Another recommended prevention strategy is to use a dental dam for any oral sexual contact. If a sexual partner has recently traveled to an area with Zika virus, the CDC recommends protected sex or abstinence for at least 8 weeks after the female partner is diagnosed with Zika virus or presents with symptoms, or for 6 months if the partner is male.³²

Zika-infected patients rarely require hospitalization. The exception is a patient who presents with Guillain-Barré syndrome (GBS) as a result of contracting Zika virus. GBS, a condition that affects the peripheral nervous system, may be extremely debilitating and is the leading cause of paralysis that is not the result of trauma. A genetic predisposition to GBS may be less of a concern than was once theorized.^40,49,50 Although there is no cure or treatment for GBS, supportive care may reduce the effects of GBS. Treatment options for GBS patients include IV immunoglobulin, ICU admission, and possibly respiratory support.⁴⁰

A vaccine for Zika virus is not available at present; however, since 2016, 45 vaccine candidates have been introduced into the research and development pipeline, some of which have moved into human clinical trials.¹ The development of a novel mouse model for Zika infections using the current viral strain responsible for outbreaks in Central and South America should facilitate the development of vaccines and other therapies.^{44-46,51,52,53}

EFFECTS IN PREGNANCY

In a 2018 report from the U.S. Zika Pregnancy and Infant Registry, a total of 1,450 children aged ≥1 year were born to mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy in the U.S. territories and freely associated states. One in seven (14%) were found to have either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both.⁵⁴ No evidence currently exists that pregnant women are more susceptible to Zika infection or experience severe disease during pregnancy; however, it is suggested that pregnant women may be viremic longer than nonpregnant women.⁵⁵ Congenital infections caused by viruses such as Zika can be transmitted to a fetus at any time during pregnancy and can affect multiple organ systems. The greatest risk of abnormalities is associated with Zika infection contracted in the first trimester.^23,50 Zika virus has a strong affinity or selectivity for the nervous system and particularly targets cells that are self-renewing or multipotent, but it may attack neuronal cells at all stages of development.⁵⁶ Some of the complications that may occur during pregnancy and affect the fetus include acquired congenital microcephaly, intracranial calcifications, and ocular abnormalities.⁵⁷ Unfortunately, recent studies have begun to describe a range of more subtle anomalies that are not captured by the original diagnosis of Congenital Zika Syndrome.⁵⁸ Couples who have traveled to areas with Zika risk should wait 2 to 3 months, depending on which person traveled.⁴⁸

Microcephaly: After examining clinical evidence, the CDC concluded that Zika virus is a cause of microcephaly and other serious brain abnormalities in infected infants.⁵⁹ Microcephaly is a neurologic condition in which an infant's head is smaller than normal compared with those in infants of the same sex or gestational age. The circumference of the head is considered a reliable assessment of the volume of the underlying brain. Microcephaly can be detected by ultrasound at 18 to 20 weeks' gestation, but it may not be evident until late in the second trimester or early in the third trimester. The causal relationship between Zika virus and microcephaly or other adverse outcomes does not mean that if a woman is infected with Zika virus during pregnancy, the infant will definitely have health problems; it means simply that the infant is at increased risk for microcephaly or other health problems.⁶⁰

Fetal Intracranial Calcifications: Fetal intracranial calcifications occur when a congenital infection such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, or Zika virus enters the central nervous system of a fetus through the placenta.⁶¹ The abnormal deposits of calcium associated with the disorder occur in certain areas of the brain, including the basal ganglia and the cerebral cortex.

Ocular Findings: Zika virus can cause symptoms such as nonpurulent conjunctivitis. Other ocular abnormalities have been observed in infants with microcephaly, according to a case series conducted in December 2015 in Salvador, Brazil. Ocular lesions, the most common of which were macular pigment mottling and chorioretinal scarring, were presumed to be due to exposure to Zika virus in utero.⁶² Optic-nerve abnormalities, iris coloboma, lens subluxation, active uveitis, and vasculitis were also observed. It is unknown whether these ocular findings are a direct result of Zika infection or are a consequence of microcephaly.⁶²

Other Congenital Effects: Additional congenital signs or symptoms that have occurred in infants whose mothers were infected with Zika virus during pregnancy include craniofacial disproportion, spasticity, seizures, irritability, and brainstem dysfunction, such as feeding difficulties.⁵⁷

Testing, Evaluation, and Clinical Considerations: Pregnant women who have had possible exposure to Zika virus and do not reside in an area with active transmission should be evaluated for Zika infection. Similarly, pregnant women who reside in an area with active Zika virus transmission should be evaluated and tested in accordance with the CDC interim guidance (Table 3). ^63,64,65

IgM antibody testing should be offered to asymptomatic pregnant women who have traveled to areas with ongoing transmission of Zika virus. Testing should be conducted between 2 and 12 weeks after a pregnant woman returns from travel to areas with ongoing Zika virus transmission. A negative IgM test result 2 to 12 weeks after known exposure suggests that a recent Zika virus infection did not occur, which may obviate the need for serial ultrasounds.

COUNSELING

Because there is no treatment for Zika infection, pharmacy staff should focus on prevention, particularly in pregnant women. Patients will have many questions related to travel, signs and symptoms, risk of infection, and preventive measures. It is important for the pharmacist and technicians need to be aware of the most common questions that may be posed, as well as suitable and relevant responses.¹⁹

What should women planning to travel to endemic areas be aware of regarding Zika virus? Pregnant women should avoid unnecessary travel to Zika-endemic areas. For those who cannot avoid such travel, extra precautions should be observed to prevent mosquito bites.^2,22 See wwwnc.cdc.gov/travel/page/zika-travel-information.

What are the signs and symptoms of Zika infection? Zika infection can cause a relatively mild illness, as evidenced by fever, headache, joint pain, muscle aches, skin rash, and eye inflammation (pinkeye). The development of GBS, although rare, has also been reported. Immediate attention must be sought if symptoms of GBS occur, such as tingling, weakness, and/or pain in the feet or legs; the inability to control eye or facial movements; incontinence or the inability to control bladder or bowel function. Most people with Zika infection have no symptoms whatsoever.^22,36,37

Which pregnant women are at risk for Zika infection? Any pregnant female living in or traveling to regions with vector-borne transmission is at risk. The most up-to-date list of endemic areas is found on the CDC website Travel Health Notices (wwwnc.cdc.gov/travel/notices). Although sexual transmission is probably less common than transmission via direct mosquito bite, pregnant females who engage in sexual intercourse with an infected partner or a partner living in or traveling to endemic areas are also at risk for infection.²²

What risks does Zika infection confer on the fetus? Current reports suggest that it is possible for infection to occur in utero. Several neurologic effects of infection have been observed, such as microcephaly, white-matter atrophy, intracranial calcification, and ocular abnormalities.^22,62

How can Zika infection be prevented, and is there a treatment? Until a vaccine becomes available, prevention is the primary form of protection. For individuals who cannot avoid travel to endemic areas, extra precautions should be observed to prevent mosquito bites, such as wearing long sleeves and pants, using insect repellent, and using mosquito netting while indoors. There is no antiviral treatment for Zika infection, so management involves rest, hydration, analgesics, and antipyretics.²²

CONCLUSION

Protection and prevention are critical in stemming the spread of Zika virus. Because there are multiple mechanisms by which Zika virus is transmitted, a clear understanding of each mechanism is essential for recommending appropriate interventions. There are many opportunities for the pharmacist to play an integral role in the education and counseling of patients who are pregnant or are planning a pregnancy. The identification of potential signs and symptoms of infection is crucially important for the pharmacy technician to be aware of when working in partnership with the pharmacist. A thorough knowledge of Zika virus, methods of transmission, and preventive measures, as well as potential effects during pregnancy, is critical to successful engagement with the patient. As methods of transmission and the spread of new cases continue to be reported, the involvement of all health-care providers is of paramount importance. Early discussions with patients prior to travel to endemic areas, in the presence of pregnancy or when pregnancy considerations are being made by couples, are particularly helpful and critical in curbing the spread of this infection.

REFERENCES

1. Progress toward discovery of Zika virus vaccines and therapeutics. World Health Organization website. July 23, 2018. http://www.who.int/emergencies/diseases/zika/discovery-of-vaccines/en/. Accessed September 5, 2018.
2. Imperato PJ. The convergence of a virus, mosquitoes, and human travel in globalizing the Zika epidemic. J Community Health. 2016;41:674-679.
3. Lazear HM, Diamond MS. Zika virus: new clinical syndromes and its emergence in the Western Hemisphere. J Virol. 2016 Apr 29;90:4864-4875.
4. Duffy MR, Chen TH, Hancock WT, et al. 2009. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536-2543.
5. de Salazar PM, Suy A, Sánchez-Montalvá A, et al. Zika fever. Enferm Infecc Microbiol Clin. 2016;34:247-252.
6. CDC. Florida investigation links four recent Zika cases to local mosquito-borne virus transmission. www.cdc.gov/media/releases/2016/p0729-florida-zika-cases.html. Accessed August 5, 2016.
7. Zika Cases in the United States. CDC website. August 2, 2018. https://www.cdc.gov/zika/reporting/case-counts.html. Accessed September 5, 2018.
8. 2017 Case Counts in the US. CDC website. August 2, 2018. https://www.cdc.gov/zika/reporting/2017-case-counts.html. Accessed September 5, 2018.
9. CDC. Zika virus. www.cdc.gov/zika. Accessed June 15, 2016.
10. Zika Travel Information. CDC website. August 14, 2018. https://wwwnc.cdc.gov/travel/page/zika-travel-information. Accessed September 5, 2018.
11. Musso D, Gubler DJ. Zika virus. Clin Microbiol Rev. 2016;29:487-524.
12. CDC. Surveillance and control of Aedes aegypti and Aedes albopictus in the United States. www.cdc.gov/chikungunya/resources/vector-control.html. Accessed June 10, 2016.
13. Petersen E, Wilson ME, Touch S, et al. Rapid spread of Zika virus in the Americas—implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic games. Int J Infect Dis. 2016;44:11-15.
14. Paixão ES, Barreto F, Teixeira Mda G, et al. History, epidemiology, and clinical manifestations of Zika: a systematic review. Am J Public Health. 2016;106:606-612.
15. Boorman J, Porterfield J. A simple technique for infection of mosquitoes with viruses; transmission of Zika virus. Trans R Soc Trop Med Hyg. 1956;50:238-242.
16. Basarab M, Bowman C, Aarons EJ, Cropley I. Zika virus. BMJ. 2016;352:i1049.
17. Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Poly-nesia, November 2013 to February 2014. Euro Surveill. 2014;19:20761.
18. CDC. Transfusion-related transmission of yellow fever vaccine virus— California 2009. MMWR Morb Mortal Wkly Rep. 2010;59:34-37.
19. Pealer LN, Marfin AA, Petersen LR, et al. Transmission of West Nile virus through blood transfusion in the United States in 2002. N Engl J Med. 2003;349:1236-1245.
20. Chuang V, Wong TY, Leung YH, et al. Review of dengue fever cases in Hong Kong during 1998 to 2005. Hong Kong Med J. 2008;14:170-177.
21. Zika and Blood Transfusion. CDC website. August 9, 2018. https://www.cdc.gov/zika/transmission/blood-transfusion.html. Accessed September 5, 2018.
22. Marrs C, Olson G, Saade G, et al. Zika virus and pregnancy: a review of the literature and clinical considerations. Am J Perinatol. 2016;33:625-639.
23. Brooks JT, Friedman A, Kachur RE, et al. Update: interim guidance for prevention of sexual transmission of Zika virus—United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65:745-747.
24. Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non–vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17:880-882.
25. Atkinson B, Hearn P, Afrough B, et al. Detection of Zika virus in semen. Emerg Infect Dis. 2016;22:940.
26. Hills SL, Russell K, Hennessey M, et al. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—conti-nental United States, 2016. MMWR Morb Mortal Wkly Rep. 2016;65:215-216.
27. Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21:359-361.
28. Nicastri E, Castilletti C, Liuzzi G, et al. Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016. Euro Surveill. 2016;21:pii=30314.
29. Turmel JM, Abgueguen P, Hubert B, et al. Late sexual transmission of Zika virus related to persistence in the semen. Lancet. 2016;387:2501.
30. Davidson A, Slavinski S, Komoto K, et al. Suspected female-to-male sexual transmission of Zika virus—New York City, 2016. MMWR Morb Mortal Wkly Rep. 2016;65:716-717.
31. Prisant N, Bujan L, Benichou H, et al. Zika virus in the female genital tract. Lancet Infect Dis. Jul 11, 2016 [Epub ahead of print].
32. CDC. Zika and sexual transmission. www.cdc.gov/zika/transmission/sexual-transmission.html. Accessed August 6, 2016.
33. Besnard M, Lastère S, Teissier A, et al. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. 2014;19:20751.
34. Grischott F, Puhan M, Hatz C, Schlagenhauf P. Non-vector-borne trans-mission of Zika virus: a systematic review. Travel Med Infect Dis. 2016;14:313-330.
35. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958.
36. CDC. Zika virus. Symptoms, testing, & treatment. www.cdc.gov/zika/symptoms. Accessed August 12, 2016.
37. World Health Organization. Zika virus fact sheet. www.who.int/media-centre/factsheets/zika/en. Accessed June 10, 2016.
38. Pierson TC, Diamond MS. The emergence of Zika virus and its new clinical syndromes. Nature. 2018;560(7720):573-581.
39. Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009;15:1347-1350.
40. Malone RW, Homan J, Callahan MV, et al. Zika virus: medical counter-measure development challenges. PLoS Negl Trop Dis. 2016;10:e0004530.
41. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374:1552-1563.
42. Faye O, Faye O, Dupressoir A, et al. One-step RT-PCR for detection of Zika virus. J Clin Virol. 2008;43:96-101.
43. CDC. Testing for Zika virus. www.cdc.gov/zika/hc-providers/diagnostic. html. Accessed August 12, 2016.
44. LaBeaud AD. Zika virus infection: an overview. UpToDate. www.upto-date.com/contents/zika-virus-infection-an-overview. Accessed June 17, 2016.
45. CDC. Dengue virus. www.cdc.gov/dengue/clinicallab/clinical.html. Accessed August 18, 2016.
46. Treatment. CDC website. February 7, 2018.  https://www.cdc.gov/zika/symptoms/treatment.html. Accessed September 5, 2018.
47. Prevent Mosquito Bites. CDC website. August 24, 2018. https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html. Accessed September 5, 2018.
48. Zika: A CDC Guide for Travelers. CDC website. August 8, 2018. https://wwwnc.cdc.gov/travel/files/zika-travel-brochure-508.pdf. Accessed September 5, 2018.
49. Cao-Lormeau VM, Blake A, Mons S, et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016;387:1531-1539.
50. CDC. Health effects & risks. www.cdc.gov/zika/healtheffects/index.html. Accessed August 12, 2016.
51. IIT Research Institute. Zika mouse model available. http://iitri.org/news-events/Zika-mouse-model-using-current-strain. Accessed May 18, 2016.
52. Shah A, Kumar A. Zika virus infection and development of murine model. Neurotox Res. 2016;30:131-134.
53. Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534:267-271.
54. Rice ME, Galang RR, Roth NM, et al. Vital Signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection - U.S. territories and freely associated states, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(31):858-867.
55. Meaney-Delman D, Oduyebo T, Polen KN, et al. Prolonged detection of Zika virus RNA in pregnant women. Obstet Gynecol. 2016; Jul 29 [epub ahead of print].
56. Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18:587-590.
57. Costello A, Dua T, Duran P, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ. 2016;94:406-406A.
58. Walker CL, Little ME, Roby JA, et al. Zika Virus and the Non-Microcephalic Fetus: Why We Should Still Worry. Am J Obstet Gynecol. 2018 Aug 29. pii: S0002-9378(18)30714-2.
59. CDC. CDC concludes Zika causes microcephaly and other birth defects. www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html. Accessed August 18, 2016.
60. Petersen EE, Polen KN, Meaney-Delman D, et al. Update: interim guidance for health care providers caring for women of reproductive age with possible Zika virus exposure—United States, 2016. MMWR Morb Mortal Wkly Rep. 2016;65:315-322.
61. Fakhry J, Khoury A. Fetal intracranial calcifications. The importance of periventricular hyperechoic foci without shadowing. J Ultrasound Med. 1991;10:51-54.
62. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol. 2016;134:529-535.
63. Testing Guidance. CDC website. February 28, 2018. https://www.cdc.gov/zika/hc-providers/testing-guidance.html. Accessed September 5, 2018.
64. Updated Interim Pregnancy Guidance: Symptomatic Pregnant Women with Possible Zika Virus Exposure. CDC website. September 15, 2017. https://www.cdc.gov/pregnancy/zika/testing-follow up/documents/Testing_Algorithm.pdf. Accessed September 5, 2018.
65. Updated Interim Pregnancy Guidance: Asymptomatic Pregnant Women with Possible Zika Virus Exposure. CDC website. July 24, 2017. https://www.cdc.gov/pregnancy/zika/testing-follow-up/documents/testing-algorithm-asymptomatic.pdf. Accessed September 5, 2018.

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