Zika virus is an arbovirus of the Flaviviridae family. It is primarily a minimally symptomatic mosquito-borne infection. However, with Zika’s 2015 to 2016 introduction into the Western Hemisphere and its dramatic and rapid spread, it has become a public health concern, in large part due to congenital abnormalities associated with infection in pregnant women. In early 2016, the World Health Organization declared the microcephaly and other neurologic conditions associated with Zika virus infection a public health emergency of international concern. This article discusses the current epidemiologic and clinical understanding of Zika virus, focusing on critical information needed by emergency providers.
Key points
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Zika virus is a mosquito borne arbovirus.
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Most individuals infected with Zika virus have minimal or no symptoms.
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If present, typical symptoms include rash, conjunctivitis, and fever.
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Pregnant women infected with Zika, particularly during the first trimester, appear to be at increased risk of having infants with congenital abnormalities such as microcephaly.
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There is currently no vaccine or treatment for Zika virus. Prevention through minimizing mosquito bites is the best means of decreasing risk of infection.
Introduction
Zika virus’ recent introduction into the Western Hemisphere and its dramatic and rapid spread during 2015 to 2016 represent a global public health challenge. Associations between Zika virus with congenital anomalies and Guillain Barre Syndrome (GBS) underscore the importance of understanding strategies for management and control of the virus. There is significant concern for risk to pregnant women/women of reproductive age and the risks associated with the spreading disease and with travel to endemic areas. Preparations for the 2016 Olympic Games in Brazil cast an increased sense of urgency on the need for improved assessment/identification, management, and containment of Zika virus. Given the potential for increased numbers of infected individuals, it is essential that emergency providers equip themselves with the knowledge and background necessary to effectively assess, manage, and counsel patients. This article provides background and epidemiologic information on Zika virus followed by a discussion of diagnostic, treatment, and management strategies.
Introduction
Zika virus’ recent introduction into the Western Hemisphere and its dramatic and rapid spread during 2015 to 2016 represent a global public health challenge. Associations between Zika virus with congenital anomalies and Guillain Barre Syndrome (GBS) underscore the importance of understanding strategies for management and control of the virus. There is significant concern for risk to pregnant women/women of reproductive age and the risks associated with the spreading disease and with travel to endemic areas. Preparations for the 2016 Olympic Games in Brazil cast an increased sense of urgency on the need for improved assessment/identification, management, and containment of Zika virus. Given the potential for increased numbers of infected individuals, it is essential that emergency providers equip themselves with the knowledge and background necessary to effectively assess, manage, and counsel patients. This article provides background and epidemiologic information on Zika virus followed by a discussion of diagnostic, treatment, and management strategies.
History
Origins
The Zika Virus was first identified in 1947 at the Yellow Fever Research Laboratory in the Zika Forest area of Uganda. During this time period, British scientists placed Asian rhesus monkeys in Africa. Blood samples from 1 sentinel rhesus monkey were injected into mice. These mice subsequently became ill. Several viruses were identified in the brain tissue of the ill mice; 1 of the isolated viruses was the Zika virus. Zika virus was also isolated from mosquitos in the region.
Epidemiology
From 1947 to 2007, there were limited and infrequent documented human cases of Zika virus infection. In 2007, scientists reported the first outbreak of Zika virus on the island of Yap within the Federated States of Micronesia. There were 49 confirmed and 59 probable cases documented over a 4-month period. Public health officials recorded a subsequent outbreak in 2013 in French Polynesia. There were 294 cases, confirmed by RNA assay, recorded over a 10-week period.
The first documented case of the Zika virus in the Americas was in 2014 with locally acquired cases in Easter Island. Subsequently, in May 2015, initial cases were confirmed in Northeast Brazil. From May 2015 until early 2016, Brazilian officials estimated that there were 1.5 million cases of Zika virus infections throughout the country. Colombia also reported more than 25,000 cases from October 2015 through the middle of February 2016. Given that infection is often subclinical, with many affected patients not seeking medical care, officials advise that cases are likely underreported.
As of March 2016, there have been no documented cases of locally acquired Zika virus infection in the continental United States. However, there have been 153 travel-associated cases within 28 states and the District of Columbia. Within the US territories, to that date, there was 1 documented travel-associated case and 107 locally acquired cases.
Virology
Classification and Structure
Zika virus is an arbovirus within the genus Flaviviridae and family Flavivirus. It is a single-stranded RNA virus with Asian and African lineage. Other flaviviruses include yellow fever, dengue fever, and West Nile virus. Within the African lineage, the life cycle of the virus is between nonhuman primates and mosquitoes. Humans are occasional, unintentional hosts within the African life cycle. Outside of Africa, humans are the primary host for infection.
Transmission
The primary transmission vector is the Aedas aegypti mosquito. Laboratory testing has shown the possibility of transmission via the Aedes albopticus mosquito.
Sexual transmission of the Zika virus has been reported. There has been at least 1 documented case of male-to-female sexual transmission of the virus as well as 1 probable case of male-to-female sexual transmission. In a third case, semen isolated from an infected male was shown to test positive for Zika virus serologic testing for 2 to 10 weeks after initial symptom onset. In all of these cases, the male patient was symptomatic. It is unclear whether sexual transmission can occur from an asymptomatic male. As of March 2016, there have been no documented cases of female-to-male transmission. In April 2016, the CDC published a report of male-to-male sexual transmission of Zika virus.
Concern has also emerged for Zika virus transmission via infected blood products. One 2014 study showed that 42 out of 1505 blood donors in the French Polynesian outbreak of 2013 to 2014 tested positive for Zika virus via nucleic acid testing. All blood donors were asymptomatic at the time of blood donation. This has prompted new US Food and Drug Administration (FDA) recommendations for blood and organ donation.
As of March 2016, for blood donors in areas without active Zika virus transmission, the FDA suggests that donation should be deferred for 4 weeks in donors who are at risk for Zika virus infection. Donors are considered to be at risk if they either have had symptoms of Zika virus infection in the past 4 weeks, have had sexual contact with persons who either traveled to or resided in an area with active Zika virus transmission within the past 3 months, or if they have travelled to areas with active transmission of the Zika virus during the past 4 weeks. For areas with active Zika virus transmission, the FDA recommends that blood/blood products should be obtained from areas of the United States without active transmission of the Zika virus. The FDA is developing screening tests for blood.
Evolving FDA recommendations for organ donation state that living donors should be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of these 2 risk factors (travel to areas with active transmission or symptoms of Zika virus infection) within the past 6 months. Further, donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they had any of these risk factors (travel to area of active transmission, sexual contact with an at-risk male, or symptoms of Zika virus infection) during their pregnancy. Finally, deceased donors should be considered ineligible if they were diagnosed with Zika infection within 6 months prior to the time of donation.
Early studies noted a temporal association between incidence of Zika virus infection and incidence of congenital microcephaly/congenital defects. This led to concerns of possible transplacental/perinatal transmission of the Zika virus. Subsequent studies have identified Zika virus genetic material in amniotic fluid samples of fetuses with microcephaly whose mothers had symptoms suggestive of Zika virus infection. Other studies have shown reverse transcription polymerase chain reaction (RT-PCR)-confirmed Zika virus infection in both mothers and fetuses within 4 days of delivery. These data raised the possibility of transplacental transmission of the virus. A subsequent March 2016 study examined the proposed molecular basis for the link between congenital microcephaly and Zika virus. The study group identified that in vitro, Zika virus infects human neural progenitor cells, which subsequently leads to attenuation of cell growth.
Clinical presentation
Initial Signs and Symptoms
The virus has an incubation period of 3 to 12 days. This is followed by a subclinical or mild illness. Symptoms, when present, typically last for 2 to 7 days. Initial symptoms are generally mild and typically self-limited. Typical symptoms of Zika infection are listed in Box 1 .
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Fever
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Conjunctivitis
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Arthralgia/myalgia
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Diffuse rash
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Headache
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Retro-orbital pain
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Peripheral edema
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Gastrointestinal upset
Acute Sequelae
Severe acute infections with Zika virus are rare. There have been fewer than 10 adult deaths caused by the Zika virus reported as of early 2016. However, investigators have detected an association, and likely a causal relationship, with the serious sequelae of Guillain–Barré syndrome (GBS). A February 2016 Lancet case–control study reported that 41 patients in the case group (98%) had anti-Zika virus immunoglobulin M (IgM) or IgG compared with 54 patients (56%) in the control group ( P <.0001). This study supported an association between Zika virus and GBS. In total, there was an estimated incidence of 0.24 cases of Zika per 1000 cases of GBS in the French Polynesian outbreak (compared with incidence of 0.25–0.65 cases of Zika per 1000 cases of GBS with Campylobacter jejuni infection). Authorities have attributed 3 deaths to GBS associated with Zika virus infection.
Congenital Complications
As the incidence of Zika virus infection rose in northeast Brazil, there was a simultaneous increase in the incidence of congenital microcephaly and other fetal complications. Subsequent studies established a possible link between Zika virus infection and congenital complications. Up until February 2016, there had been no documented cases of microcephaly in Colombia despite over 30,000 cases of Zika virus infection in the country. However, as of March 4, 2016, 3 infants who tested positive for Zika virus were diagnosed with microcephaly and other congenital anomalies. Colombian public health experts expect to see a further rise in congenital abnormalities related to Zika virus in Colombia. A New England Journal of Medicine study published in February 2016 studied 88 women in Brazil from September 2015 to February 2016. This study identified fetal abnormalities in 29% of women who tested positive for Zika virus and in 0% of women who tested negative for Zika virus. Fetal abnormalities that were identified included: 2 cases of fetal death, 5 cases of in utero growth restrictions with or without microcephaly, 7 cases of ventricular calcifications or other central nervous system lesions, and 7 cases of abnormal amniotic fluid volume or cerebral/umbilical artery flow. In April 2016, the CDC concluded that Zika virus is a cause of microcephaly and other fetal anomalies.
Testing and diagnosis
Diagnostic Criteria
As of June 2016, the Pan American Health Organization (PAHO) provisional case definition of suspected acute Zika virus infection is a rash that is typically pruritic and maculopapular ( Fig. 1 ) with two or more of the following accompanying signs/symptoms
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Arthralgia/myalgia
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Nonpurulent conjunctivitis
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Conjunctival hyperemia
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Fever (usually <38.5°C)
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Peri-articular edema
The signs and symptoms of Zika virus infection are nonspecific; thus there is a broad differential diagnosis. The differential diagnosis includes Dengue fever, chikungunya virus, initial human immunodeficiency virus (HIV) seroconversion, measles, scarlet fever, rickettsial infection, leptospirosis, parvovirus, enterovirus, rubella, and secondary syphilis. Given the nonspecific nature of the signs/symptoms and the broad differential diagnosis, clinical presentation alone is insufficient to make the diagnosis without confirmatory laboratory testing.
Laboratory Testing
As of March 2016, definitive diagnosis of Zika virus is made by RT-PCR testing of blood and saliva, which can only be accomplished with assistance from public health authorities and is not yet available at individual hospitals. Results are generally not accessible in a timely fashion. IgM antibody against the Zika virus can also be detected in serum. Data on the utility of urine and semen RT-PCR are limited. Delayed antibody testing (IgG) is less useful due to the cross-reactivity of IgG antibodies to other flaviviruses, such as dengue. Given that other flaviviruses can be endemic to the same region where there is active Zika virus transmission, false positive results are common.
Infection control and public health
Travel Recommendations/Restrictions
As of March 2016, the United States has no documented cases of locally acquired Zika virus infection, but there have been numerous travel-associated cases. The first travel-associated case of Zika virus among US travelers was reported in 2007. From 2007 to 2014, 14 returning US travelers tested positive for Zika virus at the US Centers for Disease Control and Prevention (CDC). From 2015 to 2016, at least 8 returning US travelers have tested positive for Zika virus per CDC reports. The spread of Zika virus via travel prompted the release of interim CDC travel guidance in January 2016. CDC issued a Level 2 travel alert (practice enhanced precautions) for people traveling to regions where there is ongoing active transmission of Zika virus. This includes travel to: Brazil, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela and the Commonwealth of Puerto Rico. See Box 2 for specific recommendations.
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