Zika virus: A primer for clinicians

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ABSTRACTThe ongoing outbreak of Zika virus infection that began in South America and Central America in 2014 is worrisome because of associations with fetal microcephaly and with Guillain-Barré syndrome. Here we summarize what has happened and what is known so far. As the outbreak continues to evolve, we urge clinicians to watch for updates at


  • Zika virus infection is spread by the bite of infected mosquitoes and also through sexual contact, blood transfusions, and vertical transmission.
  • Most Zika virus infections are asymptomatic, and symptomatic cases are often mild and self-limited, with rash, fever, joint pain, and nonpurulent conjunctivitis the most common symptoms.
  • Polymerase chain reaction testing can detect viral RNA in the blood, but only in the first few days after the onset of symptoms. Immunoglobulin M against the virus becomes detectable at approximately 1 week and persists for about 12 weeks, but cross-reactivity with other viruses is a problem with serologic testing.
  • As yet, there is no vaccine and no specific treatment.
  • Pregnant women and women who may become pregnant are advised to defer travel to areas where Zika virus is endemic.



On February 1, 2016, the World Health Organization declared Zika virus a public health emergency of international concern due to clusters of microcephaly and neurologic manifestations in areas of Zika virus transmission.1 On February 8, the US Centers for Disease Control and Prevention (CDC) elevated its response to level 1, its highest.2

Case reports and guidelines have been published to help clinicians better understand the epidemiology, risk, and pathogenesis of Zika virus infection, but much is still unknown. Clinicians must be ready to address the concerns of international travelers and must also consider Zika virus in the differential diagnosis of fever in the returned traveler.


Zika virus, a single-stranded RNA arthropod-borne virus (arbovirus), is transmitted by mosquitoes. It is a member of the flavivirus family, which consists of over 70 viruses including some well known for causing diseases in humans, such as dengue, yellow fever, Japanese encephalitis, and West Nile virus.3

Phylogenetically, Zika virus is most similar to and included in a clade with Spondweni virus, which, like Zika, originated in Africa.4 Genomic analysis has revealed an African and an Asian lineage. The Asian lineage is responsible for the current epidemic in the Pacific and the Western Hemisphere.4–6


Zika virus is named after a forested area in present-day Uganda, where it was first isolated in a febrile rhesus monkey that was being used to study yellow fever.7 Further studies in the 1950s confirmed its transmission to humans, as 6% of the sera tested in Ugandans showed evidence of specific antibodies to the virus.8 In 1978, antibody prevalence studies showed that up to 40% of Nigerians had Zika virus-neutralizing antibodies.9 Over the next 38 years, scattered case reports and seroprevalence studies showed infections occurring throughout Africa and Asia.9–11

In 2007, the first case of Zika virus transmission outside of Asia and Africa occurred on Yap Island in the Federated States of Micronesia.10–12 No further transmission in the Pacific was noted for 6 years until an outbreak occurred in French Polynesia in 2013.13–15 The first time Zika virus was found in the Western Hemisphere was in January 2014, when an outbreak occurred on Chile’s Easter Island.16 Genomic analysis of the Zika virus isolated on Easter Island indicated it was most closely related to isolates from French Polynesia.16 In 2014, additional cases of Zika virus infection were reported in New Caledonia and the Cook Islands.13,14

Reported transmission of Zika virus in the Americas. From US Centers for Disease Control and Prevention.

Figure 1. Reported transmission of Zika virus in the Americas.

In May 2015, the World Health Organization issued an epidemiologic alert in response to dramatic increases in the spread of Zika virus in Brazil.17 From Brazil, Zika virus has rapidly spread to most countries in South and Central America and the Caribbean (Figure 1).2,5,6


The Aedes (Stegomyia) genus of mosquitoes is a well-known source of transmission for several arboviruses, including yellow fever, dengue, chikungunya, and now Zika virus.18,19 Zika virus was originally isolated in Uganda from Aedes africanus mosquitoes.7,20 Subsequently, other species of Aedes mosquitoes have been shown to transmit Zika virus, with Aedes aegypti being the most important human vector.7,8,19–21

Another species, Aedes albopictus has been identified as a human vector in Gabon and is also suspected of being a vector in the Brazilian outbreak.22 Spread of A albopictus from Asia to Europe, the Mediterranean region, and the Americas, including 32 states in the United States, has increased the fear of potential spread of Zika virus infection to a more expansive geographic range.13,18,19 Local transmission may become established if local mosquitoes become infected when infected travelers return from endemic areas.23


While mosquito-borne transmission is the most common route of infection with Zika virus, human-to-human transmission has been documented. Potential routes of transmission include sexual intercourse, blood transfusions, and vertical (mother-to-child) transmission.

Sexual transmission. Replicative Zika virus particles were identified in the semen of a patient who presented with hematospermia in French Polynesia.24

Previously, there was a report of Zika virus being sexually transmitted from a US man who had returned from Senegal to his spouse, who had not traveled to a Zika virus-endemic region. Both patients became ill following vaginal intercourse, with the onset of the wife’s illness occurring 5 days after the onset of the husband’s illness. The husband was noted to have hematospermia.25 Neutralization testing for both patients confirmed infection with Zika virus.25

The first reported case of sexual transmission in the current outbreak in the United States occurred in a traveler returning to Texas from Venezuela.26 The CDC is currently investigating several other potential cases and an additional two laboratory-confirmed cases. All cases were in symptomatic male travelers who had condomless vaginal intercourse with their female partners after return from Zika virus-endemic areas.27

Blood transfusions. Several arboviruses are known to be transmitted via blood.

In French Polynesia, Zika virus RNA was present in 3% of blood donors.28,29 These blood donors had been screened and were asymptomatic at the time of donation. Twenty-six percent of donors who had Zika RNA reported an illness compatible with Zika virus infection in the 3 to 10 days before donation.28

Brazil has reported two cases of Zika virus infection through blood transfusion.30

From Brazil, Zika virus has rapidly spread to most countries in South and Central America and the Caribbean

In May 2015, the European Centers for Disease Control recommended that travelers to affected areas defer blood donation for 28 days.31 The Association of American Blood Banks has also recommended that travelers self-defer donating blood for 28 days after travel to an endemic area.32 Most recently the US Food and Drug Administration recommended a 4-week deferral for travelers to Zika virus-endemic areas and after resolution of symptoms for those who have had Zika virus infection.33 Additional guidance for donors who have had sexual contact with Zika virus-infected persons and areas with active transmission of Zika virus is also available.33

Vertical transmission. Perinatal and transplacental transmission have also been documented.34,35 The extent and frequency of the clinical manifestations of these infections are still being elucidated in light of reports of association with fetal abnormalities.

Although Zika virus has been detected in breast milk, no cases of transmission through breastfeeding have been reported. Currently, women are advised to continue to breastfeed in areas of known Zika virus transmission.34,36,37


Most Zika virus infections are asymptomatic, as illustrated by reports from the Yap Island outbreak, where only 19% of those with immunoglobulin M (IgM) antibodies to Zika virus had symptoms.12 The illness in symptomatic patients is often mild and self-limited, and most manifestations resolve by 7 days.12,25,38,39

Initial descriptions in the 1950s and 1960s of the clinical features of Zika virus infection in Africa included fever and headache as the most prominent symptoms.38,40 Description of the outbreak on Yap in 2007 characterized the predominant symptoms as rash, fever, arthralgia/arthritis, and nonpurulent conjunctivitis in 31 patients,12 and the current CDC case definition includes at least two of these four symptoms.41 The arthralgia and arthritis are usually of the small joints of the hands and feet and can persist for as long as a month.25,42 The rash can be pruritic.15,33,42,43

Less commonly reported manifestations of Zika virus infection include malaise, stomachaches, dizziness, anorexia, retro-orbital pain, aphthous ulcers, hematospermia, and prostatitis.14,15,24,25,44,45

The initial reports from eight patients in the outbreak in Brazil noted rash and joint pain as the most common manifestations. The maculopapular rash was present in all patients and the joint pain was characterized as severe, with the hands, ankles, elbows, knees, and wrists most consistently described.43

Differential diagnosis of Zika virus infection

The clinical presentation is similar to those of dengue and chikungunya virus infections, confounding diagnosis, as these viruses may be cocirculating in the same geographic regions (and indeed are transmitted by the same mosquito vectors).11,12,15 The conjunctivitis present in Zika virus infections can also be present in chikungunya but is much less commonly a clinical feature of dengue.15,46,47 See Table 1 for the differential diagnosis of Zika virus infection.

Severe manifestations requiring hospitalization or resulting in death are thought to be uncommon, although neurologic and fetal complications have recently been described.12,29,43,48,49


Primary infection with Zika virus is relatively benign. The greatest and most recent concerns are related to postinfectious complications and those that may occur in pregnant women.

Guillain-Barré syndrome

During the Zika virus outbreak in French Polynesia in 2013–2014, the incidence of Guillain-Barré syndrome was multiplied by a factor of 20.50 Prior to the first hospitalization of a patient with Zika virus infection and associated Guillain-Barré syndrome in French Polynesia, there had been no reported hospitalizations for Zika virus infection.50

This same association is now being seen in the recent outbreak in the Americas.50 In July 2015, Brazilian health officials in the State of Bahia reported 76 patients with neurologic syndromes, of whom 55% had Guillain-Barré syndrome.51 A history consistent with Zika virus infection was found in 62%.48

In January 2016, El Salvador also reported an unusual increase in Guillain-Barré syndrome cases since early December 2015.51 Between December 1, 2015, and January 6, 2016, there were 46 Guillain-Barré syndrome cases reported, compared with a baseline of 14 cases per month.51

Other countries where Zika virus infection is endemic are also currently investigating similar trends.51


Aedes aegypti is the most important vector, but A albopictus can also carry the virus and now lives in 32 US states

On November 17, 2015, the Pan American Health Organization issued an epidemiologic alert because of increased reports of microcephaly in the Pernambuco State of Brazil. Whereas there are typically about 10 cases per year, there had been 141 in the previous 11 months.51 Other states in Brazil such as Paraiba and Rio Grande del Norte also reported increases in the diagnosis of microcephaly. A physician alert published in Brazil described two infants from the Paraiba state who were diagnosed with fetal microcephaly.35 Testing for Zika virus by polymerase chain reaction (PCR) was negative in the maternal blood, but PCR of amniotic fluid was positive in both infants.35

In January 2016, the Brazil Ministry of Health reported that Zika virus had been detected by real-time PCR (RT-PCR) in four infants with congenital malformations in Rio Grande del Norte. Two of these cases were miscarriages and two were infants who died within 24 hours of birth. Immunohistochemistry of tissues from these infants was positive for Zika virus.

A February 2016 case report describes a European woman who developed Zika virus infection at 13 weeks gestation while working in Northeast Brazil and upon return to Europe elected to terminate the pregnancy after ultrasonography showed cerebral calcifications with microcephaly. The infant was found to have a very small brain, hypoplasia of the brainstem and spinal cord with degeneration of spinal tracts, complete absence of cerebral gyri, and severe dilatation of lateral ventricles as well as calcifications throughout the cerebral cortex.49 No genetic abnormalities or evidence of other etiologies was found, and large amounts of Zika virus RNA were found in the brain.

Most common causes of congenital microcephaly

The CDC also recently reported confirmation of Zika virus infection from fetal tissues of two miscarriages (fetal loss at 11 and 13 weeks) and two fetal deaths (36 and 38 weeks) received from the state of Rio Grande do Norte in Brazil.52 All four mothers reported clinical signs of fever and rash during their first trimester of pregnancy.52 Additional testing for toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and human immunodeficiency virus were all negative in the mothers who had miscarriages.52

Of critical note, the causality of Zika virus and microcephaly remains under investigation. See Table 2 for other causes of microcephaly.53

Macular atrophy

In January 2016, a case series of three infants with microcephaly and macular atrophy was reported.54 These infants were tested for toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis, and human immunodeficiency virus (HIV), and all the results were negative. The detection of Zika virus fulfilled the Brazilian Ministry of Health’s definition of vertical transmission of Zika virus, and laboratory diagnostic tests for Zika virus were not performed. In this series, one mother reported an illness with rash and arthralgias during the first trimester.54

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