Zika virus: A primer for clinicians
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 cdc.gov.
KEY POINTS
- 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.
LABORATORY DIAGNOSTIC METHODS
The diagnosis of Zika virus infection is challenging. The low viremia at initial presentation and cross-reactivity of serologic testing with other flaviviruses, especially dengue, can contribute to misdiagnosis.40,50
In the first 7 days of Zika virus infection, the diagnosis is based on detection of viral RNA in serum by RT-PCR.12,55,56 RT-PCR is very specific for Zika virus and is an important tool in differentiating between Zika virus and other flaviviruses often present in areas where Zika virus is circulating.12,56 After 3 to 4 days, viremia may decrease to levels that may be below the assay’s level of detection.40–42,45
While Zika virus RNA may be undetectable in the serum, other samples such as saliva, urine, and semen may be positive for longer.28,42,57 For example, urine samples were positive by RT-PCR up to 7 days beyond blood RT-PCR in the outbreak in New Caledonia.42 A recent report found semen remaining positive on RT-PCR for 62 days after the onset of confirmed Zika virus illness in a traveler returning to the United Kingdom from the Cook Islands in 2014.58
Because RT-PCR of blood is only useful early in infection, the current diagnostic guidelines recommend testing an acute-phase serum sample for Zika virus IgM collected as early as possible after the onset of illness and repeated 2 to 3 weeks after the initial set. These IgM antibodies typically develop toward the end of the first week of illness and are expected to be present for up to 12 weeks, based on experience with other flaviviruses.41 Cross-reactivity with other flaviviruses circulating in the area can occur and has been problematic in areas where dengue is circulating.12,41,45,56 IgM-positive specimens should be further tested, by plaque-reduction neutralization, to confirm the presence of Zika virus-specific neutralizing antibodies. Results can be difficult to interpret, especially in those who have been previously infected or vaccinated against other flaviviruses.12,41
If amniocentesis is done, these specimens should be tested by RT-PCR. However, the sensitivity of PCR in amniotic fluid is currently unknown.41
In infants with findings of cerebral calcifications and microcephaly, IgM serologies with RT-PCR are also recommended and should be drawn within 2 days of birth. Specimens should be drawn concurrently as it is not known which test is most reliable in infants.23 Additionally, placenta and umbilical cord samples should be collected for immunohistochemical staining at specialized laboratories.36
In the United States, providers should contact their state health departments to determine where tests can be run reliably. Refined diagnostic assays are in development at the time of this publication and are likely to be made available through CDC’s Laboratory Response Network.
See Figure 2 and Table 3 for a summary of diagnostic tests.
IMPLICATIONS, RECOMMENDATIONS
Pregnant women
The CDC now recommends that asymptomatic pregnant women who returned from travel to a Zika virus-endemic zone in the last 2 to 12 weeks be offered serologic testing.41 This includes women who may be living in an area with ongoing Zika virus transmission; however, these women should also have testing at the initiation of prenatal care and then follow-up testing in the middle of the second trimester. Of importance, these results may be difficult to interpret due to potential cross-reactivity between Zika virus and other flaviviruses, and false-positive results in recipients of yellow fever and Japanese encephalitis vaccines.41,59
If a pregnant woman with a positive travel history is symptomatic, testing should be offered during the first week of illness. After day 4 of the illness, testing should include both RT-PCR and IgM serology.41,59
A screening ultrasound scan is recommended for any pregnant woman who has traveled to a Zika virus-affected area to determine if microcephaly or cerebral or intracranial calcifications are present. Those women with confirmed Zika virus infection should continue to have monthly screening ultrasounds, while those who are negative for Zika virus should have another ultrasound at the end of the second trimester or the beginning of the third trimester to ensure that no abnormalities had developed.41,59
At present, pregnant women and women of childbearing age who may become pregnant are advised by the CDC to postpone travel to affected areas until more information becomes available about mother-to-child transmission.59
Algorithms for the care of pregnant women and women of childbearing age who may have been exposed to Zika virus are available from the CDC41 at www.cdc.gov/mmwr/volumes/65/wr/mm6505e2.htm.
Male partners of pregnant women
Since the length of time that Zika virus remains viable in semen is not known, men who have traveled to Zika virus-endemic areas and who have pregnant partners should refrain from having sex or use a condom with every sexual encounter through the duration of the pregnancy.60
Guidelines for prevention of sexual transmission of Zika virus are available from the CDC59 at www.cdc.gov/mmwr/volumes/65/wr/mm6505e1er.htm.
Infants with possible congenital Zika virus infection
Zika virus testing is recommended for any infant born with microcephaly or intracranial calcifications or whose mother has positive or inconclusive testing if the mother had visited an endemic area during her pregnancy.
Zika virus testing in infants consists of serologic IgM determination and RT-PCR for both dengue and Zika virus drawn concurrently in the first 2 days of life.36 Umbilical cord blood can be used. In addition, if cerebrospinal fluid is being collected for other reasons, it can also be tested for Zika virus. The placenta and umbilical cord should be saved for immunohistochemistry testing for Zika virus.61
An infant who tests positive or inconclusive for Zika virus, regardless of the presence of microcephaly or intracranial calcifications, should have a complete physical examination specifically evaluating growth parameters, estimated gestational age, and signs of neurologic disease, skin rashes, hepatosplenomegaly, or any dysmorphic features. Additional evaluation includes an ophthalmologic examination in the first month of life to evaluate for macular atrophy.36 An ultrasound scan of the head should be completed if it has not been done. Hearing is screened in all newborns, and hearing testing should be repeated at 6 months of age.36
Infants with microcephaly or intracranial calcifications should also have consultations with specialists in genetics, neurology, and pediatric infectious diseases.61 These infants should have blood work including complete blood cell counts and liver function testing that includes alanine aminotransferase, aspartate aminotransferase, and bilirubin levels.36
All infants with possible congenital Zika virus infection should be followed long-term with close attention to developmental milestones and growth parameters including occipital frontal head circumference measurements.61,62
Infants without microcephaly or calcifications whose mothers had negative Zika virus test results or were not tested for Zika virus should have routine care.37
Guidelines for the care of infants with Zika virus infection are available from the CDC36 at www.cdc.gov/mmwr/volumes/65/wr/mm6503e3.htm.
TREATMENT
There is no treatment for Zika virus infection, and care is supportive. Most infections are mild and self-limited.12,15 Avoidance of aspirin and other nonsteroidal anti-inflammatory drugs that may affect platelets is important until dengue infection has been ruled out.
PREVENTION
There is currently no vaccine to prevent Zika virus infection. Woman who are pregnant should avoid travel to any area where Zika virus transmission is occurring.41,59 The CDC advises pregnant women and women of childbearing age who may become pregnant to postpone travel to Zika virus-affected areas.59 Patients can find travel alerts for specific areas at wwwnc.cdc.gov/travel/notices/alert/zika-virus-south-america.
Avoiding mosquito bites is the best way to prevent the spread of Zika virus. Aedes aegypti and A albopictus, the most common vectors of Zika virus, can bite at night but are known more for being aggressive daytime biters.63 Travelers should apply an Environmental Protection Agency-registered insect repellent as directed, wear long-sleeved shirts and long pants, use permethrin-treated clothing and gear, and stay in places with screens or air conditioning. Any containers with standing water should be eliminated as they are breeding areas for mosquitoes. It is also important that symptomatic people in the first week of illness use mosquito precautions to prevent the spread of Zika virus.
Patient handouts and posters for mosquito bite prevention can be found at www.cdc.gov/zika/fs-posters/index.html.
WATCH FOR UPDATES
Many questions remain regarding the epidemiology of this infection and its relationship to neurologic and pregnancy complications. However, due to its rapid spread across the Western hemisphere and its potential for significant complications, much is being done at the local and international levels to better understand the virus and halt its spread. More information will continue to be available as results from ongoing studies are conducted and potential associations are investigated. Until more is known, providers should familiarize themselves with the latest guidelines in order to better counsel their patients who may live in or travel to Zika virus endemic areas. We advise clinicians to follow the CDC’s web site, www.cdc.gov/zika/.
