ESSENTIALS OF DIAGNOSIS
Most infected persons asymptomatically seroconvert.
Clinical symptoms are akin to those of chikungunya virus infection but with less arthritis.
Complications include microcephaly and ocular abnormalities in infants born to mothers infected during pregnancy as well as Guillain-Barré.
There is no effective antiviral or vaccine.
Zika virus is a flavivirus, akin to the viruses that cause dengue fever, Japanese encephalitis, and West Nile infection. It was originally isolated from macaques in 1947, in the Zika forest near the Entebbe airport of Uganda. The virus was named Zika in 1952, and the first human cases were noted in Nigeria in 1968 although earlier cases probably occurred in Uganda and Tanzania.
The virus was noted in Africa and Asia during the 1950s–1980s, but first spread beyond those two continents during 2007 when an outbreak occurred in Yap State, Federated States of Micronesia. A large outbreak occurred in French Polynesia in 2013. A smaller outbreak occurred on Easter Island during 2014. The virus then spread to the Western hemisphere and was first noted in northeastern Brazil in 2015, and 239,742 cases were subsequently reported between 2015 and 2018. Zika virus spread rapidly throughout the Americas, including the United States and worldwide (http://www.who.int/csr/disease/zika/en/). Autochthonous transmission of Zika virus has been reported in 87 countries and territories. In October, 2019, the first mosquito-transmitted, locally acquired cases of Zika virus were reported in Europe (Southern France). Despite distinct lineages, Zika virus exists as only one serotype.
Aedes species mosquitoes, particularly Aedes aegypti, are primarily responsible for transmission of Zika virus. The biodistribution of the species largely determines the area of prevalence for Zika virus. Aedes species mosquitoes are found primarily in the southeastern United States, but one species Aedes albopictus (the Asian tiger mosquito known to sequester in tires) may be seen as far north as Pennsylvania and New Jersey. Rarely, a few other mosquito species including Anopheles and Culex may be competent for the Zika virus. Sexual transmission is reported from males and females to partners via vaginal, anal, or oral sex. Vertical transmission from pregnant woman to fetus is prominent. Transmission via platelet transfusion is also reported.
Since the onset of the first reported cases in the United States in 2015, the number of reported Zika cases is over 43,000, with most cases from US territories (largely Puerto Rico). The territorial cases are largely locally acquired and the US state cases are largely travel-acquired. The number of annual cases is diminishing markedly in the United States with a peak in 2016 of 4897 travel-associated cases and 224 locally acquired cases (Florida, 218; Texas, 6). As of November 7, 2019, there have been 15 cases (14 in travelers and 1 laboratory-acquired case) in the US states and 51 (49 locally acquired cases and 2 travel-associated cases) in the US territories.
The incubation period is 3–14 days. The majority (50–80%) of Zika virus infections are asymptomatic. Symptoms include acute onset fever, maculopapular rash that is usually pruritic, nonpurulent conjunctivitis, and arthralgias, the latter mimicking the symptoms of the chikungunya virus. Rash may outlast the fever but is not always present. Symptoms last up to 7 days. Most infections are asymptomatic. Viral infections most often confused with Zika include dengue and chikungunya virus infections.
B. Laboratory Findings and Diagnostic Studies
The CDC recommends that persons with symptoms of Zika infection be tested if they live in or have traveled recently to an area with active transmission. The CDC no longer recommends testing for asymptomatic pregnant women.
Diagnosis is made by detecting viral RNA (nucleic acid testing) in patients presenting with onset of symptoms less than 7 days. Nucleic acid testing can be performed within 14 days of illness onset. Persons being tested 14 days or more after symptom onset should be tested using IgM serology. The Trioplex RT-PCR assay, which detects Zika virus, chikungunya virus, and dengue virus RNA, and the Zika MAC-ELISA, which detects Zika virus IgM antibodies (usually present up to 12 weeks after illness onset), are available. Matched serum and urine specimens should be tested simultaneously. Although not routinely recommended, RT-PCR can be performed on amniotic fluid, CSF, and placental tissue. A positive RT-PCR test definitively makes the diagnosis of Zika virus infection and does not require additional confirmatory testing. A negative test does not exclude the presence of the virus in other tissues and does not rule out infection. Persons with negative nucleic acid tests and symptoms of Zika infection should undergo further testing for Zika virus IgM antibody and other arboviral infections. Serologic testing for Zika virus should only be conducted by laboratories with experience in performing flavivirus serology. Recommended serologic assays include enzyme immunoassays and immunofluorescence assays (which detect IgM antibodies using viral lysate, cell culture supernatant, or recombinant proteins) as well as neutralization assays (such as plaque-reduction neutralization tests). The Zika MAC-ELISA can be performed on serum or CSF. Anti-Zika IgM antibodies are observed in CSF of children with congenital infection. Neutralizing antibodies can cross-react with dengue and other flaviviruses, so samples testing positive should be sent to public health laboratories for confirmation.
In the United States, testing for asymptomatic pregnant women is not currently recommended by the CDC even after travel to an area with Zika activity. The WHO however does still recommends testing via IgM antibody for asymptomatic pregnant women who could have had contact with vectorborne or sexually transmitted Zika virus. In areas with active Zika transmission, asymptomatic pregnant women should be tested for IgM antibody as part of routine obstetric care. Persistent Zika virus RNA in serum has been reported in pregnancy. Pregnant women with confirmed or suspected Zika virus infection may be monitored by serial ultrasounds at 3- to 4-week intervals, assessing fetal anatomy and growth. With a declining prevalence of Zika virus infection, positive antibody tests run the risk of more likely being false-positives and thus the need for the outlined assessments exists.
Two neurologic complications are of particular concern: (1) congenital microcephaly, often associated with brain calcifications and other abnormalities, first noted during the outbreak in Brazil and subsequently recognized to have occurred in French Polynesia as well; and (2) Guillain-Barré syndrome, first noted during the outbreak in French Polynesia. The incidence of Guillain-Barré syndrome is estimated at 2–3 cases per 10,000 Zika virus infections. In addition to microcephaly, Zika causes a spectrum of birth defects of the CNS that collectively are termed “congenital Zika syndrome.” These include fetal brain disruption sequence, subcortical calcifications, pyramidal and extrapyramidal signs, ocular lesions of chorioretinal atrophy, and focal pigmented mottling of the retina, and congenital contractures. Newborns of women infected with Zika virus during pregnancy have a 5–14% risk of congenital Zika syndrome and a 4–6% risk of Zika virus–associated microcephaly. Spontaneous abortions and rare deaths related to Zika virus infection are reported.
As with Ebola virus, the Zika virus can persist in semen for months; in the male reproductive tract the prostate gland and the testes are the presumed reservoirs. Persistence does not appear to occur in the female reproductive tract.
There are no antivirals approved for treatment of Zika virus; thus, management should focus on supportive care. Sofosbuvir, which is FDA-approved to treat hepatitis C, another flavivirus, shows some ability to inhibit Zika replication and infection in vitro and in mice and appears to also be synergistic with interferon-alpha and with interferon-beta. Sofosbuvir also prevents vertical transmission in a mouse model. Aspirin and NSAIDs are avoided during illness caused by the flavivirus dengue because of its propensity to cause hemorrhage. Zika virus infections, however, do not appear to be associated with major hemorrhagic complications.
The most effective means is environmental control of mosquitoes and removal of areas where water is stagnant or builds up. Such measures include screens on houses; removal of old tires and debris from endemic areas of infection; and movement toward better living conditions, including air conditioning in impoverished areas. Because of the association between microcephaly and Zika virus infection during pregnancy, pregnant women are advised to avoid travel to areas where Zika virus is circulating (http://www.who.int/csr/disease/zika/information-for-travelers/en/). Guidelines for testing of pregnant women potentially exposed are available through the CDC. Infected individuals should refrain from blood donations for several months.
No approved vaccine against Zika virus exists; however, more than 10 vaccine candidates have advanced to phase 1 clinical trials and one has begun phase 2 clinical trials. Vaccine candidate evaluation has been hampered by the declining incidence of Zika virus. The existence of only a single serotype is encouraging for vaccine development, but the need to target maternal infection and fetal neurologic tissue is a stringent and relatively unique arboviral requirement. The antibody-determined enhancement seen with dengue does not appear to be as significant with Zika patients who have previously been vaccinated against dengue virus. The encouraging current trials include 1 with Inovio® and 2 from the NIH VRC (Vaccine Research Center) with the agents entitled VRC 5283 showing the best results to date (NCT03110770). Monoclonal antibodies appear to provide some relief.
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