Clinical signs and symptoms associated with Zika virus infection are discussed here. Information specific to laboratories is available. Multiple assays and sample types are often needed to establish a definitive laboratory diagnosis of Zika virus infection due to the temporal nature of biologic analytes in the infected person.
Viral ribonucleic acid RNA is the first analyte that can be detected in an infected person in multiple specimen types.
As the immune response develops, immunoglobulin M IgM titers rise in peripheral blood and the level of viral RNA generally declines. However, viral RNA may be detectable in some infected people for longer periods in certain specimen types. Nucleic acid testing NAT is most informative in the first 6 weeks after symptom onset. IgM antibodies are most likely to be detected in the first 12 weeks after symptom onset, but may persist longer. Zika virus infection can cause signs and symptoms similar to those seen in patients with other arthropod-borne virus arbovirus infections, including dengue viruses, related flaviviruses, and chikungunya virus, an unrelated alphavirus.
A positive result for one of these viruses does not preclude infection with the others. Co-infection with Zika virus and dengue or chikungunya viruses is rare, but possible, particularly in areas where these viruses are co-circulating. Paired serum and urine are the primary diagnostic specimens for Zika virus infection. Please review assay instructions to determine acceptable specimen types for a given assay. This updated guidance makes the following recommendations for Zika virus testing in: Symptomatic pregnant women with possible exposure to Zika virus.
See areas with risk of exposure. Asymptomatic pregnant women with ongoing possible exposure to Zika virus Pregnant women with possible exposure to Zika virus who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection Non-pregnant symptomatic individuals with possible exposure to areas with risk of Zika virus transmission Zika virus testing may be considered for: Asymptomatic pregnant women with recent possible but no ongoing exposure to Zika virus i.
Although not routinely recommended, testing may be considered on a case-by case basis and in line with jurisdictional recommendations. Zika virus testing is not recommended for: Non-pregnant asymptomatic individuals Pre-conception screening Laboratories should complete ALL specimen testing, including any indicated repeat testing, before reporting test results to provider.
Clinical decisions surrounding patient management should not be made until the appropriate testing algorithm is completed. The interim guidance has been updated based on declining trends in the number of reported cases of Zika virus infection in Region of the Americas, emerging evidence on prolonged detection of Zika immunoglobulin M IgM antibodies, and new limitations for interpreting serologic tests during pregnancy.
Although IgM is most likely to be detected in the first 12 weeks after infection, emerging data indicate that Zika virus IgM may persist beyond 12 weeks in a subset of infected individuals, limiting the ability of testing to determine whether an infection occurred during or prior to pregnancy.
IgM tests are also susceptible to false positives and cross-reactivity with other flaviviruses, especially when an individual has been vaccinated against or previously infected with a related flavivirus. In the United States, as the decline in reported Zika virus cases including travel-associated cases continues, the proportion of positive tests that are false positives for Zika virus are expected to increase due to a low positive predictive value. Key changes in the updated guidance for testing pregnant women have been made taking these testing limitations into consideration.
Key updates to the guidance: Symptomatic pregnant women with possible Zika virus exposure should be tested. When testing symptomatic pregnant women, concurrent NAT and IgM testing is recommended as soon as possible, up to 12 weeks after symptom onset. Asymptomatic pregnant women with ongoing possible exposure to Zika virus should be tested. NAT testing is recommended three times during pregnancy. IgM serology testing is not routinely recommended. Recommendations for the timing of NAT testing are at the initial prenatal care visit, followed by two additional NAT tests performed during pregnancy, coinciding with non-consecutive prenatal visits.
Timing of additional NAT testing may be informed by jurisdictional trends in Zika virus transmission, the expected length of Zika virus nucleic acid detection in serum, and the duration of exposure during pregnancy. Although not routinely recommended, after pre-test counseling and individualized risk assessment, physicians and patients, through a shared decision-making model, may collaboratively elect to have IgM testing performed concurrent with NAT testing.
If a patient has previously been confirmed positive for Zika virus infection, no additional IgM serology testing is recommended.
Asymptomatic pregnant women with recent possible Zika virus exposure but no ongoing exposure i. Although not routinely recommended, testing may be considered on a case-by-case basis using a shared physician-patient decision-making model and in line with jurisdictional recommendations.
If testing of asymptomatic pregnant women is performed, the same algorithm as for symptomatic pregnant women should be followed using the timeframe from the last possible exposure to Zika virus. Pregnant women with possible exposure to Zika virus and who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection should be tested.
NAT and IgM testing should be performed on maternal serum and urine following the algorithm for symptomatic pregnant women. If amniocentesis is being performed as part of clinical care, NAT testing of amniocentesis specimens should also be performed. Testing of placental and fetal tissues may also be considered.
Testing guidance for symptomatic non-pregnant individuals remains unchanged with this updated interim guidance. Pre-conception screening and baseline serum screening are not recommended. There are currently no EUA-approved tests for screening of semen for male partners requesting screening. The updated interim guidance recommends that NAT and IgM serology testing be performed concurrently when testing symptomatic pregnant women.
The updated interim guidance recommends that NAT testing be performed concurrently on both serum AND a paired urine specimen when testing symptomatic pregnant women. When the risk of exposure to Zika virus is low, the incidence of false positive test results is increased for both NAT and IgM serology testing. Further, IgM testing does not provide a clear determination of the timing of exposure, and a positive IgM result may represent recent or persistent IgM response to Zika virus or another flavivirus infection.
Given the possibility of a false positive result, laboratory test results should not be released until all testing is complete. It is recommended that healthcare decisions not be made until testing according to the appropriate algorithm is complete.
Molecular Testing Nucleic acid test, or NAT, is a generic term referring to all molecular tests used to detect viral genomic material. Despite the specificity of molecular testing, false positive NAT results have been reported in rare cases and may depend on the type of NAT assay performed and patient population i.
This problem can be exacerbated when Zika virus testing is performed on patient populations not recommended in the Zika testing algorithms. Testing is not recommended for asymptomatic non-pregnant individuals, or for pre-conception screening for either the woman or her partner. Under updated recommendations, repeat NAT testing of the same specimen beginning with a new extraction is recommended in some circumstances.
Updated recommendations for NAT testing of pregnant women are as follows: Patients should also be evaluated for other pathogens including dengue virus circulating in areas where they have traveled or lived. Possible exposure may include travel to or residence in areas with increased risk of Zika virus infection or unprotected sex with a partner who has traveled to or lives in an area with increased risk of Zika virus exposure.
IgM antibodies usually become detectable within a week following symptom onset and decline over time, therefore a negative IgM assay result on a serum specimen collected less than 2 weeks before or more than 12 weeks after symptom onset does not rule out a recent Zika virus infection.
If both serum and urine test positive for Zika virus, repeat NAT testing is not required see Table 1. If NAT is only positive on serum or urine, and IgM antibody testing is negative, NAT should be repeated on the original, positive specimen beginning with a new extraction. If more than 12 weeks have passed since symptom onset, IgM serology testing without NAT may be considered but a negative IgM result does not rule out recent infection. Asymptomatic Pregnant Women Testing is recommended for asymptomatic pregnant women with ongoing possible exposure to Zika virus.
Ongoing exposure may include daily travel to or residence in areas with risk of Zika virus infection or unprotected sex with a partner who travels to or resides in an area with risk of Zika virus exposure. NAT testing for evidence of Zika virus infection is recommended three times during pregnancy, but IgM serology testing is not routinely recommended. Recommendations for the timing of NAT testing are at the initial prenatal care visit, followed by two additional NAT tests, the timing and frequency of which are at the discretion of the provider and dependent on the risk of exposure and the results of the initial NAT test.
While not routinely recommended, after pre-test counseling, physicians and patients may elect to have IgM testing performed concurrently with NAT testing. Testing of asymptomatic pregnant women with recent possible Zika virus exposure but no ongoing exposure i.
If testing is conducted, the testing algorithm for symptomatic pregnant women should be followed, with specimens collected as soon as possible, not to exceed 12 weeks from the last possible exposure. Pregnant Women with Prenatal Ultrasound Findings Consistent with Congenital Zika Virus Infection Pregnant women with possible exposure to Zika virus who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection should be tested.
Possible exposure may include travel to or residence in areas with risk of Zika virus infection or sex with a partner who has traveled to or lives in an area with risk of Zika virus exposure.
Data regarding the utility of amniotic fluid in diagnosing congenital Zika virus infection are limited. Symptomatic Non-Pregnant Individuals NAT testing of symptomatic non-pregnant individuals is dependent on the timing of specimen collection. NAT testing is not recommended for asymptomatic non-pregnant individuals.
Additional assay-specific information e. Information about molecular assays that have been cleared by FDA for detection of arboviruses other than Zika virus can be found in this searchable database. Serologic detection of Zika virus infection may help confirm exposure to Zika virus in settings where people have not previously been exposed to Zika virus.
The decline in reported cases of Zika virus infection in the Americas in compared to is expected to increase the proportion of false positive test results for Zika virus. These limitations are a particular challenge when Zika virus testing is performed on patient populations not recommended in the Zika testing algorithms.
Testing is not recommended for asymptomatic non-pregnant individuals or for pre-conception screening. The updated testing algorithms recommend serologic testing for the following patient populations: IgM antibodies decline over time. Therefore, a negative IgM assay result does not rule out a recent Zika virus infection.
Testing for other arboviral pathogens is not routinely recommended for asymptomatic pregnant women. IgM testing is not recommended for non-pregnant asymptomatic individuals Figure 1. Additional Serologic Test Information For explanation of a specific interpretation on Zika virus IgM serology assays, refer to the instructions for use for the specific assay performed. This information may also be found in Tables 1 and 2. Zika virus IgM assays give a presumptive positive result, and final assay interpretation depends on additional results from confirmatory testing, such as the plaque reduction neutralization test PRNT.
Given the possibility of a false positive result, most likely due to cross reactivity, which has been reported, it is recommended that healthcare decisions are not made until the testing algorithm is complete.
However, PRNT may also reflect prior infection, and cannot be used to determine the timing of Zika virus infection. Terminology indicating a non-negative IgM serology result varies by assay, and may include positive, equivocal, presumptive, or possible Zika virus results.
Neutralizing antibodies develop shortly after IgM antibodies and likely persist for many years Based on experience with other flaviviruses, previous Zika virus infection is likely to confer prolonged, possibly lifelong, immunity However, for pregnant women without a previous definitive diagnosis of Zika virus infection e.
If the decision is made to test, only NAT testing is recommended, because IgM antibody test might not be able to determine the timing of infection among pregnant women who had exposure to Zika virus before the current pregnancy.
Zika and dengue viruses have similar clinical presentations, transmission cycles, and geographic distributions, and cross-reactivity on serologic assays for these viruses is common.