CDC Interim Guidance for Zika Virus Antibody Testing and Interpretation

The Centers for Disease Control and Prevention (CDC) released interim guidance on May 31, 2016, regarding the testing and interpretation of Zika virus antibody results. The guidance emphasizes the need for a conservative approach to interpreting these tests to avoid missing diagnoses of either Zika or dengue virus infections, which require different clinical management strategies.

Zika virus is a single-stranded RNA virus belonging to the genus Flavivirus. It is closely related to several other viruses, including West Nile, Japanese encephalitis, yellow fever, and dengue viruses. Because of these close biological relationships, diagnostic testing can be complex.

The Challenge of Cross-Reactivity

A primary difficulty in diagnosing Zika virus infection is cross-reactivity. This occurs when antibody tests for Zika virus react to antibodies produced in response to other related flaviviruses. This cross-reactivity can prevent the identification of the specific virus that caused the infection.

The risk of cross-reactivity is particularly high in individuals who have been previously infected with or vaccinated against a related flavivirus. Because Zika and dengue virus share similar geographic distributions, transmission cycles, and symptoms of infection, distinguishing between the two is critical for patient care.

Diagnostic Testing Protocols

Diagnostic testing for Zika virus infection utilizes both molecular and serologic methods. The guidance outlines a specific sequence for interpreting these results.

For individuals suspected of having Zika virus disease, a positive real-time reverse transcription–polymerase chain reaction (rRT-PCR) result confirms the infection. However, a negative rRT-PCR result does not exclude the possibility of infection.

In cases where rRT-PCR results are negative, serologic testing using immunoglobulin (Ig) M and neutralizing antibody tests can be used to identify recent Zika virus infections. If the Ig M test results are inconclusive, equivocal, or positive, a plaque reduction neutralization test (PRNT) is required to confirm the diagnosis.

The CDC notes that the PRNT may also have limitations. Recent evidence indicates that a 4-fold higher titer by PRNT might not be sufficient to discriminate between anti-Zika virus antibodies and cross-reacting antibodies in all persons who have previously been vaccinated against or infected with a related flavivirus.

Clinical Management and Public Health Risks

The necessity for accurate interpretation stems from the vastly different clinical risks associated with Zika and dengue viruses.

Pregnant women with laboratory evidence of Zika virus infection require specific evaluation and management due to the risk of adverse pregnancy outcomes. These cases are reported to the Puerto Rico Zika Active Pregnancy Surveillance System or the U.S. Zika Pregnancy Registry for clinical follow-up.

In contrast, the primary concern for patients with clinically suspected dengue is the reduction of risk for shock, and hemorrhage. Proper management of dengue is essential to prevent these severe complications.

Because of these differing priorities, the CDC recommends that if serologic testing indicates a recent flavivirus infection but cannot definitively distinguish between Zika and dengue, patients should be clinically managed for both infections.

However, results of Zika virus antibody testing can be difficult to interpret because of cross-reactivity with related flaviviruses, which can preclude identification of the specific infecting virus, especially when the person previously was infected with or vaccinated against a related flavivirus.

Interim Guidance for Interpretation of Zika Virus Antibody Test Results

By adopting a more conservative approach to interpreting PRNT results, health providers aim to reduce the possibility of missing a diagnosis of either virus, ensuring that pregnant women receive the necessary monitoring and that dengue patients receive appropriate care to avoid life-threatening complications.