Detecting Vertical Zika Transmission: Emerging Diagnostic Approaches for an Emerged Flavivirus

Abstract

Zika virus (Zika) was recently responsible for a massive epidemic that spread throughout Latin America and beyond. Though Zika is typically asymptomatic or self-limiting, the sheer numbers of Zika infections led to the identification of unexpected phenotypes including sexual transmission, Guillain-Barrésyndrome, and teratogenicity. Thousands of infants in South, Central, and North America have now been born with microcephaly or one of a number of fetal anomalies constituting the congenital Zika syndrome (CZS). Diagnosing CZS is based on a combination of clinical risk assessment and laboratory testing (which includes determining whether the mother has experienced a possible Zika infection during her pregnancy). A newborn suspected of having congenital Zika infection (due to maternal Zika infection or a birth defect described in association with congenital Zika infection) is then specifically tested for presence of Zika virus in neonatal tissue or anti-Zika IgM in the blood or cerebrospinal fluid. Though the guidelines are clear, there is room for considerable practice variation to emerge from individualized patient−provider encounters, largely due to limitations in diagnostic testing for Zika. The natural history of Zika further obscures our ability to know who, when, and how to test. Molecular diagnostics are highly specific but may not serve well those with asymptomatic infection. Serologic assays expand the diagnostic window but are complicated by cross-reactivity among related flaviviruses and passive immunity transferred from mother to baby. Furthermore, existing and emerging diagnostic tools may not be widely available due to limitations in resources and infrastructure of health systems in affected areas. Improvements in assay parameters as well as advances in platforms and deployability hold promise for optimizing diagnostic approaches for congenital Zika infection. The diagnostic tools and technologies under development must be integrated with forthcoming clinical knowledge of congenital Zika infection to fully realize the value that laboratory testing holds for diagnosing in utero mother to child transmission but also for understanding, predicting, and managing the health outcomes due to congenital Zika infection.

Persistence of Anti-ZIKV-IgG over Time Is Not a Useful Congenital Infection Marker in Infants Born to ZIKV-Infected Mothers: The NATZIG Cohort

“…Fetal viremia and viruria have not yet been fully described, making it difficult to predict if fetuses exposed early in pregnancy, usually the most severely affected [2,7], would still have detectable RNA at birth [9]. Additionally, the wide variety of molecular test systems used worldwide, the lack of standardization and the resulting low concordance across different platforms/laboratories, and the overall variable and low sensitivity [24,25] are important limitations of RT-PCR for the diagnosis of ZIKV congenital infection.…”

Early maternal Zika infection predicts severe neonatal neurological damage: results from the prospective Natural History of Zika Virus Infection in Gestation cohort study

“…13 However, compared with other congenital infections, confirmation of infant ZIKV infection remains a challenge because no available nucleic acid or serological tests have been validated for this purpose. 36 Only a proportion of infants with the typical CZS phenotype are ZIKV-positive. [37][38][39] Consequently, figures based on the detection of nucleic acids or antibodies might underestimate the true vertical transmission rate, and all ZIKV-exposed babies should be considered at risk for potential late consequences.…”

“…A single study that systematically tested infants born to ZIKV‐infected mothers estimated a 20–30% maternal–fetal transmission rate 13 . However, compared with other congenital infections, confirmation of infant ZIKV infection remains a challenge because no available nucleic acid or serological tests have been validated for this purpose 36 . Only a proportion of infants with the typical CZS phenotype are ZIKV‐positive 37–39 .…”

Gross Motor Function in Children with Congenital Zika Syndrome

“…7 Therefore, no known specific criteria are capable of identifying all cases of CZS; a combination of clinical and risk assessments, clinical knowledge, and laboratory testing to create hierarchical classes of evidence of ZIKV infection, 7 as adopted in this study, is necessary. 6 Almost all clinical and socioeconomic characteristics (except for maternal age at the beginning of a GMFM-66 score (95% confidence interval). b Significant increase in the GMFM-66 score on the second assessment.…”

“…Molecular tests used to detect viral genomic material are the preferred method of diagnosis because they can provide confirmed evidence of infection, according to the Centers for Disease Control and Prevention (CDC), but due to the temporal nature of ZIKV RNA in serum and urine, these tests often produce false-negative results. 6 ZIKV immunoglobulin (Ig) M antibody testing, followed by the plate reduction neutralization test (PRNT) for ZIKV, expands the diagnostic window and is recommended by the CDC in certain situations. However, it has recently been shown that negative PRNT results do not exclude the diagnosis of CZS, since among mothers who were ZIKV-positive according to qRT-PCR (real-time quantitative polymerase chain reaction), 51.5% had a negative PRNT result.…”