Editors' ChoiceInfectious diseases

The case against Zika virus

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Science Translational Medicine  09 Mar 2016:
Vol. 8, Issue 329, pp. 329ec40
DOI: 10.1126/scitranslmed.aaf3860

Several recently published case reports and many more stories in the popular press have linked congenital malformations—in particular, an abnormally small head (microcephaly)—to maternal infection with Zika virus (ZIKV), a mosquito-borne flavivirus newly emergent in the Americas. Although normal infants display a range of head sizes, a very small skull often signifies a brain that has failed to grow properly because fetal neurodevelopment has gone awry.

In the most comprehensive case report to date, Mlakar et al. describe the clinical course of a pregnant European woman working in northeastern Brazil. The patient experienced a self-limited febrile illness with rash at the end of her first trimester, coincident with local epidemic transmission of ZIKV. Later, a third-trimester ultrasound revealed severe fetal anomalies, including growth restriction, microcephaly, and calcium deposits in brain tissue. Fetal brain calcifications are often, although not always, a sign of transplacentally transmitted infections that portend a poor neonatal prognosis, and the patient elected to terminate the pregnancy at 32 weeks. A fetal autopsy confirmed microencephaly, a severely underdeveloped brain weighing well below the first percentile for age, with evidence of neuronal damage throughout the cerebral cortex. Total RNA isolated from fetal brain tissue contained the entire ZIKV genome, which could be assembled de novo from next-generation sequencing reads. Electron microscopy of brain sections demonstrated virus-like particles with the morphological characteristics of a flavivirus. In subsequent case reports by Calvet et al. and Sarno et al., detection of the ZIKV genome or of fetal antibodies against ZIKV in the amniotic fluid or brain of three other microcephalic infants also implied that a maternal ZIKV infection had been able to cross the placenta into the fetal compartment.

But the case against ZIKV is not closed. Even thoroughly investigated case reports such as these are never free of confounders that affect our interpretation of the clinical data. By definition, case reports demonstrate selection bias; case patients are written up specifically because they show an interesting or unusual phenotype (microcephaly), but that phenotype might not be representative of the larger cohort of concern (infants with prenatal exposure to ZIKV). The rare or new findings that make for a noteworthy case report also lead to observational bias—the search for confirmatory data where they are easiest to find. For example, looking for ZIKV in microcephalic infants is like looking for dropped car keys in the light of a streetlamp. To observe the full picture, one must also look in nonobvious places, such as neurologically normal infants born to mothers infected with ZIKV during pregnancy. Better than any other form of medical literature, case reports call attention to remarkable clinical findings, suggest possible disease mechanisms, and generate hypotheses for further research. Case reports cannot, however, prove causality, even when associations are observed repeatedly. Proof of causality will require rigorous research that continues long after the Zika media hype has died down.

J. Mlakar et al., Zika virus associated with microcephaly. N. Engl. J. Med. 10.1056/NEJMoa1600651 (2016). [Full text]

G. Calvet et al., Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: A case study. Lancet Infect. Dis. 10.1016/S1473-3099(16)00095-5 (2016). [Abstract]

M. Sarno et al., Zika virus infection and stillbirths: A case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl. Trop. Dis. 10, e0004517 (2016). [Full text]

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