Zika virus infection in pregnancy: Establishing a case definition for clinical research on pregnant women with rash in an active transmission setting

Abstract

Defining cases of Zika virus (ZIKV) infection is a critical challenge for epidemiological research. Due to ZIKV’s overlapping clinical features and potential immunologic cross-reactivity with other flaviviruses and the current lack of an optimal ZIKV-specific diagnostic assay, varying approaches for identifying ZIKV infections have been employed to date. This paper presents the laboratory results and diagnostic criteria developed by the Microcephaly Epidemic Research Group for defining cases of maternal ZIKV infection in a cohort of pregnant women with rash (N = 694) recruited during the declining 2015–2017 epidemic in northeast Brazil. For this investigation, we tested maternal sera for ZIKV by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Immunoglobulin (Ig) M and IgG3 enzyme-linked immunosorbent assays (ELISAs), and Plaque Reduction Neutralization Test (PRNT50). Overall, 23.8% of participants tested positive by qRT-PCR during pregnancy (range of detection: 0–72 days after rash onset). However, the inter-assay concordance was lower than expected. Among women with qRT-PCR-confirmed ZIKV and further testing, only 10.1% had positive IgM tests within 90 days of rash, and only 48.5% had ZIKV-specific PRNT50 titers ≥20 within 1 year of rash. Given the complexity of these data, we convened a panel of experts to propose an algorithm for identifying ZIKV infections in pregnancy based on all available lines of evidence. When the diagnostic algorithm was applied to the cohort, 26.9% of participants were classified as having robust evidence of a ZIKV infection during pregnancy, 4.0% as having moderate evidence, 13.3% as having limited evidence of a ZIKV infection but with uncertain timing, and 19.5% as having evidence of an unspecified flavivirus infection before or during pregnancy. Our findings suggest that integrating longitudinal data from nucleic acid and serologic testing may enhance diagnostic sensitivity and underscore the need for an on-going dialogue regarding the optimization of strategies for defining cases of ZIKV in research.

Congenital Zika syndrome: association between the gestational trimester of maternal infection, severity of brain computed tomography findings and microcephaly at birth

“…Furthermore, it has recently been shown that a negative PRNT does not exclude CZS. Among mothers with qRT-PCR positive for ZIKV, only 48.5% had a positive PRNT 23 . Considering that this case series was performed at a referral center, it is possible that children with more severe neurological symptoms were more likely to be referred to that center, which may have led to selection bias.…”

Pediatric neurodevelopment by prenatal Zika virus exposure: A cross-sectional study of the Microcephaly Epidemic Research Group Cohort

“…13 Group 3 included 94 children without microcephaly born to mothers who tested positive for ZIKV during pregnancy by one-step reverse-transcription polymerase chain reaction (RT-PCR) using primers and probes previously described by Lanciotti and et al 14 Detailed descriptions of the laboratory testing during pregnancy have been previously published. 15 Group 4 included 46 neurotypical children with no microcephaly nor any other brain abnormalities detectable by brain ultrasound at birth who were born to mothers with no laboratory evidence of ZIKV infection during pregnancy. The children in Group 4 were recruited at birth as the control group of a case-control study of microcephaly, whose detailed descriptions of ZIKV testing and clinical evaluations have been previously published.…”

Early epilepsy in children with Zika‐related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response

“…Zika virus (ZIKV) was identified as the teratogenic agent, and intrauterine ZIKV infections were observed to have repercussions for the formation and development of the fetal nervous system. 1,2 To address the public health emergency of congenital Zika syndrome (CZS), the Microcephaly Epidemic Research Group (MERG; http://www.cpqam.fiocr uz.br/merg/) was formed in late 2015 and subsequently initiated three epidemiological investigations: a case-control study of microcephaly, for which the results have been published, [3][4][5] a cohort study of pregnant women with rash, 6 and a cohort of children with potential prenatal exposure to ZIKV. In addition, MERG reported on a large case series of children with microcephaly 2 and proposed an initial description of CZS.…”