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

Ricardo Arraes De Alencar Ximenes,Thalia Velho Barreto De Araújo,Celina Maria Turchi Martelli,Laura C Rodrigues,Wayner Vieira De Souza,Ernesto T A Marques,Priscila Mayrelle Da Silva Castanha,Rafael Dhália,Demócrito De Barros Miranda-Filho,Elizabeth B Brickley,Rafael F O França,Maria De Fatima Pessoa Militão De Albuquerque,Ulisses Ramos Montarroyos,David Harley

doi:10.1371/journal.pntd.0007763

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.

Highlights

Defining cases is a universal challenge of epidemiological studies on Zika virus (ZIKV)
On February 1, 2016, the World Health Organization declared a Public Health Emergency of International Concern following a “cluster of microcephaly cases and other neurological disorders in Brazil” and highlighted the “urgent need” for coordinated international efforts to investigate the relationship between maternal Zika virus (ZIKV) infections and microcephaly
We report the experience of the Microcephaly Epidemic Research Group in Pernambuco, Brazil, in evaluating 694 pregnant women presenting with rash during the 2015–2017 Latin American outbreak

Summary

Introduction

Defining cases is a universal challenge of epidemiological studies on Zika virus (ZIKV) This problem is exacerbated in regions with co-circulating arthropod-borne viruses (arboviruses) due to overlapping and often mild clinical features [1], the potential for immunologic crossreactivity with other flaviviruses [2,3,4], and the current lack of an optimal ZIKV-specific diagnostic assay for diagnosing recent infections [5,6,7]. The epidemiological case definitions used to define maternal ZIKV infections in recent studies reflect pragmatic considerations (e.g., availability and affordability of relevant diagnostic tests), the recency of sample collections relative to the suspected infections (e.g., timing in returning travelers), and the local epidemiological contexts (e.g., presence or absence of autochthonous transmission, circulation of other flaviviruses). In the investigation by Pomar, et al (2018), which enrolled symptomatic and asymptomatic pregnant women in western French Guiana, ZIKV exposure was laboratory-confirmed by qRT-PCR, IgM and a micro-neutralizing assay; notably, this investigation included subsequent IgM cord blood testing of the neonates to confirm congenital infection [12]

Methods

Results

Discussion

Conclusion