New England Journal of Medicine
March 10, 2016 Vol. 374 No. 10
http://www.nejm.org/toc/nejm/medical-journal

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Brief Report
Zika Virus Associated with Microcephaly
Jernej Mlakar, M.D., Misa Korva, Ph.D., Nataša Tul, M.D., Ph.D., Mara Popović, M.D., Ph.D., Mateja Poljšak-Prijatelj, Ph.D., Jerica Mraz, M.Sc., Marko Kolenc, M.Sc., Katarina Resman Rus, M.Sc., Tina Vesnaver Vipotnik, M.D., Vesna Fabjan Vodušek, M.D., Alenka Vizjak, Ph.D., Joze Pizem, M.D., Ph.D., Miroslav Petrovec, M.D., Ph.D., and Tatjana Avsic Zupanc, Ph.D.
Abstract
A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

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Editorial
Zika Virus and Microcephaly
Eric J. Rubin, M.D., Ph.D., Michael F. Greene, M.D., and Lindsey R. Baden, M.D.
DOI: 10.1056/NEJMe1601862
[Extract]
…Zika virus has spread explosively since its introduction into South America and has now been found throughout Central America and the Caribbean. The full extent of disease is not clear — most infections are asymptomatic and many are associated with only mild disease.6 But the apparent risk of microcephaly was enough for the World Health Organization to declare a public health emergency of international concern on February 1.

What more do we need to know to help us manage and control this outbreak? Certainly, understanding the disease better could have long-term benefits, including the development of protective vaccines. However, it is the information that we do not yet have that has potential immediate applications.

Although many authorities are counseling women who are pregnant or could become pregnant to avoid travel to affected areas, the millions of women who live in these places are faced with enormous uncertainty, and as the virus spreads, many more will be affected. For example, assuming the association between Zika virus and microcephaly exists, we do not know whether the timing of the infection during pregnancy has an effect on the risk of fetal abnormalities, nor do we have any idea of the magnitude of that risk. The development of rapid, scalable diagnostic tests is needed, since the current polymerase-chain-reaction assay detects viral RNA and thus should be positive only during the period of viremia, which may be relatively short.

Current serologic assays have considerable cross-reactivity with other flaviviruses, including those that are endemic in the same areas (as in the case now being reported), and serologic assays specific for Zika virus are not easily available. Thus, it may be difficult to determine retrospectively whether a woman has been infected. This will be particularly difficult in areas where dengue virus and other pathogens can cause symptoms similar to those of the Zika virus.
In addition, it is unclear whether asymptomatic or minimally symptomatic disease poses a risk to the fetus. It is possible that as is the case with mumps, early infection could result in fetal loss rather than malformations. And, as in this case report, ultrasonography may detect severe fetal abnormalities only very late in gestation — in many cases, too late to terminate the pregnancy. Is there a sensitive test that can be applied earlier? And is previous infection protective?

Although we need a good deal of research to define critical aspects of infection, there is much to do immediately. A vulnerable point for Zika virus transmission is the mosquito vector. Unfortunately, mosquito-control efforts have failed to curtail the spread of many similar pathogens, including dengue and chikungunya viruses, which are carried by the same aedes species and are spreading in the same communities currently affected by the Zika virus. Perhaps this new threat will help boost such control efforts with the use of both old and new approaches. Women need to have access to relevant health care services, including contraception, diagnostics, and pregnancy-termination services. And the many affected children need to have care. Coming shortly after the global response to the Ebola virus, the rapid spread of the Zika virus reminds us how connected we all are.7 Once again, an outbreak is going to challenge our public health infrastructure and require a substantial response.