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• W2274670328 abstract "Until the French Polynesian outbreak in 2013–14, Zika virus disease was thought to be only a mild disease. During this outbreak, the incidence of Guillain-Barré syndrome was 20 times higher than expected.1Musso D Nilles EJ Cao-Lormeau VM Rapid spread of emerging Zika virus in the Pacific area.Clin Microbiol Infect. 2014; 20: O595-O596Summary Full Text Full Text PDF PubMed Scopus (473) Google Scholar Similarly, the emergence of Zika virus in the Americas since 2015 has been associated with a dramatic increase of reported cases of microcephaly.2PAHOWHOEpidemiological update: neurological syndrome, congenital anomalies, and Zika virus infection. Jan 17, 2016. World Health Organization, Geneva2016Google Scholar As for Zika virus and Guillain-Barré syndrome in French Polynesia, the temporal association between Zika virus outbreaks and microcephaly in Brazil strongly suggests that Zika virus infection during pregnancy might cause severe neurological damage in neonates. The challenge now is to provide empirical evidence for the link between Zika virus and microcephaly, and the demonstration that Zika virus can cross the placental barrier and infect the neonate strongly favours this association. In The Lancet Infectious Diseases, Guilherme Calvet and colleagues3Calvet G Aguiar RS Melo ASO et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.Lancet Infect Dis. 2016; (published online Feb 17.)http://dx.doi.org/10.1016/S1473-3099(16)00095-5Summary Full Text Full Text PDF Scopus (813) Google Scholar describe how they detected the Zika virus genome in the amniotic fluid of two pregnant women from Paraíba State in Brazil, whose fetuses had been diagnosed with microcephaly. Preliminary results of these cases have been published previously.4Oliveira Melo AS Malinger G Ximenes R Szejnfeld PO Alves Sampaio S Bispo de Filippis AM Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.Ultrasound Obstet Gynecol. 2016; 47: 6-7Crossref PubMed Scopus (636) Google Scholar Calvet and colleagues3Calvet G Aguiar RS Melo ASO et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.Lancet Infect Dis. 2016; (published online Feb 17.)http://dx.doi.org/10.1016/S1473-3099(16)00095-5Summary Full Text Full Text PDF Scopus (813) Google Scholar detected Zika virus genome in amniotic fluid by quantitative reverse transcription PCR (RT-PCR) and next-generation sequencing. If the aim of their case study was to confirm Zika virus congenital infection, molecular detection by RT-PCR was probably sufficient. The specificity of the RT-PCR and phylogenetic analysis can be determined by sequencing the RT-PCR product. IgM antibodies against Zika virus were detected in the amniotic fluid, but a plaque reduction neutralisation test was not done to confirm this result.5Oduyebo T Petersen EE Rasmussen SA et al.Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure—United States, 2016.MMWR Morb Mortal Wkly Rep. 2016; 65: 1-6Crossref PubMed Google Scholar Thus, cross-reactions with other flaviviruses cannot be excluded. In Brazil, Zika virus has also been detected in four microcephalic neonates in Rio Grande do Norte State (including the brain of two newborn babies who died within 24 h of birth);2PAHOWHOEpidemiological update: neurological syndrome, congenital anomalies, and Zika virus infection. Jan 17, 2016. World Health Organization, Geneva2016Google Scholar, 6European Centre for Disease Prevention and ControlZika virus disease epidemic: potential association with microcephaly and Guillain-Barré syndrome (first update). Jan 21, 2016. European Centre for Disease Prevention and Control, Stockholm2016Google Scholar and from tissues samples of one neonate in Ceará State.6European Centre for Disease Prevention and ControlZika virus disease epidemic: potential association with microcephaly and Guillain-Barré syndrome (first update). Jan 21, 2016. European Centre for Disease Prevention and Control, Stockholm2016Google Scholar Unfortunately, no cell culture result of Zika virus was available for any of these cases, including the cases reported by Calvet and colleagues.3Calvet G Aguiar RS Melo ASO et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.Lancet Infect Dis. 2016; (published online Feb 17.)http://dx.doi.org/10.1016/S1473-3099(16)00095-5Summary Full Text Full Text PDF Scopus (813) Google Scholar For six of the seven cases described above, mothers reported Zika-like symptoms during pregnancy. However, Zika virus infection can be misdiagnosed as another infection, or remain asymptomatic, and asymptomatic infection during pregnancy does not necessarily mean that the fetus will not develop microcephaly. Even if all these data strongly suggest that Zika virus can cause microcephaly, the number of microcephaly cases related to Zika virus is still unknown. The next step will be to do case-control studies to estimate the potential risk of microcephaly after Zika virus infection during pregnancy, other fetal or neonatal complications, and long-term outcomes for infected symptomatic and asymptomatic neonates. Expected complications might be similar to those of other infections assessed by the TORCH screen (eg, toxoplasmosis, rubella, cytomegalovirus, and herpes infections) and include mental retardation, cerebral palsy, seizure, and sensorineural hearing and visual loss.7Adams Waldorf KM McAdams RM Influence of infection during pregnancy on fetal development.Reproduction. 2013; 146: R151-R162Crossref PubMed Scopus (192) Google Scholar, 8Ville Y Leruez-Ville M Managing infections in pregnancy.Curr Opin Infect Dis. 2014; 27: 251-257Crossref PubMed Scopus (15) Google Scholar Such information is needed to allow adequate counselling in pregnant women possibly infected with Zika virus. Amniocentesis to detect Zika virus infection is now largely recommended9Petersen EE Staples JE Meaney-Delman D et al.Interim guidelines for pregnant women during a Zika virus outbreak—United States, 2016.MMWR Morb Mortal Wkly Rep. 2016; 65: 30-33Crossref PubMed Scopus (221) Google Scholar despite the shortage of information about the predictive positive value associated with molecular detection of Zika virus in amniotic fluid on the pregnancy outcome, especially in asymptomatic fetuses. As with other teratogenic viruses (eg, those assessed by TORCH),7Adams Waldorf KM McAdams RM Influence of infection during pregnancy on fetal development.Reproduction. 2013; 146: R151-R162Crossref PubMed Scopus (192) Google Scholar, 8Ville Y Leruez-Ville M Managing infections in pregnancy.Curr Opin Infect Dis. 2014; 27: 251-257Crossref PubMed Scopus (15) Google Scholar it is unlikely that 100% of infected fetuses will develop symptoms. The predictive positive value of detection of Zika virus in amniotic fluid on pregnancy outcomes should be urgently determined before potentially unnecessary amniocenteses are done. Several recommendations have been recently issued to improve diagnosis, notifications, and assessment of infants with microcephaly born to women with possible Zika virus infection during pregnancy.9Petersen EE Staples JE Meaney-Delman D et al.Interim guidelines for pregnant women during a Zika virus outbreak—United States, 2016.MMWR Morb Mortal Wkly Rep. 2016; 65: 30-33Crossref PubMed Scopus (221) Google Scholar, 10Staples JE Dziuban EJ Fischer M et al.Interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection—United States, 2016.MMWR Morb Mortal Wkly Rep. 2016; 65: 63-67Crossref PubMed Scopus (118) Google Scholar Laboratory investigations include Zika virus RT-PCR, histopathological examination, immunohistochemistry staining, and IgM detection with confirmation by a plaque reduction neutralisation test. However, most of these tests are restricted to specialised laboratories. According to the US Centers for Disease Control and Prevention, detection of Zika virus RNA or viral antigen in any sample from the neonate, or detection of neutralising antibodies (titres ≥4 times higher than dengue virus neutralising antibody titres) in neonatal blood or cerebrospinal fluid, confirm congenital Zika virus infection.10Staples JE Dziuban EJ Fischer M et al.Interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection—United States, 2016.MMWR Morb Mortal Wkly Rep. 2016; 65: 63-67Crossref PubMed Scopus (118) Google Scholar Calvet and colleagues3Calvet G Aguiar RS Melo ASO et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.Lancet Infect Dis. 2016; (published online Feb 17.)http://dx.doi.org/10.1016/S1473-3099(16)00095-5Summary Full Text Full Text PDF Scopus (813) Google Scholar found no evidence for recombination events in the Zika virus genome that they sequenced; however, the occurrence of genetic changes responsible for phenotypic changes are suspected and has been reported in other close-related viruses.6European Centre for Disease Prevention and ControlZika virus disease epidemic: potential association with microcephaly and Guillain-Barré syndrome (first update). Jan 21, 2016. European Centre for Disease Prevention and Control, Stockholm2016Google Scholar, 11Weaver SC Reisen WK Present and future arboviral threats.Antiviral Res. 2010; 85: 328-345Crossref PubMed Scopus (966) Google Scholar With respect to the increasing number of clinical cases, publications, guidelines, recommendations, and circulating data (confirmed or not) about Zika virus, centralisation of data and standardisation of practices are urgently needed. We declare no competing interests. DB is supported by the Department Femme-Mère-Enfant, the Fondation Leenaards through the Bourse pour la relève académique, and the Swiss National Science Foundation (no. 310030_156169/1). We thank Manon Vouga for critical review of this Comment. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case studyThese findings strengthen the putative association between Zika virus and cases of microcephaly in neonates in Brazil. Moreover, our results suggest that the virus can cross the placental barrier. As a result, Zika virus should be considered as a potential infectious agent for human fetuses. Pathogenesis studies that confirm the tropism of Zika virus for neuronal cells are warranted. Full-Text PDF" @default.
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