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      Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain–Barré Syndrome: Systematic Review

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          Abstract

          Background

          The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain–Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causality require systematic assessment to guide public health actions. The objectives of this study were to update and reassess the evidence for causality through a rapid and systematic review about links between Zika virus infection and (a) congenital brain abnormalities, including microcephaly, in the foetuses and offspring of pregnant women and (b) GBS in any population, and to describe the process and outcomes of an expert assessment of the evidence about causality.

          Methods and Findings

          The study had three linked components. First, in February 2016, we developed a causality framework that defined questions about the relationship between Zika virus infection and each of the two clinical outcomes in ten dimensions: temporality, biological plausibility, strength of association, alternative explanations, cessation, dose–response relationship, animal experiments, analogy, specificity, and consistency. Second, we did a systematic review (protocol number CRD42016036693). We searched multiple online sources up to May 30, 2016 to find studies that directly addressed either outcome and any causality dimension, used methods to expedite study selection, data extraction, and quality assessment, and summarised evidence descriptively. Third, WHO convened a multidisciplinary panel of experts who assessed the review findings and reached consensus statements to update the WHO position on causality. We found 1,091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of ten causality dimensions (all except dose–response relationship and specificity), we found that more than half the relevant studies supported a causal association with Zika virus infection. For GBS, we included 36 items, of which more than half the relevant studies supported a causal association in seven of ten dimensions (all except dose–response relationship, specificity, and animal experimental evidence). Articles identified nonsystematically from May 30 to July 29, 2016 strengthened the review findings. The expert panel concluded that (a) the most likely explanation of available evidence from outbreaks of Zika virus infection and clusters of microcephaly is that Zika virus infection during pregnancy is a cause of congenital brain abnormalities including microcephaly, and (b) the most likely explanation of available evidence from outbreaks of Zika virus infection and GBS is that Zika virus infection is a trigger of GBS. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or GBS but agreed that the evidence was sufficient to recommend increased public health measures. Weaknesses are the limited assessment of the role of dengue virus and other possible cofactors, the small number of comparative epidemiological studies, and the difficulty in keeping the review up to date with the pace of publication of new research.

          Conclusions

          Rapid and systematic reviews with frequent updating and open dissemination are now needed both for appraisal of the evidence about Zika virus infection and for the next public health threats that will emerge. This systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.

          Abstract

          In a systematic review, Nicola Low and colleagues use a causality framework to examine the evidence for zika virus infection as a cause of congenital brain abnormalities and Guillain–Barré syndrome.

          Author Summary

          Why Was This Study Done?
          • In 2015, the mosquito-borne Zika virus caused epidemics of a mild viral illness for the first time in Brazil and then other countries in Latin America and the Caribbean.

          • In mid to late 2015, clinicians in northeastern Brazil reported unexpected increases in the numbers of babies born with abnormally small heads (microcephaly) and of adults with Guillain–Barré syndrome (GBS), a paralytic condition triggered by certain infections.

          • In February 2016, the World Health Organization (WHO) declared a Public Health Emergency of International Concern and called for research about the causal relationship between Zika virus and congenital brain abnormalities, including microcephaly, and GBS.

          What Did the Researchers Do and Find?
          • We developed a causality framework for Zika virus and (a) congenital brain abnormalities, and (b) GBS. For each outcome, we developed specific questions in ten different dimensions of causality: temporality; biological plausibility; strength of association; exclusion of alternative explanations; cessation; dose–response relationship; animal experimental evidence; analogy; specificity; and consistency of findings.

          • We did a systematic review of published and unpublished evidence up to May 30, 2016. We summarised the evidence descriptively. A panel of experts assessed the findings and reached a consensus about causality.

          • For congenital brain abnormalities, we assessed 72 studies that addressed questions in one or more causality dimensions. Reports of pregnancies affected by Zika virus have come from countries with circulating Zika virus in the Americas, the Pacific region, and West Africa. Clinical reports have documented Zika virus infection in pregnant women followed by foetal abnormalities, particularly with infection in the first trimester. These women did not have any other congenital infection or dengue virus infection. The risk of congenital brain abnormalities could be around 50 times higher in mothers who had Zika virus infection in pregnancy compared with those who did not. In laboratory studies, Zika virus has been shown to cross the placenta and replicate in human brain cells.

          • For GBS, we assessed 36 studies that addressed questions about one or more causality dimensions. In several countries in the Americas and the Pacific region, a temporal association has been found, with symptoms of Zika virus infection preceding the onset of GBS. In these countries, surveillance reports of cases of GBS followed the pattern of reports of Zika-like illness. During a Zika virus outbreak in French Polynesia in 2013–14, scientists estimated that around one in 4000 people with Zika virus infection developed GBS. The odds of having had a recent Zika virus infection were more than 30 times higher in patients with GBS than those without in a hospital-based study in French Polynesia. Several other infections that can trigger GBS were excluded.

          What Do These Findings Mean?
          • This systematic review found sufficient evidence to conclude that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.

          • Systematic reviews of evidence about emerging public health threats need to be updated frequently.

          Related collections

          Most cited references 63

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          Causation and causal inference in epidemiology.

          Concepts of cause and causal inference are largely self-taught from early learning experiences. A model of causation that describes causes in terms of sufficient causes and their component causes illuminates important principles such as multi-causality, the dependence of the strength of component causes on the prevalence of complementary component causes, and interaction between component causes. Philosophers agree that causal propositions cannot be proved, and find flaws or practical limitations in all philosophies of causal inference. Hence, the role of logic, belief, and observation in evaluating causal propositions is not settled. Causal inference in epidemiology is better viewed as an exercise in measurement of an effect rather than as a criterion-guided process for deciding whether an effect is present or not.
            Bookmark
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            • Article: not found

            Zika virus in Brazil and macular atrophy in a child with microcephaly.

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              • Article: not found

              Notes from the Field: Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses--Brazil, 2015.

              Zika virus is a mosquito-borne flavivirus that is related to dengue virus and transmitted primarily by Aedes aegypti mosquitoes, with humans acting as the principal amplifying host during outbreaks. Zika virus was first reported in Brazil in May 2015 (1). By February 9, 2016, local transmission of infection had been reported in 26 countries or territories in the Americas.* Infection is usually asymptomatic, and, when symptoms are present, typically results in mild and self-limited illness with symptoms including fever, rash, arthralgia, and conjunctivitis. However, a surge in the number of children born with microcephaly was noted in regions of Brazil with a high prevalence of suspected Zika virus disease cases. More than 4,700 suspected cases of microcephaly were reported from mid-2015 through January 2016, although additional investigations might eventually result in a revised lower number (2). In response, the Brazil Ministry of Health established a task force to further investigate possible connections between the virus and brain anomalies in infants (3).
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                3 January 2017
                January 2017
                : 14
                : 1
                Affiliations
                [1 ]Institute of Social and Preventive Medicine, University of Bern, Switzerland
                [2 ]Pan American Health Organization, Washington DC, United States of America
                [3 ]UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
                [4 ]Escuela de Microbiologia, Universidad Industrial de Santander, Santander, Colombia
                [5 ]Department of Social and Preventative Medicine, Laval University, Québec, Canada
                Mahidol-Oxford Tropical Medicine Research Unit, THAILAND
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: NL receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. FK and MR received salary support from WHO and/or SNSF to conduct the work. RMV was a consultant of PAHO. All other authors have declared that no competing interests exist.

                • Conceptualization: NL FK MR LR OTO NJB.

                • Data curation: FK MR AH.

                • Formal analysis: FK.

                • Funding acquisition: NL.

                • Investigation: NL FK MR LR RMV TVP AH.

                • Methodology: NL FK MR LR OTO NJB.

                • Project administration: FK NL NJB.

                • Supervision: NL NJB LR.

                • Visualization: FK MR NL.

                • Writing – original draft: FK NL LR OTO NJB.

                • Writing – review & editing: FK MR LR OTO TVP RMV AH NJB NL.

                ¶ Membership of the WHO Zika Causality Working Group is provided in the Acknowledgments.

                Article
                PMEDICINE-D-16-02753
                10.1371/journal.pmed.1002203
                5207634
                28045901
                © 2017 Krauer et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 1, Tables: 5, Pages: 27
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100004423, World Health Organization;
                Award ID: 2016/611294-0 and 2016/630126-0
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: SNSF special action fund and project grant 320030_170069
                Award Recipient :
                The review was funded by the World Health Organization ( www.who.int, contract numbers 2016/611294-0 and 2016/630126-0 awarded to NL) and the Swiss National Science Foundation ( www.snf.ch, SNSF special action fund and project grant 320030_170069 awarded to NL). The following World Health Organization staff are coauthors of the study: LR, OTO, and NJB. They were involved in the study design, data interpretation, decision to publish, and preparation of the manuscript. The WHO Zika Causality Working Group was involved in interpretation of the data and the decision to publish.
                Categories
                Research Article
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Flaviviruses
                Zika Virus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Flaviviruses
                Zika Virus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
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                Zika Virus
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                Congenital Disorders
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                All relevant data files are available from the Bern Open Repository and Information System (BORIS) ( http://boris.unibe.ch/90317/).

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