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      Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review

      systematic-review

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          Abstract

          Background: The Zika virus (ZIKV) caused a large outbreak in the Americas leading to the declaration of a Public Health Emergency of International Concern in February 2016. A causal relation between infection and adverse congenital outcomes such as microcephaly was declared by the World Health Organization (WHO) informed by a systematic review structured according to a framework of ten dimensions of causality, based on the work of Bradford Hill. Subsequently, the evidence has continued to accumulate, which we incorporate in regular updates of the original work, rendering it a living systematic review.

          Methods: We present an update of our living systematic review on the causal relation between ZIKV infection and adverse congenital outcomes and between ZIKV and GBS for four dimensions of causality: strength of association, dose-response, specificity, and consistency. We assess the evidence published between January 18, 2017 and July 1, 2019.

          Results: We found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (OR 3.8, 95% CI: 1.7-8.7, I 2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0-127.1, I 2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9-13.5, I 2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I 2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8-5.4, I 2=74.6%). In case-control studies, selection of controls from hospitals could have biased results.

          Conclusions: The conclusions that ZIKV infection causes adverse congenital outcomes and GBS are reinforced with the evidence published between January 18, 2017 and July 1, 2019.

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          Most cited references247

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          A structural approach to selection bias.

          The term "selection bias" encompasses various biases in epidemiology. We describe examples of selection bias in case-control studies (eg, inappropriate selection of controls) and cohort studies (eg, informative censoring). We argue that the causal structure underlying the bias in each example is essentially the same: conditioning on a common effect of 2 variables, one of which is either exposure or a cause of exposure and the other is either the outcome or a cause of the outcome. This structure is shared by other biases (eg, adjustment for variables affected by prior exposure). A structural classification of bias distinguishes between biases resulting from conditioning on common effects ("selection bias") and those resulting from the existence of common causes of exposure and outcome ("confounding"). This classification also leads to a unified approach to adjust for selection bias.
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            Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain–Barré Syndrome: Systematic Review

            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.
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              Zika virus and microcephaly: why is this situation a PHEIC?

              When the Director-General of WHO declared, on Feb 1, 2016, that recently reported clusters of microcephaly and other neurological disorders are a Public Health Emergency of International Concern (PHEIC), 1 it was on the advice of an Emergency Committee of the International Health Regulations and of other experts whom she had previously consulted. We are the members of the Emergency Committee, and we were identified by the Director-General from rosters of experts that had been submitted by WHO Member States. Our advice to declare a PHEIC was not made on the basis of what is currently known about Zika virus infection. During our discussions it became clear that infection with the Zika virus, unlike other arbovirus infections including dengue and chikungunya, causes a fairly mild disease with fever, malaise, and at times a maculopapular rash, conjunctivitis, or both. 2 Additional information from previous outbreaks suggested that about 20% of people infected with Zika virus develop these symptoms, and that the rest are asymptomatic. 2 Fatality from Zika virus infection is thought to be rare. 2 Our advice to declare a PHEIC was rather made on the basis of what is not known about the clusters of microcephaly, Guillain-Barré syndrome, and possibly other neurological defects reported by country representatives from Brazil and retrospectively from French Polynesia that are associated in time and place with outbreaks of Zika infection.3, 4 The Emergency Committee meeting was convened rapidly by WHO. We were contacted by the Director-General 4 days before the Emergency Committee meeting, and by the time we met WHO had thoroughly prepared the meeting. At the start of the meeting, the WHO legal counsel provided three criteria to help the Emergency Committee decide whether the present situation was a PHEIC. A PHEIC must: (1) constitute a health risk to other countries through international spread; (2) potentially require a coordinated response because it is unexpected, serious, or unusual; and (3) have implications beyond the affected country that could require immediate action. Representatives from four countries (Brazil, El Salvador, France, and the USA) that have had either outbreaks or importations of Zika virus, and a group of arbovirus specialists, took part in the meeting. Some of them had been working for the past months with the WHO Regional Office in the Americas on the Zika virus outbreaks, and before that on those caused by the dengue and chikungunya viruses. During one country representative's account of Zika virus in French Polynesia, robust and convincing retrospective data were presented about an increase in neurological disorders during the period when there was an outbreak of Zika virus. Other presentations described current clusters of microcephaly and limited information about Zika virus identified in fetuses or infants, pointing out the temporal association with circulation of the Zika virus. After these country presentations, and comments by the assembled arbovirologists, we were able to discern as a committee, and then agree unanimously in an initial poll, that the clusters of microcephaly and neurological disorders, and their possible association with the Zika virus, constituted a PHEIC. Upon further discussion, it became clear that there was no standard surveillance case definition for microcephaly. The first recommendation of the PHEIC was to call for standardised and enhanced surveillance of microcephaly in areas of known Zika virus transmission. Such surveillance is not only important in countries where there are current and recent outbreaks, but is also retrospectively relevant in African and Asian countries where outbreaks have been occurring since the Zika virus was first identified in 1947.5, 6 Further, we felt that surveillance data should become available within months. © 2016 Fabrice Coffrini 2016 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Our second recommendation under the PHEIC is for increased research into the aetiology of confirmed clusters of microcephaly and neurological disorders to determine whether there is a causative link to Zika virus, other factors, and cofactors. Neurological fetal defects occur with other viral infections such as rubella, which are preventable by vaccine, 7 and could also be caused by factors such as exposure to chemicals or toxins and other environmental factors.8, 9 We understood that this PHEIC recommendation will take much longer to implement than surveillance, and will require accumulation of scientific evidence from post-mortem analyses, case-control studies, and other studies as recommended by experts in microcephaly, obstetric and neonatal medicine, and public health. Part of our discussion also included the need for development of an animal model, and of the possibility of eventually proving Koch's postulates. After our discussion on the PHEIC, there was unanimous agreement to make recommendations for precautionary measures to prevent arboviral infection. In addition to being good public health practice, which would be intensified should the clusters of microcephaly and other neurological disorders be linked to the Zika virus, they should also result in the prevention of chikungunya and dengue outbreaks.10, 11, 12 Among those recommendations were the need for: stronger surveillance of Zika virus infection with the rapid development and sharing of diagnostics suitable for seroprevalence studies and that do not require antigen presence; improved communication about the risks of outbreaks of Zika and other arboviruses; implementation of vector control measures to decrease exposure to bites from the Aedes aegypti mosquito; and guidance to be available to pregnant women so that they better understand the present situation and are empowered to make a decision about personal protection and pregnancy. We also provided longer-term advice to the Director-General to continue discussions with vaccine developers and regulatory agencies that WHO had already begun, to provide regular and clear guidance on risks associated with travel, and to ensure that all countries share data as they work with WHO to address the recommendations of the PHEIC. Since the Emergency Committee meeting we have continued to communicate among ourselves, and our hope is that WHO will work in the way that successfully led to control of the outbreak of severe acute respiratory syndrome (SARS) in 2003 when WHO established virtual networks of experts around the world who worked by telephone and the internet to collaborate in surveillance, clinical management, and research.13, 14, 15 The networks established during the SARS outbreak worked in environments that provided the confidentiality and security necessary to freely share data used for improving public health. With policies recently developed by The Lancet and other medical journals to accept for publication data that may have previously been shared openly for better outbreak prevention and control, we believe that there should be no excuse for not creating such an environment for sharing of data collected under the PHEIC.16, 17 Since the Director-General declared the PHEIC on microcephaly and neurological disorders, many of us have had questions about how our recommendation relates to the PHEIC called by the Director-General for the 2014 Ebola outbreaks in west Africa based on the recommendation of a different Emergency Committee. The answer to us is clear. The Director-General declared the Ebola outbreaks a PHEIC because of what science knew about the Ebola virus from many years of research during outbreaks in the past, whereas she declared the current PHEIC because of what is not known about the current increase in reported clusters of microcephaly and other disorders, and how this might relate to concurrent Zika outbreaks. We were told by the Director-General that she would convene us again within 3 months to reassess the situation, as required under the International Health Regulations. We are confident that virtual meetings will allow us to review global collective action and to learn from WHO about progress in understanding the present situation of microcephaly and neurological disorders and progress in implementation of the precautionary and preparatory measures related to Zika.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: InvestigationRole: MethodologyRole: Project AdministrationRole: VisualizationRole: Writing – Original Draft Preparation
                Role: Data CurationRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – Review & Editing
                Role: Data CurationRole: ValidationRole: Writing – Review & Editing
                Role: ValidationRole: Writing – Review & Editing
                Role: ValidationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Data CurationRole: Funding AcquisitionRole: SupervisionRole: ValidationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                14 August 2019
                2019
                : 8
                : 1433
                Affiliations
                [1 ]Institute of Social and Preventive Medicine, University Bern, Bern, Switzerland
                [2 ]Acute Febrile Illnesses Laboratory, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil
                [3 ]Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
                [1 ]Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil
                [1 ]Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India
                Author notes

                No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0003-1039-6873
                https://orcid.org/0000-0002-3545-5238
                https://orcid.org/0000-0003-4817-8986
                Article
                10.12688/f1000research.19918.1
                6852328
                6cdc1fd9-662b-40e2-9318-5c2a8752da25
                Copyright: © 2019 Counotte MJ et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 August 2019
                Funding
                Funded by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
                Award ID: 320030_170069
                This work was supported by the Swiss National Science Foundation [320030_170069], end date: 31/10/2021
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Systematic Review
                Articles

                zika,disease outbreaks,arboviruses,causality,guillain-barré syndrome,congenital abnormalities

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