Zika virus infection and risk of Guillain-Barré syndrome: A meta-analysis


      • GBS cases in case reports likely included ZIKV infection as a diagnostic criterion.
      • Outbreaks of ZIKV infection were not consequentially followed by outbreaks of GBS.
      • Major biases were likely in all but one analytic study of the ZIKV-GBS association.
      • The average ZIKV-GBS odds ratio in analytic studies was 1.57 (95% CI: 0.86–2.86).
      • The available evidence is insufficient to claim ZIKV infection causes GBS.



      Findings from studies of the association between Zika virus (ZIKV) infection and Guillain-Barré syndrome (GBS) are inconsistent. I conducted a systematic review and meta-analysis to clarify the nature of this association.


      I searched PubMed, Scopus, Cochrane, CINAHL, Web of Science, Scielo, and DOAJ for case report, ecological, and analytic studies with “Zika” and “Guillain-Barré syndrome” as keywords, published up to July 1stth 2018. I evaluated if ZIKV infection status influenced the diagnosis of GBS (detection bias) in case-report and analytic studies; assessed if changes in weekly number of cases of ZIKV infection during outbreaks were followed by changes in number of GBS cases 1–8 weeks later; gauged the likelihood of selection, confounding, information, sparse data, and time-dependent bias (i.e. when ZIKV infection was ascertained after GBS onset) in analytic studies; and calculated the average ZIKV-GBS odds ratio (OR) in studies without time-dependent bias.


      In case reports, ZIKV infection prevalence in GBS cases was 2.4 to 25 times higher than expected. Changes in the number of ZIKV-infection cases during outbreaks were not consequentially followed by changes in the number of GBS cases (OR: 1.01; 95% CI: 0.99–1.03). Major biases were likely in all but one analytic study, which showed a non-significant ZIKV-GBS association. The average ZIKV-GBS OR in studies without time-dependent bias was 1.57 (95% CI: 0.86–2.86).


      These findings indicate the available evidence is insufficient to claim ZIKV infection causes GBS. Therefore, stakeholders may want to reconsider current ZIKV-GBS public health and patient care recommendations.


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        • Duffy M.R.
        • Chen T.H.
        • Hancock W.T.
        • et al.
        Zika virus outbreak on Yap Island, Federated States of Micronesia.
        N. Engl. J. Med. 2009; 360: 2536-2543
        • World Health O
        Zika Situation Report: Zika Virus, Microcephaly and Guillain-Barré Syndrome.
        • World Health O
        Zika Strategic Response Plan.
        (Revised for July 2016-December 2017) WHO Press, Geneva, Zwitzerland2016 (Available from)
        • Brasil P.
        • Sequeira P.C.
        • Freitas A.D.
        • et al.
        Guillain-Barre syndrome associated with Zika virus infection.
        Lancet. 2016; 387: 1482
        • Oehler E.
        • Watrin L.
        • Larre P.
        • et al.
        Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013.
        Eur. Surveill. 2014; 19 (Available from:)
        • Paploski I.A.
        • Prates A.P.
        • Cardoso C.W.
        • et al.
        Time lags between exanthematous illness attributed to Zika virus, Guillain-Barre syndrome, and microcephaly, Salvador, Brazil.
        Emerg. Infect. Dis. 2016; 22: 1438-1444
        • dos Santos T.
        • Rodriguez A.
        • Almiron M.
        • et al.
        Zika virus and the Guillain-Barré syndrome -case series from seven countries.
        N. Engl. J. Med. 2016; 375: 1598-1601
        • Styczynski A.R.
        • Malta J.
        • Krow-Lucal E.R.
        • et al.
        Increased rates of Guillain-Barre syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil.
        PLoS Negl. Trop. Dis. 2017 Aug; 11e0005869
        • Salinas J.L.
        • Walteros D.M.
        • Styczynski A.
        • et al.
        Zika virus disease-associated Guillain-Barré syndrome —Barranquilla, Colombia 2015-2016.
        J. Neurol. Sci. 2017; 381: 272-277
        • Simon O.
        Zika virus outbreak in New Caledonia and Guillain-Barré syndrome: a case-control study.
        J. Neuro-Oncol. 2018; 24: 362-368
        • Dirlikov E.
        • Medina N.A.
        • Major C.G.
        • et al.
        Acute Zika virus infection as a risk factor for Guillain-Barre syndrome in Puerto Rico.
        JAMA. 2017 Oct 17; 318: 1498-1500
        • GeurtsvanKessel C.H.
        • Islam Z.
        • Islam M.B.
        • et al.
        Zika virus and Guillain-Barre syndrome in Bangladesh.
        Ann. Clin. Transl. Neurol. 2018 May; 5: 606-615
        • Cao-Lormeau V.M.
        • Blake A.
        • Mons S.
        • et al.
        Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.
        Lancet. 2016; 387: 1531-1539
        • Bautista L.E.
        • Sethi A.K.
        Association between Guillain-Barre syndrome and Zika virus infection.
        Lancet. 2016; 387: 2599-2600
        • Leis A.A.
        • Stokic D.S.
        Zika virus and Guillain-Barré syndrome: is there sufficient evidence for causality?.
        Front. Neurol. 2016; 7: 170
        • Bautista L.E.
        On the temporal association of outbreaks of Zika virus infection, newborn microcephaly, and Guillain-Barré syndrome.
        JPHE. 2017;
        • Susser M.
        What is a cause and how do we know one? A grammar for pragmatic epidemiology.
        Am. J. Epidemiol. 1991; 133: 635-648
        • Fokke C.
        • van den Berg B.
        • Drenthen J.
        • Walgaard C.
        • van Doorn P.A.
        • Jacobs B.C.
        Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria.
        Brain. 2014; 137: 33-43
        • Pan_American_Health_Organization
        Guidelines for Zika Virus Disease and Complications Surveillance.
        PAHO, Washington, D.C2016 (Available from)
        • Mitchell M.
        Engauge Digitizer.
        (A free open-source software to extract data points from a graph imageHosted at)
        • Stolwijk A.M.
        • Straatman H.
        • Zielhuis G.A.
        Studying seasonality by using sine and cosine functions in regression analysis.
        J. Epidemiol. Community Health. 1999; 53: 235-238
        • Hoover K.D.
        Nonstationary time series, cointegration, and the principle of the common cause.
        Br. J. Philos. Sci. 2003; 54: 527-551
        • Harris R.J.
        • Bradburn M.J.
        • Deeks J.J.
        • Harbord R.M.
        • Altman D.G.
        • Sterne J.A.C.
        Metan: fixed- and random-effects meta-analysis.
        Stata J. 2008; 8 (Available from): 3-28
        • Sejvar J.J.
        • Baughman A.L.
        • Wise M.
        • Morgan O.W.
        Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis.
        Neuroepidemiology. 2011; 36 (03/21): 123-133
        • Tam C.C.
        • O'Brien S.J.
        • Petersen I.
        • Islam A.
        • Hayward A.
        • Rodrigues L.C.
        Guillain-Barré syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database.
        PLoS ONE. 2007; 2e344
        • Dirlikov E.
        • Major C.G.
        • Medina N.A.
        • et al.
        Clinical Features of Guillain-Barre Syndrome With vs Without Zika Virus Infection, Puerto Rico, 2016.
        JAMA Neurol. 2018; (May 21)
        • van Walraven C.
        • Davis D.
        • Forster A.J.
        • Wells G.A.
        Time-dependent bias was common in survival analyses published in leading clinical journals.
        J. Clin. Epidemiol. 2004; 57 (2004/07/01/): 672-682
        • Greenland S.
        • Schwartzbaum J.A.
        • Finkle W.D.
        Problems due to small samples and sparse data in conditional logistic regression analysis.
        Am. J. Epidemiol. 2000; 151: 531-539
        • Aubry M.
        • Teissier A.
        • Huart M.
        • et al.
        Zika virus seroprevalence, French Polynesia, 2014-2015.
        Emerg. Infect. Dis. 2017; 23: 669-672
        • Williams M.
        • Ali A.
        Zika outbreak associated neurological syndromes in Jamaica.
        West Indian Med. J. 2016; 65: 438-441
        • Watrin L.
        • Ghawche F.
        • Larre P.
        • Neau J.P.
        • Mathis S.
        • Fournier E.
        Guillain-Barre syndrome (42 cases) occurring during a Zika virus outbreak in French Polynesia.
        Medicine. 2016; 95e3257
        • Parra B.
        • Lizarazo J.
        • Jimenez-Arango J.A.
        • et al.
        Guillain-Barre syndrome associated with Zika virus infection in Colombia.
        N. Engl. J. Med. 2016; 375: 1513-1523
        • MEBD Nóbrega
        • ELDL Araújo
        • Wada M.Y.
        • PLE Leite
        • Dimech G.S.
        • Pércio J.
        Outbreak of Guillain-Barré syndrome possibly related to prior Zika virus infection, Metropolitan Region of Recife, Pernambuco, Brazil, 2015.
        Epidemiologia e Serviços de Saúde. 2018; 27
        • Méndez N.
        • Oviedo-Pastrana M.
        • Mattar S.
        • Caicedo-Castro I.
        • Arrieta G.
        Zika virus disease, microcephaly and Guillain-Barré syndrome in Colombia: epidemiological situation during 21 months of the Zika virus outbreak, 2015–2017.
        Arch. Public Health. 2017; 75 (2017/11/02): 65
        • Jacobs B.C.
        • Bvd Berg
        • Verboon C.
        • et al.
        International Guillain-Barré syndrome outcome study: protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome.
        J. Peripher. Nerv. Syst. 2017; 22 (2017/06/01): 68-76
        • Asbury A.K.
        • Cornblath D.R.
        Assessment of current diagnostic criteria for Guillain-Barré syndrome.
        Ann. Neurol. 1990; 27 (S21-S4)
        • Direction_de_la_santé_._Bureau_de_veille_sanitaire
        Bulletin de Surveillance Sanitaire. Surveillance de la dengue et du zika en Polynésie française. Données actualisées au 27 décembre 2013.
        (Available from:)
        • World Health O
        Surveillance for Zika Virus Infection, Microcephaly and Guillain-Barré Syndrome: Interim Guidance.
        • Dirlikov E.
        • Major C.G.
        • Mayshack M.
        • et al.
        Guillain-Barré syndrome during ongoing Zika virus transmission - Puerto Rico, January 1–July 31, 2016.
        MMWR Morb. Mortal. Wkly Rep. 2016; 65 (2016/09//): 910-914
        • Arias A.
        • Torres-Tobar L.
        • Hernandez G.
        • et al.
        Guillain-Barre syndrome in patients with a recent history of Zika in Cucuta, Colombia: a descriptive case series of 19 patients from December 2015 to march 2016.
        J. Crit. Care. 2016; 37: 19-23
        • McGrogan A.
        • Madle G.C.
        • Seaman H.E.
        • de Vries C.S.
        The epidemiology of Guillain-Barré syndrome worldwide.
        Neuroepidemiology. 2009; 32: 150-163
        • Hughes R.A.C.
        • Rees J.H.
        Clinical and epidemiologic features of Guillain-Barré syndrome.
        J. Infect. Dis. 1997; 176 (S92-S8)
        • Morgenstern H.
        Ecologic studies in epidemiology: concepts, principles, and methods.
        Ann. Rev. Public Health. 1995; 16: 61-81
        • Kindhauser M.K.
        • Allen T.
        • Frank V.
        • Santhana R.S.
        • Dye C.
        Zika: the origin and spread of a mosquito-borne virus.
        Bull. World Health Organ. 2016; 94 (675-86C)
        • da Silva I.R.F.
        • Frontera J.A.
        • Bispo de Filippis A.M.
        • Nascimento O.
        Neurologic complications associated with the Zika virus in Brazilian adults.
        JAMA Neurol. 2017 Oct 1; 74: 1190-1198
        • Bautista L.E.
        • Herrera V.M.
        An assessment of public health surveillance of Zika virus infection and potentially associated outcomes in Latin America.
        BMC Public Health. 2018; 18 (2018/05/24): 656
        • Wilson H.L.
        • Tran T.
        • Druce J.
        • Dupont-Rouzeyrol M.
        • Catton M.
        Neutralization assay for Zika and dengue viruses by use of real-time-PCR-based endpoint assessment.
        J. Clin. Microbiol. 2017; 55: 3104
        • Nickerson R.S.
        Confirmation bias: a ubiquitous phenomenon in many guises.
        Rev. Gen. Psychol. 1998; 2: 175-220
        • MacCoun R.
        • Perlmutter S.
        Blind analysis: Hide results to seek the truth.
        Nature. 2015; 526: 187-189
        • Gustafson P.
        • McCandless L.C.
        Probabilistic approaches to better quantifying the results of epidemiologic studies.
        Int. J. Environ. Res. Public Health. 2010; 7: 1520-1539