Highlights
- •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.
Abstract
Objective
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.
Methods
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.
Results
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).
Interpretation
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.
Keywords
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References
- Zika virus outbreak on Yap Island, Federated States of Micronesia.N. Engl. J. Med. 2009; 360: 2536-2543https://doi.org/10.1056/NEJMoa0805715
- Zika Situation Report: Zika Virus, Microcephaly and Guillain-Barré Syndrome.
- Zika Strategic Response Plan.(Revised for July 2016-December 2017) WHO Press, Geneva, Zwitzerland2016 (Available from)
- Guillain-Barre syndrome associated with Zika virus infection.Lancet. 2016; 387: 1482https://doi.org/10.1016/S0140-6736(16)30058-7
- Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013.Eur. Surveill. 2014; 19 (Available from:)https://doi.org/10.2807/1560-7917.ES2014.19.9.20720
- Time lags between exanthematous illness attributed to Zika virus, Guillain-Barre syndrome, and microcephaly, Salvador, Brazil.Emerg. Infect. Dis. 2016; 22: 1438-1444https://doi.org/10.3201/eid2208.160496
- Zika virus and the Guillain-Barré syndrome -case series from seven countries.N. Engl. J. Med. 2016; 375: 1598-1601https://doi.org/10.1056/NEJMc1609015
- Increased rates of Guillain-Barre syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil.PLoS Negl. Trop. Dis. 2017 Aug; 11e0005869https://doi.org/10.1371/journal.pntd.0005869
- Zika virus disease-associated Guillain-Barré syndrome —Barranquilla, Colombia 2015-2016.J. Neurol. Sci. 2017; 381: 272-277https://doi.org/10.1016/j.jns.2017.09.001
- Zika virus outbreak in New Caledonia and Guillain-Barré syndrome: a case-control study.J. Neuro-Oncol. 2018; 24: 362-368https://doi.org/10.1007/s13365-018-0621-9
- Acute Zika virus infection as a risk factor for Guillain-Barre syndrome in Puerto Rico.JAMA. 2017 Oct 17; 318: 1498-1500https://doi.org/10.1001/jama.2017.11483
- Zika virus and Guillain-Barre syndrome in Bangladesh.Ann. Clin. Transl. Neurol. 2018 May; 5: 606-615https://doi.org/10.1002/acn3.556
- Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.Lancet. 2016; 387: 1531-1539https://doi.org/10.1016/S0140-6736(16)00562-6
- Association between Guillain-Barre syndrome and Zika virus infection.Lancet. 2016; 387: 2599-2600https://doi.org/10.1016/S0140-6736(16)30844-3
- Zika virus and Guillain-Barré syndrome: is there sufficient evidence for causality?.Front. Neurol. 2016; 7: 170https://doi.org/10.8389/fneur.20i6.00170
- On the temporal association of outbreaks of Zika virus infection, newborn microcephaly, and Guillain-Barré syndrome.JPHE. 2017; https://doi.org/10.21037/jphe.2017.06.05
- What is a cause and how do we know one? A grammar for pragmatic epidemiology.Am. J. Epidemiol. 1991; 133: 635-648https://doi.org/10.1093/oxfordjournals.aje.a115939
- Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria.Brain. 2014; 137: 33-43https://doi.org/10.1093/brain/awt285
- Guidelines for Zika Virus Disease and Complications Surveillance.PAHO, Washington, D.C2016 (Available from)
- Engauge Digitizer.(A free open-source software to extract data points from a graph imageHosted at)
- Studying seasonality by using sine and cosine functions in regression analysis.J. Epidemiol. Community Health. 1999; 53: 235-238https://doi.org/10.1136/jech.53.4.235
- Nonstationary time series, cointegration, and the principle of the common cause.Br. J. Philos. Sci. 2003; 54: 527-551https://doi.org/10.1093/bjps/54.4.527
- Metan: fixed- and random-effects meta-analysis.Stata J. 2008; 8 (Available from): 3-28
- Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis.Neuroepidemiology. 2011; 36 (03/21): 123-133https://doi.org/10.1159/000324710
- Guillain-Barré syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database.PLoS ONE. 2007; 2e344https://doi.org/10.1371/journal.pone.0000344
- Clinical Features of Guillain-Barre Syndrome With vs Without Zika Virus Infection, Puerto Rico, 2016.JAMA Neurol. 2018; (May 21)https://doi.org/10.1001/jamaneurol.2018.1058
- Time-dependent bias was common in survival analyses published in leading clinical journals.J. Clin. Epidemiol. 2004; 57 (2004/07/01/): 672-682https://doi.org/10.1016/j.jclinepi.2003.12.008
- Problems due to small samples and sparse data in conditional logistic regression analysis.Am. J. Epidemiol. 2000; 151: 531-539https://doi.org/10.1093/oxfordjournals.aje.a010240
- Zika virus seroprevalence, French Polynesia, 2014-2015.Emerg. Infect. Dis. 2017; 23: 669-672https://doi.org/10.3201/eid2304.161549
- Zika outbreak associated neurological syndromes in Jamaica.West Indian Med. J. 2016; 65: 438-441https://doi.org/10.7727/wimj.2016.511
- Guillain-Barre syndrome (42 cases) occurring during a Zika virus outbreak in French Polynesia.Medicine. 2016; 95e3257https://doi.org/10.1097/MD.0000000000003257
- Guillain-Barre syndrome associated with Zika virus infection in Colombia.N. Engl. J. Med. 2016; 375: 1513-1523https://doi.org/10.1056/NEJMoa1605564
- 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; 27https://doi.org/10.5123/S1679-49742018000200016
- 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): 65https://doi.org/10.1186/s13690-017-0233-5
- 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): 68-76https://doi.org/10.1111/jns.12209
- Assessment of current diagnostic criteria for Guillain-Barré syndrome.Ann. Neurol. 1990; 27 (S21-S4)https://doi.org/10.1002/ana.410270707
- Bulletin de Surveillance Sanitaire. Surveillance de la dengue et du zika en Polynésie française. Données actualisées au 27 décembre 2013.(Available from:)
- Surveillance for Zika Virus Infection, Microcephaly and Guillain-Barré Syndrome: Interim Guidance.
- Guillain-Barré syndrome during ongoing Zika virus transmission - Puerto Rico, January 1–July 31, 2016.MMWR Morb. Mortal. Wkly Rep. 2016; 65 (2016/09//): 910-914https://doi.org/10.15585/mmwr.mm6534e1
- 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: 19-23https://doi.org/10.1016/j.jcrc.2016.08.016
- The epidemiology of Guillain-Barré syndrome worldwide.Neuroepidemiology. 2009; 32: 150-163https://doi.org/10.1159/000184748
- Clinical and epidemiologic features of Guillain-Barré syndrome.J. Infect. Dis. 1997; 176 (S92-S8)https://doi.org/10.1086/513793
- Ecologic studies in epidemiology: concepts, principles, and methods.Ann. Rev. Public Health. 1995; 16: 61-81https://doi.org/10.1146/annurev.pu.16.050195.000425
- Zika: the origin and spread of a mosquito-borne virus.Bull. World Health Organ. 2016; 94 (675-86C)https://doi.org/10.2471/BLT.16.171082
- Neurologic complications associated with the Zika virus in Brazilian adults.JAMA Neurol. 2017 Oct 1; 74: 1190-1198https://doi.org/10.1001/jamaneurol.2017.1703
- 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): 656https://doi.org/10.1186/s12889-018-5566-7
- Neutralization assay for Zika and dengue viruses by use of real-time-PCR-based endpoint assessment.J. Clin. Microbiol. 2017; 55: 3104https://doi.org/10.1128/JCM.00673-17
- Confirmation bias: a ubiquitous phenomenon in many guises.Rev. Gen. Psychol. 1998; 2: 175-220https://doi.org/10.1037/1089-2680.2.2.175
- Blind analysis: Hide results to seek the truth.Nature. 2015; 526: 187-189https://doi.org/10.1038/526187a
- Probabilistic approaches to better quantifying the results of epidemiologic studies.Int. J. Environ. Res. Public Health. 2010; 7: 1520-1539https://doi.org/10.3390/ijerph7041520
Article info
Publication history
Published online: June 20, 2019
Accepted:
June 17,
2019
Received in revised form:
May 23,
2019
Received:
March 25,
2019
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
