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Dirlikov E, Medina NA, Major CG, et al. Acute Zika Virus Infection as a Risk Factor for Guillain-Barré Syndrome in Puerto Rico. JAMA. 2017;318(15):1498–1500. doi:10.1001/jama.2017.11483
Guillain-Barré syndrome (GBS) is an uncommon autoimmune disorder characterized by progressive weakness and diminished deep tendon reflexes following infection or, rarely, vaccination.1 Increased GBS incidence has been reported in countries affected by Zika virus,2 a flavivirus transmitted primarily by Aedes species mosquitoes.3 During the Zika virus epidemic in Puerto Rico, we conducted a case-control study to identify risk factors associated with GBS.
This study was approved by the US Centers for Disease Control and Prevention and the University of Puerto Rico institutional review boards. Written informed consent was obtained from participants.
Potential case-patients were reported to public health authorities from 9 reference hospitals throughout Puerto Rico with a clinical suspicion of GBS and neurologic illness onset from April 2016 through December 2016. Case-patients were offered enrollment within 1 month of reported neurologic illness onset. GBS diagnosis was retrospectively confirmed by chart review using the Brighton Collaboration criteria after hospital discharge.4 Case-patients were matched to community controls 1:2 by age group (ie, 7-20, 21-39, 40-64, and >65 years) and place of residence (ie, ≤1-km radius from the residence of a case-patient). The control group included members of the community who lived continuously at the enrollment site for the previous 2 months and were enrolled within 1 week of the matched case-patient. Community control enrollment sites were identified using a randomly generated distance (ie, 0-1000 m) and degree from North (ie, 0°-359°) from each case-patient’s residence.
For all participants, a questionnaire was administered on demographics, behaviors, exposures, and medical history, including acute illness within the previous 2 months, and serum, urine, and saliva specimens were collected. Participants were defined as having acute Zika virus infection if they had a positive reverse transcription–polymerase chain reaction (RT-PCR) result in any specimen. Participants were defined as having laboratory evidence of Zika virus infection if they had a positive RT-PCR result in any specimen or anti–Zika virus immunoglobulin M (IgM) detected in serum by enzyme-linked immunosorbent assay.
Using SAS (SAS Institute), version 9.3, the Pearson χ2 test and 2 sample (2-sided) tests were used to analyze demographic variables. P values less than .05 were considered significant. Matched odds ratios (MORs) with 95% CIs were calculated to measure the association with risk factors, with CIs not including 1 considered significant.
All 47 potential case-patients reported from the 9 hospitals were enrolled, and GBS neurologic diagnosis was confirmed for 39 case-patients (83%). Compared with the 78 controls, the 39 case-patients did not differ by age, but were more often male (Table). Comparing case-patients and controls, identified GBS risk factors were acute illness within the previous 2 months (82% for case-patients vs 22% for controls; MOR, 12.8 [95% CI, 4.6-35.3]), including multiple symptoms; acute Zika virus infection (23% case-patients vs 4% controls; MOR, 16.0 [95% CI, 2.1-120.6]); and any laboratory evidence of Zika virus infection (69% case-patients vs 24% controls; MOR, 36.0 [95% CI, 4.9-262.5]). No other behaviors, exposures, or medical history variables were identified as risk factors.
By prospectively enrolling potential GBS case-patients and collecting specimens soon after onset of neurologic illness, 3 GBS risk factors were identified: acute illness within the previous 2 months (consistent with GBS pathophysiology), any laboratory evidence of Zika virus infection (consistent with a case-control study conducted in French Polynesia5), and acute Zika virus infection confirmed by RT-PCR. The latter finding adds to growing evidence of a causal association between Zika virus and GBS.
This study was limited by a small sample size, which resulted in wide CIs, unknown generalizability, inability to routinely identify alternative GBS triggers (eg, Campylobacter jejuni), and inability to assess timing of infection. The predominance of males among case-patients could be due to sampling bias because sex is not statistically associated with GBS and there was a greater proportion of female GBS patients with evidence of Zika virus infection during the 2016 Zika virus epidemic in Puerto Rico.6 The pathophysiology of Zika virus infection and risk factors for developing GBS require further investigation. Clinical trials of the Zika virus vaccine should monitor for GBS. During Zika virus outbreaks, clinical suspicion should be elevated to improve GBS patient prognosis through prompt diagnosis and treatment.
Accepted for Publication: July 27, 2017.
Corresponding Author: Emilio Dirlikov, PhD, Division of Scientific Education and Professional Development, Centers for Disease Control and Prevention, 1324 Calle Cañada, San Juan, Puerto Rico, 00920 (firstname.lastname@example.org).
Author Contributions: Dr Dirlikov had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Dirlikov, Rivera-Garcia, Sharp.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Dirlikov, Medina, Major, Sharp.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Dirlikov, Major, Sharp.
Obtained funding: Sharp.
Administrative, technical, or material support: Dirlikov, Medina, Major, Luciano, Rivera-Garcia, Sharp.
Supervision: Dirlikov, Luciano, Rivera-Garcia, Sharp.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Luciano reported grant funding from the University of Puerto Rico Medical Sciences. No other disclosures were reported.
Funding/Support: This work was supported by grant U54MD007587 from the National Institutes of Health (NIH; Dr Luciano).
Role of the Funder/Sponsor: The NIH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Disclaimer: The conclusions, findings, and opinions expressed by authors contributing to this article do not necessarily reflect the official position of the US Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention (CDC), or the authors' affiliated institutions.
Additional Contributions: We thank Dana Thomas, MD, James Sejvar, MD (both from the CDC), for their contributions to the study concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content, administrative, technical, or material support, and study supervision. We also thank Desiree Matos, RN; Roberta Lugo-Robles, MPH; Manuela Beltrán, MS; Rafael Tosado, PhD; Candimar Colon-Sanchez, MS; Damaris Laboy Fernández, BS; Koralys Torres Alicea, BS; Marrielle Mayshack, BS; Evelene Steward-Clark, MS; Peter Browning, MS; Vera Semenova, PhD; Ankit Shah, MS; Jarad Schiffer, MS; and Stephen H. Waterman, MD (all from the CDC); and Cesar A. Virgen, MD (University of California, San Diego), for their assistance in acquisition of data or administrative, technical, or material support. We thank the health practitioners and hospital staff at University District Hospital; Hospital Pediátrico Universitario; HIMA-San Pablo, Caguas and Bayamón; University of Puerto Rico Hospital—Dr Federico Trilla; Hospital Damas; Manatí Medical Center; Mayagüez Medical Center; and HealthSouth Rehabilitation Center, San Juan. These contributors did not receive compensation.
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