The association between Campylobacter infection and subsequent Guillain-Barre syndrome (GBS) has been well documented. To date, however, there exists no direct estimate of the incidence of GBS among patients with Campylobacter infection. Using the General Practice Research Database, we estimate the incidence of GBS in a cohort of patients presenting with Campylobacter enteritis to be 1.17/1000 person-years, a rate 77 times greater than that in the general population. The probability that an individual who develops Campylobacter enteritis will also develop GBS during the subsequent 2-month period is < 2/10,000

Hayward, A

Islam, A

O'Brien, SJ

Petersen, I

Rodrigues, LC

Tam, CC

English

UCL Discovery

BRIEF REPORT • JID 2006:194 (1 July) • 95BRIEF REPORTIncidence of Guillain-Barre ´ Syndromeamong Patients with CampylobacterInfection: A General Practice ResearchDatabase StudyClarence C. Tam,1,2 Laura C. Rodrigues,1 Irene Petersen,3 Amir Islam,3Andrew Hayward,3 and Sarah J. O’Brien41Infectious Disease Epidemiology Unit, Department of Epidemiologyand Population Health, London School of Hygiene and Tropical Medicine,2Environmental and Enteric Diseases Department, Health Protection AgencyCentre for Infections, and3Department of Primary Care and PopulationSciences, University College, London, and4Division of Medicineand Neuroscience, School of Medicine, University of Manchester,Salford, United KingdomThe association between Campylobacter infection and sub-sequent Guillain-Barre ´ syndrome (GBS) has been well doc-umented. To date, however, there exists no direct estimateof the incidence of GBS among patients with Campylobacterinfection. Using the General Practice Research Database, weestimate the incidence of GBS in a cohort of patients pre-senting with Campylobacter enteritis to be 1.17/1000 person-years, a rate 77 times greater than that in the general pop-ulation. The probability that an individual who developsCampylobacter enteritis will also develop GBS during thesubsequent 2-month period is !2/10,000.There is considerable evidence regarding the association be-tween Campylobacter jejuni infection and subsequent Guillain-Barre ´ syndrome (GBS) [1–4]. Estimates of the incidence ofGBS after Campylobacter infection are crucial for determiningthe true burden of disease attributable to this pathogen; how-ever, direct estimates of GBS incidence after C. jejuni infectionare lacking. McCarthy et al. [5] reported no GBS cases after 3large outbreaks of Campylobacter enteritis affecting ∼3000 peo-ple. However, outbreaks are not representative events andoftenresult from infection with clonal strains, not all of which mayReceived 21 December 2005; accepted 7 February 2006; electronically published 26 May2006.Potential conﬂicts of interest: none reported.Reprints or correspondence: Dr. Clarence C. Tam, Infectious Disease Epidemiology Unit,Dept. of Epidemiology and Population Health, London School of Hygiene and TropicalMedicine,Keppel St., London WC1E 7HT, United Kingdom (clarence.tam@lshtm.ac.uk).The Journal of Infectious Diseases 2006;194:95–7  2006 by the Infectious Diseases Society of America. All rights reserved.0022-1899/2006/19401-0014$15.00cause GBS. Using a capture-recapture approach in Sweden,McCarthy and Giesecke [6] produced an estimate of 30.4 GBS-related hospitalizations/10,000 reported Campylobacter infec-tions; the corresponding GBS incidence in the general popu-lation was 0.3/10,000. Applying this incidence ﬁgure to thesituation in England, we have elsewhere estimated that 14% ofGBS cases could be attributable to symptomatic C. jejuni in-fection in the general population [7]. In the present report, weuse data from the General Practice Research Database(GPRD),a representative sample of the primary care, or general practice(GP), population in the United Kingdom, to obtain the ﬁrstdirect estimate of the incidence of GBS in a cohort of patientswith Campylobacter enteritis.Materials and methods. The data structure of the GPRDhas been described elsewhere [8]. In brief, the GPRD consistsof 1700 GP clinics serving a representative sample of ∼5% ofthe UK population [8]. Electronic records of all consultations,diagnoses, preventive interventions, and prescriptionsareavail-able. Participating clinics provide data fulﬁlling minimum-qual-ity criteria (i.e., “up-to-standard” [UTS] data). An individual’sUTS follow-up time is deﬁned as the time during which he orshe is registered with a clinic reporting UTS data. We appliedstandard survival-analysis techniques to GPRD data from theyears 1991–2001, to estimate the incidence of GBS during the60-day period after development of Campylobacter enteritis.Approval for the study was obtained from the scientiﬁc andethics advisory group of the GPRD.Diagnoses included in the GPRD are recorded by use of Reador Oxford Medical Information Systems (Oxmis) codes. Rec-ords of all ﬁrst consultations between 1 January 1991 and 31December 2001 that were speciﬁc for Campylobacter enteritiswere abstracted from the GPRD. Repeat consultations with thesame patient were excluded, because it is difﬁcult to determinewhich of these might represent a new episode. We excludedconsultations with patients for whom !1 year of UTS data wereavailable. We also excluded consultations made 120 daysafterthe initial registration with the clinic [9], as well as those forwhich Campylobacter enteritis was diagnosed on the same dayas a “new patient screening,” so as to avoid inclusion of pastepisodes ascertained when the patient ﬁrst registered with theclinic. Finally, we excluded patients for whom the follow-uptime, either because of transfer out of the clinic or death, wasincomplete (i.e., 60 days).For patients with a ﬁrst consultation for Campylobacter en-teritis, we obtained all subsequent episodes of GBS occurring60 days after initial consultation for Campylobacter enteritis.96 • JID 2006:194 (1 July) • BRIEF REPORTMultiple consultations for the same patient were excluded. Weavoided inclusion of prevalent GBS by excluding any diagnosismade either 120 days after initial registration with the GPclinic or on the same day as a new patient screening.The follow-up period for patients with Campylobacter en-teritis was from the date of consultation for this conditionuntileither their ﬁrst consultation for GBS or theend oftheexposureperiod, whichever was earliest. The incidence of GBS after de-velopment of Campylobacter enteritis was deﬁned as the num-ber of consultations for GBS during the subsequent 60-dayperiod divided by the total eligible person-time of follow-upfor the patients with Campylobacter enteritis.We obtained, for thesametimeperiod,boththetotalnumberof ﬁrst consultations for GBS and thetotalperson-timeoffollow-up in the GPRD, to estimate the baseline incidence of GBS inthe entire GPRD cohort. The ratio of the incidence of GBS inthe cohort of patients with Campylobacter enteritis to that in theentireGPRDcohortistherelativeriskfortheassociationbetweenCampylobacter enteritis and subsequent GBS.All analyses were performed by use of Stata (version 8.0;Stata).Results. During the study period, there were 15,587 ﬁrstconsultations for Campylobacter enteritis, contributing a totalof 2560 person-years of follow-up. During the follow-up pe-riod, 3 GBS cases occurred among patients with Campylobacterenteritis, yielding an incidence of 1.17/1000 person-years (95%conﬁdence interval [CI], 0.38–3.63). The risk of GBS is believedto be elevated for only ∼2 months after development of Cam-pylobacter enteritis; this incidence thus equates to a !2/10,000probability that a patient with Campylobacter enteritis will de-velop GBS.During the study period, the entire GPRD cohort includeda total of 551 patients with a ﬁrst diagnosis of GBS. The medianage of these 551 patients was 52.3 years (interquartile range,33.1–66.2 years), and 313 (56.8%) of them were men. Of these551 patients, 272 were known to have been hospitalized; noinformation regarding hospitalization was available for the re-maining 279. During the study period, the person-time at riskof GBS in the entire GPRD cohort was 36,300,000person-years,resulting in a crude incidence of 0.015 GBS cases/1000 person-years (95% CI, 0.014–0.017); the excess risk of GBS among thosewith Campylobacter enteritis was 77.2 (95% CI, 15.9–226.8).Discussion. We have presented here the ﬁrst directestimateof the incidence of GBS in a representative cohort of patientswith Campylobacter enteritis who have been identiﬁed at theGP level; we have estimated this incidence to be ∼1/1000 per-son-years, equating to a probability of !2/10,000 that a patientwho develops Campylobacter enteritis will also develop GBS dur-ing the subsequent 2 months; this represents a 77-fold-greaterrisk than that in the general population.Our estimates do not take into account other factors thatmay inﬂuence or modify risk of GBS after development ofCampylobacter infection—factors such age and/or sex and thevirulence of the infecting strain. Because of the small numberof GBS cases in our cohort of patients with Campylobacter en-teritis, it was not possible to obtain estimates stratiﬁed by ageand sex, and information on Campylobacter strains was notavailable. The present study included only symptomatic Cam-pylobacter infections and therefore could not address the issueof development of GBS resulting from asymptomatic Campy-lobacter infection; nevertheless, the results show that the inci-dence of Campylobacter-associated GBS is far from negligible,particularly when it is considered in light of the relatively highincidence of Campylobacter infection. The incidence estimatedin the present study is slightly lower than that which McCarthyand Giesecke [6] have reported in a study of Sweden. Differ-ences between the populations and/or thedistributionsofCam-pylobacter strains in the 2 settings might account for this dis-parity: the Swedish study detected hospitalizations for GBSamong Campylobacter-enteritis cases reported in national sur-veillance, and such Campylobacter-enteritis cases are likely torepresent cases that are more severe than those presenting toGP clinics; a higher incidence of GBS might be expected ifmore-severe Campylobacter enteritis is associated with an in-creased risk of GBS. Using the Swedish incidence data, we haveelsewhere estimated that ∼14% of all admissions for GBS couldbe attributable to symptomatic C. jejuni infection in the generalpopulation [7]. If the incidence estimated by the present studyis applied to the data in our earlier study, an estimated 104Campylobacter-associated GBS cases can be expected to occurin England every year, representing 9% of all hospitalizationsfor GBS; this ﬁgure is lower than that suggested by some se-rological studies, in which the prevalence of C. jejuni infectionamong GBS cases has been reported to be 13%–72% [10]. Se-rological studies are likely to detect asymptomatic infection,which might partly account for this difference. However, theresults of such studies are difﬁcult to interpret, because it hasbeen shown that, after development of C. jejuni infection, an-tibody levels can remain high for several months and perhapseven years [11]. Serological assays are not speciﬁc for recent C.jejuniinfectionandthereforearelikelytoprovidebiasedestimatesof the proportion of GBS cases attributable to this pathogen.Studies estimating the incidence of GBS commonly use hos-pitalization data to determine the number of GBS cases [12–16]. It is commonly assumed that, because the condition is po-tentially life threatening, most such patients are hospitalized—and that hospitalization data therefore are likely to identify thevast majority of GBS cases; unfortunately, GPRD data containlimited information on hospitalization, and we could not testthis assumption in this study because information on hospi-talization was available for only approximately half of the GBScases. A GP–based study that reviewed medical records of GBSBRIEF REPORT • JID 2006:194 (1 July) • 97cases would be helpful in this respect, because this issue hasimportant implications for the population-wide surveillanceofGBS.The ﬁndings of the present study emphasize Campylobacter’srole as a major causative agent of GBS. The health impact ofCampylobacter-related GBS, as well as other sequelae, such asreactive arthritis, is considerable; studies of theburdenimposedby Campylobacter infection should take into account these in-direct effects, as well as those arising from primary infection,to obtain a more comprehensive picture of both the morbiditycaused by this pathogen and the potential impact thatstrategiesfor its control might have. Such studies will be dependent onreliable estimates of the incidence of Campylobacter-associatedcomplications, and further such studies are required. Althoughthe incidence of these complications may be low, the highincidence of Campylobacter infection means that, at the pop-ulation level, they can have a substantial impact. Our analysesusing GPRD data indicate that strategies to control Campylo-bacter infection in the general population will be key to thereduction of morbidity due to GBS, now the most commoncause of acute ﬂaccid paralysis in polio-free regions.References1. Guarino M, Casmiro M, D’Alessandro R. Campylobacter jejuni infec-tion and Guillain-Barre syndrome: a case-control study. Emilia-Ro-magna Study Group on Clinical and Epidemiological problems in neu-rology. Neuroepidemiology 1998;17:296–302.2. Ho TW, Mishu B, Li CY, et al. Guillain-Barre syndrome in northernChina: relationship to Campylobacter jejuni infection and anti-glyco-lipid antibodies. Brain 1995;118 (Pt 3):597–605.3. Mishu B, Ilyas AA, Koski CL, et al. Serologic evidence of previousCampylobacter jejuni infection in patients with the Guillain-Barre syn-drome. Ann Intern Med 1993;118:947–53.4. Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter jejuniinfection and Guillain-Barre syndrome. N Engl J Med 1995;333:1374–9.5. McCarthy N, Andersson Y, Jormanainen V, Gustavsson O, Giesecke J.The risk of Guillain-Barre syndrome following infection with Cam-pylobacter jejuni. Epidemiol Infect 1999;122:15–7.6. McCarthy N, Giesecke J. Incidence of Guillain-Barre ´ syndrome fol-lowing infection with Campylobacter jejuni. Am J Epidemiol 2001;153:610–4.7. Tam CC, RodriguesLC,O’BrienSJ.Guillain-Barre ´ syndromeassociatedwith Campylobacter jejuni infection in England, 2000–2001. ClinInfectDis 2003;37:307–10.8. Walley T, Mantgani A. The UK General Practice Research Database.Lancet 1997;350:1097–9.9. Lewis JD, Bilker WB, Weinstein RB, Strom BL. The relationship be-tween time since registration and measured incidence rates in the Gen-eral Practice Research Database. Pharmacoepidemiol Drug Saf 2005;14:443–51.10. Hadden RD, Gregson NA. Guillain-BarresyndromeandCampylobacterjejuni infection. Symp Ser Soc Appl Microbiol 2001:145S–54S.11. Taylor BV, Williamson J, Luck J, Coleman D, Jones D, McGregor A.Sensitivity and speciﬁcity of serology in determining recent acuteCam-pylobacter infection. Intern Med J 2004;34:250–8.12. Bogliun G, Beghi E. Incidence and clinical features of acute inﬂam-matory polyradiculoneuropathy in Lombardy, Italy, 1996. Acta NeurolScand 2004;110:100–6.13. Cheng Q, Jiang GX, Fredrikson S, LinkH,DePedro-CuestaJ.Incidenceof Guillain-Barre syndrome in Sweden 1996. Eur J Neurol 2000;7:11–6.14. Chroni E, Papapetropoulos S, Gioldasis G, Ellul J, Diamadopoulos N,Papapetropoulos T. Guillain-Barre syndromeinGreece:seasonalityandother clinico-epidemiological features. Eur J Neurol 2004;11:383–8.15. Cuadrado JI, de Pedro-Cuesta J, Ara JR, et al. Public health surveil-lance and incidence of adulthood Guillain-Barre syndrome in Spain,1998–1999: the view from a sentinel network of neurologists. NeurolSci 2004;25:57–65.16. Rocha MS, Brucki SM, Carvalho AA, Lima UW. Epidemiologicfeaturesof Guillain-Barre syndrome in Sao Paulo, Brazil. Arq Neuropsiquiatr2004;62:33–7.

Campylobacter jejuni infection and Guillain-Barre syndrome: a case-control study. Emilia-Romagna Study Group on Clinical and Epidemiological problems in neurology.

Campylobacter jejuni infection and Guillain-Barre syndrome.

Guillain-Barre syndrome in northern China: relationship to Campylobacter jejuni infection and anti-glycolipid antibodies.

Guillain-Barre syndromeinGreece:seasonalityand other clinico-epidemiological features.

Guillain-BarresyndromeandCampylobacter jejuni infection. Symp Ser Soc Appl Microbiol

Incidence and clinical features of acute inﬂammatory polyradiculoneuropathy in

Incidence of Guillain-Barre ´ syndrome following infection with Campylobacter jejuni.

Public health surveillance and incidence of adulthood Guillain-Barre syndrome in Spain, 1998–1999: the view from a sentinel network of neurologists.

RodriguesLC,O’BrienSJ.Guillain-Barre ´ syndromeassociated with Campylobacter jejuni infection

Sensitivity and speciﬁcity of serology in determining recent acuteCampylobacter infection.

Serologic evidence of previous Campylobacter jejuni infection in patients with the Guillain-Barre syndrome.

The relationship between time since registration and measured incidence rates in the General Practice Research Database. Pharmacoepidemiol Drug Saf

The risk of Guillain-Barre syndrome following infection with Campylobacter jejuni. Epidemiol Infect

The UK General Practice Research Database. Lancet

Incidence of Guillain-Barre syndrome among patients with Campylobacter infection: A general practice research database study

The association between Campylobacter infection and sub-sequent Guillain-Barre ́ syndrome (GBS) has been well doc-umented. To date, however, there exists no direct estimate of the incidence of GBS among patients with Campylobacter infection. Using the General Practice Research Database, we estimate the incidence of GBS in a cohort of patients pre-senting with Campylobacter enteritis to be 1.17/1000 person-years, a rate 77 times greater than that in the general pop-ulation. The probability that an individual who develops Campylobacter enteritis will also develop GBS during the subsequent 2-month period is!2/10,000. There is considerable evidence regarding the association be-tween Campylobacter jejuni infection and subsequent Guillain-Barre ́ syndrome (GBS) [1–4]. Estimates of the incidence of GBS after Campylobacter infection are crucial for determinin

Clarence C. Tam

Laura C. Rodrigues

Irene Petersen

Amir Islam

Andrew Hayward

Sarah J. O’brien

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Incidence of Guillain-Barre ́ Syndrome among Patients with Campylobacter Infection: A General Practice Research Database Study

Incidence of Guillain-Barre syndrome among patients with Campylobacter infection: A general practice research database study

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