Incidence of Guillain-Barré Syndrome following Infection with Campylobacter jejuni

Noel McCarthy1,2 and Johan Giesecke1,3

1 Swedish Institute for Infectious Disease Control, SE-171 82, Solna, Sweden.
2 European Programme for Intervention Epidemiology Training, European Commission, European Union, Brussels, Belgium.
3 Karolinska Institute, SE-171 77, Solna, Sweden.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Evidence of recent or ongoing Campylobacter jejuni infection has been found in approximately one out of every four cases of Guillain-Barré syndrome (GBS). It is increasingly accepted that C. jejuni infection is an important causal factor for GBS. However, the likelihood of GBS' occurring following an episode of C. jejuni gastroenteritis has not been measured. The authors measured the incidence of GBS in a large cohort of persons with laboratory-confirmed C. jejuni infection. Cases of C. jejuni infection were derived from the Swedish national laboratory reporting system for the years 1987–1995. Follow-up for GBS was carried out using the Swedish national hospital inpatient register. Nine cases of GBS were detected in the cohort, which comprised 29,563 cases of C. jejuni infection—a rate of 30.4 per 100,000 (95% confidence interval: 13.9, 57.8). This compares with an expected incidence of 0.3 per 100,000 in a 2-month period in the general population. GBS is an important but rare complication of C. jejuni infection. The risk of developing GBS during the 2 months following a symptomatic episode of C. jejuni infection is approximately 100 times higher than the risk in the general population.

Campylobacter infections; Campylobacter jejuni; incidence; polyradiculoneuritis

Abbreviations: GBS, Guillain-Barré syndrome.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The association between Guillain-Barré syndrome (GBS) and Campylobacter jejuni infection has been demonstrated by case reports and case series, many of which have been described in a review article (1Go), and by case-control studies (2Go, 3Go). One of these case-control studies found evidence of ongoing or recent C. jejuni infection in 26 percent of GBS cases as compared with 1–2 percent of controls (3Go). The proportion of GBS cases with evidence of recent C. jejuni infection in other studies varies from 14 percent (4Go) to 88 percent (5Go). A review of these studies estimated that 30–40 percent of GBS patients had suffered C. jejuni infection during the 2 weeks prior to onset of GBS (6Go).

A biologic mechanism involving molecular mimicry and consequent cross-reaction of the immune response formed against C. jejuni antigens with gangliosides (GM1) present in nerves has been suggested and is supported by laboratory studies (7Go, 8Go). Host factors, particularly human lymphocyte antigen type, appear to have a role in the pathogenesis of GBS following C. jejuni infection (9Go, 10Go). Equally, most studies (5Go, 7Go, 11Go), but not all (3Go), suggest that GBS is more likely to follow infection with some serotypes of C. jejuni than others.

Although understanding of the relation between C. jejuni infection and GBS has improved rapidly, the overall risk of GBS following the diagnosis of C. jejuni infection has not been measured. One case of GBS was reported following a C. jejuni outbreak involving an estimated 865 cases (12Go). Other published reports on outbreaks of C. jejuni do not describe subsequent GBS. In Sweden, there are approximately 30 times as many cases of C. jejuni infection reported each year (between 1986 and 1993, the mean was 4,149 per year) (13Go) as there are cases of GBS (in 1986–1993, the mean was 145 per year) (14Go, 15Go). Assuming that one out of every three cases of GBS were related to C. jejuni infection and that complete reporting of incident cases occurred for both conditions, the risk of GBS following C. jejuni infection would be approximately 1 percent. However, many incident cases of bacterial enteritis are not precisely diagnosed and reported, because patients with enteritis often do not seek medical care and fecal culture is not routine in the investigation of acute gastroenteritis (16Go, 17Go). Clinical cases of GBS, a more serious disease, would seem less likely to remain undiagnosed, and the Swedish hospital discharge register has been validated as containing most diagnosed cases (14Go, 15Go, 18Go). This differential level of underdiagnosis means that the real risk is likely to be much lower than 1 percent. Other investigators have used this same approach to estimate the risk of GBS among cases of C. jejuni infection in the United States. The most recently published estimate was 1 in 1,058 (6Go). This method relies on assumptions regarding the number of incident cases of C. jejuni infection, which is difficult to estimate accurately (16Go, 17Go); the proportion of GBS cases that are related to C. jejuni infection, which is not precisely known (1Go, 3GoGoGo–6Go); and the number of GBS cases occurring per year. Estimation is therefore very sensitive to imprecision in the first two of these three assumptions, reducing the validity of such estimates. To obtain a more reliable estimate of the incidence of GBS in the months after C. jejuni infection, we followed a large cohort of infected individuals using Swedish national registers.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Population registries and matching
Data from the nationwide laboratory reporting system of the Swedish Institute for Infectious Disease Control were used to assemble a cohort of people with C. jejuni infection. The cohort comprised cases of C. jejuni infection reported to the laboratory reporting system between 1987 and 1995 for which full date of birth and either name or initials were recorded in the institute's computerized database. Although most laboratories do not routinely test Campylobacter strains to confirm that they are C. jejuni, informal estimates from laboratories which test some strains indicate that well in excess of 95 percent of the strains isolated are C. jejuni.

Cases of GBS were detected through the Swedish Inpatient Register. The Inpatient Register records all discharges from hospital inpatient clinics in Sweden. Diagnoses are recorded by modified International Classification of Dis-eases codes. Individual patients are identifiable, because a 10-digit national personal identifier number is included. For the years 1986–1995, we matched the cohort of laboratory-confirmed C. jejuni cases with those entries in the Inpatient Register that had International Classification of Diseases codes indicating a diagnosis of GBS.

Initial matching was based on matching of dates of birth. If gender was recorded in both files, this was also included as a matching criterion. Matching records were then studied manually, and only those records in which the GBS had occurred between 2 months before and 6 months after the report of C. jejuni infection were kept. The full name of each patient with a record in the Inpatient Register that matched a record in the laboratory reporting system register according to the above criteria was then obtained from the National Population Register using the 10-digit identification number. This was compared with the name or initials on the laboratory report. If these were compatible with the two reports belonging to the same individual, the match was considered to represent a possible case of GBS associated with C. jejuni infection.

Permission to conduct the study was obtained from the Swedish Data Protection Board.

Follow-up of cases
For each possible case of C. jejuni-associated GBS, both the laboratory reporting the C. jejuni infection and the clinic reporting the case of GBS were contacted for additional information. Clinical details, including the date of onset of symptoms of GBS and the occurrence of any preceding symptoms of gastroenteritis, were requested from the clinic that had reported the GBS diagnosis to the Inpatient Register.

Statistical analysis
Exact confidence limits were calculated using the Poisson distribution.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The cohort consisted of 29,567 individuals with laboratory-confirmed C. jejuni infection (table 1). Matching by date of birth (and gender, when available) yielded 935 matches. Restriction of the data to GBS cases with admission between 2 months before and 6 months after the report of C. jejuni infection reduced this number to 95. Exclusion of persons for whom the name details on the C. jejuni infection report were not compatible with the GBS patient's name (obtained from national population registers) further reduced this number to 15.


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TABLE 1. Distribution of a cohort of laboratory-reported cases of Campylobacter jejuni infection for whom identification details adequate to allow matching with cases of Guillain-Barré syndrome were available, by age group, Sweden, 1987–1995

 
Patient records were reviewed for all 15 cases. The identity of the patient and the matching was confirmed as correct in each case. For two patients, the initial diagnosis of GBS was later found to be incorrect. In four cases, the diagnosis of C. jejuni infection was made because of the occurrence of GBS. These cases were excluded from the study and from the cohort being followed (which was thus reduced to 29,563). A diagnosis of GBS preceded by a diagnosis of C. jejuni infection was confirmed for the other nine patients (table 2).


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TABLE 2. Details on the cases of individuals for whom both Campylobacter jejuni infection and Guillain-Barré syndrome (GBS) were diagnosed, Sweden, 1987–1995

 
We thus detected nine cases of GBS in a cohort of 29,563 reported cases of laboratory-confirmed C. jejuni infection, or one case of GBS among every 3,285 C. jejuni cases (95 percent confidence interval: 1,729, 7,210). This can be expressed as 30.4 cases of GBS per 100,000 cases of C. jejuni infection (95 percent confidence interval: 13.9, 57.8).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The annual incidences of GBS derived from the Swedish Inpatient Register are similar to those that would be expected to occur in a European population (1.45–2.30 per 100,000 per year between 1986 and 1993, age-adjusted to a standard European population) (14Go, 15Go). In addition, the Swedish register has been validated as a sensitive method for detecting diagnosed cases of GBS in comparison with hospital records (14Go, 18Go). The risk of our having missed incident cases of GBS because of incompleteness of the register is therefore low.

We excluded four cases from the cohort because the diagnosis of C. jejuni infection in these cases was due to the occurrence and diagnosis of GBS. In each case, the clinician treating the GBS was aware of the connection between C. jejuni infection and GBS and therefore tested for C. jejuni infection following the diagnosis of GBS. Figure 1 illustrates why these four individuals were excluded from our study population. Our aim was to follow up a cohort of laboratory-confirmed cases of C. jejuni infection (B) to estimate the incidence of GBS in this group (D divided by B). The majority of incident cases of C. jejuni infection in the Swedish population during the study period are likely to have gone undiagnosed (A minus B). Some of these patients with undiagnosed cases are likely to have developed GBS (C). It is not appropriate that these cases should then enter the study population—that they should move from C to D. This would bias the result toward overestimation of the incidence of GBS among persons with C. jejuni infection.



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FIGURE 1. Subsequent Guillain-Barré syndrome among patients with Campylobacter jejuni infection in Sweden, 1987–1995. The diagram illustrates all cases of C. jejuni infection in the Swedish population during the study period (A), the study cohort of cases with reported laboratory-confirmed C. jejuni infection (B), and subsequent Guillain-Barré syndrome among unreported (C) and reported (D) cases of C. jejuni infection.

 
We included cases of GBS occurring up to 2 months before the report of C. jejuni infection, to allow for potential delays in our laboratory reporting system (19Go). The follow-up period for detection of GBS after the C. jejuni report date was 6 months for most of the cohort, but for C. jejuni cases reported between July and October of 1995, the follow-up period was shorter (2–6 months). A mean interval between symptoms of C. jejuni infection and the onset of GBS of 9 days (range, 4–20; n = 18) was reported in one study (3Go), and a mean of 10 days (range, 1–23; n = 28) was reported in a review of case series (1Go). We therefore think that inclusion of C. jejuni cases with at least 2 months' follow-up in our cohort was appropriate and did not lead to a loss of sensitivity in the detection of subsequent GBS. Exact information on the date of onset of symptoms of C. jejuni infection was not available for all of our cases, although records did indicate that symptoms of gastroenteritis were present before the onset of symptoms of GBS. In seven of the nine confirmed cases, the date of fecal sampling was clearly recorded. The sample preceded admission to hospital with GBS by a mean of 11 days (median, 9; range, 5–26) in these cases, which is consistent with earlier reports. Our study is therefore limited in terms of the amount of information it adds to the estimation of the period between infection or symptoms of gastroenteritis and subsequent GBS.

The presence of good identifier data and the individual follow-up of each match helped us avoid the risk of false matches, so that matched records from each source did represent the same person in each case. Thus, the sensitivity and specificity of the methods used in this study impart a reliable estimate of the incidence of GBS following laboratory-confirmed C. jejuni infection.

This study was based on diagnosed cases of C. jejuni infection, which were likely to have been symptomatic. It is uncertain whether asymptomatic C. jejuni infection is followed by the same incidence of GBS. Some patients with GBS related to C. jejuni infection do not recall having symptoms of gastroenteritis; five of 19 C. jejuni-positive GBS patients recalled no symptoms of gastroenteritis in one study (20Go), and eight of 27 recalled no symptoms in another study (3Go). Whether the risk is higher, lower, or the same among symptomatic cases of C. jejuni infection compared with cases without symptoms of gastroenteritis is uncertain. The risk may also vary for populations of substantially different genetic constitutions, since human lymphocyte antigen type may be important in this respect (9Go, 10Go). In this study, the estimate was for the range of serotypes found throughout Sweden over 9 years and the range experienced by Swedes traveling abroad (approximately 50 percent of C. jejuni cases reported in Sweden are acquired outside the country). A wide variety of serotypes is likely to have been involved. For populations with very different prevailing serotypes, the risk may vary somewhat, since some Penner (5Go, 7Go, 11Go, 21Go) and Lior (22Go) serotypes appear to confer a higher risk than other serotypes. Follow-up of outbreaks will provide the best opportunity to estimate serotype-specific risks (12Go, 23Go).

Another host factor contributing to the risk of GBS following C. jejuni infection may be age. The numbers of cases in this study were too small for us to draw any conclusions in this regard. However, the differences in rates of GBS following C. jejuni infection among different age groups are striking (tables 1 and 2). In children and adolescents, no cases of GBS were found. Among the 20,856 adults aged 20–59 years, three cases were detected, giving a rate of 14 per 100,000, while the six cases occurring in the 2,417 people over age 59 represented a rate of 248 per 100,000. This suggests that GBS following C. jejuni infection may be particularly common among the elderly, although further study is clearly needed.

Accepting the caveats regarding generalizability, this study estimates the incidence of GBS following symptomatic C. jejuni infection by an unknown serotype to be 30.4 per 100,000. On the basis of the current study and other published work (1Go, 3Go), the excess risk of GBS appears to be confined to the 2-month period following C. jejuni infection. This makes it appropriate to calculate attributable risk based on the background incidence expected for a 2-month period. In our cohort, the expected incidence during a 2-month period in the absence of C. jejuni infection would have been only 0.3 per 100,000 people (14Go, 15Go) as compared with the 30.4 per 100,000 observed; this yields an attributable risk of 30.1 cases of GBS per 100,000 cases of laboratory-confirmed C. jejuni infection. Expressed as a relative risk, the incidence of GBS during the 2 months following a symptomatic episode of C. jejuni enteritis would be approximately 100 times higher than the risk in the background population.

Some authors have argued that the severity of GBS means that, although it is rare, this complication of C. jejuni infection adds considerably to the total disease burden due to the infection (24Go). The result of this study permits the establishment of a more firm quantitative foundation for assessment of the importance of GBS relative to other clinical manifestations of C. jejuni infection. It confirms that GBS is an important but rare complication of C. jejuni infection.


    ACKNOWLEDGMENTS
 
Dr. Noel McCarthy received support from the European Commission Directorate General 5 through the European Programme for Intervention Epidemiology Training.

The authors thank Leif Forsberg for his work on matching cases from the two registers, Temmam Asbai for providing the data from the Swedish Institute for Infectious Disease Control register, and Johan Lindbäck for obtaining full names from the population register. The authors also thank the laboratory staff and clinicians who provided answers to their questions on the cases identified.


    NOTES
 
Reprint requests to Dr. Noel McCarthy, Department of Public Health Medicine, Oxfordshire Health Authority, Old Road, Head-ington, Oxford OX3 7LG, United Kingdom (e-mail: millermccarthy{at}aol.com).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 1, 1999. Accepted for publication June 8, 2000.