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Lack of Association between Group B Meningococcal Disease and Autoimmune Disease

  1. Michael Howitz1,
  2. Tyra Grove Krause1,
  3. Jacob Brunbjerg Simonsen1,
  4. Steen Hoffmann3,
  5. Morten Frisch2,
  6. Nete Munk Nielsen2,
  7. John Robbins4,
  8. Rachel Schneerson4,
  9. Kare Molbak1, and
  10. Mark A. Miller5
  1. 1Departments of Epidemiology, Statens Serum Institut, Copenhagen, Denmark
  2. 2Departments of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  3. 3Bacteriology, Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark
  4. 4Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, Bethesda, Maryland
  5. 5Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland
  1. Reprints or correspondence: Dr. Michael Howitz, Artillerivej 5, DK-2300 Copenhagen S, Denmark (how{at}ssi.dk).
 
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Abstract

Background. The capsular polysaccharide of group B meningococci (GBM) is structurally identical to a polysaccharide found on neural cell adhesion molecules in humans. This structural identity has raised concern that a vaccine based on the GBM capsular polysaccharide might induce autoimmune disease in vaccinated persons. Because systemic infection with GBM induces serum antibody in adults, we investigated whether persons with a history of GBM disease are at increased risk of developing autoimmune diseases.

Methods. The entire Danish population constituted our study cohort of 7,467,001 individuals, who were observed for autoimmune diseases from 1977 through 2004. At-risk years were counted as the number of uninfected years prior to the first recorded diagnosis of meningococcal disease but changed to person-years at risk at the diagnosis of GBM disease (2984 subjects) or group C meningococcal disease (914 patients). Ratios of incidence rates of autoimmune disease served as measures of the relative risk.

Results. Persons with a history of GBM disease experienced a total of 37,290 person-years at risk, ranging from 11 days to 31 years at risk after the onset of GBM disease, during which 49 cases of autoimmune disease occurred. Persons with GBM disease had no increased risk of autoimmune diseases, either compared with persons with a history of group C meningococcal disease (incidence rate ratio, 0.9; 95% confidence interval, 0.5–1.4) or compared with persons without a history of meningococcal disease (incidence rate ratio, 1.1; 95% confidence interval, 0.8–1.5).

Conclusions. Our findings suggest that invasive disease caused by GBM is not associated with autoimmune diseases in humans for up to 31 years after meningococcal disease and should lessen concerns regarding the development of a capsular-based GBM vaccine.

Neisseria meningitidis is classified into serogroups or into groups according to the capsular polysaccharides of the pathogen. Thirteen groups are known; of these, groups A, B, C, Y, and W135 account for almost all cases of meningococcal disease [1, 2]. There are licensed polysaccharide vaccines for groups A, C, Y, and W135, but there is no licensed polysaccharide vaccine against group B meningococci (GBM). GBM disease has the highest age-specific incidence among children <1 year of age (∼20 cases per 100,000 population) and causes approximately three-quarters of all meningococcal disease cases in Europe and one-third of cases in the United States [3, 4].

In 1983, Finne et al. [5] reported that material from human and rat brain bound in vitro specifically to horse group B meningococcal antiserum. This finding has not been replicated in vivo, but it has been suggested that immunological tolerance may play a role in the response to GBM, and concern has been raised that a vaccine based on GBM polysaccharide might trigger immunopathology in vaccinated persons [5, 6].

Purified GBM capsular polysaccharide, α(2→8) polysialic acid (PSA), is not immunogenic when injected into adult humans [7]. An implied suggested reason is that α(2→8)-linked PSA is a component of neural cell adhesion molecules. Therefore, α(2→8)-linked PSA-neural cell adhesion molecules are a self-antigen; they are especially abundant during the development of the vertebrate nervous system and play a crucial role in the cell migration, axonal guidance, synapse formation, and functional plasticity of the central and peripheral nervous system [8]. In adults, PSA-neural cell adhesion molecules persist in regions with a permanent capacity for structural plasticity or generation of neurons, such as the hippocampus and the olfactory system [9,10–11]. PSA expression is increased in adults with brain or muscle lesions and appears to be functionally important in the recovery of neural tissue [11,12–13]. In contrast to purified GBM capsular polysaccharide being nonimmunogenic, the GBM polysaccharide induces an antibody response when covalently bound to a protein or as a component of bacterial cells [14,15,16,17–18]. No tissue injury has been ascribed to capsular PSA antibodies, despite 2 decades of research [2, 11].

Group C meningococcal (GCM) capsular polysaccharide is closely related to PSA of GBM; however, the sialic acid is α(2→9) linked, and this difference is responsible for the specificity, with no cross reactivity, of the 2 polysaccharides [19]. Therefore, patients with a history of GCM disease may serve as a control group for patients with GBM [20]

In this historically prospective national registry linkage study, we observed survivors of GBM disease for up to 31 years and compared their incidence of autoimmune disease with that for the general Danish population and a cohort of GCM disease survivors. In particular, we focus on autoimmune diseases in the nervous and musculoskeletal systems.

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Patients and Methods

The Danish Civil Registration System. Since 1968, people living in Denmark have been assigned a personal identification number in the Civil Registration System [21]. This system enables identification of information regarding place of birth, citizenship, previous and present addresses, date of immigration and/or emigration, and date of death for each individual. Using the Civil Registration System, we established a cohort comprising all Danish citizens who were alive throughout or at some point during the period from 1 January 1977 through 31 December 2004. We began follow-up in 1977, because the National Patient Registry started registration this year. Information on meningococcal disease and autoimmune diseases was obtained by linkage with the following 3 data sources.

Database on meningococcal disease. Since 1 January 1974, the Neisseria and Streptococcus Reference Laboratory at Statens Serum Institut (Copenhagen, Denmark) has serogrouped, recorded, and collected all Neisseria meningitidis strains referred from all Danish clinical microbiology departments. We included only subjects with meningococcal disease caused by GBM or GCM. All isolates were from either blood or CSF samples. The methods used for serological characterization have been described previously [22, 23]. Seventy-eight individuals (1.9%) who could not be identified in the Civil Registration System were excluded.

Since 1 January 1980, it has been mandatory to report all verified and clinically suspected cases of meningococcal disease to the Department of Epidemiology at Statens Serum Institut. To ensure that isolates were forwarded to the Neisseria and Streptococcus Reference Laboratory from the clinical microbiology departments and notified to the Department of Epidemiology, ongoing linkage between the 2 departments has been maintained [24,25–26]. Information on the onset of meningococcal disease and clinical manifestations was obtained from the notification forms. On the basis of a capture-recapture analysis conducted in 1994, it is estimated that >95% of cases of meningococcal disease in Denmark were notified [25].

The date of meningococcal disease onset was available throughout the period 1980–2004. From 1974 through 1979, only the date of sampling was available. Reviewing the 163 meningococcal disease notifications from the year 1980, we found that the median time from disease onset until samples of blood or CSF were obtained from the patients was 1 day (mean duration, 1.4 days; range, 0–11 days). The median duration (1 day) was subtracted from the date of sampling during the period 1974–1979 to make the disease onset dates comparable throughout the period 1974–2004.

Autoimmune diseases. Since 1 January 1977, the Danish National Board of Health has recorded all hospital admissions and, since 1 January 1995, has also recorded all outpatient visits in the National Patient Registry. Information regarding individual hospital admissions is available via the identification number and includes the name of the hospital and ward, the date of hospital admission and discharge, discharge diagnoses, and the patient's home municipality [27].

A dataset was established from the National Patient Registry comprising information on all hospital admissions and outpatient visits with a primary or secondary diagnosis of 45 established or possible autoimmune diseases mentioned in Harrison's Principle of Internal Medicine (table 1) [28, 29]. In addition, we included amyotrophic lateral sclerosis, induratio penis plastica, and morbus Dupuytren. Codes from the International Classification of Diseases, Eighth Revision, were used from 1 January 1977 through 31 December 1993, and codes from the International Classification of Diseases, Tenth Revision, were used from 1 January 1994 onwards. All diagnoses of diabetes mellitus among persons ⩽20 years of age were considered to be type 1 diabetes, and diagnoses of diabetes mellitus among persons >20 years of age were excluded, because type 2 diabetes is not considered to be of autoimmune origin [30, 31].

Table 1
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Table 1

Established and possible autoimmune diseases being studied and accompanying International Classification of Diseases, Eighth Revision (ICD-8), and International Classification of Diseases, Tenth Revision (ICD-10), codes.

Statistical analysis. We established a cohort comprising all persons registered in the Danish Civil Registration System and living in Denmark after 1 January 1977. The cohort was observed until the first registered date with an autoimmune disease, death, emigration, or 31 December 2004, whichever came first. Subjects with a meningococcal disease in the period 1974–1976 entered follow-up in 1977, and subjects with >1 meningococcal disease episode were censored on the date of the second episode.

To investigate the association between time since GBM or GCM disease and incidence of autoimmune disease, a time-dependent variable was created, as follows. If a person had never had a meningococcal disease, the subject had the value “uninfected” during the whole study period. If a person had had a meningococcal disease, the subject was considered to be “uninfected” until onset of meningococcal disease. After the onset of meningococcal disease, the value was classified according to the time between infection and autoimmune disease (11 days to 2 months, 3–5 months, 6–23 months, 2–4 years, 5–9 years, and ⩾10 years).

We applied a 10-day window from onset of meningococcal disease until the start of follow-up to minimize differential diagnostic problems (e.g., misdiagnosis of petecchiae as Henoch-Schünlein purpura). Also, we assumed 10 days to be a reasonable minimum period for a detectable antibody response, because the meningococcal antibody test converts to a positive result for ∼90% of patients with culture-confirmed disease 10–15 days after onset of meningococcal disease [32]. Persons with GBM or GCM disease did not contribute follow-up time during the 10-day window in the analysis.

The incidence rate ratio (IRR) of autoimmune disease was estimated in a Poisson regression model according to GBM and GCM and time since meningococcal disease, with adjustment for age (0–4 years, 5–9 years, 10–19 years, 20–39 years, 40–59 years, 60–79 years, and ⩾80 years), sex, calendar period (1977–1979, 1980–1984, 1985–1989, 1990–1994, 1995–1999, and 2000–2004), and the interaction term age and sex.

We performed the analysis in 3 steps: first, we calculated the IRR of the first incident of autoimmune disease after infection; second, we included all incidents of different autoimmune diseases; and third, we calculated the IRR for autoimmune diseases in the nervous system and musculoskeletal system and/or connective tissue, disregarding other autoimmune diseases.

In the regression analyses, tests for homogeneity and effect modification were evaluated with the Wald statistics. The GenMod procedure of SAS, version 8.02 (SAS Institute) was used for the statistical analysis.

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Results

A total of 7,467,001 Danish persons were included in the cohort. From 1 January 1974 through 31 December 2004, 4077 subjects with GBM or GCM disease were recorded in the database of meningococcal disease. A total of 80 subjects with GBM disease and 40 subjects with GCM disease had no valid address in Denmark at the date of disease onset and were excluded, leaving 3957 subjects; of these, 3024 had GBM disease, and 933 had GCM disease (table 2). The median age was 8 years (range, 0–96 years) for patients with GBM disease and 14 years (range, 0–95 years) for patients with GCM disease.

Table 2
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Table 2

Age, sex, calendar period, clinical manifestation, and crude incidence rate (IR) for subjects with a first episode of group B meningococcal (GBM) or group C meningococcal (GCM) disease in Denmark, 1974–2004.

We excluded 59 subjects with an autoimmune disease registered before onset of meningococcal disease, leaving a total of 3898 previously infected individuals (2984 with GBM disease and 914 with GCM disease) for the main analysis. A total of 70 persons (49 with previous GBM disease and 21 with previous GCM disease) received a diagnosis of an autoimmune disease.

Table 3 presents the overall IRRs of autoimmune diseases and the time since meningococcal disease. No significant overall differences (IRR, 1.1; 95% CI, 0.8–1.5) or short- or long-term differences were observed between persons with a history of GBM disease and the general Danish population without a history of meningococcal disease. For patients with GCM disease, the overall IRR, compared with the general population, was 1.3 (95% CI, 0.8–2.0). We repeated the analysis without censoring after the first autoimmune disease, allowing other autoimmune diseases to count in the analysis. Using this approach, we located an additional 6 autoimmune diseases among patients with previous GBM disease and 1 autoimmune disease among patients with previous GCM disease; the overall adjusted IRRs changed to 1.2 (95% CI, 0.9–1.5) for patients with GBM disease and 1.2 (95% CI, 0.8–1.8) for patients with GCM disease.

Table 3
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Table 3

Incidence rate ratio (IRR) of established and possible autoimmune diseases among patients with meningococcal disease according to time since onset of meningococcal disease, compared with the general Danish population.

In supplementary analysis, we found that GBM disease was not associated with the development of autoimmune diseases of the nervous system (adjusted IRR, 1.0; 95% CI, 0.3–3.1). Likewise, the risk of autoimmune disease of the musculoskeletal system and/or connective tissue was not significantly higher among patients with GBM disease than it was among the general Danish population (adjusted IRR, 1.3; 95% CI, 0.8–2.1), based on 19 cases among patients with GBM disease, only 2 of which occurred <5 years after the GBM disease.

Table 4 shows the specific autoimmune diseases diagnosed among patients with a previous GBM or GCM disease according to time after onset of meningococcal disease. No single autoimmune disease appears to be overrepresented, and most cases of autoimmune disease arise years after meningococcal disease.

Table 4
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Table 4

Postmeningococcal occurence of specific autoimmune diseases among 2984 patients with serogroup B meningococcal disease and 914 patients with serogroup C meningococcal disease in Denmark, 1977–2004.

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Discussion

Our study indicates that persons with previous GBM disease are not at increased risk of autoimmune diseases up to 31 years after meningococcal disease, compared with persons with GCM disease and persons without a history of meningococcal disease. Specifically, persons with previous GBM disease were not at increased risk of autoimmune diseases involving the nervous system or the musculoskeletal system and/or connective tissue.

In previous studies, the registry for meningococcal disease has been found to be almost complete for patients with meningococcal disease in Denmark [25, 33]. Moreover, because serogrouping is performed by a national reference laboratory, such information was available for virtually all patients with meningococcal disease in Denmark in the period studied.

Because meningococcal disease and autoimmune diseases are both relatively rare events, we decided to increase the power of the study by including subjects with meningococcal disease from the period 1974–1976. In the years following the introduction of the National Patient Registry, we observed an increase in cases of autoimmune diseases, presumably representing patients with chronic autoimmune conditions. It follows that onset of a chronic autoimmune disease before 1977 would probably appear in the National Patient Registry after 1977 and, therefore, be included in our study. Even after including all registered meningococcal and autoimmune disease cases in Danish national registries, the 95% CIs in table 3 are still wide, but because the independent IRRs for the various periods are comparable, we have little concern about misinterpreting the results.

The information on autoimmune diseases is a complex compilation of information on 45 autoimmune diseases, including diseases that are broadly recognized as having an autoimmune etiology, as well as diseases with a less evident etiology. No systematic validation has been undertaken of the information contained in the registry for each of the 45 different autoimmune diseases studied [34]. An obvious limitation is the possible underestimation of less severe autoimmune diseases in the National Patient Registry, because patients may not need hospitalization for diagnoses and treatment. It follows that we cannot exclude differential risks of milder forms of autoimmune diseases that were only observed outside of hospitals. However, because of the morbidity associated with meningococcal disease, we would expect persons with a previous GBM or GCM meningococcal disease to be hospitalized more often than members of the general population and to have greater chances of being registered with autoimmune diseases.

In the overall analysis for all autoimmune diseases combined, persons were censored at the first diagnosis of autoimmune disease. To ensure that a variety of other autoimmune diseases did not lead to censoring of subsequent autoimmune diseases and, in particular, of autoimmune diseases in the nervous system and the musculoskeletal system and/or connective tissue, we analyzed these groups separately. We found no increased risk of autoimmune diseases at these sites among persons with previous GBM disease.

Although our study has limited statistical power, because both meningococcal diseases and autoimmune diseases are relatively rare, we found no overall risk of autoimmune diseases (and, in particular, autoimmune diseases of the nervous and musculoskeletal systems) for up to 31 years after GBM disease. The homology between GBM capsular polysaccharides and polysaccharides on neural cell adhesion molecules in humans has been a central conceptual hindrance for the development of a polysaccharide-based GBM vaccine. Our findings suggest that natural exposure to GBM antigens is not associated with autoimmune diseases in humans and should lessen concerns regarding the development of a capsular-based GBM vaccine.

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Acknowledgments

We thank Annette Hartvig Christiansen, Lene Berthelsen, and Marianne Hauge Jensen for valuable assistance in locating, scrutinizing, and interpreting early records of meningococcal disease notifications.

Financial support. The Fogarty International Center and the National Institute of Child Health and Human Development of the National Institutes of Health.

Potential conflicts of interest. All authors: no conflicts.

  • Received March 13, 2007.
  • Accepted July 6, 2007.
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  1. Clin Infect Dis. (2007) 45 (10): 1327-1334. doi: 10.1086/522190
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