Conceived and designed the experiments: CR LHO FNE PS NO. Performed the experiments: CR LHO FNE PS NO. Analyzed the data: CR LHO FNE PS NO. Contributed reagents/materials/analysis tools: CR LHO FNE PS NO. Wrote the paper: CR LHO FNE PS NO.
The authors have declared that no competing interests exist.
In contrast to the case fatality rate of patients diagnosed with meningococcal disease (MD) the long-term mortality in these patients is poorly documented.
We performed a nationwide, population-based cohort study including all Danish patients diagnosed with MD from 1977 through 2006 and alive one year after diagnosis. Data was retrieved from the Danish National Hospital Register, the Danish Civil Registration System and the Danish Register of Causes of Death. For each patient four age- and gender-matched individuals were identified from the population cohort. The siblings of the MD patients and of the individuals from the population cohort were identified. We constructed Kaplan-Meier survival curves and used Cox regression analysis, cumulative incidence function and subdistribution hazard regression to estimate mortality rate ratios (MRR) and analyze causes of death. We identified 4,909 MD patients, 19,636 individuals from the population cohort, 8,126 siblings of MD patients and 31,140 siblings of the individuals from the population cohort. The overall MRR for MD patients was 1.27 (95% confidence interval (CI), 1.12–1.45), adjusted MRR, 1.21 (95% CI, 1.06–1.37). MD was associated with increased risk of death due to nervous system diseases (MRR 3.57 (95% CI, 1.82–7.00). No increased mortality due to infections, neoplasms or cardiovascular diseases was observed. The MRR for siblings of MD patients compared with siblings of the individuals from the population cohort was 1.17 (95% CI, 0.92–1.48).
Patients surviving the acute phase of MD have increased long-term mortality, but the excess risk of death is small and stems mainly from nervous system diseases.
The case-fatality rate of meningococcal disease (MD) is well documented and reported to be approximately 10% in the developed world and substantially higher in non-industrialized countries
A recent study from Bristol indicated that the incidence of MD was increased in areas of social deprivation
We performed a nationwide, population-based cohort study to determine whether patients surviving the first year after a MD diagnosis have increased mortality compared with an age- and gender-matched population cohort. Further, we determined the specific causes of death. As a measure of unaccounted for confounders, we estimated the mortality in siblings of MD patients compared with siblings of individuals from the population cohort.
The study was approved by the Danish Data Protection Agency. The data was deidentified and anonymised at source.
The population of Denmark on January 1, 2008, was 5.5 million inhabitants
We used the unique 10-digit Central Person Registration number (CPR number), assigned to all Danish citizens at birth or immigration to track individuals in the following registers and to avoid multiple registrations.
The Danish National Hospital Register was initiated in 1977 and contains information on all patients discharged from Danish hospitals. Records for each inpatient admission include CPR number, hospital department, dates of admission and discharge diagnosis coded according to the International Classification of Diseases 8th (ICD-8) and 10th (ICD-10) revision
The Danish Civil Registration System was established in 1963 and contains demographic data and vital status of all Danish citizens
The Danish Register of Causes of Death contains information from all Danish death certificates since 1943 and is complete through 2006. Causes of death are coded according to ICD-8 and ICD-10, and registered as primary (immediate cause of death), secondary or tertiary cause of death
MD patients: From the Danish National Hospital Register, we identified all patients who were registered during the period January 1, 1977, to December 31, 2006, for the first time with a diagnosis of MD, ICD-8 codes: 036.09–036.99 and ICD-10 codes: A39.0–A39.9. Patients were excluded in case they died, emigrated or were lost to follow-up within the first year after the diagnosis of MD, and in case they were diagnosed with other neuroinfections (as specified in
Population cohort: From the Danish Civil Registration System we identified four individuals for each MD patient matched on gender and date of birth, all of whom were born in Denmark, alive and living in Denmark at the index date of the corresponding MD patient.
Cohort of siblings: From the Danish Civil Registration System, we identified all registered full and half-siblings for both MD patients and individuals from the population cohort. Siblings born before January 1, 1952 were excluded in order to reduce selection bias, as only a small fraction of individuals born before 1952 had siblings registered in the Danish Civil Registration System, but thereafter the registration is more than 98% complete
The primary study outcome was time from index date to death. The secondary outcome was time from index date to date of specific cause of death. The specific causes of death were categorized by ICD codes as listed in
Time was calculated from index date to date of death, emigration, loss to follow-up or January 1, 2008, which ever came first. In the analyses of cause specific mortality time was censored at January 1, 2007, as the Danish Register of Causes of Death was complete through 2006. Kaplan-Meier analyses were used to construct survival curves. Cox regression analyses were used to estimate mortality rate ratios (MRR) adjusted for calendar periods and for inpatient admission in the period of two years prior to the date of MD diagnosis. Calendar periods for the date of MD diagnosis were introduced as design variables grouped in the three time periods 1977–1986, 1987–1996, and 1997–2006. We adjusted for inpatient admissions during the two years prior to the date of MD diagnosis using (a) the total number of inpatient days as a continous variable and (b) a series of 18 indicator variables for the primary discharge diagnoses, as listed in
We assessed the proportional hazards assumption with plots and tests that were based on smoothed scaled Schoenfeld residuals and cumulative residuals. We stratified calculations of overall mortality by gender, age at diagnosis (0-<15, 15-<30, 30-<60 and 60 years or older) and type of MD (meningococcal meningitis or acute meningococcemia as primary diagnosis). We further calculated MRRs for the first 15 years after index date and for the period 16–30 years after the index date. A sub-analysis calculating the MRRs was performed, in which patients diagnosed with nervous system or genitourinary diseases in the first year after the MD diagnosis were excluded.
In a robustness analysis, using a Cox regression model, adjusted for age and gender we included only patients who had not been admitted to hospital in the period of two years prior to the date of MD diagnosis.
We computed the cumulative incidence of specific causes of death, taking into account that these were competing risks and used competing risks regression to estimate cumulative incidence of specific causes of death
We assessed the long-term mortality of the siblings in accordance with a previous study
We identified 5,356 patients diagnosed with MD in the period 1977–2006. Within the first year of diagnosis of MD, 445 (8.3%) patients died, one emigrated and one was lost to follow-up leaving a total of 4,909 patients and 19,636 individuals from the population cohort in the study. 62% of the patients included in the study were diagnosed before they were 15 years of age. During the period of two years preceding the date of MD diagnosis the MD patients had a significantly higher admission rate for e.g. infectious diseases, neoplasms and nervous system diseases (
Patients with MD |
Individuals from the population cohort |
P-value | |
Number of study participants | 4,909 | 19,636 | |
Males | 2,661 (54.2) | 10,644 (54.2) | |
Age, median (years, IQR) | 8.9 (2.3–17.8) | 8.9 (2.3–17.8) | |
Age at MD diagnosis | |||
0–14 years | 3,070 (62.5) | 12,280 (62.5) | |
15–29 years | 1,106 (22.5) | 4,424 (22.5) | |
30–59 years | 473 (9.6) | 1,892 (9.6) | |
60+ years | 260 (5.3) | 1,040 (5.3) | |
Primary diagnosis | |||
Meningococcal meningitis | 3,297 (67.2) | ||
Acute meningococcaemia | 1,211 (24.7) | ||
Chronic meningococcaemia | 23 (0.5) | ||
Waterhouse Friderichsen syndrome | 11 (0.2) | ||
Other specified conditions | 367 (7.5) | ||
Calender period at MD diagnosis | |||
1977–1986 | 1,513 (30.8) | 6,052 (30.8) | |
1987–1996 | 2,089 (42.6) | 8,356 (42.6) | |
1997–2006 | 1,307 (26.6) | 5,228 (26.6) | |
Observation time (years) | 73,058 | 293,585 | |
Emigration during study period | 114 (2.3) | 538 (2.7) | |
Lost to follow-up during study period | 2 (0.04) | 5 (0.03) | |
Number of study subjects with inpatient admission in the period of two years prior to the date of MD diagnosis | 1,753 (35.7) | 6,462 (32.9) | <0.001 |
Patients admitted with the following diagnosis-categories in the period of two years prior to the date of MD diagnosis | |||
Infectious diseases | 109 (2.2) | 242 (1.2) | <0.001 |
Neoplasms | 34 (0.7) | 90 (0.5) | 0.04 |
Blood/immune diseases | 11 (0.2) | 22 (0.1) | 0.06 |
Endocrine diseases | 27 (0.6) | 78 (0.4) | 0.14 |
Mental disease/drug abuse | 19 (0.4) | 46 (0.2) | 0.06 |
Nervous system diseases | 36 (0.7) | 74 (0.4) | 0.001 |
Diseases of the sensory organs | 56 (1.1) | 182 (0.9) | 0.17 |
Cardiovascular diseases | 33 (0.7) | 104 (0.5) | 0.23 |
Respiratory diseases | 215 (4.4) | 677 (3.4) | 0.002 |
Digestive system diseases | 99 (2.0) | 304 (1.5) | 0.02 |
Skin diseases | 29 (0.6) | 67 (0.3) | 0.01 |
Rheumatological diseases | 51 (1.0) | 126 (0.6) | 0.003 |
Genitourinary diseases | 51 (1.0) | 199 (1.0) | 0.87 |
Neonatal and congenital diseases. | 158 (3.2) | 397 (2.0) | <0.001 |
Pregnancy related diseases | 29 (0.6) | 155 (0.8) | 0.15 |
Injury, poisoning and external causes of morbidity | 158 (3.2) | 475 (2.4) | 0.002 |
Abnormal findings not classified otherwise | 153 (3.1) | 388 (2.0) | <0.001 |
Contacts with health services not classified above | 1,049 (21.4) | 4,267 (21.7) | 0.58 |
*If not stated otherwise data is number and percentage of MD patients or individuals from the population cohort.
8,126 siblings (5,338 full siblings (65.7%)) of MD patients and 31,140 siblings (22,181 full siblings (71.2%)) of individuals from the population cohort were available for analysis. The median age of the siblings of MD patients at index date was 8.9 years (IQR 0.6–16.9) and 8.7 years (IQR 1.3–16.9) in the siblings of the individuals from the population cohort. 4,239 (52.2%) of the siblings of the MD patients were males compared to 16,079 (51.6%) of the siblings of the individuals from the population cohort.
312 (6.4%) MD patients and 985 (5.0%) individuals from the population cohort died in the observation period (
Characteristics | Unadjusted MRR (95% CI) | Adjusted |
MD patients who died during the study period, N | Individuals from the population cohort who died during the study period, N |
Meningococcal disease (MD), all types | 1.27 (1.12–1.45) | 1.21 (1.06–1.37) | 312 | 985 |
Gender | ||||
Female | 1.28 (1.09–1.52) | 1.22 (1.03–1.44) | 180 | 564 |
Male | 1.26 (1.04–1.53) | 1.19 (0.98–1.45) | 132 | 421 |
Age of patient at MD diagnosis | ||||
0-<15 years | 1.52 (0.97–2.36) | 1.38 (0.88–2.16) | 27 | 71 |
15-<30 years | 1.24 (0.75–2.04) | 1.29 (0.78–2.14) | 20 | 65 |
30-<60 years | 1.48 (1.17–1.88) | 1.35 (1.06–1.73) | 92 | 260 |
60 years or older | 1.28 (1.08–1.52) | 1.22 (1.02–1.45) | 173 | 589 |
Type of MD | ||||
1 Meningococcal meningitis | 1.30 (1.13–1.52) | 1.31 (1.13–1.52) | 229 | 706 |
2 Acute meningococcaemia | 1.19 (0.89–1.59) | 1.11 (0.82–1.50) | 58 | 195 |
Time period after MD diagnosis | ||||
1-<16 years | 1.29 (1.12–1.50) | 1.28 (1.09–1.50) | 242 | 752 |
16–30 years | 1.27 (1.12–1.45) | 1.20 (0.97–1.67) | 70 | 233 |
*Adjusted for calendar periods and for inpatient admission prior to MD.
The MRR for siblings of MD patients compared with siblings of the individuals from the population cohort was 1.17 (95% CI, 0.92–1.48), adjusted MRR 1.15 (95% CI, 0.90–1.46). In a sub-analysis including only full siblings we found a MRR of 1.14 (95% CI, 0.83–1.55), adjusted MRR 1.11 (95% CI, 0.81–1.51). Of interest, one sibling of an individual from the population cohort died from MD compared to none of the siblings of the MD patients (data not shown). For comparison we did an analysis in which we only included MD patients and individuals from the population cohort born after January 1, 1952, and found a MRR for the MD patients of 1.51 (95% CI, 1.11–2.07), adjusted MRR 1.44 (95% CI, 1.06–1.97).
MD was associated with a statistically significant increased risk of death due to nervous system, genitourinary and digestive system diseases (
As the Danish Register of Causes of Death was only complete through 2006, patients with an index date in 2007 were not included in these analyses.
Causes of death |
Unadjusted MRR(95% CI) | Adjusted |
Number of MD patients who died from the specific causes of death during the study period |
Number of individuals from the population cohort who died from the specific causes of death during the study period |
Infectious diseases | 1.61(0.50–5.12) | 1.67(0.52–5.35) | 4 | 10 |
Neoplasms | 1.04(0.79–1.38) | 1.00(0.75–1.33) | 61 | 235 |
Blood/Immune diseases | 0.80(0.09–6.87) | 0.53(0.06–5.07) | 1 | 5 |
Endocrine diseases | 1.57(0.73–3.40) | 1.53(0.70–3.37) | 9 | 23 |
Mental disease/drug abuse | 1.13(0.54–2.37) | 1.00(0.47–2.14) | 9 | 32 |
Nervous system diseases | 3.57(1.82–7.00) | 3.15(1.59–6.23) | 16 | 18 |
Cardiovascular diseases | 1.09(0.85–1.38) | 1.00(0.78–1.28) | 84 | 311 |
Respiratory diseases | 1.15(0.74–1.77) | 1.09(0.70–1.70) | 26 | 91 |
Digestive system diseases | 2.06(1.20–3.53) | 1.99(1.16–3.43) | 20 | 39 |
Rheumatological diseases | 2.41(0.58–10.09) | 1.79(0.36–9.03) | 3 | 5 |
Genitourinary diseases | 5.02(1.35–18.70) | 6.26(1.58–24.81) | 5 | 4 |
Neonatal and congenital diseases | 1.61(0.50–5.12) | 1.12(0.34–3.70) | 4 | 10 |
Injury and poisoning | 1.32(0.86–2.03) | 1.30(0.85–2.01) | 28 | 85 |
Ill-defined causes | 1.63(0.93–2.86) | 1.65(0.94–2.90) | 17 | 42 |
Unknown cause of death | 0.62(0.14–2.74) | 0.65(0.15–2.87) | 2 | 13 |
*No causes of death due to diseases of the sensory organs, skin diseases or pregnancy related diseases were observed in the study population.
**Adjusted for calendar periods and for inpatient admission prior to MD.
***The Danish Register of Causes of Death was complete through 2006. In 2007, 23 MD patients and 62 individuals from the population cohort died and these deaths were not included in the analysis of causes of death.
MD patients were not at increased risk of death due to infections, neoplasms or cardiovascular diseases (
In this nationwide, population-based cohort study we found a slightly increased long-term mortality up to 30 years after patients were diagnosed with MD. The MD patients had increased risk of death due to nervous system, genitourinary and digestive system diseases of which the latter was associated with a diagnosis of alcohol abuse. We presume that the small excess mortality mainly stems from long-term sequelae and confounding.
The major strengths of the present study are its large sample size, the population-based design and the extensive and complete follow-up. The unique Danish Civil Registration System enabled us to identify a large control cohort of individuals well matched in terms of gender, age, and country of birth. Through the Danish national registers we had access to complete data on date of death, comorbidity, and causes of death and importantly, this data was obtained from the same data sources for both cohorts. The registers further allowed us to track all siblings of the study subjects.
Considering the limitations of the study we relied on register-based discharge diagnoses. Thereby the study population comprised MD patients irrespective of whether the diagnosis was confirmed by microbiological tests or exclusively based on clinical criteria. Although discharge diagnoses in general may not be entirely accurate, the registration of MD in the Danish National Hospital Register has been shown to be substantially valid
Due to the nature of our study with an inclusion period of 30 years and inclusion of MD patients diagnosed at all hospitals in Denmark, we did not have access to clinical and paraclinical data obtained during the hospitalizations. Our data thereby does not allow identification of clinical predictors of long-term mortality or information on neurologic sequelae in the MD patients. Also, we were not able to control for confounding from smoking including passive smoking, alcohol consumption, educational level, socioeconomic status or crowding.
Cases of MD are often categorized into septicaemia (approximately 30% in outbreaks), meningitis (10%) and mixed disease (60%)
We observed a slightly increased long-term mortality in the MD patients in all age groups. To our knowledge only one previous study has examined the long-term mortality in MD patients
We find it unlikely that comorbidity diagnosed prior to MD explains our findings, as the analysis, which only included patients not hospitalized prior to their MD diagnosis demonstrated essentially the same increased mortality as found for the complete MD study population. We were however only able to adjust for comorbidity in case it led to hospitalization and these analyses are probably hampered by unmeasured and residual confounding.
We observed an increased risk of death due to nervous system diseases, which is probably a consequence of the neurologic sequelae known to occur after MD
Some inherited immune deficiencies predispose to MD, but the prevalence of these conditions among patients with MD is low
A point of interest revealed in our study was a trend towards a slightly increased long-term mortality in siblings of MD patients, although these associations were not statistically significant. Factors other than the pathogenicity of the MD infection per se likely contribute to the increased long-term mortality in MD patients. In the present study we could not determine whether these factors are of a genetic or environmental nature.
We conclude that patients diagnosed with MD have an increased long-term mortality, but the excess mortality is small. The MD population has no increased risk of death due to infections, neoplasms or cardiovascular diseases, but suffers from increased mortality mainly due to nervous system diseases. With the actual findings, patients treated for meningococcal disease can be reassured that their long-term mortality differs only slightly from that of the general population.
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