Long-Term Mortality in Patients Diagnosed with
Meningococcal Disease: A Danish Nationwide Cohort
Casper Roed*, Lars Haukali Omland, Frederik Neess Engsig, Peter Skinhoj, Niels Obel
Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Background: In contrast to the case fatality rate of patients diagnosed with meningococcal disease (MD) the long-term
mortality in these patients is poorly documented.
Methodology/Principal Findings: 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).
Conclusions: 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.
Citation: Roed C, Omland LH, Engsig FN, Skinhoj P, Obel N (2010) Long-Term Mortality in Patients Diagnosed with Meningococcal Disease: A Danish Nationwide
Cohort Study. PLoS ONE 5(3): e9662. doi:10.1371/journal.pone.0009662
Editor: Lisa F. P. Ng, Singapore Immunology Network, Singapore
Received October 30, 2009; Accepted February 11, 2010; Published March 12, 2010
Copyright: ? 2010 Roed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was financed by The Research Foundation at Copenhagen University Hospital, Rigshospitalet and by The Faculty of Health Science,
Copenhagen University. The funders had no role in the study design; in the collection, management, analysis, and interpretation of data; in the preparation,
review, or approval of the manuscript, or in the decision to submit the article for publication.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
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 [1–3]. In contrast, long-term mortality in this patient
population is poorly documented .
A recent study from Bristol indicated that the incidence of MD
was increased in areas of social deprivation . Therefore studies
are needed, not only to establish whether MD patients suffer from
increased long-term mortality, but also to address to what extent
this potentially increased mortality could be explained by family
related risk factors.
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 . Over the last decades there has been a
declining incidence rate of MD in Denmark (1987: 5.8/100,000,
1997: 4.5/100,000 and 2007: 1.4/100,000) [7,8].
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
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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 . From this
register, we extracted date of MD diagnosis, along with data on
inpatient admissions prior to MD diagnosis.
The Danish Civil Registration System was established in 1963
and contains demographic data and vital status of all Danish
citizens . We extracted data on birth, gender, date of
immigration and emigration, loss to follow-up, date of death and
identity of siblings.
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 . From this register we
extracted specific causes of death as recorded as the primary cause
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 Appendixes S1) prior to MD, did not live in
Denmark at the date of the MD diagnosis or were born outside
Denmark. The index date of these individuals was defined as one
year after the date of first MD diagnosis.
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
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 Appendixes S1.
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
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
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 [13,14].
We assessed the long-term mortality of the siblings in
accordance with a previous study . For siblings, time was
calculated from one year of age of the sibling (to exclude peri- and
postnatal mortality) or index date of the corresponding study
participant, which ever came last, until date of death, emigration,
loss to follow-up or January 1, 2008. MRR was calculated for
siblings of MD patients compared with siblings of individuals from
the population cohort and adjusted for calendar periods (design
variable), age (design variable grouped in the age-intervals 1-,15,
15-,30, 30-,60 and 60 years or older at index date) and gender.
As only siblings born after January 1, 1952 were included in these
analyses, we calculated the MRR for MD patients compared with
individuals from the population cohort born after January 1, 1952
for comparison. SPSS version 15.0 (SPSS Inc., Chicago, Il, USA)
and R software, version 2.8.1 were used for data analysis.
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
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 (Table 2). Figure 1
presents Kaplan-Meier survival curves for MD patients and
Long-Term Mortality after MD
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corresponding individuals from the population cohort. The MRR
for patients with MD was 1.27 (95% CI, 1.12–1.45), adjusted MRR
1.21 (95% CI, 1.06–1.37) (Table 2). MD patients were at increased
risk of death throughout the study period and we saw no major
difference in MRR between genders (Figure 1 and Table 2). The
impactofMDonlong-termmortalitywas seen inallagegroups, but
was only statistically significant in those diagnosed with MD after 30
years of age. In a sub-analysis in which only patients and individuals
from the population cohort with no inpatient admissions in the
periodof two years prior to the date of MD diagnosis were included,
the MRR was 1.20 (95% CI, 1.03–1.40), adjusted MRR 1.28 (95%
CI, 1.10–1.49). In a sub-analysis in which patients diagnosed with
Table 1. Characteristics of meningococcal disease (MD) patients and individuals from the population cohort.
Patients with MD* Individuals from the population cohort*P-value
Number of study participants4,90919,636
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)
Meningococcal meningitis3,297 (67.2)
Acute meningococcaemia 1,211 (24.7)
Chronic meningococcaemia23 (0.5)
Waterhouse Friderichsen syndrome11 (0.2)
Other specified conditions367 (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) 73,058293,585
Emigration during study period114 (2.3) 538 (2.7)
Lost to follow-up during study period2 (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)
Patients admitted with the following diagnosis-categories in
the period of two years prior to the date of MD diagnosis
Infectious diseases109 (2.2)242 (1.2)
Neoplasms 34 (0.7)90 (0.5)0.04
Blood/immune diseases11 (0.2)22 (0.1) 0.06
Endocrine diseases27 (0.6) 78 (0.4)0.14
Mental disease/drug abuse19 (0.4)46 (0.2)0.06
Nervous system diseases 36 (0.7)74 (0.4)0.001
Diseases of the sensory organs56 (1.1)182 (0.9)0.17
Cardiovascular diseases33 (0.7) 104 (0.5)0.23
Respiratory diseases215 (4.4) 677 (3.4)0.002
Digestive system diseases 99 (2.0)304 (1.5) 0.02
Skin diseases29 (0.6)67 (0.3)0.01
Rheumatological diseases51 (1.0) 126 (0.6)0.003
Genitourinary diseases51 (1.0) 199 (1.0) 0.87
Neonatal and congenital diseases. 158 (3.2)397 (2.0)
Pregnancy related diseases 29 (0.6)155 (0.8)0.15
Injury, poisoning and external causes of morbidity158 (3.2) 475 (2.4) 0.002
Abnormal findings not classified otherwise153 (3.1) 388 (2.0)
Contacts with health services not classified above1,049 (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.
Long-Term Mortality after MD
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Table 2. Mortality rate ratios (MRR) for MD patients compared to individuals from the population cohort.
study period, N
Individuals from the
who died during the
study period, N
Meningococcal disease (MD), all types1.27 (1.12–1.45)1.21 (1.06–1.37) 312985
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) 2771
15-,30 years 1.24 (0.75–2.04)1.29 (0.78–2.14) 2065
30-,60 years1.48 (1.17–1.88) 1.35 (1.06–1.73) 92260
60 years or older1.28 (1.08–1.52) 1.22 (1.02–1.45)173589
Type of MD
1 Meningococcal meningitis1.30 (1.13–1.52) 1.31 (1.13–1.52)229 706
2 Acute meningococcaemia1.19 (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)242752
16–30 years 1.27 (1.12–1.45) 1.20 (0.97–1.67) 70233
*Adjusted for calendar periods and for inpatient admission prior to MD.
Figure 1. Kaplan-Meier survival curves of patients with meningococcal disease (MD) (dotted line) and individuals from the
population cohort (full line).
Long-Term Mortality after MD
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nervous system or genitourinary diseases in the first year after the
MD diagnosis were excluded the MRR was 1.21 (95% CI, 1.06–
1.39) adjusted MRR 1.16 (95% CI, 1.01–1.34).
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
1.51 (95% CI, 1.11–2.07), adjusted MRR 1.44 (95% CI, 1.06–1.97).
Cause Specific Mortality
MD was associated with a statistically significant increased risk of
death due to nervous system, genitourinary and digestive system
diseases (Table 3 and Figure 2). An analysis of the individual causes
of death due to nervous system and genitourinary diseases did not
reveal any particular pattern (data not shown). The increased risk of
death due to digestive system diseases was exclusively seen in
patients diagnosed with MD after 30 years of age (data not shown).
Further 8 of the 20 patients who died from digestive system diseases
were diagnosed with alcohol abuse (Appendixes S1) at or before
death compared with 9 of the 38 patients in the control group.
MD patients were not at increased risk of death due to infections,
neoplasms or cardiovascular diseases (Table 3 and Figure 2).
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
Considering the limitations of the study we relied on register-
based dischargediagnoses.Thereby the studypopulationcomprised
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 [8,15,16]. Pre-
hospital antibiotic treatment is mainly administered to the most
severe MD cases , and may lead to decreased sensitivity of the
microbiological tests performed after hospitalization. Thus, inclu-
sion of only bacteriologically verified cases would most likely have
biased the estimates of long-term mortality by exclusion of the most
severe MD cases. Also, from the patient’s point of view, the main
interest is the long-term prognosis according to the discharge
diagnosis. We therefore believe that our study, not only adds to the
understanding of the medical aspects of MD, but also is of
considerable relevance to the patients, who are diagnosed with MD
and have a natural interest in knowing their long-term prognosis.
Table 3. Mortality rate ratios (MRR) for cause specific death in MD patients compared to individuals from the population cohort.
Causes of death*
Number of MD patients
who died from the specific
causes of death during the
Number of individuals from
the population cohort who died
from the specific causes of death
during the study period***
Infectious diseases1.61(0.50–5.12) 1.67(0.52–5.35)4 10
Neoplasms1.04(0.79–1.38) 1.00(0.75–1.33)61 235
Endocrine diseases 1.57(0.73–3.40)1.53(0.70–3.37)9 23
Mental disease/drug abuse1.13(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 diseases1.09(0.85–1.38) 1.00(0.78–1.28) 84311
Respiratory diseases1.15(0.74–1.77) 1.09(0.70–1.70)2691
Digestive system diseases2.06(1.20–3.53)1.99(1.16–3.43) 2039
Rheumatological diseases2.41(0.58–10.09) 1.79(0.36–9.03)35
Neonatal and congenital diseases1.61(0.50–5.12)1.12(0.34–3.70)4 10
Injury and poisoning1.32(0.86–2.03) 1.30(0.85–2.01) 2885
Ill-defined causes1.63(0.93–2.86)1.65(0.94–2.90)17 42
Unknown cause of death0.62(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.
Long-Term Mortality after MD
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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, socio-
economic status or crowding.
Cases of MD are often categorized into septicaemia (approx-
imately 30% in outbreaks), meningitis (10%) and mixed disease
(60%) . The Danish National Hospital Register allows one
primary diagnosis and patients diagnosed with mixed MD are
primarily registered as meningococcal meningitis. In accordance
with this practice, we observed a somewhat higher proportion of
patients registered primarily with meningitis (67%).
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 .
The authors found an increased risk of death during the first four
years following diagnosis of bacterial meningitis, whereas the risk
of death declined to that of the background population from the
fifth year of discharge. The study, however, only included 356 MD
patients, had substantially shorter follow-up and pre-existing
comorbidity was not accounted for.
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 , though the pre-existing higher
admission rate for nervous system diseases before the diagnosis of
MD may also have lead to increased risk of neurologic death.
Nervous system diseases are known to lead to urological complica-
tions and we presume, that the increased risk of death due to
genitourinary diseases could be related to this phenomenon, or to
persistent kidney damage after MD sepsis-associated acute renal
failure . Exclusion of the patients diagnosed with nervous system
or genitourinary diseases in the first year after the MD diagnosis
reduced the estimated MRR, which further indicates that the
increased mortality in the MD patients partly stems from sequelae in
these organ systems. Several of the patients, who died from digestive
due to an increased risk of MD in alcoholics or an increased risk of
alcohol abuse after MD could not be established in the actual study.
Some inherited immune deficiencies predispose to MD, but the
prevalence of these conditions among patients with MD is low
[1,20]. Likewise we did not observe any increased risk of death due
to infections in the MD population. However, not all infections
cause death and the fact that the MD patients had more inpatient
admission for infectious diseases in the two years prior to the
diagnosis of MD than the population cohort keeps the possibility of
a specific immune defect open.
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.
at: doi:10.1371/journal.pone.0009662.s001(0.02 MB
Conceived and designed the experiments: CR LHO FNE PS NO.
Performed the experiments: CR LHO FNE PS NO. Analyzed the data:
Figure 2. Cumulative incidences of death due to nervous system diseases, neoplasms and cardiovascular diseases for MD patients
(dotted line) and individuals from the population cohort (full line). 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.
Long-Term Mortality after MD
PLoS ONE | www.plosone.org6 March 2010 | Volume 5 | Issue 3 | e9662
CR LHO FNE PS NO. Contributed reagents/materials/analysis tools: CR Download full-text
LHO FNE PS NO. Wrote the paper: CR LHO FNE PS NO.
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PLoS ONE | www.plosone.org7 March 2010 | Volume 5 | Issue 3 | e9662