Scandinavian Journal of Infectious Diseases, 2014; 46: 418–425
ORIGINAL ARTICLE
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Dexamethasone treatment and prognostic factors in communityacquired bacterial meningitis: A Danish retrospective population-based cohort study
JACOB BODILSEN1, MICHAEL DALAGER-PEDERSEN1, HENRIK CARL SCHØNHEYDER2 & HENRIK NIELSEN1 From the 1Department of Infectious Diseases, and 2Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark
Abstract Introduction: The morbidity and mortality in community-acquired bacterial meningitis (CABM) remain substantial and treatment outcomes and predictors of a poor prognosis must be assessed regularly. We aimed to describe the outcome of patients with CABM treated with dexamethasone and to assess the performance of the Dutch Meningitis Risk Score (DMRS). Methods: We retrospectively evaluated all adults with CABM in North Denmark Region, 1998–2012. Outcomes included in-hospital mortality and Glasgow Outcome Scale (GOS) score. A GOS score of 5 was categorized as a favourable outcome and scores of 1–4 as unfavourable. We used logistic analysis to compute relative risks (RRs) with 95% confidence intervals (CIs) for an unfavourable outcome adjusted for age, sex, and comorbidity. Results: We identified a total of 172 cases of CABM. In-hospital mortality was unaffected by the implementation of dexamethasone in 2003 (19% vs 20%). Dexamethasone treatment was associated with a prompt diagnosis of meningitis and a statistically insignificant decrease in the risk of an unfavourable outcome (33% vs 53%; adjusted RR 0.64, 95% CI 0.41–1.01) and in-hospital mortality (15% vs 24%; adjusted RR 0.72, 95% CI 0.35–1.48). Of the risk factors included in the DMRS, we found age and tachycardia to be significantly associated with an unfavourable outcome in the multivariate analyses. Conclusions: Patients treated with dexamethasone were more likely to have a favourable outcome, although statistical significance was not reached. Several parameters included in the Dutch risk score were also negative predictors in our cohort, although the entire risk score could not be validated due to a lack of data.
Keywords: Bacterial meningitis, epidemiology, dexamethasone, risk score, Dutch Meningitis Risk Score
Introduction The incidence as well as the prognosis of community-acquired bacterial meningitis (CABM) have changed following the implementation of vaccines against important pathogens (Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae) [1–7] and the recommendation of adjunctive treatment with dexamethasone to improve treatment outcomes [8,9]. The use of adjunctive dexamethasone treatment in bacterial meningitis has been supported by experimental animal studies demonstrating that severe inflammation in the subarachnoid space, induced by
bacterial lysis, contributes substantially to morbidity and mortality and that these processes might be reduced by dexamethasone [10,11]. In a placebocontrolled European multicenter study, dexamethasone reduced the absolute risk of an unfavourable outcome from 56% to 26% and the absolute risk of death from 34% to 14% in adults with pneumococcal meningitis [12]. However, subsequent studies, mostly from developing countries, did not confirm the efficacy of dexamethasone treatment in adults [13–15] or children (except for decreased hearing loss) [16,17]. Adding to the controversy, another experimental meningitis study demonstrated
Correspondence: J. Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, PO Box 365, 9100 Aalborg, Denmark. Tel: ⫹ 45 99326535. E-mail: [email protected] (Received 8 December 2013 ; accepted 9 January 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.887223
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Dexamethasone and prognostic factors in bacterial meningitis an increased level of neuronal apoptosis in the hippocampus and learning deficiencies in infant rats treated with dexamethasone [18]. Interestingly, a clinical study on long-term sequelae related to dexamethasone in meningitis patients could not corroborate these findings [19]. Due to a falling incidence of pneumococcal meningitis in childhood [1,6] and new treatment practices, periodic studies of risk factors and outcome are important. The recently developed Dutch Meningitis Risk Score (DMRS) for an unfavourable outcome [20] has been unsuccessfully validated in an Asian and African based study [21], but needs further assessment in other European countries. In this study we set out to assess dexamethasone treatment and the outcome of all patients with CABM in North Denmark Region through a 15-y period during which dexamethasone implementation was introduced into the treatment guidelines. Furthermore, we aimed to assess the DMRS.
Materials and methods Setting We conducted a retrospective population-based cohort study of patients with CABM older than 16 y of age from 1 January 1998 to 31 December 2012 in North Denmark Region (formerly North Jutland County). The catchment population was 493,298 inhabitants in 1998 and 580,273 in 2012; the increase in population size was due to administrative reforms that took effect in 2007 [22]. In Denmark, health care is tax-financed and provided to all residents free of charge by general practitioners and public hospitals. Private hospitals do not provide care for acute medical emergencies including infections. A unique personal identification number is assigned to all residents and this is recorded in health care databases, which facilitates extraction of information from patient records and registries. The Department of Clinical Microbiology at Aalborg University Hospital serviced all 7 hospitals within the region throughout the study period (6 district hospitals and 1 university hospital, which also served the Aalborg area). Guidelines for the initial treatment of CABM in adults recommended penicillin G as monotherapy, with the addition of gentamicin for patients over 40 y of age. An amendment in 2003 recommended dexamethasone treatment before and not later than 1 h after the administration of intravenous antibiotics [23]. In 2009, the antibiotic regimen was changed to penicillin G in combination with cefotaxime, in accordance with national guidelines [24].
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Study population Cerebrospinal fluid (CSF) culture-positive and culture-negative cases of CABM were retrieved from the laboratory information system (ADBakt, Autonik, Sweden) at the Department of Clinical Microbiology, Aalborg University Hospital. We also included results for CSF specimens referred to Statens Serum Institut (Copenhagen, Denmark) for bacterial antigen tests or bacterial 16S rRNA gene amplification. Inclusion criteria consisted of a clinical presentation strongly suggestive of CABM (e.g. headache, fever, neck stiffness, petechiae, confusion, or impaired level of consciousness) and at least 1 of the following: (1) positive CSF culture; (2) positive blood culture and 1 or more of the following CSF findings: ⬎ 10 leukocytes/μl [25], glucose index ⬍ 0.23, CSF glucose ⬍ 1.9 mmol/l, protein ⬎ 2.2 g/l [26]; (3) presence of bacteria in Gram stain of CSF; (4) non-culture detection of bacteria in CSF by either bacterial antigen test or 16S rRNA gene amplification. If a patient fulfilled multiple criteria, only the strongest criterion was noted (1 ⬎ 2 ⬎ 3 ⬎ 4). Exclusion criteria were: (1) cerebral abscess; (2) hospital-acquired bacterial meningitis as defined by the US Centers for Disease Control and Prevention (CDC) [27]; (3) implanted neurosurgical device; (4) the clinical records could not be retrieved (n ⫽ 2).
Patient data Clinical and laboratory data were obtained from the hospital records and additional information was requested if patients had been transferred to a hospital in another Danish region. Three of the included patients were foreign tourists and we were not able to obtain information beyond the primary admission. One patient was dead at admission and diagnosed with meningitis at autopsy; he was not included, as he had had no contact with secondary health care services. The Glasgow Coma Scale (GCS) score was reported in about two-thirds of the records, and if missing, a categorical classification was made based on observations in the patient’s records (GCS ⬍ 9, GCS 9–12, GCS ⬎ 12). Disseminated intravascular coagulopathy (DIC) was considered as present at admission if the patient had thrombocytopenia (platelet count ⬍ 150 ⫻ 109/l) as well as an activated plasmatic coagulation profile and/or petechiae or ecchymoses registered in the records. Fever was defined as a temperature above 38°C at admission. A course of treatment with dexamethasone (10 mg four times daily for 4 days), in accordance
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Table I. Demographic and clinical characteristics of patients with community-acquired bacterial meningitis before and after the introduction of dexamethasone into the treatment guidelines.
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1998–2002 Not implemented (reference), n ⫽ 75 Age, y, median (IQR) Sex, male, n (%) Diagnosis of meningitis at referral, n (%) Diagnosis of meningitis at admission, n (%) Comorbidity,a n (%) Duration of symptoms, days, median (IQR) Pre-hospital antibiotic treatment, n (%) Oral Intramuscular/intravenous Timing of adequate antibiotic treatment, n (%) Day 1 Day 2 Day 3 Never Predisposing infection, n (%) Pneumonia Acute otitis media Sinusitis Mastoiditis Clinical presentation, n (%) Headache Neck stiffness Fever Confusion/altered mental state Petechiae/ecchymoses Cranial nerve palsy Motor/sensory nerve deficit Seizures before admission Glasgow Coma Scale Score ⬍ 14 Glasgow Coma Scale score, estimated, n (%) GCS ⬍ 9 GCS 9–12 GCS ⬎ 12 Number of following symptoms: altered mental status, neck stiffness, and fever, n (%) 0 1 2 3 Number of following symptoms: headache, altered mental status, neck stiffness, and fever, n (%) 0 1 2 3 4 Paraclinical characteristics, n (%) CRP, mg/l, median (IQR) B-leukocytes, 109/l, median (IQR) B-thrombocytes, 109/l, median (IQR) DIC at admission CSF values, median (IQR) Leukocytes, 106/l % PMN Erythrocytes, 106/l Protein, g/l Glucose, mmol/l Glucose CSF/plasma index
55 36 27 57 24 3
(46–66) (48) (36) (76) (32) (2–5)
12 (16) 5 (7)
2003–2012, Dexamethasone Yes, n ⫽ 46 55 26 8 36 19 2
(41–70) (57) (17) (83) (41) (2–7)
No, n ⫽ 51 58 22 9 29 19 2
(50–73) (43) (18) (57) (37) (1–5)
4 (9) 3 (7)
2 (4) 3 (6)
64 6 4 1 29 15 14 3 1
(85) (8) (5) (1) (39) (20) (19) (4) (1)
42 (91) 3 (7) 1 (2) – 19 (41) 8 (17) 12 (26) 3 (7) –
42 (82) 6 (12) 3 (6) – 24 (47) 11 (22) 15 (29) 3 (6) –
44 47 61 53 24 11 5 2 45
(59) (63) (81) (71) (32) (15) (7) (3) (60)
29 36 45 36 15 4 2 7 37
27 29 44 36 14 9 5 7 35
(63) (78) (98) (78) (33) (9) (4) (15) (80)
(53) (57) (86) (71) (27) (18) (10) (14) (69)
3 (4) 28 (37) 44 (59)
11 (24) 23 (50) 12 (26)
14 (27) 15 (29) 22 (43)
6 14 26 29
(8) (19) (35) (39)
0 0 20 (43) 26 (57)
5 7 16 23
(10) (14) (31) (45)
4 10 13 31 17
(5) (13) (17) (41) (23)
0 0 8 (17) 21 (46) 17 (37)
2 4 12 25 8
(4) (8) (24) (49) (16)
219 16 199 15
(115–329) (11–23) (128–251) (20)
210 18 191 14
(116–267) (13–24) (135–286) (30)
227 17 205 9
(109–303) (12–24) (140–267) (18)
1577 94 112 4.5 1.7 0.2
(204–4875) (84–96) (20–437) (1.6–6.7) (0.1–3.5) (0–0.5)
2639 88 165 3.8 0.5 0.05
(385–7237) (76–96) (38–680) (2.5–8.5) (0.1–2.4) (0.01–0.29)
1958 88 150 3.3 0.5 0.07
(300–5805) (79–94) (16–525) (1.7–7.1) (0.1–2.8) (0.01–0.34) (Continued)
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Table I. (Continued). 1998–2002 Not implemented (reference), n ⫽ 75
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CSF Gram stain, n (%) Gram-positive cocci Gram-negative cocci Other bacteria None Aetiology, n (%) Streptococcus pneumoniae Neisseria meningitidis Other DMRSb (score/risk of unfavourable outcome)
2003–2012, Dexamethasone Yes, n ⫽ 46
No, n ⫽ 51
33 16 3 23
(44) (21) (4) (31)
27 (59) 6 (13) – 13 (28)
31 (61) 5 (10) – 15 (29)
33 22 20 19
(44) (29) (27) (16)
27 11 8 24
32 9 10 26
(59) (24) (17) (27)
(63) (18) (20) (31)
IQR, interquartile range; CRP, C-reactive protein; DIC, disseminated intravascular coagulopathy; CSF, cerebrospinal fluid; PMN, polymorphonuclear neutrophils; DMRS, Dutch Meningitis Risk Score. aComorbidity: alcoholism, asplenia, cancer, cirrhosis, congenital or acquired immunodeficiency including HIV, diabetes mellitus, heart failure (ejection fraction ⬍ 40%), renal impairment (serum creatinine ⬎ 130 μmol/l). bComplete data of parameters used in the DMRS were obtained for 101 patients. However, when GCS was categorized into 3 groups based upon record review, complete data were obtained for 142 patients (CSF leukocytes were missing for 20 patients, heart rates were missing for 9 patients, and both CSF leukocytes and heart rate were missing for 1 patient). The listed DMRS scores were calculated using the highest score in each of the 3 GCS groups (n ⫽ 142): GCS score 8 for all patients with GCS ⬍ 9, GCS score 12 for all patients with GCS 9–12, and GCS score 15 for all patients with GCS scores 13–15. The DMRS scores were then applied to the nomogram for an assessment of the risk of an unfavourable outcome [20].
with the Danish guidelines for the treatment of CABM from 2003 [23], was categorized as adequate, whereas any other regimen was considered inadequate. The time of initiation of relevant antibiotics was categorized as the day of admission, day 2, or later, as a more accurate estimate was not possible. The duration of admission was defined as the period from the day of admission to the day of discharge or transfer to a rehabilitation unit. Outcome was graded according to the Glasgow Outcome Scale (GOS) score at discharge [28]. A score of 1 corresponds to death, 2 to a vegetative state (unable to interact with the environment), 3 to severe sequelae and dependency upon others in daily life, 4 to moderate sequelae but with the ability to live independently, and 5 to no or only minor sequelae. A favourable outcome was defined as a score of 5 and an unfavourable outcome as a score of 1–4. Information on long-term sequelae was
Table II. Compliance with dexamethasone treatment in community-acquired bacterial meningitis, North Denmark Region, 1998–2012.
Compliance with dexamethasone In pneumococcal meningitis
2003–2007 Dexamethasone implemented, first 5-y period
2008–2012 Dexamethasone implemented, second 5-y period
19/52 (37%)
27/45 (60%)
11/32 (34%)
16/27 (59%)
obtained from the records pertaining to the primary and any subsequent admissions, as well as outpatient follow-up until the completion of the record review in 2012. Auditory sequelae were documented through outpatient follow-up and if hearing aid implementation was mediated through the Department of Otology at Aalborg University Hospital. However, several patients were evaluated by privately practising otologists and for these patients only a subjective report of hearing impairment was available. The Dutch Meningitis Risk Score (DMRS) The risk score consists of the following covariates: age (in 10-y increments), tachycardia ⬎ 120 beats/ min, GCS score, cranial nerve palsies, CSF leukocytes ⬍ 1000/mm3, and results of CSF Gram stain [20]. Statistical analysis Categorical data were analysed with Fisher’s exact test or the Chi-square test and continuous data were analysed with the Mann–Whitney U-test. A 2-tailed p-value of ⬍ 0.05 was considered significant. A modified Poisson regression analysis adjusted for age, sex, and comorbidity (see footnote to Table I for the list of comorbidities) was used to compute relative risks (RRs) with 95% confidence intervals (CIs) for an unfavourable outcome and case fatalities in patients treated with dexamethasone or
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Table III. Outcomes of patients with community-acquired bacterial meningitis in North Denmark Region, 1998–2012. 2003–2012
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1998–2002 Dexamethasone, No n ⫽ 75a (%) Admission to ICU Seizures during admission Unfavourable outcome Total cohort RR unadjusted RR adjusted for age, sex, comorbidity Pneumococcal meningitis RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI) Death Total cohort RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI) Pneumococcal meningitis RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI)
42 (56) 10 (13) 34 (45)
Dexamethasone, Yes n ⫽ 46a (%)
Dexamethasone, No n ⫽ 51a (%)
30 (65) 8 (17) 15 (33)
36 (71) 9 (18) 27 (53)
– – 15/33 (45) – – 14 (19)
0.62 0.64 12/27 0.89 0.73 7
(0.38–1.01) (0.41–1.01) (44) (0.51–1.54) (0.45–1.19) (15)
(Ref.) (Ref.) 16/32 (50) (Ref.) (Ref.) 12 (24)
– – 4/33 (12) – –
0.65 0.72 6/27 1.02 0.77
(0.28–1.51) (0.35–1.48) (22) (0.38–2.68) (0.34–1.74)
(Ref.) (Ref.) 7/32 (22) (Ref.) (Ref.)
ICU, intensive care unit; RR, relative risk; CI, confidence interval. aUnless specified otherwise.
the latter decreased by two-thirds over the study period (Supplementary material Appendix I to be found online at http://informahealthcare.com/doi/ abs/10.3109/00365548.2014.887223). The demographic and clinical characteristics of the patients are presented in Table I. Dexamethasone was administered in 46/97 (47%) cases from 2003 onwards. The triad consisting of fever, neck stiffness, and altered mental status was present in 49/97 (51%) patients admitted after 2002 and 26 (53%) of these were treated with dexamethasone. All patients treated with dexamethasone had at least 2 symptoms from the triad. Of patients not treated with dexamethasone, 12/51 (24%) had only 1 or even none of the symptoms from the triad. When adding headache as a symptom, 25/97 (26%) patients from 2003 onwards had a complete quartet of symptoms and 17 (83%) of these were treated
not after 2002 [29]. For covariates included in the DMRS, odds ratios (ORs) of an unfavourable outcome and death were examined by logistic regression. As GCS scores could only be assessed by categorical analysis, a complete validation of the DMRS was not possible. The study was notified to North Denmark Region in accordance with a directive from the Danish Data Protection Agency; permission from the regional health research ethics committee was not required for a registry-based study. Results We observed 172 episodes of CABM (incidence of 2.0/100,000 inhabitants/y). Bacterial aetiologies showed a predominance of S. pneumoniae (53%), followed by N. meningitidis (24%); the incidence of
Table IV. Long-term sequelae of survivors to discharge in community-acquired bacterial meningitis. 2003–2012 1998–2002 Dexamethasone, No n ⫽ 61 (%) No. of patients with sequelae Auditory deficit Requiring hearing aid Sensory/motor nerve defect Cognitive deficit Other cranial nerve paresis/paralysis Aphasia Reactive arthritis (culture and microscopy negative) Epilepsy Hydrocephalus
31 20 4 9 4 5 2 5 2 1
(51) (33) (7) (15) (7) (8) (3) (8) (3) (2)
Dexamethasone, Yes n ⫽ 39 (%) 16 5 1 6 5 4 1
(41) (13) (3) (15) (13) (10) (3) – 1 (3) –
Dexamethasone, No n ⫽ 39 (%) 19 12 2 12 8 3 3
(49) (31) (5) (31) (21) (8) (8) – – 1/51 (3)
Dexamethasone and prognostic factors in bacterial meningitis
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Table V. Risk factors for an unfavourable outcome from the Dutch Meningitis Risk Score (DMRS) and their associations with an unfavourable outcome and death among patients with community-acquired bacterial meningitis in North Denmark Region, 1998–2010; univariate and multivariate analyses.a Unfavourable outcome, OR (95% CI)
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Characteristics Age, yb Heart rate ⬎ 120 beats/min Glasgow Coma Scale scorec GCS ⬎ 12 GCS 10–12 GCS ⬍ 9 Cranial nerve palsies White-cell count ⬍ 1000/mm3 Gram stain Gram-positive cocci Gram-negative cocci Other bacteria Negative
Death, OR (95% CI)
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
1.46 (1.21–1.76) 7.14 (2.30–22.1)
1.41 (1.13–1.75) 7.63 (2.19–26.6)
1.48 (1.16–1.89) 4.60 (1.78–11.9)
1.34 (1.02–1.74) 2.99 (1.00–8.88)
1.00 1.59 1.95 2.38 1.70
(Ref.) (0.82–3.10) (0.81–4.66) (0.98–5.78) (0.91–3.16)
1.00 1.10 0.76 2.42 1.31
(Ref.) (0.50–2.41) (0.26–2.23) (0.91–6.44) (0.63–2.69)
1.00 2.36 5.66 2.46 2.01
1.00 1.90 3.70 1.93 1.74
3.74 1.00 7.00 2.45
(1.38–10.1) (Ref.) (0.54–91.1) (0.84–7.11)
1.70 1.00 4.45 1.15
(0.54–5.35) (Ref.) (0.31–62.9) (0.39–3.88)
2.11 (0.57–7.76) 1.00 (Ref.) – 2.20 (0.56–8.69)
(Ref.) (0.92–6.03) (1.97–16.2) (0.95–6.37) (0.94–4.34)
(Ref.) (0.66–5.47) (1.08–12.6) (0.66–5.61) (0.71–4.23)
0.60 (0.14–2.71) 1.00 (Ref.) – 0.87 (0.18–4.13)
OR, odds ratio; CI, confidence interval. aComplete data of parameters used in the DMRS were obtained for 101 patients. However, when GCS was categorized into 3 groups based upon record review, complete data were obtained for 142 patients (CSF leukocytes were missing for 20 patients, heart rates were missing for 9 patients, and both CSF leukocytes and heart rate were missing for 1 patient). The calculations are based upon the 142 patients. bORs per 10-y increment in age. cGCS was calculated as 3 categorical values in the North Denmark Region cohort (GCS ⬍ 9, GCS 10–12, and GCS ⬎ 12) and as continuous values in the DMRS.
with dexamethasone. The quartet of symptoms was associated with a favourable outcome (69% vs 52%, p ⫽ 0.05), but the triad was not (54% vs 57%, p ⫽ 0.65). Adjunctive treatment with dexamethasone was associated with a tentative diagnosis of meningitis at admission (83% vs 57%, p ⫽ 0.008) and a presentation of neck stiffness (78% vs 57%, p ⫽ 0.03) and fever (98% vs 86%, p ⫽ 0.06). As shown in Table II, compliance with dexamethasone treatment was significantly higher in the second period of implementation (60% vs 37%, p ⫽ 0.03). For the entire 15-y period, the in-hospital mortality was 19% (14- and 30-day mortalities were 15% and 17%, respectively), and in-hospital mortality remained unchanged before and after the implementation of dexamethasone (19% vs 20%) (Table III). However, after implementation, the risks of both an unfavourable outcome (33% vs 53%, adjusted RR 0.64, 95% CI 0.41–1.01) and a fatal outcome (15% vs 24%, adjusted RR 0.72, 95% CI 0.35–1.48) tended to decrease in patients treated with dexamethasone compared to patients not treated with dexamethasone. In patients with pneumococcal meningitis, dexamethasone was associated with a trend towards a decreased risk of an unfavourable outcome (44% vs 50%, adjusted RR 0.73, 95% CI 0.45–1.19) and a decrease in in-hospital mortality (22% vs 22%, adjusted RR 0.77, 95% CI 0.34–1.74) in the adjusted analyses only.
Treatment with dexamethasone had no discernible impact on long-term sequelae, although fewer patients with hearing loss were observed (treatment vs non-treatment 13% vs 31%, p ⫽ 0.10) (Table IV). Regarding the DMRS, we found that age, heart rate, and Gram-positive cocci on CSF microscopy were associated with an unfavourable outcome in the univariate analysis, but only age and heart rate remained significant in the multivariate analysis (Table V). Discussion In our retrospective Danish cohort study we found dexamethasone to be associated with a nearly halved risk of an unfavourable outcome and in-hospital mortality, although the differences did not reach statistical significance. The beneficial effects of dexamethasone were less pronounced than anticipated in patients with pneumococcal meningitis, but an improvement was suggested in the adjusted analyses. The fact that in-hospital mortality did not change markedly during the study period makes it pertinent to assess the risk factors recently identified in the DMRS. In our setting, age (per 10-y increment), tachycardia, and Gram-positive cocci on CSF microscopy were associated with an unfavourable outcome, but only age and heart rate remained statistically significant on multivariate analysis.
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The in-hospital mortality of 19% in our study is similar to reports from other Western countries [30–33] and was unchanged after 2002. Contributing factors could be the low compliance with adjunctive treatment with dexamethasone (47%) and a relatively low mortality already reached in the first years of the study (1998–2002). Of note, the proportion of meningococcal meningitis declined considerably during the study period – a disease with a relatively low mortality compared to pneumococcal meningitis (mortality of meningococcal meningitis was 12% in our cohort and 7–10% in other studies [7,15,34]). Unexpectedly, we found dexamethasone to be associated with a beneficial effect in non-pneumococcal meningitis (risk of unfavourable outcome 16% vs 58%, p ⫽ 0.02). This may be explained in part by a more focused diagnostic process and more attention to acute care in Danish hospitals in recent years. A large prospective Dutch study of patients with meningitis from 1998 to 2002 showed an in-hospital mortality of 30% for patients with pneumococcal meningitis (n ⫽ 352) [33]. Only 17% of the patients (n ⫽ 118) were given dexamethasone as compared to 47% of cases with pneumococcal meningitis included in our study after 2002. A follow-up study of the aforementioned Dutch study including patients with meningitis from 2006 to 2009 (n ⫽ 357), of whom 77% had been treated adequately with dexamethasone, reported a mortality of 20%, which is comparable to ours [9]. Our study does not add conclusive evidence to the use of dexamethasone.The positive trend between the use of dexamethasone and outcomes may have been confounded by an association between a rapid tentative diagnosis of meningitis at admission and treatment with dexamethasone, and thereby the immediate initiation of correct diagnostic and treatment algorithms. The association observed between typical signs of meningitis on patient management and the risk of an unfavourable outcome supports this assumption. Our study had both significant strengths and limitations. The health care system, with universal coverage and the use of a unique personal identifier for all health care contacts, limited selection bias and secured long-term follow-up of surviving patients. Thus, we were able to precisely specify the use of dexamethasone and outcome for every patient. Furthermore, we also included patients with CABM diagnosed upon stringent criteria other than a positive CSF culture, which makes our material more representative of the everyday clinical situation. The main limitation of the study was the limited number of cases included, which may explain why
some associations remained insignificant, particularly concerning patients with pneumococcal meningitis. Imprecision regarding timing of appropriate antibiotic therapy is also a weakness inherent in our retrospective record-based study. Some information bias must also be acknowledged, as the records were not always complete in terms of clinical and paraclinical parameters. In particular, the GCS score was recorded in only two-thirds of cases. Future studies are needed to evaluate the effect of the implementation of dexamethasone in the treatment of meningitis in adults in high-income countries. Furthermore, the focus should continue to be on prompt recognition and treatment of meningitis. In conclusion, in this Danish cohort study, in-hospital mortality was 19% and treatment with dexamethasone was associated with fewer unfavourable outcomes and fatalities, although statistical significance was not reached. The beneficial effect was notably weak in patients with pneumococcal meningitis. The use of dexamethasone was associated with neck stiffness and fever, as well as a tentative diagnosis of meningitis at admission. A complete validation of the DMRS was not possible due to a lack of data, but we confirmed age (per 10-y increment) and heart rate ⬎ 120 beats/min at admission to be associated with an unfavourable outcome. Declaration of interest: All authors report no conflicts of interests.
References [1] Harboe ZB, Valentiner-Branth P, Benfield TL, Christensen JJ, Andersen PH, Howitz M, et al. Early effectiveness of heptavalent conjugate pneumococcal vaccination on invasive pneumococcal disease after the introduction in the Danish Childhood Immunization Programme. Vaccine 2010;28:2642–7. [2] Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine 2001;20(Suppl 1):S58–67. [3] Snape M, Pollard A. Meningococcal polysaccharide–protein conjugate vaccines. Lancet Infect Dis 2005;5:21–30. [4] Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010;23:467–92. [5] Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 2012;307:573–82. [6] McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012;380:1703–11.
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Dexamethasone and prognostic factors in bacterial meningitis [7] Stephens D, Chang Q, Tzeng YL. Meningococcal disease: changes in epidemiology and prevention. Clin Epidemiol 2012;4:237–45. [8] Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267–84. [9] Brouwer M, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010;75:1533–9. [10] Scheld WM, Dacey RG, Winn HR, Welsh JE, Jane JA, Sande MA. Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. J Clin Invest 1980;66:243–53. [11] Täuber MG, Khayam-Bashi H, Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis 1985;151:528–34. [12] de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549–56. [13] Nguyen TH, Tran TH, Thwaites G, Ly VC, Dinh XS, Ho Dang TN, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007; 357:2431–40. [14] Scarborough M, Gordon SB, Whitty CJ, French N, Njalale Y, Chitani A, et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007;357:2441–50. [15] Heckenberg SG, Brouwer MC, van der Ende A, van de Beek D. Adjunctive dexamethasone in adults with meningococcal meningitis. Neurology 2012;79:1563–9. [16] Peltola H, Roine I, Fernández J, Zavala I, Ayala SG, Mata AG, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2007;45:1277–86. [17] Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211–8. [18] Leib S, Heimgartner C, Bifrare YD, Loeffler JM, Täauber MG. Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatr Res 2003;54:353–7. [19] Weisfelt M, Hoogman M, van de Beek D, de Gans J, Dreschler WA, Schmand BA. Dexamethasone and long-term outcome in adults with bacterial meningitis. Ann Neurol 2006;60:456–68.
Supplementary material available online Supplementary material Appendix I.
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[20] Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. A risk score for unfavorable outcome in adults with bacterial meningitis. Ann Neurol 2008;63:90–7. [21] Schut ES, Brouwer MC, Scarborough M, Mai NT, Thwaites GE, Farrar JJ, et al. Validation of a Dutch risk score predicting poor outcome in adults with bacterial meningitis in Vietnam and Malawi. PLoS One 2012;7:e34311. [22] StatBank Denmark [Internet]. statbank.dk. Statistics Denmark; 2013. Available at: http://statbank.dk/statbank5a/ default.asp?w ⫽ 1920 (accessed December 2013). [23] Møller KK, Pedersen SS, Skinhøj PP. [Dexamethasone to adults with acute bacterial meningitis]. Ugeskr Laeg 2003; 165:243–4. [24] Guidelines og retningslinier—Dansk Selskab for Infektionsmedicin [Internet]. infmed.dk. Danish Society for Infectious Diseases; 2013. Available at: http://www.infmed. dk/guidelines (accessed November 2013). [25] McMillan DA, Lin CY, Aronin SI, Quagliarello VJ. Community-acquired bacterial meningitis in adults: categorization of causes and timing of death. Clin Infect Dis 2001;33:969–75. [26] Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700–7. [27] Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128–40. [28] Teasdale GM, Pettigrew LE, Wilson JT, Murray G, Jennett B. Analyzing outcome of treatment of severe head injury: a review and update on advancing the use of the Glasgow Outcome Scale. J Neurotrauma 1998;15:587–97. [29] Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702–6. [30] Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328:21–8. [31] Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997;337:970–6. [32] Swartz MN. Bacterial meningitis—a view of the past 90 years. N Engl J Med 2004;351:1826–8. [33] van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849–59. [34] Heckenberg SG, de Gans J, Brouwer MC, Weisfelt M, Piet JR, Spanjaard L, et al. Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis. Medicine (Baltimore) 2008;87:185–92.
ORIGINAL ARTICLE
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Dexamethasone treatment and prognostic factors in communityacquired bacterial meningitis: A Danish retrospective population-based cohort study
JACOB BODILSEN1, MICHAEL DALAGER-PEDERSEN1, HENRIK CARL SCHØNHEYDER2 & HENRIK NIELSEN1 From the 1Department of Infectious Diseases, and 2Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark
Abstract Introduction: The morbidity and mortality in community-acquired bacterial meningitis (CABM) remain substantial and treatment outcomes and predictors of a poor prognosis must be assessed regularly. We aimed to describe the outcome of patients with CABM treated with dexamethasone and to assess the performance of the Dutch Meningitis Risk Score (DMRS). Methods: We retrospectively evaluated all adults with CABM in North Denmark Region, 1998–2012. Outcomes included in-hospital mortality and Glasgow Outcome Scale (GOS) score. A GOS score of 5 was categorized as a favourable outcome and scores of 1–4 as unfavourable. We used logistic analysis to compute relative risks (RRs) with 95% confidence intervals (CIs) for an unfavourable outcome adjusted for age, sex, and comorbidity. Results: We identified a total of 172 cases of CABM. In-hospital mortality was unaffected by the implementation of dexamethasone in 2003 (19% vs 20%). Dexamethasone treatment was associated with a prompt diagnosis of meningitis and a statistically insignificant decrease in the risk of an unfavourable outcome (33% vs 53%; adjusted RR 0.64, 95% CI 0.41–1.01) and in-hospital mortality (15% vs 24%; adjusted RR 0.72, 95% CI 0.35–1.48). Of the risk factors included in the DMRS, we found age and tachycardia to be significantly associated with an unfavourable outcome in the multivariate analyses. Conclusions: Patients treated with dexamethasone were more likely to have a favourable outcome, although statistical significance was not reached. Several parameters included in the Dutch risk score were also negative predictors in our cohort, although the entire risk score could not be validated due to a lack of data.
Keywords: Bacterial meningitis, epidemiology, dexamethasone, risk score, Dutch Meningitis Risk Score
Introduction The incidence as well as the prognosis of community-acquired bacterial meningitis (CABM) have changed following the implementation of vaccines against important pathogens (Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae) [1–7] and the recommendation of adjunctive treatment with dexamethasone to improve treatment outcomes [8,9]. The use of adjunctive dexamethasone treatment in bacterial meningitis has been supported by experimental animal studies demonstrating that severe inflammation in the subarachnoid space, induced by
bacterial lysis, contributes substantially to morbidity and mortality and that these processes might be reduced by dexamethasone [10,11]. In a placebocontrolled European multicenter study, dexamethasone reduced the absolute risk of an unfavourable outcome from 56% to 26% and the absolute risk of death from 34% to 14% in adults with pneumococcal meningitis [12]. However, subsequent studies, mostly from developing countries, did not confirm the efficacy of dexamethasone treatment in adults [13–15] or children (except for decreased hearing loss) [16,17]. Adding to the controversy, another experimental meningitis study demonstrated
Correspondence: J. Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, Mølleparkvej 4, PO Box 365, 9100 Aalborg, Denmark. Tel: ⫹ 45 99326535. E-mail: [email protected] (Received 8 December 2013 ; accepted 9 January 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.887223
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Dexamethasone and prognostic factors in bacterial meningitis an increased level of neuronal apoptosis in the hippocampus and learning deficiencies in infant rats treated with dexamethasone [18]. Interestingly, a clinical study on long-term sequelae related to dexamethasone in meningitis patients could not corroborate these findings [19]. Due to a falling incidence of pneumococcal meningitis in childhood [1,6] and new treatment practices, periodic studies of risk factors and outcome are important. The recently developed Dutch Meningitis Risk Score (DMRS) for an unfavourable outcome [20] has been unsuccessfully validated in an Asian and African based study [21], but needs further assessment in other European countries. In this study we set out to assess dexamethasone treatment and the outcome of all patients with CABM in North Denmark Region through a 15-y period during which dexamethasone implementation was introduced into the treatment guidelines. Furthermore, we aimed to assess the DMRS.
Materials and methods Setting We conducted a retrospective population-based cohort study of patients with CABM older than 16 y of age from 1 January 1998 to 31 December 2012 in North Denmark Region (formerly North Jutland County). The catchment population was 493,298 inhabitants in 1998 and 580,273 in 2012; the increase in population size was due to administrative reforms that took effect in 2007 [22]. In Denmark, health care is tax-financed and provided to all residents free of charge by general practitioners and public hospitals. Private hospitals do not provide care for acute medical emergencies including infections. A unique personal identification number is assigned to all residents and this is recorded in health care databases, which facilitates extraction of information from patient records and registries. The Department of Clinical Microbiology at Aalborg University Hospital serviced all 7 hospitals within the region throughout the study period (6 district hospitals and 1 university hospital, which also served the Aalborg area). Guidelines for the initial treatment of CABM in adults recommended penicillin G as monotherapy, with the addition of gentamicin for patients over 40 y of age. An amendment in 2003 recommended dexamethasone treatment before and not later than 1 h after the administration of intravenous antibiotics [23]. In 2009, the antibiotic regimen was changed to penicillin G in combination with cefotaxime, in accordance with national guidelines [24].
419
Study population Cerebrospinal fluid (CSF) culture-positive and culture-negative cases of CABM were retrieved from the laboratory information system (ADBakt, Autonik, Sweden) at the Department of Clinical Microbiology, Aalborg University Hospital. We also included results for CSF specimens referred to Statens Serum Institut (Copenhagen, Denmark) for bacterial antigen tests or bacterial 16S rRNA gene amplification. Inclusion criteria consisted of a clinical presentation strongly suggestive of CABM (e.g. headache, fever, neck stiffness, petechiae, confusion, or impaired level of consciousness) and at least 1 of the following: (1) positive CSF culture; (2) positive blood culture and 1 or more of the following CSF findings: ⬎ 10 leukocytes/μl [25], glucose index ⬍ 0.23, CSF glucose ⬍ 1.9 mmol/l, protein ⬎ 2.2 g/l [26]; (3) presence of bacteria in Gram stain of CSF; (4) non-culture detection of bacteria in CSF by either bacterial antigen test or 16S rRNA gene amplification. If a patient fulfilled multiple criteria, only the strongest criterion was noted (1 ⬎ 2 ⬎ 3 ⬎ 4). Exclusion criteria were: (1) cerebral abscess; (2) hospital-acquired bacterial meningitis as defined by the US Centers for Disease Control and Prevention (CDC) [27]; (3) implanted neurosurgical device; (4) the clinical records could not be retrieved (n ⫽ 2).
Patient data Clinical and laboratory data were obtained from the hospital records and additional information was requested if patients had been transferred to a hospital in another Danish region. Three of the included patients were foreign tourists and we were not able to obtain information beyond the primary admission. One patient was dead at admission and diagnosed with meningitis at autopsy; he was not included, as he had had no contact with secondary health care services. The Glasgow Coma Scale (GCS) score was reported in about two-thirds of the records, and if missing, a categorical classification was made based on observations in the patient’s records (GCS ⬍ 9, GCS 9–12, GCS ⬎ 12). Disseminated intravascular coagulopathy (DIC) was considered as present at admission if the patient had thrombocytopenia (platelet count ⬍ 150 ⫻ 109/l) as well as an activated plasmatic coagulation profile and/or petechiae or ecchymoses registered in the records. Fever was defined as a temperature above 38°C at admission. A course of treatment with dexamethasone (10 mg four times daily for 4 days), in accordance
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Table I. Demographic and clinical characteristics of patients with community-acquired bacterial meningitis before and after the introduction of dexamethasone into the treatment guidelines.
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1998–2002 Not implemented (reference), n ⫽ 75 Age, y, median (IQR) Sex, male, n (%) Diagnosis of meningitis at referral, n (%) Diagnosis of meningitis at admission, n (%) Comorbidity,a n (%) Duration of symptoms, days, median (IQR) Pre-hospital antibiotic treatment, n (%) Oral Intramuscular/intravenous Timing of adequate antibiotic treatment, n (%) Day 1 Day 2 Day 3 Never Predisposing infection, n (%) Pneumonia Acute otitis media Sinusitis Mastoiditis Clinical presentation, n (%) Headache Neck stiffness Fever Confusion/altered mental state Petechiae/ecchymoses Cranial nerve palsy Motor/sensory nerve deficit Seizures before admission Glasgow Coma Scale Score ⬍ 14 Glasgow Coma Scale score, estimated, n (%) GCS ⬍ 9 GCS 9–12 GCS ⬎ 12 Number of following symptoms: altered mental status, neck stiffness, and fever, n (%) 0 1 2 3 Number of following symptoms: headache, altered mental status, neck stiffness, and fever, n (%) 0 1 2 3 4 Paraclinical characteristics, n (%) CRP, mg/l, median (IQR) B-leukocytes, 109/l, median (IQR) B-thrombocytes, 109/l, median (IQR) DIC at admission CSF values, median (IQR) Leukocytes, 106/l % PMN Erythrocytes, 106/l Protein, g/l Glucose, mmol/l Glucose CSF/plasma index
55 36 27 57 24 3
(46–66) (48) (36) (76) (32) (2–5)
12 (16) 5 (7)
2003–2012, Dexamethasone Yes, n ⫽ 46 55 26 8 36 19 2
(41–70) (57) (17) (83) (41) (2–7)
No, n ⫽ 51 58 22 9 29 19 2
(50–73) (43) (18) (57) (37) (1–5)
4 (9) 3 (7)
2 (4) 3 (6)
64 6 4 1 29 15 14 3 1
(85) (8) (5) (1) (39) (20) (19) (4) (1)
42 (91) 3 (7) 1 (2) – 19 (41) 8 (17) 12 (26) 3 (7) –
42 (82) 6 (12) 3 (6) – 24 (47) 11 (22) 15 (29) 3 (6) –
44 47 61 53 24 11 5 2 45
(59) (63) (81) (71) (32) (15) (7) (3) (60)
29 36 45 36 15 4 2 7 37
27 29 44 36 14 9 5 7 35
(63) (78) (98) (78) (33) (9) (4) (15) (80)
(53) (57) (86) (71) (27) (18) (10) (14) (69)
3 (4) 28 (37) 44 (59)
11 (24) 23 (50) 12 (26)
14 (27) 15 (29) 22 (43)
6 14 26 29
(8) (19) (35) (39)
0 0 20 (43) 26 (57)
5 7 16 23
(10) (14) (31) (45)
4 10 13 31 17
(5) (13) (17) (41) (23)
0 0 8 (17) 21 (46) 17 (37)
2 4 12 25 8
(4) (8) (24) (49) (16)
219 16 199 15
(115–329) (11–23) (128–251) (20)
210 18 191 14
(116–267) (13–24) (135–286) (30)
227 17 205 9
(109–303) (12–24) (140–267) (18)
1577 94 112 4.5 1.7 0.2
(204–4875) (84–96) (20–437) (1.6–6.7) (0.1–3.5) (0–0.5)
2639 88 165 3.8 0.5 0.05
(385–7237) (76–96) (38–680) (2.5–8.5) (0.1–2.4) (0.01–0.29)
1958 88 150 3.3 0.5 0.07
(300–5805) (79–94) (16–525) (1.7–7.1) (0.1–2.8) (0.01–0.34) (Continued)
Dexamethasone and prognostic factors in bacterial meningitis
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Table I. (Continued). 1998–2002 Not implemented (reference), n ⫽ 75
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CSF Gram stain, n (%) Gram-positive cocci Gram-negative cocci Other bacteria None Aetiology, n (%) Streptococcus pneumoniae Neisseria meningitidis Other DMRSb (score/risk of unfavourable outcome)
2003–2012, Dexamethasone Yes, n ⫽ 46
No, n ⫽ 51
33 16 3 23
(44) (21) (4) (31)
27 (59) 6 (13) – 13 (28)
31 (61) 5 (10) – 15 (29)
33 22 20 19
(44) (29) (27) (16)
27 11 8 24
32 9 10 26
(59) (24) (17) (27)
(63) (18) (20) (31)
IQR, interquartile range; CRP, C-reactive protein; DIC, disseminated intravascular coagulopathy; CSF, cerebrospinal fluid; PMN, polymorphonuclear neutrophils; DMRS, Dutch Meningitis Risk Score. aComorbidity: alcoholism, asplenia, cancer, cirrhosis, congenital or acquired immunodeficiency including HIV, diabetes mellitus, heart failure (ejection fraction ⬍ 40%), renal impairment (serum creatinine ⬎ 130 μmol/l). bComplete data of parameters used in the DMRS were obtained for 101 patients. However, when GCS was categorized into 3 groups based upon record review, complete data were obtained for 142 patients (CSF leukocytes were missing for 20 patients, heart rates were missing for 9 patients, and both CSF leukocytes and heart rate were missing for 1 patient). The listed DMRS scores were calculated using the highest score in each of the 3 GCS groups (n ⫽ 142): GCS score 8 for all patients with GCS ⬍ 9, GCS score 12 for all patients with GCS 9–12, and GCS score 15 for all patients with GCS scores 13–15. The DMRS scores were then applied to the nomogram for an assessment of the risk of an unfavourable outcome [20].
with the Danish guidelines for the treatment of CABM from 2003 [23], was categorized as adequate, whereas any other regimen was considered inadequate. The time of initiation of relevant antibiotics was categorized as the day of admission, day 2, or later, as a more accurate estimate was not possible. The duration of admission was defined as the period from the day of admission to the day of discharge or transfer to a rehabilitation unit. Outcome was graded according to the Glasgow Outcome Scale (GOS) score at discharge [28]. A score of 1 corresponds to death, 2 to a vegetative state (unable to interact with the environment), 3 to severe sequelae and dependency upon others in daily life, 4 to moderate sequelae but with the ability to live independently, and 5 to no or only minor sequelae. A favourable outcome was defined as a score of 5 and an unfavourable outcome as a score of 1–4. Information on long-term sequelae was
Table II. Compliance with dexamethasone treatment in community-acquired bacterial meningitis, North Denmark Region, 1998–2012.
Compliance with dexamethasone In pneumococcal meningitis
2003–2007 Dexamethasone implemented, first 5-y period
2008–2012 Dexamethasone implemented, second 5-y period
19/52 (37%)
27/45 (60%)
11/32 (34%)
16/27 (59%)
obtained from the records pertaining to the primary and any subsequent admissions, as well as outpatient follow-up until the completion of the record review in 2012. Auditory sequelae were documented through outpatient follow-up and if hearing aid implementation was mediated through the Department of Otology at Aalborg University Hospital. However, several patients were evaluated by privately practising otologists and for these patients only a subjective report of hearing impairment was available. The Dutch Meningitis Risk Score (DMRS) The risk score consists of the following covariates: age (in 10-y increments), tachycardia ⬎ 120 beats/ min, GCS score, cranial nerve palsies, CSF leukocytes ⬍ 1000/mm3, and results of CSF Gram stain [20]. Statistical analysis Categorical data were analysed with Fisher’s exact test or the Chi-square test and continuous data were analysed with the Mann–Whitney U-test. A 2-tailed p-value of ⬍ 0.05 was considered significant. A modified Poisson regression analysis adjusted for age, sex, and comorbidity (see footnote to Table I for the list of comorbidities) was used to compute relative risks (RRs) with 95% confidence intervals (CIs) for an unfavourable outcome and case fatalities in patients treated with dexamethasone or
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Table III. Outcomes of patients with community-acquired bacterial meningitis in North Denmark Region, 1998–2012. 2003–2012
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1998–2002 Dexamethasone, No n ⫽ 75a (%) Admission to ICU Seizures during admission Unfavourable outcome Total cohort RR unadjusted RR adjusted for age, sex, comorbidity Pneumococcal meningitis RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI) Death Total cohort RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI) Pneumococcal meningitis RR unadjusted (95% CI) RR adjusted for age, sex, comorbidity (95% CI)
42 (56) 10 (13) 34 (45)
Dexamethasone, Yes n ⫽ 46a (%)
Dexamethasone, No n ⫽ 51a (%)
30 (65) 8 (17) 15 (33)
36 (71) 9 (18) 27 (53)
– – 15/33 (45) – – 14 (19)
0.62 0.64 12/27 0.89 0.73 7
(0.38–1.01) (0.41–1.01) (44) (0.51–1.54) (0.45–1.19) (15)
(Ref.) (Ref.) 16/32 (50) (Ref.) (Ref.) 12 (24)
– – 4/33 (12) – –
0.65 0.72 6/27 1.02 0.77
(0.28–1.51) (0.35–1.48) (22) (0.38–2.68) (0.34–1.74)
(Ref.) (Ref.) 7/32 (22) (Ref.) (Ref.)
ICU, intensive care unit; RR, relative risk; CI, confidence interval. aUnless specified otherwise.
the latter decreased by two-thirds over the study period (Supplementary material Appendix I to be found online at http://informahealthcare.com/doi/ abs/10.3109/00365548.2014.887223). The demographic and clinical characteristics of the patients are presented in Table I. Dexamethasone was administered in 46/97 (47%) cases from 2003 onwards. The triad consisting of fever, neck stiffness, and altered mental status was present in 49/97 (51%) patients admitted after 2002 and 26 (53%) of these were treated with dexamethasone. All patients treated with dexamethasone had at least 2 symptoms from the triad. Of patients not treated with dexamethasone, 12/51 (24%) had only 1 or even none of the symptoms from the triad. When adding headache as a symptom, 25/97 (26%) patients from 2003 onwards had a complete quartet of symptoms and 17 (83%) of these were treated
not after 2002 [29]. For covariates included in the DMRS, odds ratios (ORs) of an unfavourable outcome and death were examined by logistic regression. As GCS scores could only be assessed by categorical analysis, a complete validation of the DMRS was not possible. The study was notified to North Denmark Region in accordance with a directive from the Danish Data Protection Agency; permission from the regional health research ethics committee was not required for a registry-based study. Results We observed 172 episodes of CABM (incidence of 2.0/100,000 inhabitants/y). Bacterial aetiologies showed a predominance of S. pneumoniae (53%), followed by N. meningitidis (24%); the incidence of
Table IV. Long-term sequelae of survivors to discharge in community-acquired bacterial meningitis. 2003–2012 1998–2002 Dexamethasone, No n ⫽ 61 (%) No. of patients with sequelae Auditory deficit Requiring hearing aid Sensory/motor nerve defect Cognitive deficit Other cranial nerve paresis/paralysis Aphasia Reactive arthritis (culture and microscopy negative) Epilepsy Hydrocephalus
31 20 4 9 4 5 2 5 2 1
(51) (33) (7) (15) (7) (8) (3) (8) (3) (2)
Dexamethasone, Yes n ⫽ 39 (%) 16 5 1 6 5 4 1
(41) (13) (3) (15) (13) (10) (3) – 1 (3) –
Dexamethasone, No n ⫽ 39 (%) 19 12 2 12 8 3 3
(49) (31) (5) (31) (21) (8) (8) – – 1/51 (3)
Dexamethasone and prognostic factors in bacterial meningitis
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Table V. Risk factors for an unfavourable outcome from the Dutch Meningitis Risk Score (DMRS) and their associations with an unfavourable outcome and death among patients with community-acquired bacterial meningitis in North Denmark Region, 1998–2010; univariate and multivariate analyses.a Unfavourable outcome, OR (95% CI)
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Characteristics Age, yb Heart rate ⬎ 120 beats/min Glasgow Coma Scale scorec GCS ⬎ 12 GCS 10–12 GCS ⬍ 9 Cranial nerve palsies White-cell count ⬍ 1000/mm3 Gram stain Gram-positive cocci Gram-negative cocci Other bacteria Negative
Death, OR (95% CI)
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
1.46 (1.21–1.76) 7.14 (2.30–22.1)
1.41 (1.13–1.75) 7.63 (2.19–26.6)
1.48 (1.16–1.89) 4.60 (1.78–11.9)
1.34 (1.02–1.74) 2.99 (1.00–8.88)
1.00 1.59 1.95 2.38 1.70
(Ref.) (0.82–3.10) (0.81–4.66) (0.98–5.78) (0.91–3.16)
1.00 1.10 0.76 2.42 1.31
(Ref.) (0.50–2.41) (0.26–2.23) (0.91–6.44) (0.63–2.69)
1.00 2.36 5.66 2.46 2.01
1.00 1.90 3.70 1.93 1.74
3.74 1.00 7.00 2.45
(1.38–10.1) (Ref.) (0.54–91.1) (0.84–7.11)
1.70 1.00 4.45 1.15
(0.54–5.35) (Ref.) (0.31–62.9) (0.39–3.88)
2.11 (0.57–7.76) 1.00 (Ref.) – 2.20 (0.56–8.69)
(Ref.) (0.92–6.03) (1.97–16.2) (0.95–6.37) (0.94–4.34)
(Ref.) (0.66–5.47) (1.08–12.6) (0.66–5.61) (0.71–4.23)
0.60 (0.14–2.71) 1.00 (Ref.) – 0.87 (0.18–4.13)
OR, odds ratio; CI, confidence interval. aComplete data of parameters used in the DMRS were obtained for 101 patients. However, when GCS was categorized into 3 groups based upon record review, complete data were obtained for 142 patients (CSF leukocytes were missing for 20 patients, heart rates were missing for 9 patients, and both CSF leukocytes and heart rate were missing for 1 patient). The calculations are based upon the 142 patients. bORs per 10-y increment in age. cGCS was calculated as 3 categorical values in the North Denmark Region cohort (GCS ⬍ 9, GCS 10–12, and GCS ⬎ 12) and as continuous values in the DMRS.
with dexamethasone. The quartet of symptoms was associated with a favourable outcome (69% vs 52%, p ⫽ 0.05), but the triad was not (54% vs 57%, p ⫽ 0.65). Adjunctive treatment with dexamethasone was associated with a tentative diagnosis of meningitis at admission (83% vs 57%, p ⫽ 0.008) and a presentation of neck stiffness (78% vs 57%, p ⫽ 0.03) and fever (98% vs 86%, p ⫽ 0.06). As shown in Table II, compliance with dexamethasone treatment was significantly higher in the second period of implementation (60% vs 37%, p ⫽ 0.03). For the entire 15-y period, the in-hospital mortality was 19% (14- and 30-day mortalities were 15% and 17%, respectively), and in-hospital mortality remained unchanged before and after the implementation of dexamethasone (19% vs 20%) (Table III). However, after implementation, the risks of both an unfavourable outcome (33% vs 53%, adjusted RR 0.64, 95% CI 0.41–1.01) and a fatal outcome (15% vs 24%, adjusted RR 0.72, 95% CI 0.35–1.48) tended to decrease in patients treated with dexamethasone compared to patients not treated with dexamethasone. In patients with pneumococcal meningitis, dexamethasone was associated with a trend towards a decreased risk of an unfavourable outcome (44% vs 50%, adjusted RR 0.73, 95% CI 0.45–1.19) and a decrease in in-hospital mortality (22% vs 22%, adjusted RR 0.77, 95% CI 0.34–1.74) in the adjusted analyses only.
Treatment with dexamethasone had no discernible impact on long-term sequelae, although fewer patients with hearing loss were observed (treatment vs non-treatment 13% vs 31%, p ⫽ 0.10) (Table IV). Regarding the DMRS, we found that age, heart rate, and Gram-positive cocci on CSF microscopy were associated with an unfavourable outcome in the univariate analysis, but only age and heart rate remained significant in the multivariate analysis (Table V). Discussion In our retrospective Danish cohort study we found dexamethasone to be associated with a nearly halved risk of an unfavourable outcome and in-hospital mortality, although the differences did not reach statistical significance. The beneficial effects of dexamethasone were less pronounced than anticipated in patients with pneumococcal meningitis, but an improvement was suggested in the adjusted analyses. The fact that in-hospital mortality did not change markedly during the study period makes it pertinent to assess the risk factors recently identified in the DMRS. In our setting, age (per 10-y increment), tachycardia, and Gram-positive cocci on CSF microscopy were associated with an unfavourable outcome, but only age and heart rate remained statistically significant on multivariate analysis.
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The in-hospital mortality of 19% in our study is similar to reports from other Western countries [30–33] and was unchanged after 2002. Contributing factors could be the low compliance with adjunctive treatment with dexamethasone (47%) and a relatively low mortality already reached in the first years of the study (1998–2002). Of note, the proportion of meningococcal meningitis declined considerably during the study period – a disease with a relatively low mortality compared to pneumococcal meningitis (mortality of meningococcal meningitis was 12% in our cohort and 7–10% in other studies [7,15,34]). Unexpectedly, we found dexamethasone to be associated with a beneficial effect in non-pneumococcal meningitis (risk of unfavourable outcome 16% vs 58%, p ⫽ 0.02). This may be explained in part by a more focused diagnostic process and more attention to acute care in Danish hospitals in recent years. A large prospective Dutch study of patients with meningitis from 1998 to 2002 showed an in-hospital mortality of 30% for patients with pneumococcal meningitis (n ⫽ 352) [33]. Only 17% of the patients (n ⫽ 118) were given dexamethasone as compared to 47% of cases with pneumococcal meningitis included in our study after 2002. A follow-up study of the aforementioned Dutch study including patients with meningitis from 2006 to 2009 (n ⫽ 357), of whom 77% had been treated adequately with dexamethasone, reported a mortality of 20%, which is comparable to ours [9]. Our study does not add conclusive evidence to the use of dexamethasone.The positive trend between the use of dexamethasone and outcomes may have been confounded by an association between a rapid tentative diagnosis of meningitis at admission and treatment with dexamethasone, and thereby the immediate initiation of correct diagnostic and treatment algorithms. The association observed between typical signs of meningitis on patient management and the risk of an unfavourable outcome supports this assumption. Our study had both significant strengths and limitations. The health care system, with universal coverage and the use of a unique personal identifier for all health care contacts, limited selection bias and secured long-term follow-up of surviving patients. Thus, we were able to precisely specify the use of dexamethasone and outcome for every patient. Furthermore, we also included patients with CABM diagnosed upon stringent criteria other than a positive CSF culture, which makes our material more representative of the everyday clinical situation. The main limitation of the study was the limited number of cases included, which may explain why
some associations remained insignificant, particularly concerning patients with pneumococcal meningitis. Imprecision regarding timing of appropriate antibiotic therapy is also a weakness inherent in our retrospective record-based study. Some information bias must also be acknowledged, as the records were not always complete in terms of clinical and paraclinical parameters. In particular, the GCS score was recorded in only two-thirds of cases. Future studies are needed to evaluate the effect of the implementation of dexamethasone in the treatment of meningitis in adults in high-income countries. Furthermore, the focus should continue to be on prompt recognition and treatment of meningitis. In conclusion, in this Danish cohort study, in-hospital mortality was 19% and treatment with dexamethasone was associated with fewer unfavourable outcomes and fatalities, although statistical significance was not reached. The beneficial effect was notably weak in patients with pneumococcal meningitis. The use of dexamethasone was associated with neck stiffness and fever, as well as a tentative diagnosis of meningitis at admission. A complete validation of the DMRS was not possible due to a lack of data, but we confirmed age (per 10-y increment) and heart rate ⬎ 120 beats/min at admission to be associated with an unfavourable outcome. Declaration of interest: All authors report no conflicts of interests.
References [1] Harboe ZB, Valentiner-Branth P, Benfield TL, Christensen JJ, Andersen PH, Howitz M, et al. Early effectiveness of heptavalent conjugate pneumococcal vaccination on invasive pneumococcal disease after the introduction in the Danish Childhood Immunization Programme. Vaccine 2010;28:2642–7. [2] Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine 2001;20(Suppl 1):S58–67. [3] Snape M, Pollard A. Meningococcal polysaccharide–protein conjugate vaccines. Lancet Infect Dis 2005;5:21–30. [4] Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010;23:467–92. [5] Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 2012;307:573–82. [6] McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012;380:1703–11.
Scand J Infect Dis Downloaded from informahealthcare.com by Tufts University on 10/14/14 For personal use only.
Dexamethasone and prognostic factors in bacterial meningitis [7] Stephens D, Chang Q, Tzeng YL. Meningococcal disease: changes in epidemiology and prevention. Clin Epidemiol 2012;4:237–45. [8] Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267–84. [9] Brouwer M, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010;75:1533–9. [10] Scheld WM, Dacey RG, Winn HR, Welsh JE, Jane JA, Sande MA. Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. J Clin Invest 1980;66:243–53. [11] Täuber MG, Khayam-Bashi H, Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis 1985;151:528–34. [12] de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549–56. [13] Nguyen TH, Tran TH, Thwaites G, Ly VC, Dinh XS, Ho Dang TN, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007; 357:2431–40. [14] Scarborough M, Gordon SB, Whitty CJ, French N, Njalale Y, Chitani A, et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007;357:2441–50. [15] Heckenberg SG, Brouwer MC, van der Ende A, van de Beek D. Adjunctive dexamethasone in adults with meningococcal meningitis. Neurology 2012;79:1563–9. [16] Peltola H, Roine I, Fernández J, Zavala I, Ayala SG, Mata AG, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2007;45:1277–86. [17] Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211–8. [18] Leib S, Heimgartner C, Bifrare YD, Loeffler JM, Täauber MG. Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatr Res 2003;54:353–7. [19] Weisfelt M, Hoogman M, van de Beek D, de Gans J, Dreschler WA, Schmand BA. Dexamethasone and long-term outcome in adults with bacterial meningitis. Ann Neurol 2006;60:456–68.
Supplementary material available online Supplementary material Appendix I.
425
[20] Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. A risk score for unfavorable outcome in adults with bacterial meningitis. Ann Neurol 2008;63:90–7. [21] Schut ES, Brouwer MC, Scarborough M, Mai NT, Thwaites GE, Farrar JJ, et al. Validation of a Dutch risk score predicting poor outcome in adults with bacterial meningitis in Vietnam and Malawi. PLoS One 2012;7:e34311. [22] StatBank Denmark [Internet]. statbank.dk. Statistics Denmark; 2013. Available at: http://statbank.dk/statbank5a/ default.asp?w ⫽ 1920 (accessed December 2013). [23] Møller KK, Pedersen SS, Skinhøj PP. [Dexamethasone to adults with acute bacterial meningitis]. Ugeskr Laeg 2003; 165:243–4. [24] Guidelines og retningslinier—Dansk Selskab for Infektionsmedicin [Internet]. infmed.dk. Danish Society for Infectious Diseases; 2013. Available at: http://www.infmed. dk/guidelines (accessed November 2013). [25] McMillan DA, Lin CY, Aronin SI, Quagliarello VJ. Community-acquired bacterial meningitis in adults: categorization of causes and timing of death. Clin Infect Dis 2001;33:969–75. [26] Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700–7. [27] Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128–40. [28] Teasdale GM, Pettigrew LE, Wilson JT, Murray G, Jennett B. Analyzing outcome of treatment of severe head injury: a review and update on advancing the use of the Glasgow Outcome Scale. J Neurotrauma 1998;15:587–97. [29] Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702–6. [30] Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328:21–8. [31] Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997;337:970–6. [32] Swartz MN. Bacterial meningitis—a view of the past 90 years. N Engl J Med 2004;351:1826–8. [33] van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849–59. [34] Heckenberg SG, de Gans J, Brouwer MC, Weisfelt M, Piet JR, Spanjaard L, et al. Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis. Medicine (Baltimore) 2008;87:185–92.
