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Cohort Betamethasone and Dexamethasone in Adult Community Acquired
Cohort Betamethasone and Dexamethasone in Adult Community Acquired
e7
Original article
a r t i c l e i n f o a b s t r a c t
Article history: Acute bacterial meningitis (ABM) is a highly lethal disease. Available data support the use of cortico-
Received 26 April 2016 steroids in high-income countries, but the effect on mortality is still controversial. The effects of corti-
Received in revised form costeroids on mortality and sequelae were evaluated in the national Swedish quality registry. In total,
21 June 2016
during 1995e2014 1746 adults with ABM were included, of whom 989 were treated with corticosteroids
Accepted 26 June 2016
Available online 9 July 2016
(betamethasone, n ¼ 766; dexamethasone, n ¼ 248; methylprednisolone, n ¼ 2), 498 were not given
corticosteroids and in 259 patients data for corticosteroids were missing. Fatal outcome was observed in
Editor: Professor L. Leibovici 8.9% of the patients in the corticosteroid-treated group vs. 17.9% in the non-corticosteroid-treated group
(p <0.001), resulting in an odds ratio (OR) of 0.57 with a 95% confidence interval (CI) of 0.40e0.81
Keywords: adjusted for age, sex, mental status, and door-to-antibiotic time. In patients with meningitis caused by
Bacterial meningitis S. pneumoniae, mortality was 10.2% in the corticosteroid-treated group and 21.3% in the non-
Betamethasone corticosteroid-treated group (p <0.001) with an adjusted OR of 0.50 (95% CI 0.31e0.80). In ABM pa-
Corticosteroid treatment tients with non-pneumococcal aetiology the adjusted OR was 0.71 (95% CI 0.40e1.26). Lower mortality
Dexamethasone
was observed in the corticosteroid-treated group with impaired mental status, whereas no significant
Mortality
difference was found in patients with unaffected mental status. The adjusted ORs for betamethasone and
dexamethasone were 0.49 (95% CI 0.28e0.84) and 0.61 (95% CI 0.37e1.01), respectively. Corticosteroid
treatment decreases mortality in ABM and should be administered initially with antibiotics in adult ABM
patients with impaired mental status regardless of presumed aetiology. Betamethasone seems to be at
least as effective as dexamethasone. M. Glimåker, CMI 2016;22:814.e1e814.e7
© 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
http://dx.doi.org/10.1016/j.cmi.2016.06.019
1198-743X/© 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
M. Glimåker et al. / Clinical Microbiology and Infection 22 (2016) 814.e1e814.e7 814.e2
Table 1
Characteristics of patients during the different study periods by groups with different corticosteroid treatment
RLS ¼ reaction level scale. The RLS is as follows: 1, mentally alert; 2, drowsy or confused, responsive to light stimulation; 3, very drowsy or confused, responsive to strong
stimulation; 4, unconscious, localizes but does not ward off pain; 5, unconscious, withdrawing movements on pain; 6, unconscious, stereotype flexion on pain; 7, unconscious,
stereotype extension on pain; 8, unconscious, no response [20]. Conversion of Glasgow coma scale (GCS) to RLS is as follows: GCS 14e15 ¼ RLS 1, GCS 12e13 ¼ RLS 2, GCS
10e11 ¼ RLS 3, GCS 8e9 ¼ RLS 4, GCS 6 ¼ RLS 5, GCS 5 ¼ RLS 6, GCS 4 ¼ RLS 7, and GCS 3 ¼ RLS 8 [21].
a
Treatment with betamethasone (n ¼ 744), dexamethasone (n ¼ 243), or methylprednisolone (n ¼ 2).
b
The sex of the patient was not noted in 104 patients (two with dexamethasone treatment, three without corticosteroids, and 99 with no data for corticosteroids).
c
Streptococci (n ¼ 115), H. influenzae (n ¼ 98), L. monocytogenes (n ¼ 77), S. aureus (n ¼ 75), Enterobacteriacae (n ¼ 33), other bacteria (n ¼ 33), and unknown (n ¼ 224).
814.e3 M. Glimåker et al. / Clinical Microbiology and Infection 22 (2016) 814.e1e814.e7
Fig. 1. Annual proportion (%) of adult patients with community-acquired bacterial meningitis treated with corticosteroids (betamethasone or dexamethasone) administered
concomitant with the start of antibiotics in 1995 to 2014. The annual number (n) of patients is shown on the x-axis. In addition, two patients, one in 1996 and one in 1997, were
treated with methylprednisolone.
M. Glimåker et al. / Clinical Microbiology and Infection 22 (2016) 814.e1e814.e7 814.e4
Table 2
Multivariate analyses of corticosteroid treatment in relation to mortality (patients
not treated with corticosteroids were used as reference)
No corticosteroid Corticosteroid
treatment treatment
was observed in those with L. monocytogenes (8/33 ¼ 24.2% vs. 8/ Corticosteroids vs. no corticosteroids in relation to mental status
37 ¼ 21.6%, p ¼ 0.78).
The corticosteroid-treated patients were younger and started on Data for mental status on admission and corticosteroid
antibiotic treatment earlier but were more comatose than the non- treatment were available in 843 patients. The effect of cortico-
corticosteroid-treated patients (Table 1). However, mortality steroids on mortality in relation to mental status at admission is
adjusted for sex, age, door-to-antibiotic time, and mental status on depicted in Fig. 3. The adjusted analysis showed decreased
admission still resulted in an OR of 0.57 (95% CI 0.40e0.81) in the mortality with corticosteroid treatment for the group with
total material (Table 2). In cases with pneumococcal meningitis, the moderately impaired mental status (RLS 2e3) and a trend to
adjusted OR for death was 0.50 (95% CI 0.31e0.80). However, after lower mortality in the comatose patients (RLS 4e8), whereas
adjustment for confounders, the reduction in mortality in patients there was no notable effect in patients without impaired mental
with non-pneumococcal aetiology did not reach statistical signifi- status (RLS 1) (Table 2).
cance, with an adjusted OR of 0.71 (95% CI 0.40e1.26). Reduction in
adjusted mortality was virtually similar over different time periods Corticosteroids vs. no corticosteroids in relation to time to treatment
(Table 2).
Among the 1310 survivors, data were available for hearing and Data for corticosteroid treatment and door-to-antibiotic time
neurological sequelae at follow-up in 1166 patients with similar were reported in 1250 patients. After adjustment for potential
outcomes irrespective of whether corticosteroids were given confounders, significantly lower mortality was observed in the
(Fig. 2b). Hearing deficit was noted in 24.8% of survivors in the corticosteroid group treated with antibiotics <1 hour from admis-
corticosteroid treated-group vs. 21.6% (p ¼ 0.24) in those without sion (OR 0.40, 95% CI 0.18e0.88), as well as in those treated later OR
corticosteroids. 0.60, 95% CI 0.40e0.89).
814.e5 M. Glimåker et al. / Clinical Microbiology and Infection 22 (2016) 814.e1e814.e7
Fig. 3. Outcomes related to mental status on admission. Mortality during hospital stay (a) and sequelae (hearing, neurological deficits, or both) at 2e6-month follow-up (b) in adult
patients treated in 1995e2014 with or without corticosteroids. RLS, reaction level scale.
Betamethasone vs. dexamethasone sequelae [14e16]. However, a reduction in mortality could not be
established [14].
During 1995e2007, data for type of corticosteroid and mortality To the authors' knowledge, the present quality registry study
were available in 521 patients. Mortality was 13.2% and 9.7% over 20 years is the largest investigation of the efficacy of cortico-
(p ¼ 0.2) in dexamethasone- and betamethasone-treated patients, steroids in community-acquired ABM in adults. The risk of fatal
respectively. Adjusted analysis revealed that the effect of betame- outcome was halved in patients with corticosteroid treatment in
thasone was similar or better than that of dexamethasone (Table 2). comparison with those without such treatment (8.9% vs. 17.9%).
In the surviving patients, hearing or neurological sequelae were Despite falling overall mortality over time, the decreased mortality
more often observed in dexamethasone-treated than in in the corticosteroid-treated patients remained virtually the same.
betamethasone-treated patients: 109/198 (55.1%) vs. 106/238 Lower age and earlier antibiotic treatment were observed in the
(44.5%, p <0.05). corticosteroid-treated patients, but these patients had worse
mental status on admission, resulting in an almost identical
Discussion reduction in mortality in the adjusted analysis. These results agree
with those from the randomized placebo-controlled study by de
Despite modern antibiotic treatment and intensive care, mor- Gans et al., which included 301 patients [9]. As in that study, the
tality and morbidity still remain high in ABM [1]. Because increased present study found that the beneficial effect of corticosteroids was
intracranial pressure (ICP) is the underlying mechanism for most most evident in patients with pneumococcal meningitis, and that
deaths in ABM, different measures to counteract elevated ICP corticosteroids do not seem to increase sequelae in survivors.
should have the greatest potential to improve outcome. The path- Although not reaching statistical significance in the adjusted
ophysiological mechanisms resulting in increased ICP in ABM are analysis, the present results indicate that corticosteroids may be
multifactorial. Release of bacterial components in the subarachnoid beneficial rather than harmful in adults with ABM caused by
space leads to an inflammatory response that contributes to N. meningitidis, other bacteria, or with unknown aetiology (Fig. 2a,
increased permeability of the blood-brain barrier causing cerebral Table 2). These results are also in agreement with earlier studies
extracellular oedema, impaired CSF-absorption with increased CSF- [1,9,17,28] in which trends towards a positive effect were seen in
volume, a cytotoxic intracellular brain oedema, and increased ce- patients with ABM caused by bacteria other than S. pneumoniae. In
rebral blood flow (hyperaemia); all adding to elevated ICP [25]. a recent prospective cohort study the effect of dexamethasone
Glycerol causes an osmotic pressure gradient that can counteract decreased mortality in patients with pneumococcal and non-
brain oedema, but the results from clinical studies are conflicting pneumococcal aetiology [1]. However, the study was not
[26]. For severe cases of ABM with impending cerebral herniation, designed to specifically study corticosteroid treatment and the
neuro-intensive care with ICP monitoring and CSF drainage may be proportion of patients not treated with corticosteroids constituted
beneficial [22,27]. only 11%. In the present study L. monocytogenes was the only
High-dose corticosteroid treatment is the most studied adjuvant pathogen for which a trend towards negative outcome was
ABM-treatment with widespread adoption in clinical practice. observed in the corticosteroid-treated group. Thus, no support was
Corticosteroids have been shown to reduce mortality and neuro- found for corticosteroid treatment in Listeria meningitis. However,
logical sequelae in randomized controlled trials in Europe but have the power of the study was not sufficient to prove or disprove a
failed to do so in several large studies performed in Africa, South positive or negative effect in different specific aetiologies, apart
America, and Asia [8e13]. Aggregate data from available high- from S. pneumoniae.
quality studies support the recommendation to use corticoste- The frequency of sequelae was similar whether corticosteroids
roids in high-income countries based on a decrease of neurological were given or not, indicating that the reduced mortality did not
M. Glimåker et al. / Clinical Microbiology and Infection 22 (2016) 814.e1e814.e7 814.e6
result in increased sequelae in survivors at the follow-up major limitation, i.e. its retrospective non-interventional design
2e6 months after discharge, a finding consistent with those re- with lack of randomization and control of the original data. A risk of
ported in short- and long-term follow-up in adult ABM [1,29]. confounding by indication must be considered but adjustment for
The present results suggest that corticosteroids are beneficial in important confounding variables was performed. The large amount
patients with impaired mental status (RLS 2), whereas a similar of missing data on mental status is a drawback, but imputation
low mortality of about 3% was observed in mentally unaffected analyses were used to compensate for this. Furthermore, the
cases (RLS 1), regardless of corticosteroid treatment. These results number of corticosteroid-treated patients increased over time,
are in accordance with the findings of de Gans et al. [9]. Based on especially after the publication of the study by de Gans et al. in 2002
160 patients with GCS 12e14 in that study and 314 with RLS 1 in the [9], along with a decrease in mortality, probably caused by imple-
present study, these results indicate that the beneficial effect is mentation of advanced neuro-intensive care and new recommen-
limited in mentally alert patients, and consequently, that the sup- dations aiming at prompt lumbar puncture associated with earlier
port for adjunctive corticosteroid treatment in this patient group treatment [3,22]. However, regardless of the time period, the
may be questioned. adjusted OR for a treatment effect remained in the interval of 0.53
The findings of the present study, in conjunction with others, to 0.66. Finally, adjustment for immunocompromised states and
strongly support empirical corticosteroid treatment in mentally important clinical measures of disease severity, such as septic shock
affected patients with ABM, and that treatment should not be and seizures, would have been desirable but these data were not
discontinued in cases in which S. pneumoniae is not found. How- available in the registry.
ever, corticosteroid treatment should be considered in all ABM An important strength of the study is the large sample size that
cases, not only in cases with impaired mental status, because timely enabled consideration of several important confounders, such as
adequate treatment is pivotal for a favourable outcome [3,4], age, aetiology, calendar time, mental status, and time to treatment
deterioration may occur rapidly after presentation and treatment by stratified and multivariate analyses, which thereby consolidate
start at admission [30,31], and corticosteroids are shown to be the results. The outcome was consistent and generally pointed at
effective only if given together with the first doses of antibiotics. favourable effects of corticosteroids vs. no corticosteroids in these
Unambiguous clinical guidelines are also important in a fulminant analyses, implicating a high external validity of the present
disease such as ABM. The importance of timely management of findings.
corticosteroids has not yet been fully assessed other than that this
may be beneficial when administered together with the start of Conclusion
antibiotics. This study indicates that corticosteroids retain their
effect even in patients in whom antibiotic treatment has been The present study increases the strength of evidence indicating
delayed for various reasons. that corticosteroid treatment decreases ABM mortality in resource-
The optimal duration of corticosteroid treatment has not been rich countries and should be administered initially together with
thoroughly investigated. A 4-day regimen is usually recommended the start of antibiotics in mentally affected adult patients with
simply because this has been practiced in most studies [14]. How- community acquired ABM, regardless of presumed aetiological
ever, in a study on children 2-day treatment was as effective as agent. The results further indicate that betamethasone is equally as
4 days [32]. With adequate antibiotic treatment, the elevated ICP effective as dexamethasone. The value and importance of registry
most probably peaks very early in the course of a disease [22,27] studies, especially in clinical situations where randomized trials are
and declines after 24e48 hours. Thus, a shorter duration than unlikely to take place, is demonstrated.
4 days may be appropriate, at least in cases with rapid clinical
improvement. The results of the present study also indicate that
Transparency declaration
corticosteroids should probably be withdrawn if L. monocytogenes
are detected as the causative bacteria. In this study the duration of
No conflict of interest. The Swedish Quality Registry for bacterial
corticosteroid treatment was not defined, but 2e4 days has been
meningitis is funded by the Swedish Association of Local Author-
the recommendation in Sweden since 2004.
ities and Regions.
Most studies have involved dexamethasone, and the effect of
other corticosteroids in ABM is considered to be an important
unanswered issue [14]. Dexamethasone has a high penetration into References
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