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Bacterial meningitis in adults: Host and pathogen factors, treatment and outcome

Heckenberg, S.G.B.

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Citation for published version (APA):Heckenberg, S. G. B. (2013). Bacterial meningitis in adults: Host and pathogen factors, treatment and outcome

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Download date: 16 Sep 2018

Chapter 1

Introduction

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Chapter 1

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Bacterial meningitis occurs when bacteria invade the subarachnoid space

surrounding the brain and spinal cord. This infection and the ensuing

inflammatory response cause severe, life-threatening disease. Until the

advent of antibacterial agents effective treatment was lacking. After initial

success using intrathecal meningococcal antiserum in the first decades of the

twentieth century, the introduction of sulfonamides in the 1930s provided the

first effective antibiotic therapy for bacterial meningitis caused by Haemophilus

influenzae type B and Neisseria meningitidis. Subsequently, penicillin treatment

for pneumococcal meningitis was implemented in the 1940s. In meningococcal

disease, increasing resistance to sulfonamides prompted its replacement by

penicillin. 1, 2

Epidemiology

To monitor the epidemiology of bacterial meningitis, the Netherlands Reference

Laboratory for Bacterial Meningitis was officially established in 1975 and

isolates from cerebrospinal fluid (CSF) from patients with bacterial meningitis

have been stored and collected. The implementation of conjugate vaccination

against type B H. influenzae, group C N. meningitidis, and most recently, the

pneumococcal vaccine have reduced the incidence of bacterial meningitis

in the Netherlands. Currently, approximately 85% percent of all bacterial

meningitis is caused by N. meningitidis and Streptococcus pneumoniae. Other

causes are Listeria monocytogenes, H. influenzae and Streptococcus agalactiae.3

N. meningitidis (the meningococcus) is a common inhabitant of the human

nasopharynx. Carriage is found exclusively in humans. Disease occurs when

meningococci invade the mucosal space and enter the bloodstream. Invasive

disease can progress swiftly and fatally, mainly through sepsis and meningitis.

The incidence of meningococcal meningitis in adults in the Netherlands is

approximately 1 per 100,000. In the Netherlands, the most common serogroups

are B and C, while serogoup A is the cause of severe epidemics in the “meningitis-

belt” in sub-Saharan Africa. Since the implementation of vaccination with the

MenC vaccine, the incidence of group C disease has decreased substantially in

the Netherlands. In 1998, a new method of typing meningococci was described

using nucleotide sequencing of meningococcal genes. Multilocus sequence

typing (MLST) has provided a useful tool for the unambiguous characterisation

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Ch

apt

er 1of meningococci and allows for rapid identification of invasive lineages of

meningococci.4

S. pneumoniae (the pneumococcus) is a major cause of respiratory infections,

sepsis and meningitis worldwide. In pneumococcal meningitis, mortality

remains high (20-30%) despite effective antiobiotic treatment. Over 90

serotypes have been described. Increasing antibiotic resistence is an emerging

challenge worldwide with rates of resistance exceeding 50% in parts of the

United States. However, antibiotic resistance in the Netherlands remains low. In

2006, the heptavalent pneumococcal vaccine was implemented in the national

vaccination program in the Netherlands.

Treatment and outcome

Although the prognosis of patients with bacterial meningitis has improved

greatly through effective antibiotic treatment, substantial morbidity and

mortality has remained, fuelling research into adjunctive treatment. Following

experimental animal studies, attenuation of the severe inflammatory

response emerged as an important pathway for improving clinical outcome.

Since the 1960s, clinical trials with adjunctive corticosteroid treatment have

been performed with conflicting results. However, meta-analyses showed a

reduction in hearing loss in patients treated with adjunctive corticosteroids.5

In 2002, a European randomized clinical trial showed beneficial effect of

adjunctive dexamethasone in adults with bacterial meningitis. The effect was

most pronounced in pneumococcal meningitis and mortality in those patients

was reduced by 10%. However, these results were not reproduced in clinical

trials from other parts of the world. An individual patient data-analysis and

subsequent Cochrane review supported the continued use of dexamethasone

in children and adults in high-income countries. 6-8

Adequate antibiotic and adjunctive therapy in combination with supportive

care have reduced the mortality of bacterial meningitis, but neurologic

sequelae in patients surviving bacterial meningitis are common, particularly

in pneumococcal meningitis. They include cognitive impairment, hearing loss,

epilepsy and other focal neurological deficits. 9-11

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Chapter 1

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Aims and outline of this thesis

In chapter 2 we present the results of a nationwide study in adults with

meningococcal meningitis. Details of clinical characteristics, therapy and

outcome are presented, as well as the correlation of bacterial genotype,

acquired through MLST analysis, and clinical characteristics. Chapter 3

describes the collaborative effort of our research group with the Netherlands

Vaccine Institute. The discovery of meningococci with an impaired potential

to induce cytokine production is described. Furthermore, the mutations in

bacterial genome are revealed and the relationship with clinical characteristics

in patients from our nationwide cohort studies is investigated. In chapters 4

and 5, we present the results of nationwide studies from 2006-2009 on the

implementation of dexamethasone treatment in the Netherlands. Outcome in

patients was compared to a cohort of 1998-2002, before the implementation

of dexamethasone. The influence of dexamethasone treatment on outcome in

meningococcal meningitis is described in chapter 4. Chapter 5 describes the

change in outcome in adults wih pneumococcal meningitis and we compare

the observed outcome with that in a prognostic model. Chapter 6 describes the

incidence of hearing loss following pneumococcal meningitis, combining two

nationwide studies of adults with bacterial meningitis, from 1998-2002 and from

2006-2009. The association between clinical characteristics, pneumococcal

serotype and occurrence of hearing loss is described. In Chapter 7 the results

of our cooperation with a research group in Munich, Germany are presented.

We describe the association of unfavorable outcome with a single nucleotide

polymorphism (SNP) coding for complement factor C5. Next, C5 fragment

levels in CSF and the relationship with clinical characteristics were investigated.

Finally, a mouse model of C5a deficient mice and adjuvant treatment with

C5-specific monoclonal antibodies are described. In chapter 8, we conclude

with a general discussion describing the epidemiology, pathophysiology and

treatment of bacterial meningitis incorporating the results of the presented

studies and suggestions for future research are proposed.

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er 1References

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