S.G.B. Heckenberg

Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis

Streptococcus pneumoniae and Neisseria meningitidis can cause sepsis and meningitis. Several risk factors for pneumococcal and meningococcal disease have been identified, but the cause of basic differences in susceptibility between individuals and populations is unknown. Single-nucleotide polymorphisms are thought to explain interindividual differences in susceptibility. New technologies provide the opportunity to study the genetic basis of susceptibility to these diseases. In recent years, several studies have been published on these polymorphisms in pneumococcal and meningococcal disease, many with apparently conflicting results. Herein we provide a systematic overview of all polymorphisms studied for a relation with susceptibility to pneumococcal and meningococcal disease. We also propose an initiative to pool genetic data on pneumococcal and meningococcal meningitis in one biobank.

Community-Acquired Listeria monocytogenes Meningitis in Adults

BACKGROUND Listeria monocytogenes is the third most common cause of bacterial meningitis. METHODS We prospectively evaluated 30 episodes of community-acquired L. monocytogenes meningitis, confirmed by culture of cerebrospinal fluid specimens, in a nationwide study in The Netherlands. Outcome was graded using the Glasgow outcome score; an unfavorable outcome was defined as a score of 1-4. RESULTS We found 30 episodes of L. monocytogenes meningitis. All patients were immunocompromised or > 50 years old. In 19 (63%) of 30 patients, symptoms were present for > 24 h; in 8 patients (27%), symptoms were present for > or = 4 days. The classic triad of fever, neck stiffness, and change in mental status was present in 13 (43%) of 30 patients. An individual cerebrospinal fluid indicator of bacterial meningitis was present in 23 (77%) of 30 cases. Gram staining of cerebrospinal fluid samples revealed the causative organism in 7 (28%) of 25 cases. The initial antimicrobial therapy was amoxicillin based for 21 (70%) of 30 patients. The coverage of initial antimicrobial therapy was microbiologically inadequate for 9 (30%) of the patients. The mortality rate was 17% (5 of 30), and 8 (27%) of 30 patients experienced an unfavorable outcome. Inadequate initial antimicrobial therapy was not related to outcome. CONCLUSIONS In contrast with previous reports, we found that patients with meningitis due to L. monocytogenes do not present with atypical clinical features; however, typical cerebrospinal fluid findings predictive for bacterial meningitis might be absent. A high proportion of patients received initial antimicrobial therapy that did not cover L. monocytogenes.

Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis

Background: In this nationwide prospective cohort study, we evaluated the implementation of adjunctive dexamethasone therapy in Dutch adults with pneumococcal meningitis. Methods: From March 2006 through January 2009, all Dutch patients over 16 years old with community-acquired pneumococcal meningitis were prospectively evaluated. Outcome was classified as unfavorable (defined by a Glasgow Outcome Scale score of 1 to 4 points at discharge) or favorable (a score of 5). Clinical characteristics and outcome were compared with a similar nationwide cohort of 352 patients with pneumococcal meningitis from a previous period before guidelines recommended dexamethasone therapy (1998–2002). A multivariable prognostic model was used to adjust for differences in case mix between the 2 cohorts. Results: We evaluated 357 episodes with pneumococcal meningitis in 2006–2009. Characteristics on admission were comparable with the earlier cohort (1998–2002). Dexamethasone was started with or before the first dose of antibiotics in 84% of episodes in 2006–2009 and 3% in 1998–2002. At discharge, unfavorable outcome was present in 39% in 2006–2009 and 50% in 1998–2002 (odds ratio [OR] 0.63; 95% confidence interval [CI] 0.46–0.86; p = 0.002). Rates of death (20% vs 30%; p = 0.001) and hearing loss (12% vs 22%; p = 0.001) were lower in 2006–2009. Differences in outcome remained after adjusting for differences in case mix between cohorts. Conclusions: Dexamethasone therapy has been implemented on a large scale as adjunctive treatment of adults with pneumococcal meningitis in the Netherlands. The prognosis of pneumococcal meningitis on a national level has substantially improved after the introduction of adjunctive dexamethasone therapy. Classification of evidence: This study provides Class III evidence that dexamethasone (10 mg IV, given every 6 hours for 4 days started before or with the first dose of parenteral antibiotics) reduced the proportion of patients with unfavorable outcomes (Glasgow Outcome Scale score of 1 to 4) in the 2006–2009 cohort, as compared to the 1998–2002 cohort (39% vs 50%; OR 0.63; 95% CI 0.46–0.86; p = 0.002). Mortality rate (20% vs 30%; absolute risk difference 10%; 95% CI 4%–17%; p = 0.001) was also lower in 2006–2009.

Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis: a prospective cohort study.

Abstract Meningococcal meningitis remains a life-threatening disease. Neisseria meningitidis is the leading cause of meningitis and septicemia in young adults and is a major cause of endemic bacterial meningitis worldwide. The Meningitis Cohort Study was a Dutch nationwide prospective observational cohort study of adults with community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid, from October 1998 to April 2002. Patients underwent a neurologic examination at discharge, and outcome was graded with the Glasgow Outcome Scale. Serogrouping, multi-locus sequence typing, and susceptibility testing of meningococcal isolates were performed. The study identified 258 episodes of meningococcal meningitis in 258 patients. The prevalence of the classical triad of fever, neck stiffness, and change in mental status was low (70/258, 27%). When rash was added to the classical triad, 229 of 258 (89%) patients had at least 2 of 4 signs. Systolic hypotension was associated with rash (22/23 vs. 137/222, p = 0.002) and absence of neck stiffness (6/23 vs. 21/220, p = 0.05). Neuroimaging before lumbar puncture was an important cause of delay of therapy: antibiotics were not initiated before computed tomography (CT) scan in 85% of patients who underwent CT scan before lumbar puncture. Unfavorable outcome occurred in 30 of 258 (12%) patients, including a mortality rate of 7%. Neurologic sequelae occurred in 28 of 238 (12%) patients, particularly hearing loss (8%). Factors associated with sepsis and infection with meningococci of clonal complex 11 (cc11) are related with unfavorable outcome. Abbreviations: cc = clonal complex, CRP = C-reactive protein, CSF = cerebrospinal fluid, CT = computed tomography, ESR = erythrocyte sedimentation rate, GCS = Glasgow Coma Scale, IQR = interquartile range, MLST = multi-locus sequence typing, WBCC = white blood cell count.

Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.

Naturally Occurring Lipid A Mutants in Neisseria meningitidis from Patients with Invasive Meningococcal Disease Are Associated with Reduced Coagulopathy

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease.

Adjunctive dexamethasone in adults with meningococcal meningitis

Objectives: We evaluated the implementation and effectiveness of adjunctive dexamethasone in adults with meningococcal meningitis. Methods: We compared 2 Dutch prospective nationwide cohort studies on community-acquired meningococcal meningitis. A total of 258 patients with CSF culture-proven meningitis were enrolled between 1998 and 2002, before routine dexamethasone therapy was introduced, and 100 patients from March 2006 to January 2011, after guidelines recommended dexamethasone. Results: Dexamethasone was administered in 43 of 258 (17%) patients in the 1998–2002 cohort and in 86 of 96 (90%) patients in the 2006–2011 cohort (p < 0.001), and was started with or before the first dose of antibiotics in 12 of 258 (5%) and 85 of 96 (89%) patients (p < 0.001). Rates of unfavorable outcome were similar between cohorts (12 of 100 [12%] vs 30 of 258 [12%]; p = 0.67), also after correction for meningococcal serogroup. The rates of hearing loss (3 of 96 [3%] vs 19 of 237 [8%]; p = 0.10) and death (4 of 100 [4%] vs 19 of 258 [7%]; p = 0.24) were lower in the 2006–2011 cohort, but this did not reach significance. The rate of arthritis was lower in patients treated with dexamethasone (32 of 258 [12%] vs 5 of 96 [5%], p = 0.046). Dexamethasone was not associated with adverse events. Conclusions: Adjunctive dexamethasone is widely prescribed for patients with meningococcal meningitis and is not associated with harm. The rate of arthritis has decreased after the implementation of dexamethasone. Classification of evidence: This study provides Class III evidence that adjuvant dexamethasone in adults with meningococcal meningitis does not increase negative outcomes such as deafness, death, or negative Glasgow Outcome Scale measures.

Hearing loss in adults surviving pneumococcal meningitis is associated with otitis and pneumococcal serotype

We assessed the incidence of hearing loss and its relationship with clinical characteristics and pneumococcal serotypes in adults surviving pneumococcal meningitis. We analysed hearing loss in 531 adults surviving pneumococcal meningitis included in two prospective nationwide cohort studies performed from April 1998 through to October 2002 and March 2006 through to January 2009. Hearing loss was evaluated on admission and discharge for all patients. Severe hearing loss was assessed by pure tone average on audiology and corrected for age, or by the combination of hearing loss on discharge and a score on the Glasgow Outcome Scale below 5, which could not be explained by other neurological sequelae. A total of 531 episodes of pneumococcal meningitis with non-lethal outcome were included. Predisposing conditions for pneumococcal meningitis were present in the majority of patients (64%), most commonly otitis (36%). Hearing loss was present at discharge in 116 patients (22%) and was classified as mild in 53% and severe in 47%. Hearing loss was related to otitis (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.66-4.02; p < 0.001) and inversely related to serotype 23 F infection (OR, 0.36; 95% CI, 0.13-0.98; p = 0.025), but not with parameters of disease severity or indicators of cerebrospinal fluid inflammation severity. Meningitis due to pneumococcal serotype 3 was associated with the highest rate of hearing loss. Hearing loss frequently complicates pneumococcal meningitis. Risk factors for hearing loss were infection with pneumococcal serotype 23 F and otitis, but not disease severity. Otitis and resulting perilympathic inflammation contribute to meningitis-associated hearing loss.

Chapter 93 - Bacterial meningitis

Bacterial meningitis is a neurologic emergency. Vaccination against common pathogens has decreased the burden of disease. Early diagnosis and rapid initiation of empiric antimicrobial and adjunctive therapy are vital. Therapy should be initiated as soon as blood cultures have been obtained, preceding any imaging studies. Clinical signs suggestive of bacterial meningitis include fever, headache, meningismus, and an altered level of consciousness but signs may be scarce in children, in the elderly, and in meningococcal disease. Host genetic factors are major determinants of susceptibility to meningococcal and pneumococcal disease. Dexamethasone therapy has been implemented as adjunctive treatment of adults with pneumococcal meningitis. Adequate and prompt treatment of bacterial meningitis is critical to outcome. In this chapter we review the epidemiology, pathophysiology, and management of bacterial meningitis.

VERTEBRAL OSTEOMYELITIS COMPLICATING PNEUMOCOCCAL MENINGITIS

Bacterial meningitis is a serious and life-threatening disease with a broad spectrum of complications.1 Vertebral osteomyelitis is a rare complication of bacterial meningitis and has only been described in patients with meningitis due to uncommon pathogens.2,3 Herein we describe two cases of vertebral osteomyelitis complicating community-acquired bacterial meningitis due to Streptococcus pneumoniae . ### Case reports. #### Case 1. A 51-year-old man with a history of depressive mood disorder and chronic low back pain presented to the emergency room (ER) with a 4-day history of fever and backache followed by confusion. On examination he had a temperature of 35.8°C, opened his eyes and bent his arms on painful stimuli, and moaned (score on Glasgow Coma Scale, 7). Neurologic examination showed neck stiffness and right-sided facial nerve palsy. Empirical therapy was started with dexamethasone (10 mg) and penicillin (2 million IU). CT scan of the head showed no abnormalities. Subsequent lumbar puncture (LP) revealed a CSF leukocyte count of 33 leukocytes/mL (90% neutrophils), protein of 2.36 g/L, and glucose less than 0.1 mmol/L; CSF Gram staining showed Gram-positive cocci and cultures grew S pneumoniae (serogroup 10), sensitive for penicillin. During hospital stay he improved quickly although a mild backache persisted. Neurologic examination at discharge showed mild right-sided facial nerve palsy but was otherwise …