Pneumococcal Meningitis Patients Research Articles

Effect of the COVID-19 pandemic on clinical characteristics and outcomes of adult pneumococcal meningitis patients - a Dutch prospective nationwide cohort study.

To investigate clinical characteristics and outcomes of patients with pneumococcal meningitis during the COVID-19 pandemic. In a Dutch prospective cohort, risk factors and clinical characteristics of pneumococcal meningitis episodes occurring during the COVID-19 pandemic (starting March 2020) were compared with those from baseline and the time afterwards. Outcomes were compared with an age-adjusted logistic regression model. We included 1,699 patients in 2006-2020, 50 patients in 2020-2021, and 182 patients in 2021-2023. After March 2020 relatively more alcoholism was reported (2006-2020, 6.1%; 2020-2021, 18%; 2021-2023, 9.7%; P = 0.002) and otitis-sinusitis was less frequently reported (2006-2020, 45%; 2020-2021, 22%; 2021-2023, 47%; P = 0.006). Other parameters, i.e. age, sex, symptom duration or initial C-reactive protein level, remained unaffected. Compared to baseline, lumbar punctures were more frequently delayed (on admission day, 2006-2020, 89%; 2020-2021, 74%; 2021-2022, 86%; P = 0.002) and outcomes were worse ('good recovery', 2020-2021, OR 0.5, 95% CI 0.3-0.8). During the COVID-19 pandemic, we observed worse outcomes in patients with pneumococcal meningitis. This may be explained by differing adherence to restrictions according to risk groups or by reduced health care quality.

Serum cytokine profile of pediatric patients with laboratory confirmed pneumococcal meningitis

BackgroundStreptococcus pneumoniae infection is a leading cause of bacterial meningitis in children with severe sequelae. Cytokines are important molecules in regulating of host inflammatory and anti-inflammatory responses. So far, the cytokine profile of bacterial meningitis caused by single pathogen has been rarely reported. The aim of this study was to explore serum cytokine profile in pediatric patients with pneumococcal meningitis (PM) and its clinical relevance which could be considered as a valuable tool for differential diagnosis of PM. MethodsDuring 2015–2018, 95 children with laboratory-confirmed PM were included. Of them, 63 had serum samples at admission. Ten cytokines including TNF-α, IL-12p40, IL-17A, IL-1β, IFN-γ, GM-CSF, IL-10, CXCL-1, IL-8 and IL-13 were measured by multiplex immunoassay in sera of 63 PM patients and 55 age-matched healthy controls (HCs). Level of serum cytokines was compared with different clinical features of patients. ResultsSignificantly higher level of IL-10 was observed in patients than HCs (median, 2.19 vs. 1.92 pg/mL, p = 0.017). Significantly lower levels of serum IL-12p40, IL-17A and IL-1β were observed in patients than HCs (median, 0.68 vs. 10.12 pg/mL, p < 0.0001; 1.14 vs. 1.14 pg/mL, p = 0.004; 1.00 vs. 5.09 pg/mL, p < 0.0001, respectively). No difference was found in levels of other cytokines between patients and controls. A negative correlation was noticed between percentages of blood neutrophils and concentrations of IL-10 (p = 0.048, r = −0.25). Significantly lower levels of IL-12p40 and CXCL-1 were observed in PM patients with sepsis than those without (median 0.68 vs. 1.64 pg/mL, p = 0.026; 7.25 vs. 12.84 pg/mL, p = 0.043, respectively). ConclusionsOur results suggested that there might be significant changes in serum pro-inflammatory and anti-inflammatory cytokines in PM children and that the determination of these cytokines may have limited value for evaluation of clinical outcome of pediatric PM.

Long-term neurologic and cognitive outcome and quality of life in adults after pneumococcal meningitis

ObjectivesTo perform a cross-sectional cohort study on long-term neurologic, cognitive and quality-of-life outcome in adults surviving pneumococcal meningitis. MethodsAdult survivors of community-acquired pneumococcal meningitis from a Dutch nationwide prospective cohort study were evaluated 1 to 5 years after acute illness. The control group consisted of partners or proxies of patients. Neurologic examination was performed and cognitive domains were tested with the Vienna Test System Cognitive Basic Assessment Test set (VTS COGBAT). The Research and Development (RAND)-36 and adapted Cognitive and Emotional Consequences of Stroke (CLCE)-24 questionnaires assessed perceived cognitive functioning and quality of life. Differences between group scores were tested with multivariate analyses of variance. ResultsA total of 80 pneumococcal meningitis patients and 69 controls were evaluated. After a median of 2 years (interquartile range, 2–3) after acute illness, 27 (34%) of 79 patients had persistent neurologic sequelae, most commonly hearing loss (21/79, 27%). On overall neuropsychologic evaluation, patients performed worse than the controls (MANCOVA; p 0.008), with alertness (z score −0.33, p 0.011) and cognitive flexibility (z score −0.33, p 0.027) as the most affected domains. Cognitive impairment was present in 11 (14%) of 79 patients. CLCE-24 questionnaires revealed cognitive impairment on all domains, most commonly for cognitive speed (53/75, 71%), attention (45/75, 60%) and memory (46/75, 61%). Patients had lower quality-of-life scores than controls (item physical functioning, (median) patients vs. controls, 80 vs. 95, p < 0.001; social functioning, (median) 81 vs. 100, p 0.003; perceived health, (mean) 59 vs. 70, p 0.005), which correlated with cognitive complaints (R = 0.66, p < 0.001). ConclusionsAdults after pneumococcal meningitis are at high risk of long-term neurologic and neuropsychologic deficits impairing daily life activities and quality of life.

Prognostic factors in pediatric pneumococcal meningitis patients in mainland China: a retrospective multicenter study.

Background: Prognosis of pneumococcal meningitis (PM) remains very poor, especially in less developed countries. Currently, few multi-centric studies on pediatric PM have been reported in mainland China.Objectives: This study aimed to explore the correlation of clinical and laboratory findings with complications and prognosis in pediatric PM.Methods: The pediatric PM patients were retrospectively recruited from ten pediatric tertiary hospitals across China between January 2013 and June 2018. Clinical, biochemical, and microbiological data and follow-up information were collected. Predictive factors for complications and prognostic factors for overall survival (OS) and sequelae-free survival (SFS) were analyzed.Results: A total of 132 pediatric PM patients were included. Seventy-one patients had complications, 25 patients died, and 39 patients had neurological sequelae. Multivariate logistic regression suggested that age less than 28 months (adjusted OR=2.654, 95%CI=1.067–6.600, P=0.036) and lower white blood cells in blood (aOR=3.169, 95%CI=1.395–7.202, P=0.006) were associated with high risk of complications. Multivariate Cox’s proportional hazard regression suggested that age less than 28 months (aHR=6.479, 95%CI=1.153–36.404, P=0.034), coma (aHR=9.808, 95%CI=2.802–34.323, P=0.000), and non-adjuvant steroid therapy (aHR=4.768 95%CI=1.946–11.678, P=0.001) were independent prognostic factors for poor OS; coma (aHR=5.841, 95%CI=2.652–12.864, P=0.000), septic shock on admission (aHR=2.949, 95%CI=1.049–8.290, P=0.040), and lower glucose level in cerebrospinal fluid (CSF) (aHR=2.523, 95%CI=1.336–4.765, P=0.004) were independent prognostic factors for poor SFS.Conclusion: Age, coma, and adjuvant steroid therapy were independent factors for OS, while coma, septic shock on admission, and lower glucose level in CSF were independent factors for SFS in pediatric PM patients. These factors might be used to identify PM patients with poor prognosis and guide individual treatment.

A multicentric clinical study on clinical characteristics and drug sensitivity of children with pneumococcal meningitis in China

Objective: To understand clinical characteristics of children with pneumococcal meningitis (PM) in China and to analyze the drug sensitivity of Streptococcus pneumoniae isolates and associated impacts on death and sequelae. Methods: The clinical data, follow-up results and antimicrobial sensitivity of isolated strains of 155 children (including 98 males and 57 females, age ranged from 2 months to 15 years) with PM in 10 tertiary-grade A class hospitals of Infectious Diseases Surveillance of Pediatrics (ISPED) from 2013 to 2017 were collected and analyzed retrospectively. Patients were divided into different groups according to the following standards: ≤1 year old group,>1-3 years old group and >3 years old group according to age; death group and non-death group according to the death within 30 days after PM diagnosis; complication group and non-complication group according to the abnormal cranial imaging diagnosis; sequelae group and no-sequelae group according to the follow-up results. Bonfereoni chi-square segmentation and Kruskal-Wallis H test were used for statistical analysis. Results: There were 64 cases (41.3%) in the ≤1 year old group, 39 cases in the >1-3 years old group (25.2%), and 52 cases (33.5%) in the >3 years old group. The most common clinical manifestation was fever (151 cases, 97.4%). The mortality was 16.8% (26/155) during hospitalization. The neurological complication rate was 49.7% (77/155) during hospitalization, including the most common complication, subdural effusion and (or) empyema in 50 cases (32.3%) and hearing impairment in 6 cases. During follow-up after discharge, no death was found and focal neurological deficits were found in 47 cases (30.3%), including the frequent neurological sequelae: cognitive and mental retardation of different degree in 22 cases and hearing impairment in 14 cases (9.0%). The rate of cure and improvement on discharge was 74.8% (116/155) and the lost to follow-up rate was 8.4% (13/155). The proportions of died cases, neurological complications during hospitalization and proportions of peripheral white blood cell count <12 × 10(9)/L before admission in ≤1 year old group were significantly higher than those in >3 years old group (25.0% (16/64) vs. 5.8% (3/52), 75.0% (48/64) vs. 25.0% (13/52), 48.4% (31/64) vs. 15.4% (8/52), χ(2)=7.747, 28.767, 14.044; P=0.005, 0.000, 0.000). The proportions of headache, vomiting, neck resistance and high risk factors of purulent meningitis in >3 years old group were significantly higher than those in ≤ 1 year old group (67.3%(35/52) vs. 1.6%(1/64), 80.8% (42/52) vs. 48.4% (31/64), 69.2% (36/52) vs. 37.5% (24/64), 55.8% (29/52) vs. 14.1%(9/64), χ(2)=57.940, 12.856, 11.568, 22.656; P=0.000, 0.000, 0.001, 0.000). Streptococcus pneumoniae isolates were completely sensitive to vancomycin (100.0%, 152/152), linezolid (100.0%, 126/126), moxifloxacin (100.0%, 93/93) and ofloxacin (100.0%,41/41); highly sensitive to levofloxacin (99.3%, 142/143) and ertapenem (84.6%, 66/78); moderately sensitive to ceftriaxone (48.4%, 45/93), cefotaxime (40.0%, 44/110) and meropenem (38.0%, 38/100); less sensitive to penicillin (19.6%, 27/138) and erythromycin (4.2%, 5/120). The proportions of non-sensitive strains of penicillin (21/21) and meropenem (17/18) in the death group were significantly higher than those (90/117, 45/82) in the survived group(χ(2)=4.648 and 9.808, P=0.031 and 0.002). Conclusions: The children's PM is mainly found in infants under 3 years old in China. Death and neurological complications are more common in PM children under 1 year old. The clinical manifestations and peripheral blood inflammatory markers of PM patients under 1 year old are not typical. Fever is the most common clinical manifestation and subdural effusion and (or) empyema is the most common complication. Long-term hearing impairment is common in PM and the follow-up time must be prolonged. The dead PM cases had high in sensitive rates to penicillin and meropenem.

Molecular studies of meningococcal and pneumococcal meningitis patients in Ethiopia.

Neisseria meningitidis infections in sub-Saharan Africa usually present with distinct symptoms of meningitis but very rarely as fulminant septicemia when reaching hospitals. In Europe, development of persistent meningococcal shock and multiple organ failure occurs in up to 30% of patients and is associated with a bacterial load of >106/ml plasma or serum. We have prospectively studied 27 Ethiopian patients with meningococcal infection as diagnosed and quantified with real-time PCR in the cerebrospinal fluid (CSF) and serum. All presented with symptoms of meningitis and none with fulminant septicemia. The median N. meningitidis copy number (NmDNA) in serum was < 3.5 × 103/ml, never exceeded 1.8 × 105/ml, and was always 10–1000 times higher in CSF than in serum. The levels of LPS in CSF as determined by the limulus amebocyte lysate assay were positively correlated to NmDNA copy number (r = 0.45, P = 0.030), levels of IL-1 receptor antagonist, (r = 0.46, P = 0.017), and matrix metallopeptidase-9 (MMP-9; r = 0.009). We also compared the inflammatory profiles of 19 mediators in CSF of the 26 meningococcal patients (2 died and 2 had immediate severe sequelae) with 16 patients with Streptococcus pneumoniae meningitis (3 died and 3 with immediate severe sequelae). Of 19 inflammatory mediators tested, 9 were significantly higher in patients with pneumococcal meningitis and possibly linked to worse outcome.

330. Head and Spine Injuries Increase Risk of Streptococcus pneumoniae Meningitis in Adults

BackgroundIn the United States, Streptococcus pneumoniae is responsible for 50% of bacterial meningitis cases. However, pneumococcal vaccines were not recommended for routine childhood immunization until pneumococcal conjugate vaccine became available in 2000, and much of the adult population has not received pneumococcal conjugate or polysaccharide vaccine. Limited case reports and series suggest that a history of neurosurgery or skull fractures may be associated with an increased risk for pneumococcal meningitis.MethodsA case–control study was conducted within the Kaiser Permanente Northern California (KPNC) patient population to evaluate the association of prior head injury (HI) or head or spine surgery (H/SS) with pneumococcal meningitis. Cases were pneumococcal meningitis patients ≥18 years of age diagnosed from January 1, 2008 through October 31, 2017. Controls were individually matched 2:1 by age, sex, KPNC facility and membership length. A blinded chart review was done to identify history of HI and H/SS. Analyses were performed using conditional logistic regression.ResultsEighty-four patients were found to have pneumococcal meningitis and were matched with 168 controls. Fifteen of the 84 cases (17.9%) and 6 of the 168 controls (3.6%) had prior HI or H/SS. Case histories included concussion (n = 3), mastoidectomy (n = 2), nasal surgery (n = 3), neurosurgery (n = 3), and spine surgery (n = 5). One case was noted to have two surgical histories. Ten of the 15 cases with HI or H/SS (66.7%) had not received pneumococcal vaccine. Cases had 5.0 times higher odds of having a history of HI or H/SS (95% confidence interval (CI) 1.9–12.9). These odds remained significantly elevated for H/SS only (odds ratio (OR) 10.0, 95% CI 1.2 – 85.6), but not for HI (OR 3.0, 95% CI 0.5 – 18.0). As no skull fractures were detected, HI consisted of concussions only.ConclusionPrior HI or H/SS significantly increased the odds for pneumococcal meningitis. Surveillance data from the Centers of Disease Control and Prevention indicate that 60–75% of invasive pneumococcal disease in adults is due to serotypes included in the pneumococcal vaccines. Given the number of unvaccinated cases, some of these cases may have been vaccine preventable. Such patients may benefit from pneumococcal immunization to reduce the risk of pneumococcal meningitis.Disclosures All authors: No reported disclosures.

Pneumococcal Meningitis in Adults after Introduction of PCV7 and PCV13, Israel, July 2009-June 20151.

The indirect effect of pneumococcal conjugate vaccine on adult pneumococcal meningitis has not been thoroughly investigated. We present data from active surveillance on pneumococcal meningitis in adults in Israel occurring during July 2009–June 2015. Pneumococcal meningitis was diagnosed for 221 patients, 9.4% of all invasive pneumococcal disease (IPD) cases. Although overall IPD incidence decreased during the study period, meningitis increased nonsignificantly from 0.66 to 0.85 cases/100,000 population. Incidence of vaccine type (VT) pneumococcal meningitis (VT13) decreased by 70%, but non-VT13 pneumococcal meningitis increased from 0.32 to 0.75 cases/100,000 population (incident rate ratio 2.35, 95% CI 1.27–4.35). Pneumococcal meningitis patients were younger and healthier than nonmeningitis IPD patients, and 20.2% had a history of previous head surgery or cerebrospinal fluid leak compared with <2.0% of nonmeningitis patients (p<0.0001). Non-VT13 types that rarely cause IPD (15B/C, 6C, 23A, 23B, 24F) seem to be emerging as common causes of meningitis.

Epidemiological Aspects of Pneumococcal Meningitis in the Russian Federation

Introduction. Pneumococcal meningitis (PM) refers to severe manifestations of pneumococcal disease with high mortality and frequent post-infectious complications. In the context of the introduction of vaccination against pneumococcal infections in the Russian Federation healthcare practice increases the importance of close monitoring of the spread of the PM in the country, identifying areas of concern, the definition of risk and serotype structure of pneumococcus, which is an essential component of the assessment of the effectiveness of vaccination. Materials and methods. We collected 1380 cases identified by the PM on the territory of the Russian Federation in 2010 - 2014. We analyzed the incidence, mortality, mortality, age distribution, social belonging PM patients in the whole country, and in the federal districts. Determined serotype affiliation 35 pneumococcal strains isolated from patients with PM in Russia in 2015. Results. The proportion of pneumococci in the etiological structure of bacterial meningitis during the 2010 - 2014 fluctuated in the range of 18.4 - 24.8% and averaged 22.1%. The incidence of the PM in the Russian Federation in 2010 - 2014 determined at the level of 0.19, the death rate - 0.03. The level of mortality in pneumococcal meningitis in the Russian Federation in 2010 - 2014 increased from 13 (2010) to 21.1% (2014), the average was 17.1%. The most vulnerable age groups were adults over 25 years old and children up to 6 years. Among children under the age of 6 years mortality was 10.7%. The study of serotypes of 35 pneumococcal strains showed that in 2015 serotype structure of invasive pneumococcal vaccine serotypes maintained dominance, the proportion reached 75% for PCV13 and 54% for PCV10. Conclusion. The problem of pneumococcal meningitis remains valid in the Russian Federation. Active use of vaccines, especially in children, will reduce the incidence of this infection and the severity of its consequences.

Variation of 46 Innate Immune Genes Evaluated for their Contribution in Pneumococcal Meningitis Susceptibility and Outcome

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease.Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome.Strongest signals for susceptibility were rs56078309 CXCL1 (p=4.8e−04) and rs2008521 in CARD8 (p=6.1e−04). For meningitis outcome the rs2067085 in NOD2 (p=5.1e−04) and rs4251552 of IRAK4 were the strongest associations with unfavorable outcome (p=6.7e−04). Haplotype analysis showed a haplotype block, determined by IRAK4 rs4251552, significantly associated with unfavorable outcome (p=0.004). Cytokine measurements from cerebrospinal fluid showed that with the IRAK4 rs4251552 G risk allele had higher levels of IL-6 compared to individuals with A/A genotype (p=0.04).We show that genetic variation within exons and flanking regions of 46 innate immunity genes does not yield significant association with pneumococcal meningitis. The strongest identified signal IRAK4 does imply a potential role of genetic variation in pneumococcal meningitis.

Global Pneumococcal Disease and Policies for Control

Global Pneumococcal Disease and Policies for Control

Genetic Variation and Cerebrospinal Fluid Levels of Mannose Binding Lectin in Pneumococcal Meningitis Patients

It has been suggested that genetic variants in mannose binding lectin (MBL2) influence susceptibility and outcome of invasive pneumococcal disease. We assessed the influence of genetic variation in MBL2 on susceptibility, outcome and causative serotype of pneumococcal meningitis in a prospective nationwide cohort study including 299 white patients and 216 controls. We assessed functionality of the genetic polymorphisms by measuring levels of MBL, C3a, iC3b, C5a and sC5b-9 in cerebrospinal fluid. We also performed a meta-analysis of studies on MBL2 polymorphisms and susceptibility to invasive pneumococcal disease. The risk of contracting pneumococcal meningitis was substantially increased for white individuals homozygous with the defective MBL2 0/0 genotype (odds ratio [OR] 8.21, 95% confidence interval [CI] 1.05–64.1; p = 0.017). CSF MBL levels were significantly lower in patients with the A/0 and 0/0 genotype compared to homozygotes for the wild-type alleles (A/A; p<0.001). CSF MBL levels were positively correlated with C3a and iC3b levels, indicating complement activation by the lectin pathway. The effect of MBL2 genetic variants on susceptibility remained robust in a meta-analysis including 5 studies with 287 patients (OR 2.33, 99% CI 1.39–3.90). We conclude that MBL2 polymorphisms influence CSF MBL levels and substantially increase the risk of pneumococcal meningitis.

Polymorphisms in Toll-like receptors 2, 4, and 9 are highly associated with hearing loss in survivors of bacterial meningitis.

Genetic variation in innate immune response genes contributes to inter-individual differences in disease manifestation and degree of complications upon infection. We recently described an association of single nucleotide polymorphisms (SNPs) in TLR9 with susceptibility to meningococcal meningitis (MM). In this study, we investigate the association of SNPs in multiple pathogen recognition and immune response genes with clinical features that determine severity and outcome (especially hearing loss) of childhood MM and pneumococcal meningitis (PM). Eleven SNPs in seven genes (TLR2, TLR4, TLR9, NOD1, NOD2, CASP1, and TRAIL) were genotyped in 393 survivors of childhood bacterial meningitis (BM) (327 MM patients and 66 PM patients). Genotype distributions of single SNPs and combination of SNPs were compared between thirteen clinical characteristics associated with severity of BM. After correction for multiple testing, TLR4+896 mutant alleles were highly associated with post-meningitis hearing loss, especially MM (p = 0.001, OR 4.0 for BM, p = 0.0004, OR 6.2 for MM). In a multigene analysis, combined carriership of the TLR2+2477 wild type (WT) with TLR4+896 mutant alleles increases the risk of hearing loss (p<0.0001, OR 5.7 in BM and p = 0.0001, OR 7.6 in MM). Carriage of one or both mutant alleles in TLR4+896 and TLR9 -1237 increases the risk for hearing loss (p = 0.0006, OR 4.1 in BM). SNPs in immune response genes contribute to differences in clinical severity and outcome of BM. The TLR system seems to play an important role in the immune response to BM and subsequent neuronal damage as well as in cochlear inflammation. Genetic markers may be used for identification of high-risk patients by creating prediction rules for post-meningitis hearing loss and other sequelae, and provide more insight in the complex immune response in the CNS possibly resulting in new therapeutic interventions.

Long-Term Mortality in Patients Diagnosed With Pneumococcal Meningitis: A Danish Nationwide Cohort Study

The objective of the study was to determine the long-term mortality and the causes of death in patients diagnosed with pneumococcal meningitis. The authors performed a nationwide, population-based cohort study including all Danish patients diagnosed with pneumococcal meningitis from 1977 through 2006 and alive 1 year after diagnosis. Data were retrieved from medical databases in Denmark. The absolute and relative risks of all-cause and cause-specific death were analyzed by using Kaplan-Meier survival curves, Poisson regression analysis, Cox regression analysis, and cumulative incidence functions. The authors identified 2,131 pneumococcal meningitis patients and an age- and gender-matched, population-based cohort of 8,524 individuals. Compared with the background population, the pneumococcal meningitis patients had an increased long-term mortality varying from an 8-fold increased mortality in the age category 0-<20 years to a 1.5-fold increased mortality in those aged 60-<80 years. The increased risk of death stemmed from neoplasms, liver diseases, and nervous system diseases. The excess mortality due to neoplasms stemmed mainly from a 5-fold increased risk of death due to hematologic neoplasms. To improve survival in patients surviving the acute phase of pneumococcal meningitis, physicians should meticulously screen this patient population for neurologic sequelae and comorbidity predisposing to the disease.

Reply: neuropsychological sequelae of bacterial meningitis: the influence of alcoholism and adjunctive dexamethasone therapy

Van de Beek et al. present new important data concerning the clinical outcome of patients with alcoholism and pneumococcal meningitis. The data was derived from a subgroup analysis of the patient population of their comparative key study on neuropsychological sequelae after pneumococcal versus meningococcal meningitis (van de Beek et al., 2002). With respect to our paper, they raised three issues: (i) Absence of statistically significant differences between patients after Streptococcus pneumoniae and Neisseria meningitidis meningitis in our study. Van de Beek et al. reported that only 2 of 26 patients of the pneumococcal meningitis group who were actually examined neuropsychologically suffered from alcoholism. In contrast to our findings (Schmidt et al., 2006), van de Beek et al. found significant neuropsychological differences between patients who survived pneumococcal and meningococcal meningitis. Before we received the information from van de Beek et al. by this communication, we presumed that one of several possible reasons for this discrepancy was the different proportion of patients with alcoholism in our study versus those in van de Beek’s study. This now can be ruled out. Searching for further explanations, van de Beek et al. suggest that different Glasgow Outcome Scores (GOS) or differing intervals between hospital stay and re-examination of the respective meningitis group might have led to this discrepancy. Patients examined after pneumococcal meningitis in our study had a significantly lower mean GOS value than patients examined after meningococcal meningitis. Therefore, the differences should have been even more pronounced. The interval between hospital admission and neuropsychological testing was not significantly different in our pneumococcal and meningococcal patient groups. Van de Beek et al. pointed out that a group size of 16 patients per group might not yield enough statistical power to discriminate differences. This is true, especially for domains with only limited inter-group differences. We think that the reported difference between meningococcal and pneumococcal meningitis patients in van de Beek’s study (or in other terms the non-existing difference in our study) might be a result of different statistical approaches: In contrast to our colleagues’ work we compared the groups using two-sided tests (not assuming a priori one group to be more severely affected than the other). This approach results in an alpha error twice as high as with one-sided testing. If one-tailed tests are used, it is recommended to calculate with half the alpha error that would have been used with a twotailed study [according to the ICH topic E9 (EMEA, 1998)]. Applying a P-value of 0.025, only 3 out of 14 neuropsychological examinations for which van de Beek et al. gave mean T-values with standard deviations were significantly different (Visuospatial reasoning, WMS-R immediate memory, Trailmaking B) after their univariate analysis of covariance. Comparing the T-values of van de Beek’s groups in our way with two-sided t-tests for independent samples, only the items Visuospatioal reasoning and Trailmaking B yielded statistically significant differences in van de Beek’s study groups. Contrary to our analysis of alertness functions (performed after age-related transformation into z-values), reaction speed (dominant/non-dominant hand) and a two-choice paradigm in van de Beek’s paper were significantly slower for the pneumococcal than for the meningococcal meningitis group. In contrast to all other domains, for the comparison of the reaction speed, a transfer of the raw data into age-adapted zor T-values (derived from age-matched controls or with the standard values from the respective test manuals) was not

Influence of the blood bacterial load on the meningeal inflammatory response in Streptococcus pneumoniaemeningitis

BackgroundDespite bacteraemia is present in the majority of patients with pneumococcal, little is known about the influence of the systemic infection on the meningeal inflammatory response.MethodsTo explore the role of systemic infection on the meningeal inflammation, experimental meningitis was induced by intracisternal injection of ~1 × 106 CFU Streptococcus pneumoniae, type 3, and the 26 rabbits were either provided with ~1 × 106 CFU S. pneumoniae intravenously at 0 hour ("bacteraemic" rabbits, n = 9), immunized with paraformaldehyde-killed S. pneumoniae for 5 weeks prior to the experiment ("immunized" rabbits", n = 8), or not treated further ("control" rabbits, n = 9). WBC and bacterial concentrations were determined in CSF and blood every second hour during a 16 hours study period together with CSF IL-8 and protein levels. We also studied CSF and blood WBC levels in 153 pneumococcal meningitis patients with and without presence of bacteraemia.ResultsAs designed, blood bacterial concentrations were significantly different among three experimental groups during the 16 hours study period (Kruskal Wallis test, P < 0.05), whereas no differences in CSF bacterial levels were observed (P > 0.05). Blood WBC decreased in bacteraemic rabbits between ~10–16 hours after the bacterial inoculation in contrast to an increase for both the immunized rabbits and controls (P < 0.05). The CSF pleocytosis was attenuated in bacteraemic rabbits as compared to the two other groups between 12–16 hours from time of infection (P < 0.017), despite accelerated CSF IL-8 levels in bacteraemic rabbits.In patients with pneumococcal meningitis, no significant difference in CSF WBC was observed between patients with or without bacteraemia at admission (n = 103, 1740 cells/μL (123–4032) vs. n = 50, 1961 cells/μL (673–5182), respectively, P = 0.18), but there was a significant correlation between CSF and blood WBC (n = 127, Spearman rho = 0.234, P = 0.008).ConclusionOur results suggest that a decrease in peripheral WBC induced by enhanced bacteraemia in pneumococcal meningitis results in an attenuated CSF pleocytosis.

Long-term beneficial effects of dexamethasone on intellectual and neuropsychological outcome of children with pneumococcal meningitis

A Substantial ratio of bacterial meningitis survivors suffers mild or serious intellectual and neuropsychological handicaps. We organized eighty subjects into three groups: 1) Pneumococcal meningitis (PM) who did not receive dexamethasone, 2) PM who received dexamethasone, 3) Other bacterial meningitis with different etiology. All subjects underwent Bender Visual Motor Gestalt test and age-appropriate Intelligence quotient (IQ) tests. The mean full-scale IQ scoring fell within normal range (90+/-17) in the post-meningitic cohort. There was no statistical difference between two pneumococcal groups regarding full scale IQ testing (88+/-16 and 91+/-18) and Bender-Gestalt scoring (4.0+/-3.3 and 3.8+/-2.6), respectively. However, the subjects with full scale IQ score <85 (below the average) were statistically less in the group with steroid therapy. PM patients who received dexamethasone therapy had statistically better academic performance. As a result, adjuvant steroid therapy has no significant impact on overall intellectual tests in PM subjects. However, dexamethasone seems to diminish development of below the average IQ scoring in PM cases. In addition, PM subjects who received steroids showed better academic achievement. These findings may support the idea of dexamethasone administration prior to first antibiotic dose in PM subjects.

Pneumococcal Meningitis in Adults

A retrospective study was conducted to examine the clinical features and outcome of 31 adult pneumococcal meningitis patients during the years 1981-92. The incidence was 1.0/100,000 adults/year. The case fatality rate was 16% (5/31), and in patients older than 70 years, 33% (3/9). Sequelae were seen in 29% (7/24), mostly otoneurologic symptoms. In 27/28 bacterial isolates the serotypes found were included in the 23-valent unconjugated polysaccharide vaccine in current use. All 28 isolates were fully sensitive to penicillin. 49/51 non-meningitis blood isolates had MIC values < or = 0.06 mg/l, 2 isolates had MIC values of 0.125 mg/l and 0.25 mg/l, and 50/50 were serotypes included in the 23-valent vaccine. Pneumococcal meningitis is a disease causing considerable mortality and morbidity. The relatively low case fatality rate found in the present study may be due to the patients' good health prior to admission, rapid specific microbiological diagnosis, absence of penicillin-resistant pneumococci among the meningitis strains, and immediate institution of specific and supportive therapy.