Irene Koomen

Prediction of academic and behavioural limitations in school-age survivors of bacterial meningitis.

Aim: To develop a prediction rule to identify postmeningitic children at high risk of academic and behavioural limitations. Methods: 182 children (mean age 10 y; range 5–14) were selected from a cohort of 674 school‐age survivors of bacterial meningitis. These children had neither meningitis with “complex onset”, nor prior cognitive or behavioural problems, nor severe disease sequelae. On average, 7 y after the meningitis, they were evaluated using an “Academic Achievement Test”, and their parents filled in the “Child Behaviour Checklist”. By reviewing the medical records, potential risk factors for academic and/or behavioural limitations were collected. Independent predictors were identified using multivariate logistic regression analysis, leading to the formulation of a prediction rule. Results: The cumulative incidence of academic and/or behavioural limitations among children who survived bacterial meningitis without severe disease sequelae was 32%. The prediction rule was based on nine independent risk factors: gender, birthweight, educational level of the father, S. pneumoniae, cerebrospinal fluid leukocyte count, delay between admission and start of antibiotics, dexamethasone use, seizures treated with anticonvulsive therapy, and prolonged fever. When 10 was taken as a cut‐off point for the risk score computed using this rule, 76% of the children with limitations could be identified, while 38% of the children in the cohort were selected as at risk for these limitations.

Parental perception of educational, behavioural and general health problems in school-age survivors of bacterial meningitis

Aim: To determine the occurrence of educational, behavioural and general health problems in Dutch school‐age survivors of bacterial meningitis. Methods: A cohort of 680 school‐age survivors of meningitis caused by the most common Gram‐positive and Gram‐negative bacteria was established approximately 6 y after the childrens illness. Children with Haemophilus influenzae type b (Hib) meningitis were excluded because this form of the disease has virtually disappeared. Parents completed questionnaires on educational, behavioural and general health problems. The reference group comprised 304 school‐age siblings and peers. Results: Postmeningitic children were more likely than controls to under achieve at school: 20% vs 5% (odds ratio 5.6; 95% confidence interval 3.0–10.7). The postmeningitic children repeated a year twice as often as the children in the reference group (16% vs 8%, odds ratio: 2.5, 95% confidence interval 1.5–4.2) and were referred to a special‐needs school four times more frequently (8% vs 2%, odds ratio: 5.5; 95% confidence interval 2.0–15.4). Parents also reported more behavioural problems at home. More than half of the postmeningitic children experienced general health problems. The causative pathogen or age at infection had no influence on the relative frequency of educational and behavioural problems, and reduced auditory functioning played only a small part in these problems.

Neuropsychology of academic and behavioural limitations in school-age survivors of bacterial meningitis.

Neuropsychological impairments possibly underlying academic and/or behavioural limitations were studied in 149 school‐age survivors of bacterial meningitis, 68 with and 81 without academic and/or behavioural limitations. Academic limitations affected mathematics, reading, and writing. Behavioural limitations were inferred from scores in the clinical range on the Child Behaviour Checklist. These children had been selected from a cohort of 674 children (57% males) who had recovered from non‐Haemophilus influenzae type B bacterial meningitis and who had a mean age at infection of 2 years 4 months (range 1mo to 9y 5mo). They had neither‘complex onset’meningitis, prior cognitive or behavioural problems, nor severe disease sequelae. They were assessed with standardized assessment methods a mean of 7.8 years (range 4 to 10.4) after meningitis. Children with limitations (32% of the cohort) performed generically poorly on measures of cognitive functioning, speed, and motor steadiness, rather than having impairments in specific neuropsychological domains. The presence of two or more minor neurological signs was more frequent in the group with than in the group without limitations (30% versus 9%); this may explain the relatively poor speed and motor steadiness of the group with limitations.

Independent validation of an existing model enables prediction of hearing loss after childhood bacterial meningitis

Objective This study aimed external validation of a formerly developed prediction model identifying children at risk for hearing loss after bacterial meningitis (BM). Independent risk factors included in the model are: duration of symptoms prior to admission, petechiae, cerebral spinal fluid (CSF) glucose level, Streptococcus pneumoniae and ataxia. Validation helps to evaluate whether the model has potential in clinical practice. Study design 116 Dutch school-age BM survivors were included in the validation cohort and screened for sensorineural hearing loss (>25 dB). Risk factors were obtained from medical records. The model was applied to the validation cohort and its performance was compared with the development cohort. Validation was performed by application of the model on the validation cohort and by assessment of discrimination and goodness of fit. Calibration was evaluated by testing deviations in intercept and slope. Multiple imputation techniques were used to deal with missing values. Results Risk factors were distributed equally between both cohorts. Discriminative ability (Area Under the Curve, AUC) of the model was 0.84 in the development and 0.78 in the validation cohort. Hosmer-Lemeshow test for goodness of fit was not significant in the validation cohort, implying good fit concerning the similarity of expected and observed cases. There were no significant differences in calibration slope and intercept. Sensitivity and negative predicted value were high, while specificity and positive predicted value were low which is comparable with findings in the development cohort. Conclusions Performance of the model remained good in the validation cohort. This prediction model might be used as a screening tool and can help to identify those children that need special attention and a long follow-up period or more frequent auditory testing.

Mannose-binding lectin in term newborns and their mothers : Genotypic and phenotypic relationship

Functional mannose-binding lectin (f-MBL) plays an important role in the innate neonatal immune system. We studied the origin of f-MBL in umbilical cord blood (UCB) by measuring maternal MBL (n=47), collected before elective cesarean section, and neonatal MBL (n=43) in arterial umbilical cord blood. In a subgroup, arterial and venous UCB MBL levels were measured. In addition, MBL expression was correlated with genetic mutations. The f-MBL levels in term infants were lower than in their mothers (0.70 microg/ml vs 1.11 microg/ml, p<0.01) and maternal and neonatal MBL levels were only weakly correlated (R=0.32, p<0.001), which suggests a fetal origin of f-MBL. Arterial and venous UCB median MBL levels did not differ (0.98 microg/ml vs. 1.40 microg/ml, p=0.20). No homozygous mutations were found. MBL was lower in mothers and infants with a (compound) heterozygous mutation than in those with a wild type. One new (HYPB) and two rare haplotypes (HXPA, LYPD) were reported in our population. Levels of MBL differed depending on the genotype of the mother or the infant. Because the role of MBL in host defense is still unclear, both f-MBL and haplotype should be measured to determine the clinical implications of MBL deficiency in infants.

No structural cerebral differences between children with a history of bacterial meningitis and healthy siblings

Aim: After bacterial meningitis, about one‐third of children develops academic and/or behavioural limitations. The aim of our study was to search for structural differences in the brain, with a special focus on the hippocampus, between childhood survivors of bacterial meningitis with and without academic and/or behavioural limitations and healthy siblings.

Validating and updating a prediction rule for neurological sequelae after childhood bacterial meningitis

Recently, a prediction rule for developing neurological sequelae after childhood bacterial meningitis was developed on a small derivation set. Before implementing in practice a prediction rule must first be tested in new patients (external validation). Our aim was to study the external validity of this rule and, if necessary, to update the rule. The prediction rule was tested on newly available data (validation set) by assessing the rules calibration and discrimination. We updated the prediction rule by adding extra predictors and re-estimating the regression coefficients of the original predictors in the combined datasets. The rule showed poor agreement between predicted risks and observed frequencies. The ROC area was 0.65 (95% CI 0.57–0.72), which was statistically significantly lower than in the derivation set (0.87 (0.78–0.96)), p-value <0.01. The updated prediction rule showed adequate performance in the combined data sets; the ROC area was 0.77 (95% CI 0.72–0.82). Further study of the generalizability of this updated rule may stimulate application in clinical practice.

Addition of host genetic variants in a prediction rule for post meningitis hearing loss in childhood: A model updating study

BackgroundSensorineural hearing loss is the most common sequela in survivors of bacterial meningitis (BM). In the past we developed a validated prediction model to identify children at risk for post-meningitis hearing loss. It is known that host genetic variations, besides clinical factors, contribute to severity and outcome of BM. In this study it was determined whether host genetic risk factors improve the predictive abilities of an existing model regarding hearing loss after childhood BM.MethodsFour hundred and seventy-one Dutch Caucasian childhood BM were genotyped for 11 single nucleotide polymorphisms (SNPs) in seven different genes involved in pathogen recognition. Genetic data were added to the original clinical prediction model and performance of new models was compared to the original model by likelihood ratio tests and the area under the curve (AUC) of the receiver operating characteristic curves.ResultsAddition of TLR9-1237 SNPs and the combination of TLR2 + 2477 and TLR4 + 896 SNPs improved the clinical prediction model, but not significantly (increase of AUC’s from 0.856 to 0.861 and from 0.856 to 0.875 (p = 0.570 and 0.335, respectively). Other SNPs analysed were not linked to hearing loss.ConclusionsAlthough addition of genetic risk factors did not significantly improve the clinical prediction model for post-meningitis hearing loss, AUC’s of the pre-existing model remain high after addition of genetic factors. Future studies should evaluate whether more combinations of SNPs in larger cohorts has an additional value to the existing prediction model for post meningitis hearing loss.

Simulated effect of pneumococcal vaccination in the Netherlands on existing rules constructed in a non-vaccinated cohort predicting sequelae after bacterial meningitis

BackgroundPreviously two prediction rules identifying children at risk of hearing loss and academic or behavioral limitations after bacterial meningitis were developed. Streptococcus pneumoniae as causative pathogen was an important risk factor in both. Since 2006 Dutch children receive seven-valent conjugate vaccination against S. pneumoniae. The presumed effect of vaccination was simulated by excluding all children infected by S. pneumoniae with the serotypes included in the vaccine, from both previous collected cohorts (between 1990-1995).MethodsChildren infected by one of the vaccine serotypes were excluded from both original cohorts (hearing loss: 70 of 628 children; academic or behavioral limitations: 26 of 182 children). All identified risk factors were included in multivariate logistic regression models. The discriminative ability of both new models was calculated.ResultsThe same risk factors as in the original models were significant. The discriminative ability of the original hearing loss model was 0.84 and of the new model 0.87. In the academic or behavioral limitations model it was 0.83 and 0.84 respectively.ConclusionIt can be assumed that the prediction rules will also be applicable on a vaccinated population. However, vaccination does not provide 100% coverage and evidence is available that serotype replacement will occur. The impact of vaccination on serotype replacement needs to be investigated, and the prediction rules must be validated externally.

Unsuccessful validation of 2004 model for predicting academic or behavioural limitations after childhood bacterial meningitis

In 2004, a model identifying children at risk of academic or behavioural limitations after bacterial meningitis (BM) was presented. Risk factors were male gender, low birthweight, lower educational level of the father, Streptococcus pneumoniae, lower cerebrospinal fluid (CSF) leucocyte count, delay between admission and start of antibiotics, dexamethasone <2 days, seizures and prolonged fever. The aim of this study was to validate that prediction model in an independent cohort.