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Prediction of bacterial meningitis in children with meningeal signs:reduction of lumbar punctures

Physicians often have to perform a lumbar puncture to ascertain the diagnosis in patients with meningeal signs, because of the serious consequences of missing bacterial meningitis The aim of this study was to derive and validate a clinical rule to predict bacterial meningitis in children with meningeal signs, to guide decisions on the performance of lumbar punctures. Information was collected from records of patients (aged 1 mo to 15 y) consulting the emergency department of the Sophia Childrens Hospital between 1988 and 1998 with meningeal signs. Bacterial meningitis was defined as cerebrospinal fluid (CSF) leucocyte count >5 cells μl−1 with a positive bacterial culture of CSF or blood. The diagnostic value of predictors was judged using multivariate logistic modelling and area under the receiver operating characteristic curves (ROC area). In the derivation set (286 patients, years 1988–1995) the duration of the main complaint, vomiting, meningeal irritation, cyanosis, petechiae and disturbed consciousness were independent clinical predictors of bacterial meningitis. The ROC area of this model was 0.92. The only independent predictor from subsequent laboratory tests was the serum C‐reactive protein concentration, increasing the ROC area to 0.95. Without missing a single case, this final model identified 99 patients (35%) without bacterial meningitis. Validation on 74 consecutive patients in 3 subsequent years (1996–1998) yielded similar results.

Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

BACKGROUND Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months. METHODS In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8-16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20-40 mg per day in months 3-12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150. FINDINGS We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo -1·3 IQ points [95% CI -3·8 to 1·3]; p=0·33), attention problems (-1·6 T-score points [-4·3 to 1·0]; p=0·23), and internalising behavioural problems (-0·1 T-score points [-3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively. INTERPRETATION 12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20-40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended. FUNDING The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).

Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study.

Objective To derive, cross validate, and externally validate a clinical prediction model that assesses the risks of different serious bacterial infections in children with fever at the emergency department. Design Prospective observational diagnostic study. Setting Three paediatric emergency care units: two in the Netherlands and one in the United Kingdom. Participants Children with fever, aged 1 month to 15 years, at three paediatric emergency care units: Rotterdam (n=1750) and the Hague (n=967), the Netherlands, and Coventry (n=487), United Kingdom. A prediction model was constructed using multivariable polytomous logistic regression analysis and included the predefined predictor variables age, duration of fever, tachycardia, temperature, tachypnoea, ill appearance, chest wall retractions, prolonged capillary refill time (>3 seconds), oxygen saturation <94%, and C reactive protein. Main outcome measures Pneumonia, other serious bacterial infections (SBIs, including septicaemia/meningitis, urinary tract infections, and others), and no SBIs. Results Oxygen saturation <94% and presence of tachypnoea were important predictors of pneumonia. A raised C reactive protein level predicted the presence of both pneumonia and other SBIs, whereas chest wall retractions and oxygen saturation <94% were useful to rule out the presence of other SBIs. Discriminative ability (C statistic) to predict pneumonia was 0.81 (95% confidence interval 0.73 to 0.88); for other SBIs this was even better: 0.86 (0.79 to 0.92). Risk thresholds of 10% or more were useful to identify children with serious bacterial infections; risk thresholds less than 2.5% were useful to rule out the presence of serious bacterial infections. External validation showed good discrimination for the prediction of pneumonia (0.81, 0.69 to 0.93); discriminative ability for the prediction of other SBIs was lower (0.69, 0.53 to 0.86). Conclusion A validated prediction model, including clinical signs, symptoms, and C reactive protein level, was useful for estimating the likelihood of pneumonia and other SBIs in children with fever, such as septicaemia/meningitis and urinary tract infections.

Sequelae after bacterial meningitis in childhood

The neurological outcome of bacterial meningitis in children was evaluated retrospectively. Data were obtained from a large study on children aged between 1 month and 15 y who initially visited the emergency department of Sophia Childrens Hospital, Rotterdam, The Netherlands with meningeal signs. This study presents data from 103 patients in whom bacterial meningitis was diagnosed. Neisseria meningitidis was the dominant pathogen of meningitis. We found a 2% case-fatality rate in children with bacterial meningitis and a 13% rate of sequelae among survivors: 7% hearing impairment and 7% neurological sequelae. Children with bacterial meningitis caused by Streptococcus pneumoniae and those with acute focal neurological symptoms tended to have the worst prognosis.

Signs of meningeal irritation at the emergency department : How often bacterial meningitis?

Objective Although signs of meningeal irritation are highly indicative of meningitis, they are not pathognomonic. In this study, we described the final diagnoses in children with signs of meningeal irritation, and we assessed the frequency of bacterial meningitis related to specific signs of meningeal irritation. Methods Information was collected from records of 326 patients (aged 1 month to 15 years) who visited the emergency department of the Sophia Children’s Hospital between 1988 and 1998 with signs of meningeal irritation, assessed by either the general practitioner or the pediatrician. Results Bacterial meningitis was diagnosed in 99 patients (30%), viral or aseptic meningitis in 43 (13%). Other diagnoses were pneumonia (8%), other serious bacterial infections (2%), and upper respiratory tract infections or other self-limiting diseases (46%). Presence of one of the signs of meningeal irritation assessed by the pediatrician was related to bacterial meningitis in 39%. Specific tests eliciting meningeal irritation, such as Brudzinski’s and Kernig’s signs, were not related to a higher frequency of bacterial meningitis than neck stiffness and the tripod phenomenon. In children ≤1 year, bacterial meningitis is more frequently related to presence of irritability and a bulging fontanel. Conclusion Bacterial meningitis is present in 30% of children with signs of meningeal irritation. Presence of meningeal irritation as assessed by the pediatrician is related to bacterial meningitis in 39%. A better prediction of bacterial meningitis was not achieved by using more specific tests for signs of meningeal irritation.

Prediction of vesico-ureteric reflux in childhood urinary tract infection: a multivariate approach.

In this study, independent predictors obtained from patient history, physical examination and laboratory results for vesico‐ureteric reflux (VUR) in children of 0‐5 y with a first urinary tract infection (UTI) were assessed and the added value of renal ultrasound (US) investigated. Information was collected from children visiting the paediatric outpatient department with a first proven UTI, defined as a urine monoculture with ≥105 organism/ml, with clinical symptoms and possible white cell count ≥ 20 per high‐power field of spun fresh urine. Children with neurologic bladder dysfunction were excluded. VUR was determined by voiding cystourethrography (VCUG) and graded from I to V. The diagnostic value of predictors was judged using multivariate logistic modelling with the area under the receiver operating characteristic (ROC area). A risk score was derived based on the regression coefficients of the independent predictors in the logistic model. In 140 children (51 boys and 89 girls) VUR was diagnosed in 37. Independent predictors for VUR were male gender, age, family history for uropathology, serum C‐reactive protein level (CRP) and dilatation of the urinary tract on US. The ROC area of this model was 0.78 (95% CI: 0.69‐0.87). This prediction model identified 12% (95% CI: 7‐18) of the patients without VUR without missing one case of VUR. If we used VUR ≥ grade 3 as a threshold, the model assessed VUR to be absent in 34% (95% CI: 26‐42).

Health-Related Quality of Life in Children with Neurofibromatosis Type 1: Contribution of Demographic Factors, Disease-Related Factors, and Behavior

OBJECTIVE To investigate health-related quality of life (HR-QOL) in children with neurofibromatosis type 1 (NF1) with parental reports and childrens self-reports, and to investigate the potential contribution of demographic factors, disease-specific factors, and problems in school performance or behavior. STUDY DESIGN In a prospective observational study, parents of 58 children with NF1 (32 boys, 26 girls, age 12.2 +/- 2.5 years) visiting a university clinic, and their 43 children 10 years or older were assessed with the Child Health Questionnaire (CHQ). Potential determinants of domain scores were assessed in 3 explorative regression models. RESULTS Parents reported a significant impact of NF1 on 9/13 CHQ scales, with moderate effect sizes on 8 (general health perceptions, physical functioning, general behavior, mental health, self esteem, family activities, role functioning emotional/behavioral, and parent emotional impact). Children report an impact on bodily pain, and an above average general behavior. Multiple CHQ scales were sensitive to demographic factors and behavioral problems, and 1 to NF1 severity. NF1 visibility and school problems did not influence HR-QOL. CONCLUSIONS Parents, but not the children with NF1, report a profound impact of NF1 on physical, social, behavioral, and emotional aspects of HR-QOL. Multiple HR-QOL domains were most sensitive to behavioral problems, which points to an exciting potential opportunity to improve HR-QOL in children with NF1 by addressing these behavioral problems.

Validity of Different Pediatric Early Warning Scores in the Emergency Department

OBJECTIVE: Pediatric early warning scores (PEWS) are being advocated for use in the emergency department (ED). The goal of this study was to compare the validity of different PEWS in a pediatric ED. METHODS: Ten different PEWS were evaluated in a large prospective cohort. We included children aged <16 years who had presented to the ED of a university hospital in The Netherlands (2009−2012). The validity of the PEWS for predicting ICU admission or hospitalization was expressed by the area under the receiver operating characteristic (ROC) curves. RESULTS: These PEWS were validated in 17 943 children. Two percent of these children were admitted to the ICU, and 16% were hospitalized. The areas under the ROC curves for predicting ICU admission, ranging from 0.60 (95% confidence interval [CI]: 0.57−0.62) to 0.82 (95% CI: 0.79–0.85), were moderate to good. The area under the ROC curves for predicting hospitalization was poor to moderate (range: 0.56 [95% CI: 0.55–0.58] to 0.68 [95% CI: 0.66–0.69]). The sensitivity and specificity derived from the ROC curves ranged widely for both ICU admission (sensitivity: 61.3%–94.4%; specificity: 25.2%–86.7%) and hospital admission (sensitivity: 36.4%–85.7%; specificity: 27.1%–90.5%). None of the PEWS had a high sensitivity as well as a high specificity. CONCLUSIONS: PEWS can be used to detect children presenting to the ED who are in need of an ICU admission. Scoring systems, wherein the parameters are summed to a numeric value, were better able to identify patients at risk than triggering systems, which need 1 positive parameter.

Early prediction of neurological sequelae or death after bacterial meningitis

This study determined independent predictors of the occurrence of permanent neurological sequelae or death after childhood bacterial meningitis. Data were used from a large study on children (aged 1 mo to 15 y) initially presenting with meningeal irritation. A nested case‐control study was performed on children with (n= 23) and without (n= 70) permanent neurological sequelae (hearing impairment, locomotor dysfunction, mental retardation or epilepsy) or death after bacterial meningitis. Predictors obtained from clinical evaluation and laboratory tests at presentation and during the clinical course were identified by multivariate logistic regression and receiver operating characteristic (ROC) curve analyses. The study population comprised 23 cases and 70 controls (52% boys, median age 2.8 y). Independent predictors for an adverse outcome after bacterial meningitis were male gender, atypical convulsions in history, low body temperature at admission and the pathogen Streptococcus pneumoniae. The area under the ROC curve of this prediction rule was 0.87 (95% confidence interval: 0.78–0.96), which was not improved by adding other characteristics. A score including these independent predictors could classify patients into categories with increasing risk for an adverse outcome.

A diagnostic decision rule for management of children with meningeal signs

In a previous study we devised a diagnostic decision rule to improve management of children with meningeal signs, suspected of having bacterial meningitis. The decision rule aimed to guide decisions on (1) whether a lumbar puncture is necessary in children with meningeal signs, and (2) which children need hospitalisation and empirical antibiotic treatment for bacterial meningitis. In this study we assessed the validity of this rule in an external population of four (paediatric) hospitals in The Netherlands. The decision rule included two scoring algorithms using symptoms, signs and quickly available blood and cerebrospinal fluid (CSF) laboratory tests. To evaluate the discriminative value of both algorithms, the absolute numbers of correctly diagnosed patients and the area under the receiver operator characteristic curve were estimated, and compared with the results from the original population (n = 360). In a 18 month period, we included 226 children, median age 2.2 years, who visited the emergency department with meningeal signs. Bacterial meningitis was present in 25 (11%). Using the scoring algorithms patients could be categorised in groups of increasing risk of bacterial meningitis. The discriminative values of the clinical and CSF algorithm in this new population were similar to those in the original population. In the total population of 586 children with meningeal signs, the rule selected 205 children (35%) who did not need a lumbar puncture and 366 children who did not need empirical treatment (62%). In conclusion, this diagnostic rule performed well in a new population of children with meningeal signs. This diagnostic decision rule is a valuable tool for the clinician when deciding to treat these children for bacterial meningitis and thus improving their management.