Marc Raes

IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease

Background: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained. Objective: To report two cases of otherwise healthy, unrelated children with recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-κB(NF-κB)-dependent immunity. Results: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation. The other child carried a hemizygous mutation in NEMO, associated with a broader impairment of NF-κB activation, with an impaired cellular response to IL-1R, TLR and tumour necrosis factor receptor stimulation. The two patients shared a narrow clinical phenotype, associated with two related but different genotypes. Conclusions: Otherwise healthy children with recurrent IPD should be explored for underlying primary immunodeficiencies affecting the IRAK4-dependent and NEMO-dependent signalling pathways.

Effectiveness of rotavirus vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium: case-control study

Objective To evaluate the effectiveness of rotavirus vaccination among young children in Belgium. Design Prospective case-control study. Setting Random sample of 39 Belgian hospitals, February 2008 to June 2010. Participants 215 children admitted to hospital with rotavirus gastroenteritis confirmed by polymerase chain reaction and 276 age and hospital matched controls. All children were of an eligible age to have received rotavirus vaccination (that is, born after 1 October 2006 and aged ≥14 weeks). Main outcome measure Vaccination status of children admitted to hospital with rotavirus gastroenteritis and matched controls. Results 99 children (48%) admitted with rotavirus gastroenteritis and 244 (91%) controls had received at least one dose of any rotavirus vaccine (P<0.001). The monovalent rotavirus vaccine accounted for 92% (n=594) of all rotavirus vaccine doses. With hospital admission as the outcome, the unadjusted effectiveness of two doses of the monovalent rotavirus vaccine was 90% (95% confidence interval 81% to 95%) overall, 91% (75% to 97%) in children aged 3-11 months, and 90% (76% to 96%) in those aged ≥12 months. The G2P[4] genotype accounted for 52% of cases confirmed by polymerase chain reaction with eligible matched controls. Vaccine effectiveness was 85% (64% to 94%) against G2P[4] and 95% (78% to 99%) against G1P[8]. In 25% of cases confirmed by polymerase chain reaction with eligible matched controls, there was reported co-infection with adenovirus, astrovirus and/or norovirus. Vaccine effectiveness against co-infected cases was 86% (52% to 96%). Effectiveness of at least one dose of any rotavirus vaccine (intention to vaccinate analysis) was 91% (82% to 95%). Conclusions Rotavirus vaccination is effective for the prevention of admission to hospital for rotavirus gastroenteritis among young children in Belgium, despite the high prevalence of G2P[4] and viral co-infection.

Reduction in pediatric rotavirus-related hospitalizations after universal rotavirus vaccination in Belgium.

Background: This study investigated the effect of pediatric vaccination against rotavirus on the number of rotavirus-related hospitalizations of children in Belgium. Methods: This retrospective database study was conducted at 12 pediatric hospitals in Belgium (546 pediatric beds, 30.6% of Belgian total). Children ≤5 years attending hospital for any reason were eligible if they had a rotavirus stool test at one of the study centers. The number of rotavirus-positive stool tests and hospitalizations for acute gastroenteritis (AGE) were compared for prevaccination (June 2004–May 2006) and postvaccination (June 2007–May 2009) study periods. Results: The number of rotavirus-positive stool tests in children who were ≤5 years of age decreased from an average of 881 in the prevaccination period to 368 in the first year postvaccination period and 199 in the second. In children 2 to 24 months of age, the percentage reductions were 65% (95% confidence interval [CI]: 62%, 69%) and 80% (95% CI: 77%, 83%) in the first and second years after vaccination, respectively, compared with prevaccination. In children <2 months, the reductions were 50% (95% CI: 36%, 64%) and 64% (95% CI: 49%, 76%), respectively, and in children >24 months the corresponding values were 20% (95% CI: 14%, 28%) and 64% (95% CI: 56%, 72%). The number of AGE-driven hospital admissions and hospitalization days for AGE declined by 33% and 36%, respectively, from prevaccination to the second year postvaccination in children ≤2 years of age. Conclusions: Pediatric rotavirus vaccination in Belgium significantly reduced rotavirus-related hospitalizations in the first and second years after introduction.

Rotavirus vaccines in Belgium: policy and impact.

Background: The current Belgian experience with rotavirus vaccination provides a unique perspective to look at the effect of vaccination. Shortly after introduction, a nation-wide recommendation was issued and despite the fact that both rotavirus vaccines are offered through partial reimbursement, vaccine uptake has already reached a high level (at least 90%). Methods: For the purpose of looking at the effectiveness of the Belgian rotavirus vaccination policy, 3 years after introduction, we retrospectively collated the publicly available data on the number of laboratory-confirmed rotavirus cases reported to a national network of sentinel laboratories during 1999 to 2010 and compared them with the available data on hospitalizations due to rotavirus gastroenteritis. Results: Both data sources (reported laboratory-diagnosed cases to a sentinel network as well as data on hospitalizations due to rotavirus gastroenteritis) show a decrease in the number of rotavirus infections and a 4- to 6-week delay in the onset of disease and the peak of incidence in the postvaccination period. Conclusions: Because this decline coincides with the increased vaccine uptake and is sustained during consecutive rotavirus seasons, the effect is mainly attributed to the rotavirus vaccination. The rapid increase in vaccine coverage, despite the partial reimbursement for the vaccines, is remarkable. Continued postlicensure surveillance is necessary to further investigate the effectiveness of the vaccines and to document the public health impact of the vaccination in reducing disease burden.

Omeprazole in infants with cimetidine-resistant peptic esophagitis

Twelve neurologically normal infants (age 2.9+/-0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine (in addition to positioning, cisapride, and Gaviscon) were treated with omeprazole, 0.5 mg/kg once a day, for 6 weeks. The effectiveness of omeprazole was evaluated in all infants by clinical assessment and endoscopy before and after treatment and by 24-hour gastric pH monitoring during treatment in seven infants. Omeprazole therapy led to a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity.

Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial.

We investigated the potential yield of incorporating fractional exhaled nitric oxide (FeNO) measurements in childhood allergic asthma management.

Evaluation of platelet function on cord blood in 80 healthy term neonates using the Platelet Function Analyser (PFA-100): shorter in vitro bleeding times in neonates than adults

Although healthy neonates do not show a clinical bleeding tendency, in vitro tests of neonatal platelet function (aggregometry and flow cytometry) demonstrate hyporeactivity compared with platelet function in adults. This is in contrast to the in vivo bleeding time which is shorter in neonates than adults [4]. The Platelet Function Analyser PFA-100 is an in vitro test for the evaluation of the global process of platelet adhesion and aggregation in whole blood, based on the combination of high shear stress and chemical agonists: collagen combined with epinephrine (COL/EPI) and with adenosine phosphate (COL/ADP). Results are reported in seconds as closure time (CT), the in vitro equivalent of the bleeding time [5]. Our aim was to establish neonatal reference ranges for the PFA-100 in cord blood using a large study group and to compare these with values in adults. A few studies have addressed the evaluation of neonatal platelet function with the PFA-100, but they included smaller numbers of samples [1, 2, 3, 6]. The study was performed on citrated whole blood (1 part 3.8% sodium citrate to 9 parts blood) drawn with a 21 gauge needle. Cord blood samples were collected from the umbilical cord vein within 5 min of delivery in 80 full-term neonates (gestational age >37 weeks). The mothers had a history of uncomplicated pregnancy and were not on medication known to affect platelet function. The neonates had Apgar scores of ‡7 at 1 min and ‡9 at 5 min and were without evidence of congenital or acquired illness. Blood samples were collected from an antecubital vein in 20 healthy adults to validate adult reference ranges (COL/EPI CT: 85–165 s, COL/ADP CT: 72–120 s). Blood was assayed within 4 h of collection. In cord blood, the central 95% reference range (with 90% confidence intervals) was 49–168 s (±9.5 s) for COL/EPI CT and 40–92 s (±4.5 s) for COL/ADP CT (Table 1). Compared with adult reference ranges, both the neonatal COL/EPI and COL/ADP CT reference ranges were shorter (two-sample t-test, P<0.001). Our in vitro results are compatible with the reported shorter in vivo bleeding times in neonates compared with adults [4]. Although similar findings with the PFA100 have been made in smaller groups of neonates, a significant difference in the CTs of neonates and adults could not always be demonstrated [1, 2, 3, 6]. Haematocrit values are consistently higher in neonates than in adults, but have been shown to only marginally explain the observed difference [2, 3]. Another consistent difference is the increased neonatal presence of high molecular weight multimers of the von Willebrand factor (vWF) [4]. vWF plays an important role in primary platelet related haemostasis allowing platelet adhesion, especially under high shear stress conditions as in the PFA-100 [5]. A recent experimental study provided evidence of this role of vWF on CTs in neonates [6]. Finally, one has to be aware of potential pitfalls in the use of the PFA-100, especially the lack of control of preanalytic variables: both the concentration of sodium citrate used and the time interval until analysis affect CTs significantly [5]. Our study has established specific reference ranges for the PFA-100 in cord blood in a large number of healthy term neonates enabling clinicians to conveniently screen neonates at risk for bleeding. Eur J Pediatr (2003) 162: 212–213 DOI 10.1007/s00431-002-1093-7

Higher proportion of G2P[4] rotaviruses in vaccinated hospitalized cases compared with unvaccinated hospitalized cases, despite high vaccine effectiveness against heterotypic G2P[4] rotaviruses

The overall vaccine effectiveness of the monovalent rotavirus vaccine in an observational, prospective, multicentre, hospital-based case-control study in Belgium (RotaBel) was 90%. However, rotavirus genotype and co-infecting pathogens are important parameters to take into account when assessing vaccine effectiveness. In this study we specifically investigated the effect of rotavirus genotypes and co-infecting pathogens on vaccine effectiveness of the monovalent vaccine. In addition, we also investigated the effect of co-infecting pathogens on disease severity. From February 2008 to June 2010 stool samples of rotavirus gastroenteritis cases of a random sample of 39 Belgian hospitals were collected and subsequently genotyped. Fishers exact tests were performed to investigate the relationships between rotavirus genotype, co-infecting pathogens and disease severity. The vaccine effectiveness of a full series of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by G1P[8] rotavirus strains was 95% (95% CI 77.5-98.7). Against G2P[4], the vaccine effectiveness was 85% (95% CI: 63.7-93.8). G4P[8]- and G3P[8]-specific vaccine effectiveness was 90% (95% CI 19.2-98.7) and 87% (95% CI -5.2 to 98.4), respectively. A post-hoc analysis showed that the genotype distribution was significantly related to the vaccination status (p <0.001), whereby G2P[4] strains were proportionally more prevalent in vaccinated cases than in unvaccinated cases. No statistical associations were found between co-infection status and vaccination status, Vesikari severity score or rotavirus genotype. The high vaccine effectiveness against the individual genotypes implies robust protection of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by the major human rotavirus genotypes. The prevalence of G2P[4] requires continued monitoring.

Lymphocyte subpopulations in healthy newborn infants: Comparison of cord blood values with values five days after birth

Significant differences (p < 0.0001) were demonstrated in lymphocyte subpopulations both in cord blood and in venous blood samples obtained at day 5 from the same healthy infants. Numbers of T lymphocytes increased, especially CD4+/CD45RA+ cells, whereas numbers of B lymphocytes and natural killer cells decreased without changes in CD8+ and other cytotoxic cells.

Impact of rotavirus vaccination on hospitalisations in Belgium: comparing model predictions with observed data.

Background Published economic assessments of rotavirus vaccination typically use modelling, mainly static Markov cohort models with birth cohorts followed up to the age of 5 years. Rotavirus vaccination has now been available for several years in some countries, and data have been collected to evaluate the real-world impact of vaccination on rotavirus hospitalisations. This study compared the economic impact of vaccination between model estimates and observed data on disease-specific hospitalisation reductions in a country for which both modelled and observed datasets exist (Belgium). Methods A previously published Markov cohort model estimated the impact of rotavirus vaccination on the number of rotavirus hospitalisations in children aged <5 years in Belgium using vaccine efficacy data from clinical development trials. Data on the number of rotavirus-positive gastroenteritis hospitalisations in children aged <5 years between 1 June 2004 and 31 May 2006 (pre-vaccination study period) or 1 June 2007 to 31 May 2010 (post-vaccination study period) were analysed from nine hospitals in Belgium and compared with the modelled estimates. Results The model predicted a smaller decrease in hospitalisations over time, mainly explained by two factors. First, the observed data indicated indirect vaccine protection in children too old or too young for vaccination. This herd effect is difficult to capture in static Markov cohort models and therefore was not included in the model. Second, the model included a ‘waning’ effect, i.e. reduced vaccine effectiveness over time. The observed data suggested this waning effect did not occur during that period, and so the model systematically underestimated vaccine effectiveness during the first 4 years after vaccine implementation. Conclusions Model predictions underestimated the direct medical economic value of rotavirus vaccination during the first 4 years of vaccination by approximately 10% when assessing hospitalisation rates as compared with observed data in Belgium.