Ronald de Groot

Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age.

To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172). Control groups of children with similar ages were vaccinated against hepatitis B. All participants received three injections. Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins. Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA. The meningococcal hexavalent OMV vaccine was well tolerated. No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine. The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100%. Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.

Safety and immunogenicity of a novel recombinant subunit respiratory syncytial virus vaccine (BBG2Na) in healthy young adults

A novel recombinant respiratory syncytial virus (RSV) subunit vaccine, designated BBG2Na, was administered to 108 healthy adults randomly assigned to receive 10, 100, or 300 microg of BBG2Na in aluminum phosphate or saline placebo. Each subject received 1, 2, or 3 intramuscular injections of the assigned dose at monthly intervals. Local and systemic reactions were mild, and no evidence of harmful properties of BBG2Na was reported. The highest ELISA and virus-neutralizing (VN) antibody responses were evident in the 100- and 300-microg groups; second or third injections provided no significant boosts against RSV-derived antigens. BBG2Na induced > or 2-fold and > or =4-fold increases in G2Na-specific ELISA units in up to 100% and 57% of subjects, respectively; corresponding RSV-A-specific responses were 89% and 67%. Furthermore, up to 71% of subjects had > or =2-fold VN titer increases. Antibody responses to 2 murine lung protective epitopes were also highly boosted after vaccination. Therefore, BBG2Na is safe, well tolerated, and highly immunogenic in RSV-seropositive adults.

Reviewing Omenn syndrome

Abstract. Omenn syndrome is a form of severe combined immunodeficiency associated with high mortality. Early recognition is required in order to initiate life-saving therapy. This review provides information on the clinical symptoms, laboratory parameters and pathology of the disease, supporting early diagnosis in suspected patients. A literature search was performed using Medline, encompassing the period 1965–1999. Sixty-seven cases were identified and with the addition of a recently diagnosed patient at our hospital, 68 children were included. Median age at onset of symptoms was 4 weeks. Key symptoms were erythematous rash (98%), hepatosplenomegaly (88%), lymphadenopathy (80%), often accompanied by recurrent infections (72%) and alopecia (57%). An elevated WBC (55%) was frequently observed, due to eosinophilia and/or lymphocytosis. B-cell counts were significantly decreased whereas T-cell counts were elevated. A high serum IgE was another frequent finding (91%). Therapeutic options include bone marrow transplantation or cord blood stem cell transplantation; however, the mortality still was 46%. Conclusion: Omenn syndrome is a fatal disease if untreated. The mortality may be reduced when diagnosis is established early and treatment is initiated rapidly by using early compatible bone marrow transplantation or cord blood stem cell transplantation.

Ceftazidime pharmacokinetics in preterm infants: Effects of renal function and gestational age

The objectives of this study were (1) to determine the effects of gestational age on ceftazidime pharmacokinetics in the preterm infant, (2) to relate these effects to changes in glomerular filtration rate (GFR), and (3) to establish appropriate dosage recommendations for preterm infants on day 3 of life.

Serum bactericidal activity and isotype distribution of antibodies in toddlers and schoolchildren after vaccination with RIVM hexavalent PorA vesicle vaccine

A clinical phase II trial with the RIVM hexavalent OMV vaccine containing six different PorAs was carried out in toddlers (2-3 years) and schoolchildren (7-8 years) in The Netherlands. Children were vaccinated three times (0, 2, 8 months). Sera after two and three vaccinations were analysed for serum bactericidal activity (SBA) and isotype distribution in whole cell enzyme linked immunosorbent assay (ELISA). The SBA after vaccination against the six PorAs was significantly different. We investigated whether the age specific and PorA specific differences in SBA titers correlated with differences in PorA specific IgG isotype distribution. The SBA titers were higher in toddlers compared with schoolchildren. After vaccination, IgG1 antibodies dominated the response followed by IgG3 antibodies. IgG2 levels were low, whereas IgG4 was not detected. Irrespective of PorA, IgG total and isotype specific titers after two and three vaccinations were significantly higher in toddlers than in schoolchildren. A weak correlation was found between IgG total or IgG1 and SBA. Although the immunogenicity of the six PorAs is very different, the isotype distribution was similar for all six tested PorAs. We conclude that the RIVM hexavalent PorA vesicle vaccine induces bactericidal antibodies mainly of the IgG1 and IgG3 isotypes that are considered to be most important for protection against disease. The isotype distribution of the response is not age-dependent.

MEROPENEM PHARMACOKINETICS IN THE NEWBORN

ABSTRACT We studied meropenem in 23 pre-term (gestational age, 29 to 36 weeks) and 15 full-term (gestational age, 37 to 42 weeks) neonates. Meropenem doses of 10, 20, and 40 mg/kg were administered as single doses (30-min intravenous infusion) on a random basis. Blood was obtained for determining the meropenem concentration nine times. Each child required other antimicrobials for proven/suspected bacterial infections. Samples were assayed by high-performance liquid chromatography analysis. Population pharmacokinetic parameter values were obtained by employing the BigNPAG program. Model building was performed by the likelihood ratio test. The final model included estimated creatinine clearance (CLcr) (Schwartz formula) and weight (Wt) in the calculation of clearance (meropenem clearance = 0.00112 × CLcr + 0.0925 × Wt + 0.156 liter/hr). The overall fit of the model to the data was good (observed = 1.037 × predicted − 0.096; r2 = 0.977). Given the distributions of estimated creatinine clearance and weight between pre-term and full-term neonates, meropenem clearance was substantially higher in the full-term group. A Monte Carlo simulation was performed using the creatinine clearance and weight distributions for pre-term and full-term populations separately, examining 20- and 40-mg/kg doses, 8- and 12-h dosing intervals, and 0.5-h and 4-h infusion times. The 8-h interval produced robust target attainments (both populations). If more resistant organisms were to be treated (MIC of 4 to 8 mg/liter), the 40-mg/kg dose and a prolonged infusion was favored. Treating clinicians need to balance dose choices for optimizing target attainment against potential toxicity. These findings require validation in clinical circumstances.

Autoimmune Lymphoproliferative Syndrome (ALPS) in a Child from Consanguineous Parents: A Dominant or Recessive Disease?

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive.

Results of 2 Years of Treatment with Protease-Inhibitor–Containing Antiretroviral Therapy in Dutch Children Infected with Human Immunodeficiency Virus Type 1

Clinical, virologic, and immunologic responses to treatment that contained either indinavir or nelfinavir (both regimens included zidovudine and lamivudine) were determined in 32 children infected with human immunodeficiency virus type 1 (HIV-1) who participated for >/= 96 weeks in a prospective, open, uncontrolled multicenter trial. The pharmacokinetics of indinavir and of nelfinavir were determined and showed large interindividual differences. After 96 weeks of therapy, 69% and 50% of the patients had an HIV-1 RNA load that was below the HIV assays detection limits of 500 and 40 copies/mL, respectively. Virologic failure was associated with poor compliance and younger age (independent of baseline virus load and receipt of pretreatment). Relative CD4 cell counts increased significantly in relation to the median of the age-specific reference value, from a median of 44% at baseline to 94% after 96 weeks. In a high percentage of the children, clinical, virologic, and immunologic response rates to combination therapy were optimal during the initial 2 years of therapy.

CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity.

IntroductionChemokines are a superfamily of small peptides involved in leukocyte chemotaxis and in the induction of cytokines in a wide range of infectious diseases. Little is known about their role in meningococcal sepsis in children and their relationship with disease severity and outcome.MethodsMonocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP) 1α, growth-related gene product (GRO)-α and interleukin (IL)-8 were measured in 58 children with meningococcal sepsis or septic shock on admission and 24 hours thereafter. Nine patients died. Serum chemokine levels of survivors and nonsurvivors were compared, and the chemokine levels were correlated with prognostic disease severity scores and various laboratory parameters.ResultsExtremely high levels of all chemokines were measured in the childrens acute-phase sera. These levels were significantly higher in nonsurvivors compared with survivors and in patients with septic shock compared with patients with sepsis (P < 0.0001). The cutoff values of 65,407 pg/ml, 85,427 pg/ml and 460 pg/ml for monocyte chemoattractant protein, for IL-8 and for macrophage inflammatory protein 1α, respectively, all had 100% sensitivity and 94–98% specificity for nonsurvival. Chemokine levels correlated better with disease outcome and severity than tumor necrosis factor (TNF)-α and correlated similarly to interleukin (IL)-6. In available samples 24 hours after admission, a dramatic decrease of chemokine levels was seen.ConclusionInitial-phase serum levels of chemokines in patients with meningococcal sepsis can predict mortality and can correlate strongly with disease severity. Chemokines may play a key role in the pathophysiology of meningococcal disease and are potentially new targets for therapeutic approaches.

Pharmacokinetics of Antiretroviral Therapy in HIV-1-Infected Children

The initiation of antiretroviral therapy has resulted in an impressive reduction in the rate of disease progression in AIDS and HIV-1-related deaths in children; however, there are still several major challenges to be faced in order to improve therapy. A major topic that needs to be dealt with is the establishment of the optimal dosage of antiretroviral therapy for children. This review presents the currently available peer-reviewed data on the pharmacokinetics of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion inhibitors (FIs) in children. In addition, the data are discussed in relation to the currently available European and US guidelines and the US FDA-approved drug labels.High intra- and interpatient variability in pharmacokinetics are often observed for all antiretroviral drugs. The number of children included in the pharmacokinetic studies is often small and children are often divided into divergent groups using different dosage levels and/or drug formulations. For a substantial number of antiretroviral drugs, dosage recommendations, especially for young children, are still absent in the European and US guidelines. The recommended drug dosages in the guidelines are often different from that in the officially approved drug product label. In addition, the recommended drug dosages may deviate between the European and US guidelines. Thus, while practioners aim to meet the recommendations in the official guidelines, patients may receive highly divergent dosages of medication.The high intra- and interpatient variability in pharmacokinetics of antiretroviral drugs in children hampers the application of fixed dosages of antiretroviral drugs. For PIs and NNRTIs, plasma drug levels correlate with viral suppression and drug toxicity. NRTIs are prodrugs that are intracellularly converted to their active triphosphate form and, therefore, plasma NRTI levels correlate poorly with viral suppression. Therapeutic drug monitoring of PIs and NNRTIs should be considered to optimise HIV therapy in children.