Neijens, H.J.

The acquisition of tolerance toward cow's milk through probiotic supplementation: A randomized, controlled trial (Article)

2008-06-01T00:00:00Z

Background: Cow's milk allergy (CMA) is the most frequently diagnosed food allergy in infancy. In general, patients have a good prognosis because the majority acquire tolerance within the first years. Interventions have been proposed to accelerate tolerance and reduce morbidity. Probiotic supplementation could be effective through modulation of the immune system. Objective: We sought to determine whether supplementation with a combination of probiotics (Lactobacillus casei CRL431 and Bifidobacterium lactis Bb-12) accelerates tolerance to cow's milk (CM) in infants with CMA. Methods: We performed a double-blind, randomized, placebo-controlled trial in 119 infants with CMA. Infants received CRL431 and Bb-12 supplemented to their standard treatment of extensively hydrolyzed formula for 12 months. Primary outcome was clinical tolerance to CM at 6 and 12 months of treatment. Furthermore, we analyzed T- and B-lymphocyte subsets (CD3+, CD3+CD4+, CD3+CD8+, and CD20+) in peripheral blood at randomization and at 12 months with flow cytometry and examined the presence of viable probiotic strains in fecal samples. Results: The cumulative percentage of tolerance to CM at 6 and 12 months was similar in both groups: 56 (77%) in the probiotics group versus 54 (81%) in the placebo group. Infants in the placebo group had higher percentages of CD3+and CD3+CD4+lymphocytes compared with those seen in probiotic-treated infants. Probiotic intake was confirmed because probiotics were isolated from feces more often in treated infants than in the placebo group. Conclusion: Supplementation of CRL431 and Bb-12 to extensively hydrolyzed formula does not accelerate CM tolerance in infants with CMA.

Timing of infection and prior immunization with respiratory syncytial virus (RSV) in RSV-enhanced allergic inflammation (Article)

2004-05-15T00:00:00Z

Respiratory syncytial virus (RSV) infection has been shown to be a risk factor for the development of allergy in humans and mice. The allergy-enhancing properties of RSV may be dependent on atopic background and an individual's history of RSV infection. We examined the influence of the timing of infection and prior inoculation with RSV in a mouse model of allergic asthma. Mice were sensitized to and challenged with ovalbumin (OVA) and were inoculated with RSV either before or during the sensitization or challenge period. One group of mice was inoculated with RSV both before sensitization to OVA and during challenge with OVA. Increased pulmonary expression of interleukin (IL)-4, IL-5, and IL-13 mRNA and aggravated alveolitis and hypertrophy of mucus-producing cells were observed only when OVA-sensitized mice were inoculated with RSV shortly before or during challenge with OVA. Despite protection against viral replication, prior inoculation with RSV did not abrogate RSV-enhanced, OVA-induced expression of T helper 2 (Th2) cytokines in the lung. In conclusion, inoculation with RSV enhances allergic disease only when the immune system has already been Th2-primed by the allergen (i.e., OVA). This RSV-enhanced allergy is not completely abrogated by prior inoculation with RSV.

Moderate Local and Systemic Respirator Syncytial Virus-Specific T-Cell Responses Upon Mild or Subclinical RSV Infection (Article)

2003-06-01T00:00:00Z

Respiratory syncytial virus (RSV) infections are a major cause of severe respiratory disease in infants. It has been shown that there is an increased frequency of childhood wheezing in ex-bronchiolitic preteen children. This was postulated to be mediated by a vigorous virus-specific Th2 response influencing the further development of the immune system. Little is known about the possible role of the immune response to clinically mild RSV infections in this respect. We have studied the RSV-specific cellular immune response in infants with a laboratory-confirmed RSV upper respiratory tract infection (URTI; n = 13, mean age 12 months, range 2-22 months) in comparison with infants with non-RSV mediated URTI (n = 9, mean age 9.3 months, range 4-18 months) or infants with severe RSV bronchiolitis (n = 11, mean age 2.3 months, range 1-6 months). RSV-specific cytokine-producing cells were enumerated using the ELISPOT method in peripheral blood mononuclear cells and nasal brush T-cells, collected during the acute and convalescent phase of the infection. Mixed Th1 (IFN-gamma) and Th2 (IL-4 and IL-13) responses were detected in all three groups. Frequencies of RSV-specific T-cells were lower in both URTI groups than in the RSV bronchiolitis group, and not significantly different between the RSV URTI and the non-RSV URTI group. The absence of vigorous virus-specific Th2 responses upon mild RSV infection does not support the hypothesis that these infections influence the development of the immune system and that they predispose for the development of atopic disease.

Early respiratory and skin symptoms in relation to ethnic background: the importance of socioeconomic status; the PIAMA study (Article)

2002-01-01T00:00:00Z

AIMS: To evaluate ethnic differences in the prevalence of respiratory and skin symptoms in the first two years of life. METHODS: A total of 4146 children participated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Parents completed questionnaires on respiratory and skin symptoms, ethnic background, and other potential confounders during pregnancy, and at 3 months, 1 year, and 2 years of age. RESULTS: In the first year, "non-Dutch" children (compared with "Dutch" children) had a higher prevalence of runny nose with itchy/watery eyes (11.0% versus 5.0%). In the second year, a higher prevalence of wheeze at least once (26.7% versus 18.5%), night cough without a cold (24.6% versus 15.5%), runny nose without a cold (34.1% versus 21.3%), and runny nose with itchy/watery eyes (13.7% versus 4.6%) was found. Adjustment for various confounders, especially adjustment for socioeconomic factors, reduced most associations between ethnicity and respiratory symptoms. Only runny nose with itchy/watery eyes in the second year of life was independently associated with non-Dutch ethnicity (adjusted odds ratio 2.89, 95% CI 1.3-6.4). CONCLUSIONS: Non-Dutch children more often had respiratory symptoms in the first two years of life than Dutch children. This could largely be explained by differences in socioeconomic status. Follow up of the cohort will determine whether this higher prevalence of respiratory symptoms in children with non-Dutch ethnicity represents an increased risk of developing allergic disease rather than non-specific or infection related respiratory symptoms.

Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent RSV infection (Article)

2002-01-01T00:00:00Z

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalin-inactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines.

Respiratory infections in infants: interaction of parental allergy, child care, and siblings-- The PIAMA study (Article)

2001-01-01T00:00:00Z

OBJECTIVE: To investigate the association between contacts with other children and the development of respiratory infections in the first year of life in children with or without genetic predisposition for allergy. METHODS: Children (n = 4146) who participate in a prospective birth cohort study (Prevention and Incidence of Asthma and Mite Allergy study) were investigated. Questionnaires were used to obtain information on doctor-diagnosed upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI), child care attendance, having siblings, family history of allergic disease, and various potential confounders. RESULTS: Child care attendance in the first year of life was associated with doctor-diagnosed URTI (adjusted odds ratio [AOR]: 2.7; 95% confidence interval [CI]: 2.1-3.4 for large child care facility vs no child care) and doctor-diagnosed LRTI (AOR: 5.6; 95% CI: 3.9-7.9). Having siblings was associated with doctor-diagnosed LRTI (AOR: 2.6; 95% CI: 2.0-3.4). In addition, children who have allergic parents and attend child care or have older siblings have a higher risk of developing doctor-diagnosed LRTI than do children who have nonallergic parents. CONCLUSIONS: Child care attendance or having siblings increases the risk of developing doctor-diagnosed LRTI in the first year of life to a greater extent in allergy-prone children than in children who are not allergy prone.

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease? (Article)

2000-01-01T00:00:00Z

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.

Type 1-like immune response is found in children with Respiratory Syncytial Virus infection regardless of clinical severity. (Article)

2000-01-01T00:00:00Z

The immunological response of infants younger than six months to infection with respiratory syncytial virus (RSV) was studied in relation to clinical severity. IL-6 and IL-8 were found more frequently and at higher levels in the plasma samples of more severely ill patients and no significant differences were found in the levels of cytokines differentiating between Type 1 and Type 2 responses. Cellular infiltrates in nasopharyngeal washings consisted mainly of polymorphonuclear granulocytes and monocytes. Eosinophils, IgE positive cells and tryptase positive cells were found sporadically. Analyses of RSV stimulated T cell cultures established from peripheral blood mononuclear cells, for intracellular and secreted cytokines showed that, irrespective of clinical severity, the responses were dominated by the production of IFN-γ, and that only low levels of IL-4 and IL-10 were detectable. Collectively these data do not indicate an association between clinical severity and a Type 2-like T cell response.

Respiratory syncytial virus specific serum antibodies in infants under six months of age: limited serological response upon infection. (Article)

1997-01-01T00:00:00Z

The decline of maternal respiratory syncytial virus (RSV) specific serum antibodies was studied in 45 children during the first 6 months of life, using a virus neutralization assay and competition ELISAs measuring fusion protein and glycoprotein specific antibodies. In all children RSV neutralizing antibodies were demonstrated at birth, with titers ranging from 33 to 1382. The calculated mean half life of these antibodies was 26 days. Furthermore, in a group of 38 children with suspected RSV infection, all younger than 6 months of age on admission, the diagnostic value of serological assays was evaluated. In 32 children RSV infection was confirmed by virus isolation, direct immune fluorescence and RT-PCR. In 7 patients of this group a significant titer rise in virus neutralization assay was demonstrated. Six additional RSV infected children could be identified by showing the presence of RSV-specific IgM or IgA serum antibodies or by showing an increase in fusion protein or glycoprotein specific antibodies. All serological tests together identified 13 (41%) of the 32 RSV infected patients. It is concluded that in children of this age group, which represent the majority of patients hospitalized with RSV infections, serological assays not only have a limited diagnostic value but are of limited value for sero-epidemiological studies.

Intrathecal production of interleukin-12 and gamma interferon in patients with bacterial meningitis (Article)

1997-01-01T00:00:00Z

To assess the role of interleukin-12 (IL-12) and gamma interferon (IFN-gamma) in children with bacterial meningitis, bioactive IL-12 (p70) and the inactive subunit p40 and IFN-gamma were measured in serum and cerebrospinal fluid (CSF) from 35 children with bacterial meningitis and 10 control subjects. The production of IFN-gamma is induced by IL-12 with tumor necrosis factor alpha (TNF-alpha) as a costimulator and inhibited by IL-10. CSF concentrations of IL-12 p40 as well as those of IFN-gamma were markedly elevated, whereas IL-12 p70 was hardly detectable. Detectable CSF levels of IFN-gamma correlated positively with IL-12 p40 (r = 0.40, P = 0.02) and TNF-alpha (r = 0.46, P = 0.04) but not with IL-6, IL-8, or IL-10. In contrast to CSF levels of TNF-alpha, IL-12, and IL-10, those of IFN-gamma were significantly higher in patients with pneumococcal meningitis than in children with meningitis caused by Haemophilus influenzae and Neisseria meningitidis, presumably because of a high CSF TNF-alpha/IL-10 ratio in the former. We suggest that IL-12- and TNF-alpha-induced IFN-gamma production may contribute to the natural immunity against microorganisms in the CSF compartment during the acute phase of bacterial meningitis.

Once-daily versus twice-daily administration of ceftazidime in the preterm infant (Article)

1995-01-01T00:00:00Z

Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life. Patients with suspected septicemia were randomized on day 1 of life in two groups. One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily. Both groups also received 25 mg of amoxicillin per kg twice daily. Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection. An additional blood sample was taken at 24 h from the group dosed once a day. High-performance liquid chromatography was used to determine serum ceftazidime concentrations. The pharmacokinetics of ceftazidime were best described by using a one-compartment model. The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups. The ceftazidime/inulin clearance ratio was 0.72 for both groups. However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter). The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens. We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily.

Kindergeneeskunde in ontwikkeling (Inaugural Lecture)

1987-06-03T00:00:00Z

Rede, uitgesproken bij de aanvaarding van het ambt van hoogleraar in de Kindergeneeskunde aan de Erasmus Universiteit te Rotterdam, op 3 juni 1987

Bronchial responsiveness in children (Doctoral Thesis)

1981-09-30T00:00:00Z

The aim of the research described in this thesis is to get more insight into various aspects of bronchial responsiveness. The literature is reviewed and discussed in the first part of this thesis (chapters 2-5) and emphasis is placed on recent developments. In the review results from studies in animals and in humans are correlated as much as possible. Our own studies are designed to analyse various aspects of the mechanisms in bronchial responsiveness in children, as well as the role of bronchial responsiveness in the occurrence of symptoms. These studies, started in 1976, are divided into three groups: a. Dose- and time-response relationships using inhaled histamine. These are analysed and the methods for the measurement of bronchial responsiveness considered (chapter 6). b. Studies on mechanisms of: 1. The relative contribution of the autonomic and the mast cell system in the pathogenesis of bronchial responsiveness using exercise is studied by means of protective agents (paragraph 7.1). 2. The pattern of bronchial obstruction after exercise is evaluated with flowvolume curves using air and helium/oxygen mixtures (paragraph 7.2). 3. The feasibility of leucocytes as a model for hyperresponsiveness at a cellular level are performed by measuring the release of mediators (paragraphs 7.3 and 7.4). c. The clinical significance of the relationship between bronchial responsiveness and the occurrence of bronchial obstruction after contact with allergens and after exercise (chapter 8).