Radvan Urbanek

Randomized, Double-Blind, Placebo-Controlled Trial of Probiotics for Primary Prevention: No Clinical Effects of Lactobacillus GG Supplementation

BACKGROUND. The value of probiotics for primary prevention is controversial. Published trials vary considerably in study design and the applied probiotics, thereby limiting comparability of the results. OBJECTIVE. The purpose of this trial was to study the preventive effect of the probiotic Lactobacillus GG on the development of atopic dermatitis. METHODS. In a double-blind, placebo-controlled prospective trial, 105 pregnant women from families with ≥1 member (mother, father, or child) with an atopic disease were randomly assigned to receive either the probiotic Lactobacillus GG (American Type Culture Collection 53103; 5 × 109 colony-forming units of Lactobacillus GG twice daily) or placebo. Ninety-four families (89.5%) completed the trial. The supplementation period started 4 to 6 weeks before expected delivery, followed by a postnatal period of 6 months. The primary end point was the occurrence of atopic dermatitis at the age of 2 years. Secondary outcomes were severity of atopic dermatitis, recurrent episodes of wheezing bronchitis, and allergic sensitization at the age of 2 years. RESULTS. Atopic dermatitis was diagnosed in 14 (28%) of 50 in the Lactobacillus GG group and in 12 (27.3%) of 44 in the placebo group. The risk of atopic dermatitis in children on probiotics relative to placebo was 0.96 (confidence interval 0.38–2.33). Severity of atopic dermatitis was comparable between the 2 groups. Notably, children with recurrent (≥5) episodes of wheezing bronchitis were more frequent in the Lactobacillus GG group (26%; n = 13), as compared with the placebo group (9.1%; n = 4). No difference was observed between both groups in total immunoglobulin E concentrations or numbers of specific sensitization to inhalant allergens. CONCLUSIONS. Supplementation with Lactobacillus GG during pregnancy and early infancy neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis. Therefore, Lactobacillus GG cannot be generally recommended for primary prevention.

Five-year follow-up on the PAT study : specific immunotherapy and long-term prevention of asthma in children

Background:  A 3‐year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long‐term preventive effect, we performed a follow up – 2 years after termination of immunotherapy.

Direct evidence for transplacental allergen transfer

Allergies are increasing, and despite deeper insights into the immunologic basis of these diseases, preventive measures are not yet efficient. As the induction of allergic diseases is often triggered in early childhood, perinatal or prenatal preventive strategies would be beneficial. We investigated the transfer of inhalant and nutritive allergens across the human placenta. For this purpose, the maternal side of a placental cotyledon was perfused in vitro with an allergen-containing medium, and a specific ELISA was used to detect the allergens on the fetal side. Both allergens evaluated, birch pollen major allergen Bet v1 and the milk allergen beta-lactoglobulin, could be shown to cross the placenta. The nutritive allergen beta-lactoglobulin was not only transferred across the placenta in all eight experiments, but was also detectable within the first minutes of perfusion. The peak allergen concentration on the fetal side could be increased by addition of human immunoglobulin. For the inhalant allergen Bet v1, transfer was observed in two of 10 placental experiments, and only if human immunoglobulin was added. A pulsatility wave with a frequency of 30–35 min suggested an active transfer mechanism. We conclude that allergens are actively and selectively transferred across the placenta. Therefore, controlled maternal allergen exposure might offer new ways to induce tolerance to specific allergens in the fetus.

Human Milk–Derived Oligosaccharides and Plant-Derived Oligosaccharides Stimulate Cytokine Production of Cord Blood T-Cells In Vitro

Human milk contains large amounts of free oligosaccharides (HMOs). HMOs have been shown to exert antiinflammatory properties, and evidence for their immunomodulatory effects is increasing. The purpose of this study was to evaluate influences of two human breast milk–derived oligosaccharide samples (neutral and acidic oligosaccharides), and of a low-molecular-weight fucoidan on cytokine production and activation of cord blood mononuclear cells. Cord blood mononuclear cells from randomly chosen healthy newborns were co-cultured with the oligosaccharide samples. By means of flow cytometry, intracellular cytokine production (d 20) and surface marker expression of T cells (d 5) were measured. In vitro–induced Ig levels were quantified nephelometrically (total IgG1) and by ELISA (total IgE) in the supernatant of cell cultures. The acidic oligosaccharide fraction increased the percentage of interferon-γ producing CD3+CD4+ and CD3+CD8+ cells (p < 0.05) and the IL-13 production in CD3+CD8+ cells (p < 0.05). In acidic oligosaccharide cultures, CD25+ expression on CD3+CD4+ cells was significantly elevated (p < 0.05). Low-molecular-weight fucoidan induced IL-4 production in CD3+CD4+ T cells (p < 0.05) and IL-13 production in CD3+CD8+ T cells (p < 0.05), whereas interferon-γ production remained unaffected in both T-cell populations. Ig production (total IgE and total IgG1) remained unaffected. Human milk–derived oligosaccharides and plant-derived oligosaccharides affect the cytokine production and activation of cord blood derived T cells in vitro. Therefore, oligosaccharides and, in particular, acidic oligosaccharides may influence lymphocyte maturation in breast-fed newborns.

1α, 25(OH)2D3 inhibits not only th1 but also Th2 differentiation in human cord blood T cells

Human naive CD4+ T helper (Th) and CD8+ cytotoxic (Tc) T cells, which only produce IL-2, may differentiate into Th1/Tc1- or Th2/Tc2-like lymphocytes, characterized by their cytokine production profile. 1α,25-dihydroxyvitamin D3 (1α, 25(OH)2D3) has been reported to inhibit Th1/Tc1-related, but increase Th2/Tc2-associated cytokines in T cells from adults. In industrialized countries, vitamin D supplementation for prevention of rickets is initiated within the first days of life and continued throughout the entire first year. Epidemiologic studies suggest an association of vitamin D exposure in newborns with the incidence of allergic diseases in later life. This study addresses the effects of 1α, 25(OH)2D3 on Th1/Tc1 versus Th2/Tc2 differentiation in long term cell cultures of (naive) cord blood T lymphocytes. Our results show that in CD4+ as well as CD8+ cord blood cells, 1α, 25(OH)2D3 inhibits not only IL-12-generated IFN-γ production, but also suppresses IL-4 and IL-13 expression induced by IL-4. Thus, in cord blood 1α, 25(OH)2D3 induces a T cell population without predominance of Th2 related cytokines.

Particulate matter and lung function growth in children: a 3-yr follow-up study in Austrian schoolchildren

The effects of particulate matter <10 µm in diameter (PM10) and other air pollutants on lung function were assessed in 975 schoolchildren, from eight communities in Lower Austria between 1994–1997. In each community, air pollution data were collected. Spirometry was performed twice a year. PM10 concentration (mean concentration between two subsequent lung-function measures in spring and autumn (summer interval) or between autumn and spring (winter interval)) showed a mean value of 17.36 µg·m−3 in the summer interval and 21.03 µg·m−3 in the winter interval. A slower increase in the forced expiratory volume in one second (FEV1) and midexpiratory flow between 25 and 75% of the forced vital capacity (MEF25–75) with age in children exposed to higher summer PM10 was observed in the 3-yr study period. After adjusting for potential confounders (sex, atopy, passive smoking, initial height, height difference, site, initial lung function) an increase of summer PM10 by 10 µg·m−3 was associated with a decrease in FEV1 growth of 84 mL·yr−1 and 329 mL·s−1·yr−1 for MEF25–75. Nitrogen dioxide and ozone also showed a negative effect on lung-function growth, confirming previous work. The authors concluded that long-term exposure to particulate matter <10 µm in diameter had a significant negative effect on lung-function proxy for the development of large (forced expiratory volume in one second) and small (midexpiratory flow between 25 and 75% of the forced vital capacity) airways, respectively, with strong evidence for a further effect of ozone and nitrogen dioxide on the development of forced vital capacity and forced expiratory volume in one second.

Prenatal Contact with Inhalant Allergens

Pollen contact in early infancy may enhance the risk for subsequent pollen allergy. In this study likelihood of a prenatal antigen contact, as a result of inhalation of pollen allergens by the mother, was investigated. Due to the seasonal occurrence of allergens studied, the date of priming can be estimated, and this can supply data about the maturation of the fetal immune system. Proliferative responses of umbilical cord blood mononuclear cells (UCB MNCs) to the recombinant major allergens of birch (rBet v 1) and timothy grass(rPhl p 1) were analyzed throughout the whole year. A positive proliferative response was regarded as the criterion for a prenatal contact of the immune system with the allergen. Prenatal priming with both allergens was observed. Timothy grass pollen displayed considerably higher antigenicity than did birch pollen. The susceptibility of the fetal immune system to be primed by these allergens varies during the gestation period. The majority of positive responses to rPhl p 1 and rBet v 1 were found in UCB samples in which antigen contact (the respective pollen season) took place in the first 6 mo of pregnancy. Our results offer indirect evidence that, shortly after migration of T cell precursors to the epithelial thymus, T cells are mature enough for priming with antigens. No relationship was found between the susceptibility of the fetal immune system to be primed by these allergens and the clinical history of the family concerning type I allergy.

Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. Our objective was to prevent sensitization to house‐dust mite and food allergens, as well as the development of atopic symptoms during infancy, by the combination of an educational package and the use of mite allergen‐impermeable mattress encasings. A multicentre European, population‐based, randomized, controlled study of children at increased atopic risk [Study on the Prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, the UK, and Lithuania), and included three cohorts – schoolchildren, toddlers, and newborns. We report on the newborn cohort. A total of 696 newborns were included from Austria, the UK, and Germany. Inclusion criteria were: a positive history of parental allergy; and a positive skin‐prick test or specific immunoglobulin E (IgE) (IgE ≥ 1.43 kU/L) against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age, the overall sensitization rate against the tested allergens [dust‐mite allergens: Dermatophagoides pteronyssinus and Dermatophagoides farinae (Der p and Der f)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we were able to demonstrate, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero‐ and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy‐to‐perform preventive measures.

Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthmatic signs in children

BACKGROUND To describe the natural history of asthma between the ages of 7 and 10 years and to analyze risk factors for prevalences, as well as new onset of asthma-like symptoms, a longitudinal study of 1812 children was conducted. METHODS In four surveys, each 1 year apart, four asthma-like symptoms and several hypothetical risk factors were ascertained through standardized questionnaires. Sensitization to seven common inhalant allergens was measured by skin prick testing. Exposure to mite allergens (Der p I, Der f I) was assessed by measuring the antigen concentrations in the dust of each childs mattress. Occurrence of more than one asthma-like symptom closely related to the practioners diagnoses of bronchial asthma and recurrent wheezy bronchitis was used as the outcome variable. RESULTS After an initial prevalence of 14.5%, new onset of symptoms in children unaffected at the beginning was reported in 7.2% during the 3 years. Of the factors explaining prevalence and persistence of asthma-like symptoms (sensitization to mite allergens and animal danders, history of hay fever and eczema, low gestational age, male gender, parental atopy), only sensitization to mite allergens (odds ratio = 2.3, 95% confidence interval = 1.1-4.7) and parental atopy (odds ratio = 2.1, 95% confidence interval = 1.2-3.7) were also significantly associated with new onset. In a relatively small number of sensitized subjects with new onset of symptoms (n = 31), mite antigen concentration did not appear to be associated with incidence of symptoms. CONCLUSION Sensitization to mite allergens antedated the onset of asthma-like symptoms, and no strong effect of allergen exposure on clinical development could be found. Thus the primary focus should be on preventing sensitization to mite allergens by implementing avoidance measures in infancy or at early school age in order to reduce the onset of asthma at a later stage.

Parental farming protects children against atopy: longitudinal evidence involving skin prick tests

Background There is growing evidence that the development of allergic sensitization can be influenced by environmental co‐factors. Studies showed that growing up on a farm can protect children against allergic sensitization. However, little is known whether this ‘farming effect’ can only be observed in early lifetime or whether it also plays a role in later childhood.