Background The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. Objective We sought to investigate the ...effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. Methods We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cow's milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. Results The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cow's milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. Conclusion The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age.
Objective To assess the association between the introduction of solid foods in the first 12 months and the occurrence of eczema during the first 4 years of life in a prospective study of newborns. ...Study design Data were taken from annually administered questionnaires from a large birth cohort (recruited 1995–1998) comprised of an intervention and a nonintervention group. Outcomes were doctor-diagnosed and symptomatic eczema. Multiple generalized estimation equation models were performed for the 2 study groups. Results From the 5991 recruited infants, 4753 (79%) were followed up. The 2 study groups were different in their family risk of allergies and feeding practices. No association was found between the time of introduction of solids or the diversity of solids and eczema. In the nonintervention group, a decreased risk was observed for avoidance of soybean/nuts, but an increased risk was seen in doctor-diagnosed eczema for the avoidance of egg in the first year. Conclusion The evidence from this study supports neither a delayed introduction of solids beyond the fourth month nor a delayed introduction of the most potentially allergenic solids beyond the sixth month of life for the prevention of eczema. However, effects under more extreme conditions cannot be ruled out.
Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, ...despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.
The IL-1 family member 7b (IL-1F7b) is a novel homolog of the IL-1 cytokine family discovered by computational cloning. We have reported that IL-1F7b shares critical amino acid residues with IL-18 ...and binds the IL-18-binding protein; in doing so, IL-1F7b augments the inhibition of IFN-gamma by the IL-18-binding protein. IL-1F7b also binds IL-18Ralpha but neither induces signal nor acts as a receptor antagonist. Hence, the function of IL-1F7b remains unknown. In the present study, we analyzed the intracellular expression pattern of IL-1F7b. Using two variants of GFP fusion constructs of human IL-1F7b stably expressed in RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor-but not the N-terminal propiece-specifically translocates to the nucleus following LPS stimulation. IL-1F7b, like IL-1beta, IL-18, and IL-33, is processed by caspase-1 to generate the mature cytokines. Therefore, we tested whether caspase-1-mediated cleavage of the IL-1F7b precursor is required for mature IL-1F7b to translocate actively into the nucleus. Indeed, a specific caspase-1 inhibitor markedly reduced nuclear entry of IL-1F7b. In stable transfectants of human IL-1F7b in RAW macrophages stimulated with LPS, levels of TNF-alpha, IL-1alpha, IL-6, as well as the chemokine MIP-2, were substantially reduced (72-98%) compared with LPS-stimulated cells transfected with the empty plasmid. These results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines, consistent with IL-1F7b being an anti-inflammatory member of the IL-1 family.
Background The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. Objective We performed a follow–up of the ...German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cow's milk formula (CMF) in a randomized, double-blind trial. Methods Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. Results In the intent-to-treat analysis the relative risk of a physician's diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. Conclusion The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.
Background: The potential of extensively or partially hydrolyzed formulas to reduce the risks for allergies is controversial. Objective: We sought to assess the preventive effect of differently ...hydrolyzed formulas compared with cow's milk formula (CMF) in high-risk infants. Methods: Between 1995 and 1998, 2252 infants with a hereditary risk for atopy were enrolled in the German Infant Nutritional Intervention Study and randomly assigned at birth to one of 4 blinded formulas: CMF, partially hydrolyzed whey formula, extensively hydrolyzed whey formula, and extensively hydrolyzed casein formula (eHF-C). The primary end point at 1 year of age was the presence of allergic manifestation, which was defined as atopic dermatitis (AD), gastrointestinal manifestation of food allergy, allergic urticaria, or a combination of these factors. Results: At 12 months per protocol, analysis was performed on 945 infants exposed to study formula: 304 (13.5%) infants had left the study, 138 (6.1%) infants were excluded because of noncompliance, and 865 infants were exclusively breast-fed the first 4 months of life. The incidence of allergic manifestation was significantly reduced by using eHF-C compared with CMF (9% vs 16%; adjusted OR, 0.51; 95% CI, 0.28-0.92), and the incidence of AD was significantly reduced by using eHF-C (OR, 0.42; 95% CI, 0.22-0.79) and partially hydrolyzed whey formula (OR, 0.56; 95% CI, 0.32-0.99). Family history of AD was a significant risk factor and modified the preventive effect of the hydrolysates. Conclusions: Prevention of allergic diseases in the first year of life is feasible by means of dietary intervention but influenced by family history of AD. The preventive effect of each hydrolyzed formula needs to be clinically evaluated. (J Allergy Clin Immunol 2003;111:533-40.)
Background Recommendations for primary prevention of allergic diseases in high-risk children include feeding with hydrolyzed formulas if breast-feeding is insufficient. Objective The primary ...objective of the German Infant Nutritional Intervention study was to investigate the allergy preventive effect of 3 hydrolyzed formulas compared with cow's milk formula in the first 3 years of life in a randomized, double-blind trial. Methods Between 1995 and 1998, 2252 newborns with atopic heredity were allocated to a group receiving cow's milk formula, partially or extensively hydrolyzed whey formula, or extensively hydrolyzed casein formula as a milk substitute for the first 4 months if breast-feeding was insufficient. Main outcome parameters were allergic manifestations, atopic dermatitis (AD), and asthma. Results After 3 years, 396 of 2252 children (17.6%) had dropped out. Breast-fed infants without formula feeding during the intervention (n = 889) were considered separately. A significant reduction of the incidence of AD was achieved with the extensively hydrolyzed casein formula in the intention-to-treat (ITT; n = 1363) and per protocol (PP; n = 904) analyses (ITT: population odds ratio 95% CI, 0.67 0.45-0.99; PP: adjusted odds ratio ORadj , 0.53 0.32-0.88), and with the partially hydrolyzed whey formula in the PP analysis (ITT: population odds ratio, 0.76 0.52-1.11; PP:ORadj , 0.60 0.37-0.97). None of the formulas reduced the incidence of asthma. Conclusion The risk for AD, but not for asthma, can be reduced with certain cow's milk hydrolyzates in high-risk infants when breast-feeding is insufficient. Clinical implications Early nutritional intervention in high-risk children has significant influence on the incidence of AD, but not of asthma.
Gastroesophageal reflux has been suggested as an underlying cause of chronic lung disease. The aim of this study was to assess the value of pepsin and bile acids, both components of GI secretions, in ...the lungs of children with chronic lung diseases as possible markers for gastroesophageal reflux disease and their relation to oxidation and inflammation.
BAL was performed in 96 children with different chronic lung diseases. Gastroesophageal reflux was analyzed by two-channel, 24-h esophageal pH measurements. Lung pepsin and bile acids were measured in BAL enzymatically, interleukin (IL)-8 by enzyme-linked immunosorbent assay, and protein carbonyls by slot blot immunoassay.
Sixty-five of the 96 children (68%) had an extensive proximal acidic reflux index. Children with reflux had higher pepsin concentrations in their BAL fluid (BALF), compared to children without reflux despite low specificity. No differences were observed for bile acids. Percentages of neutrophils, levels of protein carbonyls, and levels of IL-8 in BALF correlated with the number of proximal reflux events.
Pulmonary microaspiration as demonstrated by pepsin detection in BALF is common in children with chronic lung diseases, suggesting that gastroesophageal reflux may contribute significantly to the disease pathogenesis. BALF pepsin concentration correlates positively with the number of proximal reflux events. Protein oxidation in BALF is higher in children with extensive proximal acidic reflux, suggesting that pulmonary microaspirations contribute to lung damage.
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