Background The evolution of the IgE response to the numerous allergen molecules of Dermatophagoides pteronyssinus is still unknown. Objectives We sought to characterize the evolutionary patterns of ...the IgE response to 12 molecules of D pteronyssinus from birth to adulthood and to investigate their determinants and clinical relevance. Methods We investigated the clinical data and sera of 722 participants in the German Multicenter Allergy Study, a birth cohort started in 1990. Diagnoses of current allergic rhinitis (AR) related to mite allergy and asthma were based on yearly interviews at the ages of 1 to 13 years and 20 years. IgE to the extract and 12 molecules of D pteronyssinus were tested by means of ImmunoCAP and microarray technology, respectively, in sera collected at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Exposure to mites at age 6 and 18 months was assessed by measuring Der p 1 weight/weight concentration in house dust. Results One hundred ninety-one (26.5%) of 722 participants ever had IgE to D pteronyssinus extract (≥0.35 kUA /L). At age 20 years, their IgE recognized most frequently Der p 2, Der p 1, and Der p 23 (group A molecules; prevalence, >40%), followed by Der p 5, Der p 7, Der p 4, and Der p 21 (group B molecules; prevalence, 15% to 30%) and Der p 11, Der p 18, clone 16, Der p 14, and Der p 15 (group C molecules; prevalence, <10%). IgE sensitization started almost invariably with group A molecules and expanded sequentially first to group B and finally to group C molecules. Early IgE sensitization onset, parental hay fever, and higher exposure to mites were associated with a broader polymolecular IgE sensitization pattern. Participants reaching the broadest IgE sensitization stage (ie, ABC) had significantly higher risk of mite-related AR and asthma than unsensitized participants. IgE to Der p 1 or Der p 23 at age 5 years or less predicted asthma at school age. Conclusions Parental hay fever and early exposure to D pteronyssinus allergens promote IgE polysensitization to several D pteronyssinus molecules, which in turn predicts current mite-related AR and current/future asthma. These results might inspire predictive algorithms and prevention strategies against the progression of IgE sensitization to mites toward AR and asthma.
Background The efficacy and safety of the 300−index of reactivity (IR) dose of 5-grass-pollen sublingual immunotherapy (SLIT) tablets (Stallergènes, Antony, France) have been demonstrated for the ...treatment of hay fever in adults. Objective We sought to assess the efficacy and safety of this tablet in children and adolescents with grass pollen–related allergic rhinitis. Methods In this multinational, randomized, double-blind, placebo-controlled study, 278 children (5–17 years of age) with grass pollen–related rhinoconjunctivitis (confirmed by means of a positive grass pollen skin prick test response and serum-specific IgE measurement) received once-daily SLIT tablets or placebo. Treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was the rhinoconjunctivitis total symptom score (RTSS), a sum of 6 individual symptom scores: sneezing, runny nose, itchy nose, nasal congestion, watery eyes, and itchy eyes. Secondary end points included rescue medication intake, individual scores, and safety. Results The intent-to-treat population included 266 children (mean age, 10.9 ± 3.22 years). The RTSS for the 300-IR group was highly significantly different from that of the placebo group ( P = .001). The 300-IR group showed a mean improvement for the RTSS of 28.0% over that seen with placebo and a median improvement of 39.3%. Significant differences between the 300-IR and placebo groups were also observed regarding rescue medication score and proportion of days using rescue medication during the pollen season ( P = .0064 and P = .0146, respectively). Adverse events were generally mild or moderate in intensity and expected. No serious side effects were reported. Conclusion Five-grass-pollen SLIT tablets (300 IR) reduce both symptom scores and rescue medication use in children and adolescents with grass pollen–related rhinoconjunctivitis.
Background Most infants developing atopic dermatitis have a low risk for atopy. Primary prevention of atopic dermatitis is difficult. Objective To assess the effect of supplementation of an infant ...and follow-on formula with prebiotic and immunoactive oligosaccharides on the occurrence of atopic dermatitis in the first year of life. Methods Healthy term infants from 5 European countries with low atopy risk were recruited before the age of 8 weeks, either having started with formula feeding or being on full breast-feeding (breast-feeding group). Formula-fed infants were randomized to feeding with a regular formula containing a specific mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). Results A total of 414 infants were randomized to the prebiotic group and 416 infants to the control group. A total of 300 infants were followed in the breast-feeding group. Up to the first birthday, atopic dermatitis occurred in significantly fewer infants from the prebiotic group (5.7%) than from the control group (9.7%; P = .04). The cumulative incidence of atopic dermatitis in the prebiotic group was in the low range of the breast-feeding group (7.3%). In a Cox regression model, the rate of atopic dermatitis was significantly lower by 44% in the prebiotic group versus the control group ( P = .04). The number needed to prevent 1 case of atopic dermatitis by supplementation of prebiotics was 25 infants. Conclusion Formula supplementation with a specific mixture of oligosaccharides was effective as primary prevention of atopic dermatitis in low atopy risk infants.
Background The lack of longitudinal data analyses from birth to adulthood is hampering long-term asthma prevention strategies. Objective We aimed to determine early-life predictors of asthma ...incidence up to age 20 years in a birth cohort study by applying time-to-event analysis. Methods In 1990, the Multicenter Allergy Study included 1314 newborns in 5 German cities. Children were evaluated from birth to age 20 years at 19 time points. Using a Cox regression model, we examined the associations between 36 early-life factors and onset of asthma based on a doctor's diagnosis or asthma medication (primary outcome), typical asthma symptoms, or allergic asthma (including positive IgE measurements). Results Response at 20 years was 71.6%. Two hundred eighteen subjects met the primary outcome criteria within 16,257 person years observed. Asthma incidence was lower in participants who were vaccinated (measles, mumps, and rubella vaccine/tick-borne encephalitis vaccine/BCG vaccine: adjusted hazard ratio HR, 0.66 95% CI, 0.47-0.93). Up to age 20 years, asthma incidence was higher in subjects who had parents with allergic rhinitis (adjusted HR, 2.24 95% CI, 1.67-3.02), started day care early or late (before 18 months: adjusted HR, 1.79 95% CI, 1.03-3.10; after 3 years: adjusted HR, 1.64 95% CI, 0.96-2.79), had mothers who smoked during pregnancy (adjusted HR, 1.79 95% CI, 1.20-2.67), had poor parents (adjusted HR, 1.55 95% CI, 1.09-2.22), and had parents with asthma (adjusted HR, 1.65 95% CI, 1.17-2.31). Not associated with asthma were aspects of diet and breast-feeding, pet ownership, presence of older siblings, and passive smoking. Conclusion Parental asthma and nasal allergy increase asthma incidence in offspring up to adulthood. Avoiding tobacco smoke exposure during pregnancy, receiving vaccinations in early childhood, and starting day care between 1.5 and 3 years of age might prevent or delay the development of asthma.
Background IgE sensitization against grass pollen is a cause of seasonal allergic rhinitis. Objective We sought to investigate the evolution at the molecular level and the preclinical predictive ...value of IgE responses against grass pollen. Methods The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was administered yearly, and blood samples were collected at 1, 2, 3, 5, 6, 7, 10, and 13 years of age. Grass pollen–related seasonal allergic rhinitis (SARg) was diagnosed according to nasal symptoms in June/July. Serum IgE antibodies to Phleum pratense extract and 8 P pratense molecules were tested with immune-enzymatic singleplex and multiplex assays, respectively. Results One hundred seventy-seven of the 820 examined children had SARg. A weak monomolecular/oligomolecular IgE response to P pratense was observed very frequently before SARg onset. These initial IgE responses increased in concentration and molecular complexity during the preclinical and clinical process. A typical progression of IgE sensitization was observed: Phl p 1 (initiator in >75% of cases); then Phl p 4 and Phl p 5; then Phl p 2, Phl p 6, and Phl p 11; and then Phl p 12 and Phl p 7. At age 3 years, IgE sensitization predicted SARg by age 12 years (positive predictive value, 68% 95% CI, 50% to 82%; negative predictive value, 84% 95% CI, 80% to 87%). At this preclinical prediction time, the number of recognized molecules and the serum levels of IgE to P pratense were significantly lower than at 3 or more years after SARg onset. Conclusions The IgE response against grass pollen molecules can start years before disease onset as a weak monosensitization or oligosensitization phenomenon. It can increase in serum concentration and complexity through a “molecular spreading” process during preclinical and early clinical disease stages. Testing IgE sensitization at a preclinical stage facilitates prediction of seasonal allergic rhinitis at its molecular monosensitization or oligosensitization stage.
Background The only treatment option for peanut allergy is strict avoidance. Objective To investigate efficacy and safety of oral immunotherapy (OIT) in peanut allergy. Methods Twenty-three children ...(age, 3.2-14.3 years) with IgE-mediated peanut allergy confirmed by positive double-blind, placebo-controlled food challenge (DBPCFC) received OIT following a rush protocol with roasted peanut for 7 days. If a protective dose of at least 0.5 g peanut was not achieved, patients continued with a long-term buildup protocol using biweekly dose increases up to at least 0.5 g peanut. A maintenance phase for 8 weeks was followed by 2 weeks of peanut avoidance and a final DBPCFC. Immunologic parameters were determined. Results After OIT using the rush protocol, patients tolerated a median dose of only 0.15 g peanut. Twenty-two of 23 patients continued with the long-term protocol. After a median of 7 months, 14 patients reached the protective dose. At the final DBPCFC, patients tolerated a median of 1 g (range, 0.25-4 g) in comparison with 0.19 g peanut at the DBPCFC before OIT (range, 0.02-1 g). In 2.6% of 6137 total daily doses, mild to moderate side effects were observed; in 1.3%, symptoms of pulmonary obstruction were detected. OIT was discontinued in 4 of 22 patients because of adverse events. There was a significant increase in peanut-specific serum IgG4 and a decrease in peanut-specific IL-5, IL-4, and IL-2 production by PBMCs after OIT. Conclusion Long-term OIT appears to be safe and of some benefit in many patients with peanut allergy. With an increase in threshold levels and a reduction of peanut-specific TH 2 cytokine production, the induction of tolerance may be feasible in some patients.
Background Threshold levels for peanut allergy determined by using oral challenges are important for the food industry with regard to allergen labeling. Moreover, the utility of biological markers in ...predicting threshold levels is uncertain. Objective We sought to use a modified oral food challenge regimen that might determine threshold levels for peanut allergy mimicking a more real-life exposure and to correlate the eliciting dose (ED) and severity of clinical reaction in children with peanut allergy with B-cell, T-cell, and effector cell markers. Methods A modified food challenge procedure with doses scheduled 2 hours apart was used in 63 children with peanut allergy. All children received a maximum of 8 semi-log increasing titration steps of roasted peanuts ranging from 3 to 4500 mg of peanut protein until objective allergic reactions occurred. Severity of symptoms was graded from I to V. Biological markers were measured before challenge. Results Forty-five of 63 patients showed objective symptoms after greater than 30 minutes, with a median latency of clinical reaction of 55 minutes. By using a log-normal dose-distribution model, the ED5 was calculated to be 1.95 mg of peanut protein. The ED was significantly and inversely correlated with peanut- and Ara h 2–specific IgE levels, skin prick test responses, basophil activation, and TH 2 cytokine production by PBMCs. Symptom severity did not correlate with any of the markers or the ED. Conclusion This modified food challenge procedure might better reflect threshold levels for peanut allergy than the standard procedure because most of the patients reacted at a time interval of greater than 30 minutes. By using this model, threshold levels, but not severity, could be correlated with biological markers.
Background Rhinitis in older children and adults has been shown to be a predictor for adolescent- and adult-onset asthma. These findings suggest an interaction between the upper and lower airways. ...Whether rhinitis is a predictor for childhood-onset asthma is unknown. Objective We sought to investigate whether rhinitis in early childhood is an independent predictor for wheezing between the ages of 5 and 13 years in the German Multicentre Allergy Study birth cohort. Methods The German Multicentre Allergy Study cohort initially included 1314 healthy children. They were followed from birth to the age of 13 years with regular questionnaires and interviews. Specific IgE levels were measured at yearly intervals. Airway hyperresponsiveness was assessed at 7 years. Results Allergic rhinitis until the age of 5 years was found to be a predictor for developing wheezing between the ages of 5 and 13 years, with an adjusted relative risk of 3.82 ( P < .001). This association was not attributable to the type of sensitization, the severity of sensitization, or atopic dermatitis during the first 2 years of life. In this group of children, 41.5% of all new cases of wheezing occurred among children with preceding allergic rhinitis. Conclusions The first manifestation of allergic rhinitis occurs in preschool children in whom it is a predictor for subsequent wheezing onset. Preschool children with rhinitis might thus benefit from early assessment of allergic sensitization to identify the children at high risk of wheezing.
Background Studies of a limited number of allergens suggested that nonsensitized children produce IgG responses mainly to foodborne allergens, whereas IgE-sensitized children also produce strong IgG ...responses to the respective airborne molecules. Objective We sought to systematically test the hypothesis that both the route of exposure and IgE sensitization affect IgG responses to a broad array of allergenic molecules in early childhood. Methods We examined sera of 148 children participating in the Multicentre Allergy Study, a birth cohort born in 1990. IgG to 91 molecules of 42 sources were tested with the ImmunoCAP Solid-Phase Allergen Chip (ISAC; TFS, Uppsala, Sweden). IgE sensitization at age 2 and 7 years was defined by IgE levels of 0.35 kUA /L or greater to 1 or more of 8 or 9 extracts from common allergenic sources, respectively. Results The prevalence and geometric mean levels of IgG to allergenic molecules in nonsensitized children were lower at age 2 years than in IgE-sensitized children, and they were extremely heterogeneous: highest for animal food (87% ± 13%; 61 ISAC Standardized Units ISU, 95% CI, 52.5-71.5 ISU), intermediate for vegetable food (48% ± 27%; 13 ISU 95% CI, 11.2-16.1 ISU), and lowest for airborne allergens (24% ± 20%; 3 ISU 95% CI, 2.4-3.4 ISU; P for trend < .001 for percentages, P for trend < .001 for levels). IgG4 antibodies were infrequent (<5%) and contributed poorly (<3%) to overall IgG antibody levels. IgG responses at age 2 years were slightly more frequent and stronger among children with than in those without IgE sensitization at age 7 years. Conclusion The children's repertoire of IgG antibodies at 2 years of age to a broad array of animal foodborne, vegetable foodborne, and airborne allergenic molecules is profoundly dependent on the route of allergen exposure and the child's IgE sensitization status and only marginally involves the IgG4 isotype.
Background Allergen-specific subcutaneous immunotherapy (SCIT) of seasonal allergic rhinitis (SAR) is usually considered a “second-line,” slow-acting, disease-modifying treatment. Objective We sought ...to test whether SCIT is as effective as antisymptomatic treatment in the control of symptoms in patients with SAR in the first year of treatment. Methods We reviewed meta-analyses with 5 or more randomized, double-blind, placebo-controlled trials of SCIT or antisymptomatic treatment in patients with SAR. We then selected trials measuring the total nasal symptom score (TNSS), the total symptom score (TSS), or both during the first pollen season after treatment initiation. Efficacy was determined as the percentage reduction in TSSs and TNSSs obtained with active treatment compared with placebo (relative clinical impact RCI) and the standardized mean difference (SMD) of treatment verses placebo (effect size ES). Results The weighted mean RCI of SCIT on TNSSs (−34.7% ± 6.8%) was higher than those of mometasone (−31.7% ± 16.7%, P < .00001) and montelukast (−6.3% ± 3.0%, P < .00001). The weighted mean RCI of SCIT on TSSs (−32.9% ± 12.7%) was higher than that of desloratadine (−12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs (SMD, −0.94; 95% CI, −1.45 to −0.43) was similar to that of mometasone (SMD, −0.47; 95% CI, −0.63 to −0.32; P > .05) and higher than that of montelukast (SMD, −0.24; 95% CI, −0.33 to −0.16; P < .05). The overall ES of SCIT in terms of TSSs (SMD, −0.86; 95% CI, −1.17 to −0.55) was comparable with that of desloratadine (SMD, −1.00; 95% CI, −1.68 to −0.32; P > .05). Conclusions Our data provide indirect but consistent evidence that SCIT is at least as potent as pharmacotherapy in controlling the symptoms of SAR as early as the first season of treatment.
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