Der p 23-specific IgE response throughout childhood and its association with allergic disease: A birth cohort study.

BACKGROUND: The Dermatophagoides pteronyssinus molecule Der p 23 is a major allergen whose clinical relevance has been shown in cross-sectional studies. We longitudinally analysed the trajectory of Der p 23-specific IgE antibody (sIgE) levels throughout childhood and youth, their early-life determinants and their clinical relevance for allergic rhinitis and asthma. METHODS: We obtained sera and clinical data of 191 participants of the German Multicentre Allergy Study, a prospective birth cohort. Serum samples from birth to 20 years of age with sIgE reactivity to Der p 23 in a customised semiquantitative microarray were newly analysed with a singleplex quantitative assay. Early mite exposure was assessed by measuring the average content of Der p 1 in house dust at 6 and 18 months. RESULTS: Der p 23-sIgE levels were detected at least once in 97/191 participants (51%). Prevalence of Der p 23 sensitisation and mean sIgE levels increased until age 10 years, plateaued until age 13 years and were lowest at age 20 years. Asthma, allergic rhinitis (AR) and atopic dermatitis (AD) were more prevalent in Der p 23-sensitised children, including those with monomolecular but persistent sensitisation (11/97, 11%). A higher exposure to mites in infancy and occurrence of AD before 5 years of age preceded the onset of Der p 23 sensitisation, which in turn preceded a higher incidence of asthma. CONCLUSIONS: Der p 23 sensitisation peaks in late childhood and then decreases. It is preceded by early mite exposure and AD. Asthma and AR can occur in patients persistently sensitised to Der p 23 as the only mite allergen, suggesting the inclusion of molecular testing of Der p 23-sIgE for subjects with clinical suspicion of HDM allergy but without sIgE to other major D.pt. allergens.

Growth curves of "normal" serum total IgE levels throughout childhood: A quantile analysis in a birth cohort.

BACKGROUND: Previous studies of serum total IgE (t-IgE) were not able to discriminate well-enough atopic from non-atopic subjects, that is, with or without serum-specific IgE antibodies to allergens. OBJECTIVES: To model growth curves of the total IgE levels in children without atopic sensitization (hereafter defined as "normal" t-IgE levels) and to test their usefulness in predicting atopic sensitization. METHODS: The German Multicentre Allergy Study (MAS), a birth cohort with 1314 recruited newborns, began in 1990 and examined the participants until age 20 years. Total and specific IgE (t-IgE, s-IgE) were analyzed with a fluorescent enzyme immunoassay ImmunoCAP (TFS, Sweden) at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Participants were classified as "never atopic" if all their available serum samples had negative response (cutoff: <0.35 kUA /L) for s-IgE to the nine common foodborne and airborne allergenic extracts (milk, egg, soy, wheat, house dust mite, cat, dog, birch, and grass) tested in the MAS birth cohort. By contrast, participants were defined as atopic if they had, for at least at one available serum sample, s-IgE≥0.35 kUA /L to at least one allergenic extract tested. The evolution of t-IgE levels in the "never atopic" children was described by growth curves, estimated by exploiting a quantile regression model. A "reference" percentile, based on the t-IgE value measured at age 5 years, was assigned to each child with no IgE sensitization at that age. Upward deviations from the own "reference" quantile of t-IgE in atopic and "never atopic" children were calculated and a ROC analysis was used to identify the best cutoff point for predicting atopic sensitization. RESULTS: Overall, 1113 of 1314 children were included in this analysis. Of these, 469 were "never atopic" and 644 atopic. Quantile trajectories of t-IgE levels in "never atopic" subjects were stable from 5 years of age, increased to a plateau at age 10-13 years, and decreased slightly afterward. The onset of atopic s-IgE responses was characterized by an upward deviation of serum t-IgE levels from their "reference" trajectory. T-IgE quantiles predicted the onset of atopy with high efficiency (AUC>80%). ROC analysis showed that deviations from the t-IgE level "reference" quantile above 0.32, 0.41, 0.42, 0.30, and 0.58 kU/L (log-units) at 6, 7, 10, 13, and 20 years of age, respectively, predicted an atopic sensitization. CONCLUSION: The growth curves of "normal" serum t-IgE concentrations were estimated in "never atopic" children; for each individual who was non-atopic at 5 years of age a "reference" quantile was identified that represented the individual's "normal" level of t-IgE production. Upward deviations of observed t-IgE levels from the own "reference" quantile, from 6 to 20 years of age, predicted at each year the occurrence of atopic sensitization. CLINICAL IMPLICATIONS: The trajectory of t-IgE levels can be elaborated since age 5 years in non-atopic children. A child whose t-IgE levels are consistently higher than those predicted by his/her growth curve may have developed atopic sensitization.

Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life.

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.

"Default" versus "pre-atopic" IgG responses to foodborne and airborne pathogenesis-related group 10 protein molecules in birch-sensitized and nonatopic children.

BACKGROUND: The route and dose of exposure are believed to be relevant factors in the sensitization process. Pathogenesis-related group 10 protein (PR-10) molecules are a family of allergenic proteins shared by many pollens (eg, birch and alder) and foods (eg, apple, peach, and soy). Children are exposed to both pollen-derived (inhaled) and food-derived (ingested) PR-10 molecules. OBJECTIVE: We sought to investigate the role of route and dose of exposure in the evolution of IgG and IgE responses to recombinant PR-10 molecules. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. Blood samples were collected at the ages of 1, 2, 3, 5, 6, 7, 10, and 13 years. Participants were included in the present analysis if they had (1) at least 1 serum sample at each of the 4 age periods or time points (1-3 years, 5-7 years, 10 years, and 13 years) and (2) IgE responses to birch (children with birch atopy) or no IgE response at all to 9 common aeroallergens and food allergens (nonatopic children). Therefore serum IgE antibodies to a panel of 4 airborne and 5 foodborne extracts, as well as to Bet v 1, were measured in singleplex assays, whereas IgG and IgE antibodies to a panel of 3 airborne PR-10 molecules (rBet v 1, rAln g 1, and rCor a 1.0101) and 7 foodborne PR-10 molecules (rCor a 1.0401, rMal d 1, rPru p 1, rGly m 4, rAra h 8, rApi g 1, and rDau c 1) were tested by using a multiplex microarray. RESULTS: In the present analyses we included 28 children with birch atopy and randomly selected 28 nonatopic children from the 190 children fulfilling the inclusion criteria. Two different patterns of IgG responses to PR-10 molecules were identified. Among nonatopic subjects, a "default" IgG response was directed mostly against foodborne PR-10, started often before age 2 years, stayed weak, and was mostly transient. Among all atopic subjects, the default IgG response at age 1 year was overwhelmed after age 2 years by an "pre-atopic" IgG response, which started with or shortly before the IgE response and was intense and persistent. This atopic IgG response, as well as the IgE response, involved progressively more foodborne PR-10 proteins with frequencies and levels related to their homology with Bet v 1. CONCLUSIONS: The results suggest that children have a default antibody response to PR-10 molecules, which is early, weak, and transient; does not involve IgE; and is initiated by foodborne PR-10. By contrast, an atopic antibody response to PR-10 molecules is delayed, strong, and persistent; involves both IgG and IgE; and is initiated by airborne PR-10.

Parental hay fever reinforces IgE to pollen as pre-clinical biomarker of hay fever in childhood.

BACKGROUND: An early IgE response to grass or birch pollen can anticipate seasonal allergic rhinitis to pollen later in life or remain clinically silent. OBJECTIVE: To identify risk factors early in life that allow discriminating pathogenic from non-pathogenic IgE responses and contribute to the development of seasonal allergic rhinitis to grass pollen. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was yearly administered and blood samples collected at age 1,2,3,5,6,7,10,13 yr. The definition of the primary outcome grass- and birch-pollen-related seasonal allergic rhinitis (SARg, SARb) was based on nasal symptoms in June/July and April, respectively. Serum IgE antibodies to Phleum pratense and Betula verrucosae extracts were monitored with immune-enzymatic singleplex assays. RESULTS: Of the 820 examined children, 177 and 148 developed SARg and SARb, respectively. Among healthy children aged 3 or more years, IgE to grass pollen was the strongest risk factor of SARg (OR 10.39, 95%CI 6.1-17.6, p < 0.001), while parental hay fever was the only risk factor in early childhood independently associated with future SARg (1 parent: OR 2.56, 95%CI 1.4-4.5, p < 0.001; 2 parents: OR 4.17, 95%CI 1.7-10.1) and SARb (1 parent OR: 5.21, 95%CI 2.20-12.4, p < 0.001; 2 parents: OR 8.02, 95%CI 2.0-32.9, p < 0.001). Parental hay fever was associated with an increase of the concentration of pollen-specific IgE in seropositive subjects, after the age of 6 and was also a hallmark of molecularly more complex specific IgE responses to grass or birch pollen at age 6 or older. CONCLUSIONS: Parental hay fever and specific IgE to grass and/or birch pollen are strong pre-clinical determinants and potentially good predictors of seasonal allergic rhinitis.

Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever.

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.