Susanne Lau

Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study

BACKGROUND In a prospective birth-cohort study, we assessed the relevance of mite and cat allergen exposure for the development of childhood asthma up to age 7 years. METHODS Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children. Assessments included repeated measurement of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months, and 3 years of age, and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial hyper-responsiveness was measured in 645 children. FINDINGS At age 7, the prevalence of wheezing in the past 12 months was 10.0% (94 of 938), and 6.1% (57 of 939) parents reported a doctors diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze, and increased bronchial responsiveness. However, no relation between early indoor allergen exposure and the prevalence of asthma, wheeze, and bronchial hyper-responsiveness was seen. INTERPRETATION Our data do not support the hypothesis that exposure to environmental allergens causes asthma in childhood, but rather that the induction of specific IgE responses and the development of childhood asthma are determined by independent factors.

Indoor allergen exposure is a risk factor for sensitization during the first three years of life

BACKGROUND The purpose of the study was to investigate the influence of environmental allergen exposure on allergic sensitization in infancy and early childhood. METHODS A cohort of 1314 newborns was recruited and followed up prospectively at the ages 12, 24, and 36 months. The levels of major mite (Der p 1 and Der f 1) and cat (Fel d 1) allergens were determined from domestic carpet dust samples by sandwich ELISA. Specific serum IgE antibodies to mite and cat allergens were determined by CAP fluoroimmunoassay (Pharmacia). Logistic regression was used to assess the effects of allergen exposure, age, family history, and cord blood IgE simultaneously on the risk of sensitization. RESULTS Children, who had been found to be sensitized at least once during the first 3 years of life, were found to be exposed to significantly higher house dust mite (median, 868 ng/gm vs 210 ng/mg; p = 0.001) and cat (median, 150 ng/gm vs 64 ng/gm; p = 0.011) allergen concentrations in domestic carpet dust compared with the group without sensitization. In homes with low (< or = 25th percentile) dust concentrations, the risk of sensitization to mite (1.6%), and cat (2.0%) is low, compared with 6.5% for mite and 6.3% for cat if the domestic exposure is above the 75th percentile. The dose-response relationships between allergen levels and sensitization indicate that the increase in sensitization risk at low allergen levels is more pronounced in cat allergy (p = 0.002) than in mite allergy (p = 0.026). In the group with a positive family history, lower mite and cat allergen concentrations are needed to achieve specific sensitization compared with the group with a negative family history. CONCLUSION Our data indicate that avoidance measures in the domestic environment aimed at the primary prevention of allergen-driven sensitization should be introduced at the earliest possible stage, if possible during infancy.

Effect of pre‐ and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life

Background: The study aimed to assess the effect of pre‐ and postnatal tobacco smoke exposure on specific sensitization to food allergens and inhalant allergens during the first 3 years of life.

The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS)

Epidemiological surveys have indicated that there has been a notable increase in the prevalence of both asthma and other allergic symptoms in children and young adults. Since it seems unlikely that genetic factors would contribute to the rising trend, environmental factors might play a major part in the development of childhood asthma. In a prospective birth-cohort study, we assessed the relevance of different exposures such as mite and cat allergen exposure, environmental tobacco smoke (ETS) exposure, early infectious diseases and vaccinations for the development of childhood asthma up to the age of 10 years. Data up to 7 years of age have been evaluated. Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children (72%). Assessments included repeated measurements of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months and 3 years of age and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial responsiveness was determined in 645 children. At age 7, the prevalence of wheezing in the past 12 months was 10% (94 out of 938), and 6.1% (57 out of 939) parents reported a doctors diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness. However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. During the first 3 years of life, intra-uterine tobacco and consistent ETS exposure have an adjuvant effect on allergic sensitisation that is transient and restricted to children with a genetic predisposition for allergy. Children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88). Children with repeated episodes (> or =2) of runny nose before the age of 1 year were less likely to develop asthma by the age of 7 years (OR = 0.52; 95% CI = 0.29-0.92). Our data do not support the hypothesis that exposure to environmental allergens directly causes asthma in childhood but that induction of specific IgE responses and the development of childhood asthma are determined by independent factors. Indoor allergen avoidance is recommended as first line treatment in secondary and tertiary prevention; however, conclusions should be drawn with caution about the possible effect of primary preventative measures. Since allergic asthma seems to be a Th2-disease, immunomodulating factors such as early childhood infections, LPS-exposure or other factors influencing gene-environment interaction and individual susceptibility seem to be relevant for the development of childhood asthma.

Evaluation of the CD14 C-159 T polymorphism in the German Multicenter Allergy Study cohort

Background Multiple genetic studies have shown linkage of atopy‐related phenotypes to chromosome 5q31. In this region several candidate genes for atopy are localized such as the Th2 cytokines IL‐4, IL‐5 and IL‐13, but also CD14, a receptor for LPS. Recently, a functional CD14 promoter polymorphism was related to total and specific IgE responsiveness.

Interactions between genes and environmental factors in asthma and atopy: new developments

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.

Socioeconomic status is a risk factor for allergy in parents but not in their children.

Allergic diseases are more prevalent in affluent countries, which has been attributed to life‐style factors. Life‐style habits may also differ between socioeconomic (SES) classes. The objective of this paper therefore was to evaluate if SES had an impact on the development of atopic disorders.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7‐CP‐IP; Project No: 261357; 2010–2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large‐scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy‐related diseases. To complement the population‐based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Down-Regulation of IgE and IgG4 Antibodies to Tetanus Toxoid and Diphtheria Toxoid by Covaccination with Cellular Bordetella pertussis Vaccine

Pertussis (P) toxin acts as adjuvant for IgE formation against simultaneously administered Ags in animal models. P vaccination may also have an adjuvant impact on IgE formation against coadministered diphtheria (D) and tetanus (T) Ags in humans. Sera of 103 D-T-P-immunized and 319 D-T-immunized children aged 2 years were analyzed for IgE, IgG4, and IgG to D and T (radioallergosorbent test), total IgE and IgE against common inhalant allergens (CAP radioallergosorbent test fluoroenzyme immunoassay). Fewer D-T-P- than D-T-immunized children had sera positive for T-IgE (12.6 vs 53.6%, p < 0.001), T-IgG4 (71.6 vs 89.2%, p < 0.001), D-IgE (31.0 vs 70.5%, p < 0.001), and D-IgG4 (85.2 vs 93.4%, p = 0.039). Suppression of T-IgE was not dependent on the cutoff chosen for a positive test result, but was dependent on the proportion of D-T immunizations given with P. The risk for sensitization to common environmental allergens did not differ (odds ratio 0.953, 95% confidence interval 0.815–1.114). No significant differences between D-T- and D-T-P-immunized children were found with regard to T-IgG or D-IgG. In summary, IgE and IgG4 (but not IgG) serum levels to coadministered D- and T-Ags are suppressed among P-immunized children as compared with nonimmunized children. These results suggest that the presence of a microbial product during Ag exposure can down-regulate an IgE/IgG4 response in humans.

No association of histamine‐ N‐methyltransferase polymorphism with asthma or bronchial hyperresponsiveness in two German pediatric populations

Histamine plays an important role in the allergic inflammation. Histamin N‐Methyltransferase (HNMT) catalyses the major pathway of histamine metabolism in the human lung. A common functional single nucleotide polymorphism (SNP) within the HNMT gene (C314T) was recently related to asthma. We tested this SNP for associations with asthma and asthma associated traits in two German pediatric populations (1. MAS‐cohort, n = 888, 85 children with asthma; 2. asthmatic children from Freiburg, n = 176). Non‐asthmatic (n = 515) and non‐atopic (n = 211) children from the MAS‐cohort were used as controls. For genotyping melting curve analyses (Light Cycler System) were applied. In contrast to a previous study, no association of the HNMT 314T allele with asthma, bronchial hyperresponsiveness (BHR) or other asthma related phenotypes could be observed in either study population. We conclude that this SNP might not play a major role in the pathogenesis of asthma or BHR in German children.