Christoph Grüber

Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study

BACKGROUND Reduced lung function is a feature of chronic asthma, which becomes apparent at school age. Unknown factors between birth and school age determine the progressive loss of pulmonary function in children with persistent asthma. We investigated the role of allergic sensitisation and allergen exposure early in life. METHODS The German Multicentre Allergy Study followed 1314 children from birth to 13 years of age. We regularly interviewed parents about their childs asthma and measured IgE levels. Allergen exposure was assessed at age 6 months, 18 months, and at 3, 4, and 5 years; lung function was assessed at 7, 10, and 13 years; post-bronchodilator response at 10 and 13 years; and a bronchial histamine challenge was done at 7 years. RESULTS 90% of children with wheeze but no atopy lost their symptoms at school age and retained normal lung function at puberty. By contrast, sensitisation to perennial allergens (eg, house dust mite, cat and dog hair) developing in the first 3 years of life was associated with a loss of lung function at school age. Concomitant exposure to high levels of perennial allergens early in life aggravated this process: forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was 87.4 (SD 7.4) for those sensitised and with high exposure compared with 92.6 (6.0) for those not sensitised, p<0.0001; and maximal expiratory flow at 50% (MEF50) 86.4 (25.1) for sensitised and with high exposure compared with 101.5 (23.2; p=0.0031) for those not sensitised. Such exposure also enhanced the development of airway hyper-responsiveness in sensitised children with wheeze. Sensitisation and exposure later in life had much weaker effects and sensitisation to seasonal allergens did not play a part. INTERPRETATION The chronic course of asthma characterised by airway hyper-responsiveness and impairment of lung function at school age is determined by continuing allergic airway inflammation beginning in the first 3 years of life. However, children with a non-atopic wheezing phenotype lose their symptoms over school age and retain normal lung function at puberty.

BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model

BACKGROUND Epidemiologic studies suggest an inverse correlation between infections and development of atopy. The purpose of this study was to test the hypothesis whether a preexisting Th1-type immune response elicited by BCG immunization could suppress allergic sensitization and airway hyperreactivity in an animal model. METHODS BALB/c mice were immunized with BCG and/or sensitized to ovalbumin. RESULTS BCG immunization alone resulted in cutaneous type-IV hypersensitivity reactions to tuberculin and granulomatous lesions in the liver. Splenic mononuclear cells (MNCs) produced increased levels of IFN-gamma after activation by Concanavalin A (ConA). Ovalbumin sensitization alone resulted in increased production of IL-4 after activation by ConA. Ovalbumin-sensitized animals also demonstrated markedly elevated anti-ovalbumin IgE/IgG1 serum antibody titers and increased airway reactivity after allergen challenges by means of the airways. BCG immunization 14 days before the start of ovalbumin sensitization markedly hindered the development of allergic responses as indicated by (1) increased IFN-gamma and normalized IL-4 and IL-10 production by splenic MNCs after activation with ConA, (2) a reduced proliferation rate of splenic MNCs after ovalbumin restimulation, (3) partial prevention of ovalbumin-specific IgE/IgG1 serum antibody titers but elevated (nonallergic) anti-ovalbumin IgG2a serum antibody titers, (4) prevention of airway responsiveness, (5) reduced eosinophilic influx into the airway lumen, and (6) reduced levels of IL-4 and IL-5 in broncho alveolar lavage fluids. CONCLUSION In this model BCG immunization established a Th1-type immune response that hinders allergic sensitization and the development of increased airway reactivity.

Side-effects of complementary and alternative medicine.

Complementary and alternative medicine are increasingly used to diagnose or treat allergic diseases, and numerous studies have reported benefits of this type of medicine. This article presents a review of the literature on risks of these methods. The potential sensitizing capacity of numerous herbal remedies may lead to allergic contact dermatitis and more rarely to IgE‐mediated clinical symptoms. Mechanical injuries may be observed following acupuncture leading to pneumothorax, cardiac tamponade or spinal injury. Infectious complications after acupuncture include hepatitis and bacterial endocariditis. Organ toxicity has been observed associated with various herbal preparations involving the liver, kidneys, and the heart. Some herbs may have cancerogenic properties. Severe nutritional deficiencies can occur in infants and small children given strict alternative diets, resembling ‘kwashiorkor’. Finally, among other miscellaneous adverse effects, adulteration with steroids, and herbal and drug interactions are discussed. The pattern of side‐effects is similar to that observed by the use of conventional medicine. Therefore, caution may be justified using both conventional and unconventional methods. Only if the benefit is proven and the side‐effects are established, should a given method be chosen.

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.

Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder and a major manifestation of allergic disease. AD typically presents in early childhood often preceding the onset of an allergic airway disease, such as asthma or hay fever. We previously mapped a susceptibility locus for AD on Chromosome 3q21. To identify the underlying disease gene, we used a dense map of microsatellite markers and single nucleotide polymorphisms, and we detected association with AD. In concordance with the linkage results, we found a maternal transmission pattern. Furthermore, we demonstrated that the same families contribute to linkage and association. We replicated the association and the maternal effect in a large independent family cohort. A common haplotype showed strong association with AD (p = 0.000059). The associated region contained a single gene, COL29A1, which encodes a novel epidermal collagen. COL29A1 shows a specific gene expression pattern with the highest transcript levels in skin, lung, and the gastrointestinal tract, which are the major sites of allergic disease manifestation. Lack of COL29A1 expression in the outer epidermis of AD patients points to a role of collagen XXIX in epidermal integrity and function, the breakdown of which is a clinical hallmark of AD.

Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood--report of the German Multicentre Allergy Study (MAS 90).

Background:  Controversial data have emerged regarding the question whether cat exposure in childhood favours or decreases the risk of sensitization and allergic airway disease. In a prospective birth‐cohort study, we assessed the association between longitudinal cat allergen exposure, sensitization (immunoglobulin E, IgE), IgG antibody (ab) levels to cat and the development of asthma in children up to the age of 10 years.

Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence

Childhood asthma is frequently perceived as a disease with uniform clinical pathways. This perception might be an oversimplification. The aim of the present study was to investigate the incidence and natural course of wheeze over the first 13 yrs of life and analyse the risk factors predicting wheeze at 11–13 yrs of age. The Multicentre Allergy Study, a German birth cohort, recruited 1,314 children in 1990. Physical examinations, interviews on atopic diseases, immunoglobulin (Ig)E and lung function tests were performed up to 13 yrs of age. Complete data on the course of wheeze were available for 441 children. It was found that incidence of wheezing declined with age. The first wheezing episode was reported by 29, 9 and 9% of participants at ≤3 (early wheezers), 3–6 (late wheezers), and >6 yrs (very late wheezers) of age, respectively. Wheezing at the age of 13 yrs was associated with parental atopy, and with IgE sensitisation to common allergens, elevated total IgE and exposure to high levels of indoor allergens in early life. All these associations were remarkably stronger among early wheezers than among early nonwheezers. In conclusion, the relevance of an early expression of atopy as a predictor of wheezing at age 13 yrs declines with increasing age of wheezing onset.

Is early BCG vaccination associated with less atopic disease? An epidemiological study in German preschool children with different ethnic backgrounds

We investigated the association of bacille Calmette‐Guérin (BCG) vaccination and atopic manifestations among children. Because many children in the study area were from minority ethnic groups, the effect of ethnicity on disease prevalence was also analyzed. A mandatory health survey included all preschool children from Berlin in 1994. Trained medical personnel asked parents whether their child had ever had a diagnosis of atopic dermatitis (AD), bronchial asthma (BA), and hay fever (HF) or symptoms suggestive of these conditions. BCG‐vaccination status was recorded from official vaccination documents. Ethnicity of the child was defined by maternal citizenship. We included 38 808 children in our study (20 813 children from former west Berlin), on average aged 6 years. The proportion of children with a foreign family background was 2.1% in East Berlin and 27.5% in West Berlin. BCG vaccination was more common in East Berlin than in West Berlin (94.2% vs. 16.5%) and in West Berlin more common among children with a foreign family background compared with Germans (25.3% vs. 13.2%). The adjusted odds ratio (95% CI) for BA was 0.85 (0.71–1.00) for BCG‐vaccinated individuals. BCG vaccination was not significantly associated with AD or HF. Among non‐German children, the odds ratios were 0.35 (0.30–0.42) for AD, 0.58 (0.48–0.70) for BA, and 0.72 (0.54–0.92) for HF. The OR for AD among children living in eastern Berlin was 1.19 (1.04–1.36), no significant regional differences were found for BA or HF. This study demonstrated a weak protective effect of BCG vaccination against asthma but a much stronger protective effect of non‐German ethnicity against atopic manifestations among preschool children from Germany.

Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: longitudinal analysis from birth to 10 years.

Background:  The role of passive smoking for allergies and asthma in children above the age of 3 years remains unclear and possible interactive effects with parental allergies have not been formally evaluated in long‐term studies. To examine the interaction of passive smoking and an allergic predisposition regarding allergic sensitization, allergic airway symptoms and respiratory infections during the first 10 years of life.

The asthma-obesity link in childhood: open questions, complex evidence, a few answers only.

Obesity and asthma are public health priorities in developed countries. Genes which may contribute to the control of both conditions include those encoding for the β2‐adrenergic receptor, tumour necrosis factor‐α (TNF‐α) and the insulin‐like growth factor 1 (IGF‐1). Prospective studies consistently supported a link between obesity and reported wheezing or asthma diagnosis in children. However, there are still no clear explanations for such a link. On one hand, overweight asthmatic children may perceive their asthma as worse. On the other hand, atopic sensitization and bronchial hyper‐reactivity do not explain the observed associations. After puberty, the association between asthma and obesity tends to be stronger in girls than in boys. It is conceivable that severe obesity in adolescent females may aggravate asthma through mechanisms different from those linking prepubertal obesity to unremitting asthma in males. Future studies should therefore address multiple age‐ and gender‐specific hypotheses about the mechanisms that link obesity to asthma throughout childhood.