Richard Sporik

Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study.

BACKGROUND AND METHODS Children with asthma commonly have positive skin tests for inhaled allergens, and in the United Kingdom the majority of older children with asthma are sensitized to the house-dust mite. In a cohort of British children at risk for allergic disease because of family history, we investigated prospectively from 1978 to 1989 the relation between exposure to the house-dust mite allergen (Der p I) and the development of sensitization and asthma. RESULTS Of the 67 children studied in 1989, 35 were atopic (positive skin tests), and 32 were nonatopic. Of the 17 with active asthma, 16 were atopic (P less than 0.005), all of whom were sensitized to the house-dust mite, as judged by positive skin tests and levels of specific IgE antibodies (P less than 0.001). For house-dust samples collected from the homes of 59 of the children in 1979 and from 65 homes in 1989, the geometric means for the highest Der p I exposure were, respectively, 16.1 and 16.8 micrograms per gram of sieved dust. There was a trend toward an increasing degree of sensitization at the age of 11 with greater exposure at the age of 1 (P = 0.062). All but one of the children with asthma at the age of 11 had been exposed at 1 year of age to more than 10 micrograms of Der p I per gram of dust; for this exposure, the relative risk of asthma was 4.8 (P = 0.05). The age at which the first episode of wheezing occurred was inversely related to the level of exposure at the age of 1 for all children (P = 0.015), but especially for the atopic children (r = -0.66, P = 0.001). CONCLUSIONS In addition to genetic factors, exposure in early childhood to house-dust mite allergens is an important determinant of the subsequent development of asthma.

Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study

BACKGROUND Although asthma is strongly associated with immediate hypersensitivity to indoor allergens, several studies have suggested that a cat in the house can decrease the risk of asthma. We investigated the immune response to cat and mite allergens, and asthma among children with a wide range of allergen exposure. METHODS We did a population-based cross-sectional study of children (aged 12-14 years), some of whom had symptoms of asthma and bronchial hyper-reactivity. Antibodies to mite (Der f 1) and cat (Fel d 1) allergens measured by isotype (IgG and IgG4) specific radioimmunoprecipitation assays were compared with sensitisation and allergen concentrations in house dust. FINDINGS 226 children were recruited, 47 of whom had symptoms of asthma and bronchial hyper-reactivity. Increasing exposure to mite was associated with increased prevalence of sensitisation and IgG antibody to Der f 1. By contrast, the highest exposure to cat was associated with decreased sensitisation, but a higher prevalence of IgG antibody to Fel d 1. Thus, among children with high exposure, the odds of sensitisation to mite rather than cat was 4.0 (99% CI 1.49-10.00). Furthermore, 31 of 76 children with 23 microg Fel d 1 at home, who were not sensitised to cat allergen had >125 units of IgG antibody to Fel d 1. Antibodies to Fel d 1 of the IgG4 isotype were strongly correlated with IgG antibody in both allergic and non-allergic children (r=0.84 and r=0.66, respectively). Sensitisation to mite or cat allergens was the strongest independent risk factor for asthma (p<0.001). INTERPRETATION Exposure to cat allergen can produce an IgG and IgG4 antibody response without sensitisation or risk of asthma. This modified T-helper-2 cell response should be regarded as a form of tolerance and may be the correct objective of immunotherapy. The results may also explain the observation that animals in the house can decrease the risk of asthma.

Quantitative assessment of exposure to dog (Can f 1) and cat (Fel d 1) allergens: Relation to sensitization and asthma among children living in Los Alamos, New Mexico

BACKGROUND Our objective was to identify the allergens associated with asthma among schoolchildren in an area of the United States where dust mite growth is expected to be poor. Los Alamos, N.M., was chosen because it has low rainfall and is at high altitude (7200 feet) making it very dry. One hundred eleven children (12 to 14 years old) from the middle school who had been previously classified according to bronchial hyperreactivity to histamine (BHR) were studied. METHODS Sera were assayed for IgE antibodies to mite, cat, dog, cockroach, Russian thistle, and grass pollen, with both CAP system fluoroimmunoassay (Kabi Pharmacia, Uppsala, Sweden) and conventional RAST. Allergens were measured in dust samples from 108 homes with two-site assays for mite (Der p 1 and Der f 1), cat (Fel d 1), dog (Can f 1), and cockroach (Bla g 2). RESULTS Concentrations of dog and cat allergens were elevated in almost all houses with pets but were also high in a significant proportion of the houses without pets. Levels of mite allergen were less than 2 micrograms/gm in 95% of the houses, and cockroach was undetectable in all but two of the houses. Among the 21 with BHR who had symptoms, 67% had IgE antibody to dog and 62% had IgE antibody to cat. For these allergens IgE antibody was strongly associated with asthma (p < 0.001). By contrast, the presence of IgE antibody to mite, cockroach, or grass pollen was not significantly associated with asthma. CONCLUSION The high prevalence of IgE antibody to cat and dog allergens among these children is in keeping with the presence of cat and/or dog allergen in most of the houses. Furthermore, sensitization (as judged by IgE antibodies) to cat and dog allergens was strongly associated with asthma. On the other hand, no clear relationship was found between sensitization or symptoms and the current level of allergen in individual houses. The results show that in this mite-and cockroach-free environment sensitization to domestic animals was the most significant association with asthma.

Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools

BACKGROUND The amount of allergen necessary to sensitise genetically “at risk” children is unclear. The relation between allergen exposure and asthma is also uncertain. METHODS To ensure a wide range of allergen exposures the data from case-control studies of asthma in children aged 12–14 years attending three schools in Los Alamos, New Mexico and Central Virginia were combined. Skin prick tests to indoor and outdoor allergens and bronchial hyperreactivity to histamine were assessed in children with and without symptoms of asthma. The concentration of mite, cat, and cockroach allergens in dust from the children’s homes was used as a marker of exposure. RESULTS Three hundred and thirty two children (157 with asthmatic symptoms and 175 controls) were investigated. One hundred and eighty three were classified as atopic on the basis of allergen skin prick tests and 68 as asthmatic (symptoms plus bronchial responsiveness). The prevalence and degree of sensitisation to mite and cockroach, but not cat, was strongly associated in atopic children with increasing domestic concentrations of these allergens. Asthma was strongly associated with sensitisation to indoor allergens (p<10-6) and weakly to outdoor allergens (p = 0.026). There was an association between current asthma and the concentration of mite allergen amongst atopic children (p = 0.008) but not amongst those who were specifically mite sensitised (p = 0.16). CONCLUSIONS The domestic reservoir concentration of mite and cockroach, but not cat, allergen was closely related to the prevalence of sensitisation in atopic children. However, the prevalence of current asthma had a limited relationship to these allergen measurements, suggesting that other factors play a major part in determining which allergic individuals develop asthma.

Epidemiology of the Relationship between Exposure to Indoor Allergens and Asthma

A very high prevalence of immediate hypersensitivity to common indoor allergens can be demonstrated among children and young adults, with asthma. Recent progress in the immunochemistry of cat, dust mite and cockroach allergens has made it possible to measure exposure to these allergens and to start to define threshold levels of exposure which increase the risk of sensitization and symptomatic asthma. Indeed, it is already clear that exposure to greater than 2 micrograms group I dust mite allergen (or 100 mites) per gram of dust increases the risk of children developing sensitization and asthma. Furthermore, from studies on patients presenting to emergency rooms with asthma, it is clear that the risk of sensitization to allergens derived from cats or cockroaches or grass pollen is restricted to patients who are exposed to high levels of these allergens. Given the increasing morbidity and mortality of asthma it is clear that therapeutic efforts should be focused on identifying relevant allergens and advising patients about techniques for reducing exposure.

Association of sensitization to Alternaria allergens with asthma among school-age children

BACKGROUND Molds in the Alternaria genus, normally found on outdoor vegetation, produce some of the most common fungal allergens to elicit a skin test response. OBJECTIVES The objectives of this study were to evaluate a serum assay for IgE antibodies to Alternaria allergens and to establish the prevalence of sensitization to Alternaria allergens among children and adults enrolled in epidemiologic studies of asthma. In addition, the significance of sensitization to Alternaria allergens as a risk factor for asthma was compared with that of sensitization to indoor allergens or pollens. METHODS Using the Pharmacia Capsulated Hydrophobic Carrier Polymer (CAP) system, we have evaluated the significance of Alternaria allergens by using sera from several epidemiologic studies of asthma. RESULTS Comparisons between serum assays and skin test results suggest that this in vitro assay yields results similar to those for traditional RASTs and is as sensitive as skin prick testing. In each of the groups studied, sensitization to Alternaria allergens was more common among asthmatic than control subjects, and in two studies the relationship was highly significant. Alternaria allergens were significantly associated with asthma in middle schools in Charlottesville, Virginia and Los Alamos, New Mexico but not in Albemarle County, Virginia. Logistic regression analysis of the results for the three schools identified an association between sensitization to Alternaria allergens and asthma independent of, but not as strong as, that found between sensitization to indoor allergens and asthma (p < 0.001). CONCLUSIONS The Pharmacia CAP system is a useful tool for measuring specific IgE to Alternaria allergens. Although not as important as sensitization to dominant local indoor allergens, sensitization to Alternaria allergens appears to be a significant independent risk factor for asthma in children in some locations of the United States.

Exposure to house dust mite allergen of children admitted to hospital with asthma.

Eighty‐two children admitted to hospital with exacerbations of asthma were studied to determine how many were exposed to house dust mites at the time of admission and displayed immediate hypersensitivity to house dust mites. The concentration of house dust mite allergen (Der p I) was measured in dust obtained from the childs mattress, bedroom floor and living room floor. Sixty‐two (75%) children admitted had been exposed to > 10 μg Der p I/g. Sixty‐seven (82%) children were sensitive to house dust mite(RAST 1 +, or weal 3 mm): 49 (60%) children were both exposed and sensitive. In contrast in a control group of 44 children, 31 (70%)(n.s.) were exposed to > 10μg Der p I/g, 10 (23%) (P < 0.001) were sensitive to house dust mite, and 7 (16%) (P < 0.001) were both exposed and sensitive. Seventy‐three homes were revisited 6 months after the childs initial admission. During the preceding month 14 children had been readmitted, 12 were fully investigated; of these 10 were both sensitive to house dust mite and still exposed to > 10 μg Der p I/g. In contrast, of the remaining 62 children who were not readmitted, only 19 were both sensitive and still exposed to > 10μg Der p I/g (P < 0.001). In conclusion, the majority of children admitted to hospital with exacerbations of asthma were exposed to house dust mite allergen and were house dust mite sensitive. Further the results suggest that continued exposure to higher concentrations of mite allergen may be associated with the risk of readmission.

Environmental exposure to Aspergillus fumigatus allergen (Asp f I)

Asp f I is a major allergen produced by the mycelia of Aspergillus fumigatus. It is not present in spores and can be used as a specific marker for the detection of germination of this fungus. We investigated the domestic and outdoor concentration of Asp f I in Poole, U.K. and Charlottesville, VA, U.S.A. Asp f I was undetectable in 95% (281/296) of house dust extracts and present at low levels (< 0.17 μg/g of sieved dust, mean 0.038 μg/g) in the remainder. In contrast, Asp f I could be detected in 65% (15/23) of cultures of house dust, suggesting the presence of viable, but ungerminated, A. fumigatus in the majority of homes. Asp f I was detectable in 80% (28/35) of extracts of leaves and compost, but present in these outdoor samples at low levels (<0.11 μg/g, mean 0.27 μg/g). Air sampling for Asp f I was undertaken before and after vigorous disturbances at indoor (n= 5) and outdoor (n= 6) sites. Airborne Asp f I was not detected in domestic samples or in undisturbed outdoor samples. Following disturbance it could be measured in outdoor samples (range 7.6–29 ng/m3). The results suggest that while exposure to A. fumigatus is common, exposure to Asp f I and germinating A. fumigatus is uncommon. It is probable that those individuals who develop antibody responses to Asp f I have been exposed to A. fumigatus which has germinated in their respiratory tract.

Serum IgG and IgG4 Antibodies to Fel d 1 among Children Exposed to 20 μg Fel d 1 at Home: Relevance of a Nonallergic Modified Th2 Response

Exposure to foreign antigens is an essential element of all immune responses, including allergic sensitization. For some allergens (e.g. mite and cockroach), the prevalence of sensitization is directly correlated with exposure. However, for allergens derived from domestic animals, several studies have suggested that children with a cat in the home have a decreased risk of sensitization and asthma. We have now shown that many children exposed to greater than 20 µg of Fel d 1/g of dust at home made an IgG and IgG4 antibody response to Fel d 1 without IgE antibody. This modified Th2 response is not associated with symptoms and should be regarded as a form of immunological tolerance. The fact that the dose-response relationship between cat exposure and sensitization is bell shaped, while that for mite exposure and sensitization is linear, is highly relevant to understanding the role of allergens in the increase in allergic disease.

Detection of inhaled cat allergen

Measuring personal exposure to airborne allergens is important in understanding the association between asthma and allergen exposure. Personal exposure to cat allergen (Fel d 1) is likely to involve a more complex pattern of exposure than indicated by either reservoir dust or long-term air Fel d 1 concentrations. An additional limitation of current methods of air sampling is that the quantity of allergen recovered is low compared with the sensitivity of detection methods. We have developed a passive air sampler worn in each nostril which collects inhaled particles (mainly >5 m) and a method that detects the allergen eluted from each particle. Nasal air samplers were worn by the same individual for 10 min during five replicates of a range of exposure situations in a living room with a cat (31·7 g Fel d 1 per g carpet dust, 569·6 g Fel d 1 per g sofa dust) and in the low-allergen environment of a tea room in the University (2·8 g Fel d 1 per g floor dust). In one sampler, inhaled particles were collected by impaction on to a protein-binding membrane and were immunostained with monoclonal antibodies specific to Fel d 1 (Indoor Biotechnologies, University of Virginia) to detect allergen localised around the inhaled particles. The total number of particles collected and the number of particles containing Fel d 1 were counted, and are expressed as medians. In the other sampler, particles were collected on a non-protein-binding membrane and the eluted allergen measured by ELISA. The detection of Fel d 1 by these methods was compared with a standard personal air sampler (Institute of Occupational Medicine [IOM], Edinburgh) and eluted allergen detected by ELISA. 23 particles containing Fel d 1 were inhaled per nostril, in 10 min, while grooming a cat (figure). In the University tea room, only three particles containing Fel d 1 were collected while wearing clean clothing, but this increased to 20 particles while wearing clothing previously contaminated by exposure to a cat (12·5 g Fel d 1 per g of clothes dust). Cat allergen was detected on 3–19% of all inhaled particles, depending on the activity. By contrast, airborne Fel d 1 was only detected in samples eluted from the nasal filter during the high-exposure activity of cat grooming (three of five samples, maximum ~17·5 ng Fel d 1 per m, assuming an inspiratory flow rate of 10 L/min), while walking in a room with a cat (two of five samples [figure], maximum ~33·3 ng/m), and from the IOM telephoned non-respondents and for each of the different specialties dealing with breast cancer. Almost all these breast-cancer doctors (99%) would generally use tamoxifen in older women with N+ disease, but only half (54%) would do so in younger women with N+ disease. These percentages were smaller (78% and 33%, respectively) for women with node-negative disease (figure, A). Although age and, to a lesser extent, nodal status strongly affect whether adjuvant tamoxifen is prescribed, they had little effect on the usual duration of the regimen used which, for 75% of these doctors, was at least 5 years (figure, B). 12% of clinicians used a longer regimen, however, indicating that a significant minority of these opinion leaders hope for additional benefit from continuing tamoxifen beyond the initial 5 years. That may be justified, but such continuation still needs reliable assessment. As the evidence from the randomised trials of adjuvant tamoxifen continues to evolve, patterns of tamoxifen use will continue to change. The trials, as summarised by the most recent quinquennial worldwide review, now show that, at least for women with some oestrogen-receptor protein detectable on their primary tumour (and for women with no oestrogen-receptor assay done), about 5 years of tamoxifen substantially delays recurrence and improves 10-year survival. This is true not only for older women but also for younger women, irrespective of nodal status. Hence, if the general willingness to use tamoxifen for postmenopausal women with N+ disease were to be extended to those with Ndisease, and to younger women, many more deaths could be avoided. Even for those who receive chemotherapy as part of their adjuvant treatment, addition of tamoxifen confers extra benefit. More than a million women worldwide are now prescribed tamoxifen, but the present heterogeneity in practice is disturbing, particularly with respect to the treatment of younger women (among whom only half of the respondents in our survey would use tamoxifen).