Clinical Immunology Review Series: An approach to the patient with allergy in childhood.

Allergic conditions are common, with asthma being the most common chronic illness in childhood in most developed countries. Some 80% of asthmatic children are sensitized to aeroallergens, usually indoor animal dander and house dust mite. Some 80% of asthmatics also have rhinitis. Rhinitis and eczema receive less medical attention than asthma, but they can cause longterm morbidity and have substantial direct and indirect economic costs. Food allergy and anaphylaxis are increasingly recognised and are usually easily diagnosed and managed.Clinicians can use in vivo and in vitro measurements of allergen-specific immunoglobulin E to better time reintroduction of implicated foods. Specific parenteral and sublingual immunotherapy is widely practiced internationally but is uncommon in the UK. It may alter the natural history of aeroallergen reactive diseases in the upper and lower airways. Specific oral tolerance induction represents the current cutting edge in clinical allergy research. It remands resource intensive at present and cannot be adopted into routine clinical practice at this time.

Asthma and indoor air: contrasts in the dose response to cat and dust-mite.

UNLABELLED: The role of the indoor environment in asthma is of major concern because (i) the disease has become more severe; (ii) we spend>or=90% of our lives indoors and (iii) a large proportion of asthmatic children and young adults are allergic to allergens found indoors. Recent evidence that children raised in a home with animals, i.e. indoor cat or dog, are less likely to become allergic has provided a great opportunity to understand the mechanisms controlling the prevalence of allergic disease. In addition the results pose a challenge to many of the hypotheses about reasons for the increase in asthma. The evidence that children or adults who make a modified TH2 response i.e. immunoglobulin (Ig)G and IgG4 ab without IgE, are not at increased risk of asthma strongly supports the role of IgE in asthma. Equally the results may give insight into a form of tolerance that could be a target for protecting patients against allergic disease. PRACTICAL IMPLICATIONS: Evidence for the immune response to cat allergen shows that the alternative response to an allergy, TH2 response, is a controlled or modified form of the response not a Th1 response. Furthermore, avoiding cats in the home in most communities would not decrease the prevalence of sensitization to cats because there is cat allergen distributed in schools, other public buildings, and homes without a cat.

Early life risk factors for adult asthma: a birth cohort study of subjects at risk.

BACKGROUND: Prediction of adult asthma is important, and early prevention strategies should be targeted at those most at risk. Identifying high-risk children at an early age, however, is currently difficult. OBJECTIVE: We sought to determine those factors present in early life that predict an increased risk of adult asthma. METHODS: A prospective cohort study of subjects at risk of asthma and atopy was undertaken in Poole, England. One hundred babies of atopic parents were recruited at birth. During the first 5 years of life, subjects were recalled annually, all respiratory events were reported, and skin prick tests and total serum IgE measurements were performed. At 11 and 22 years, bronchial hyperresponsiveness was also measured. Seventy-three subjects were followed up at 5 years, 67 at 11 years, and 63 at 22 years. RESULTS: Twenty-three (37%) adult subjects reported wheezing within the previous 12 months. Fifteen (25%) of these subjects showed signs of bronchial hyperresponsiveness and were regarded as asthmatic. Wheezing before the age of 2 years occurred in 28% and was not significantly related to adult asthma (odds ratio, 0.3; 95% CI, 0.03-1.7; P = .19). A positive skin prick test response to hen's egg, cow's milk, or both in the first year was independently predictive of adult asthma (odds ratio, 10.7; 95% CI, 2.1-55.1; P = .001; sensitivity, 57%; specificity, 89%). CONCLUSION: Prediction of adult asthma remains difficult. In this study of subjects at risk of atopy, skin sensitivity to hen's egg or cow's milk in the first year was predictive of adult asthma.

Serum IgG and IgG4 antibodies to Fel d 1 among children exposed to 20 microg 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 microg 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.

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.

Continued increase in the prevalence of asthma and atopy.

AIMS: To describe the change in the prevalence of wheeze, diagnosed asthma, and atopy in Wagga Wagga, NSW, Australia, between 1992 and 1997, and to compare this to the increase in prevalence reported between 1982 and 1992. METHODS: A cross sectional study of the prevalence of respiratory symptoms and atopy in schoolchildren aged 8-11 years (n = 1016, response rate 71%) in 1997 compared with studies of similar design in 1992 (response rate 83%, n = 850) and 1982 (response rate 88%, n = 769). Main outcome measures were respiratory symptoms measured by parent completed questionnaire and atopy measured by skin prick tests. RESULTS: Between 1992 and 1997, the prevalence of wheeze increased by 5.1% (95% CI 1.2 to 9.0), asthma diagnosis by 8.1% (95% CI 3.8 to 12.4), and atopy by 6.7% (95% CI 2.2 to 11.2). Similar increases in prevalence had been found between 1982 and 1992. CONCLUSIONS: The prevalence of wheeze, asthma diagnosis, and atopy in Wagga Wagga has continued to increase.

Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children.

BACKGROUND: The specificity of allergen skin prick testing to diagnose clinically relevant food allergy is controversial. OBJECTIVES: To determine the specificity of the allergen weal diameter to correctly identify children who react on formal open food challenges. METHODS: Over a 9-year period children referred to a tertiary allergy clinic for the evaluation of suspected food allergy were prospectively studied. Allergen skin prick testing to cow milk, egg white and peanut extracts (Dome-Hollister-Stier, Spokane, WA, USA) was undertaken using a lancet technique. All children underwent open food challenges to the relevant food(s) in a hospital clinic. Challenges were classified as positive, if objective signs were seen; negative, if the child could tolerate normal quantities of the food, daily, for one week; or inconclusive if none of the former criteria were met. RESULTS: Five hundred and fifty-five challenges were undertaken in 467 children: 339 challenges to cow milk, 121 to egg, and 95 to peanut. Fifty-five percentage of challenges were positive, 37% negative, and 8% inconclusive. For each food it was possible to identify a skin weal diameter at, and above, which negative reactions did not occur: cow milk, 8 mm; egg, 7 mm; peanut, 8 mm. In contrast, positive reactions could occur with a skin wheal diameter of 0 mm. CONCLUSIONS: In this high risk referral population it was possible to define skin weal diameters to egg, milk and peanut above which open oral food challenges were positive (100% specificity). By utilizing these measurements the need for formal food challenges can be reduced.

The association of atopic dermatitis in infancy with immunoglobulin E food sensitization.

OBJECTIVE: To prospectively investigate the association of high levels of immunoglobulin E (IgE) sensitization to foods and the presence of atopic dermatitis (judged by reported topical steroid use during the first 16 months of life) in a birth cohort of 620 Australian children "at risk" of allergic disease because of family history. RESULTS: A total of 559 of the children in the cohort were fully evaluated, and the cumulative prevalence of atopic dermatitis was 24%. More children in the cohort who had atopic dermatitis had strongly positive skin test results (> or = 4+, histamine equivalent units, > or = approximately 6-mm wheal), consistent with IgE food sensitization to either cow's milk, egg, or peanut at 6 months (22% vs 5%, chi(2) = 35; P < 10(-6)) and at 12 months (36% vs 11%, chi(2) = 41; P < 10(-6)) than those without atopic dermatitis. The calculated attributable risk percent for IgE food sensitization as a cause of atopic dermatitis was 65% and 64% at these times. In a separate group of infants with severe atopic dermatitis, the equivalent rates of IgE food sensitization at 6 months was 83% and at 12 months, 65%. CONCLUSION: IgE food sensitization is a major risk factor for the presence of atopic dermatitis in infancy.

Detection of inhaled Der p 1.

BACKGROUND: Measurement of personal exposure to Der p 1 aeroallergen has previously been limited by the low quantity of material collected by sampling systems and the assay sensitivity. This has meant that exposure could only be detected if long sampling periods were used or reservoir dust was artificially disturbed. We have developed a sampling method to sample true personal exposure and combined it with a novel method which is sensitive enough to measure allergen exposure over shorter time frames. OBJECTIVE: To describe normal domestic exposure to dust mite allergen during a range of activities in houses in Sydney, Australia. METHODS: Inhaled particles containing mite allergen Der p 1 were collected using a nasal air sampler which impacts particles (> approximately 5 microm) onto a protein-binding membrane coated with a thin, porous, adhesive film. The allergen is bound to the membrane in the immediate vicinity of the particle and detected by immunostaining with monoclonal antibodies specific for Der p 1. In addition, samples were collected using a standard Institute of Occupational Medicine (IOM) personal air sampler and the amount of eluted Der p 1 was assayed by ELISA. RESULTS: The median number (range) of inhaled particles containing Der p 1 collected in each 10-min sampling period was: dust raising 5 (2-10); lying in bed, 0 (0-2); sitting on the bed, 1 (0-2); walking around the bedroom, 0 (0-2). This represented 0-5.1% of all particles captured. The Der p 1 concentration of floor and bed dust was 19.4 and 55.1 microg/g, respectively. The standard IOM personal sampler and ELISA were unable to detect Der p 1 for any of the activities performed. CONCLUSIONS: We were able to count individual allergen-carrying particles inhaled over short time periods, during different domestic exposure situations. This will offer new insight into several aspects of personal allergen exposure.

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.

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.

The Melbourne House Dust Mite Study: long-term efficacy of house dust mite reduction strategies.

BACKGROUND: Asthma severity among mite-sensitized individuals appears to be related to the degree of mite allergen exposure. OBJECTIVES: The objective of this study was to assess the long-term effectiveness of mite avoidance measures in the homes of asthmatic children in Melbourne, Australia. METHODS: The concentration of house dust mite allergen (Der p 1) was measured on the child's mattress surfaces and bedroom floors in 85 homes on 10 occasions over a 16-month period. After the first three visits, all mattresses were covered with a semipermeable encasement, and carpeted bedroom floors were randomly allocated to regular applications of a placebo or an "anti-mite" shampoo. RESULTS: The concentration of Der p 1 recovered was initially high in the carpeted bedrooms (n = 66) (41.1, 95% confidence interval, 30.7 to 55.0 microg Der p 1 per gm) and mattresses (n = 85) (39.6, 27.2 to 57.7). During the initial observation period the concentration of mite allergen fell in the treatment, placebo, and parental control groups. During the seven treatment periods, no differences were seen between the Der p 1 concentrations in the groups using the "anti-mite" shampoo, placebo shampoo, or the parental control group (e.g., at visit 4; 12.6, 8.2 to 19.5; 14.8, 8.6 to 25.1; and 12.0, 8.1 to 17.7 microg/gm, respectively). In contrast, the concentration of Der p 1 in samples from uncarpeted floors and mattress encasements was low (4.1, 2.1 to 8.0 microg/gm and 4.2, 2.6 to 6.5 microg/gm, respectively) and insufficient dust for analysis was frequently obtained from these sites. CONCLUSIONS: There was no additional benefit from the use of an "anti-mite" shampoo. The absence of carpets and the use of mattress encasements was a useful long-term strategy for mite allergen avoidance.

Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia. Multiple regression analysis of a population-based study.

Factors influencing asthma were investigated in a population of school children in central Virginia. A survey of 1,054 children in two middle schools (one urban and one suburban) identified 135 students with symptoms suggestive of asthma. Eighty-eight symptomatic children and 123 control subjects were randomly selected for further evaluation by skin testing using common indoor and outdoor allergens; serum assays for total IgE and specific IgE; dust samples assayed for mite (Der p 1 Der f 1), cat (Fel d 1), and cockroach (Bla g 2) allergens; and provocation with histamine to test for bronchial hyperreactivity. Forty-eight of the children with symptoms responded to < or = 3.9 mumol of histamine and were considered to have asthma. Marginal analysis identified elevated total IgE and dust mite, cat, and cockroach sensitization as significant risk factors for asthma. Using multiple regression, only dust mite sensitization was independently associated with asthma (odds ratio = 6.6; p < 0.0001). Dust from 81% of the houses contained high levels of mite allergen (> 2 micrograms/g), while approximately 40% of the children were exposed to cat and 17% were exposed to cockroach allergen. In this population, there was no significant association between asthma and race, socioeconomic status, home smoking, sensitization to outdoor allergens, or allergen concentration in the child's home. In an area where there is a high prevalence of asthma and most houses contain high concentrations of dust mite allergen, sensitization to this allergen is the dominant risk factor for asthma defined as symptomatic bronchial hyperreactivity

Lung involvement in the multisystem syndrome CHARGE association.

The CHARGE association is a multisystem syndrome, with a wide range of phenotypic expression, causing mortality, especially in childhood. We performed a hospital audit, in order to quantify the pulmonary implications, in 28 boys and 19 girls aged 0.02-23 yrs, with a definite diagnosis of CHARGE. A review of the records of these children with CHARGE association revealed that aspiration was common during infancy, as a result of inco-ordination of swallowing and gastro-oesophageal reflux. Aspiration was suspected in 22 of the 47 cases (47%), recurrent chest infections occurred in 22 cases (47%), and lung involvement contributed to 7 out of 17 deaths (41%). We conclude that respiratory morbidity and mortality is common in CHARGE, and decreases with age. Early diagnosis and treatment affords the best prognosis.