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 childhood wheezing.

This review touches on what is being learned about wheezing in infants, how it differs from wheezing in later childhood, and what has been relearned about its natural history. Wheeze is a common symptom with a number of different causal mechanisms and has a better prognosis in infants than in older children. The current ability to measure the lung function of infants has clearly shown the harmful effects of exposure to tobacco smoke. These effects begin in utero and continue during infancy and childhood. Improved viral isolation techniques have confirmed the important role of infections with respiratory syncytial virus, rhinovirus, and adenovirus in wheezing episodes. In later childhood, allergen sensitization and allergen exposure become of increasing importance.

Epidemiology of dust-mite-related disease.

For many years it has been suggested that allergens derived from the house dust mite played a major role in the pathogenesis of asthma, eczema and some cases of allergic rhinitis. Recently, house dust mite allergens have been purified and specific immunoassays developed with which exposure to house dust mites and their allergens can be more easily determined. Using these tools, epidemiological studies have provided confirmatory evidence that not only is house dust mite exposure associated with the majority of cases of asthma in children and young adults, but that it is causally related to the development of asthma.

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.

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.

Natural history of asthma in childhood--a birth cohort study.

A cohort of 67 babies at risk of developing atopic disorders was followed up prospectively for 11 years. Clinical assessment and skin prick allergen sensitivity testing were performed annually over the first five years. At 11 years the cohort was restudied, symptoms were assessed by questionnaire, and bronchial reactivity (BHR) to histamine was measured. On the basis of skin testing, 35 children were atopic and 32 remained non-atopic. The expression of atopy increased with age. The lifetime prevalence of eczema, wheeze, and hay fever were 46%, 63%, and 56% respectively. The yearly period prevalence of hay fever increased with age, that of eczema declined, while that for wheeze showed a bimodal distribution with a peak before the age of 2 years and a gradual increase thereafter. Of the 21 children who wheezed before their second birthday, most never wheezed again and did not show BHR at 11 years. Of the 21 children whose first wheezing was after 2 years of age, 17 were still wheezing at 11 years and 12 showed BHR. Of the children who wheezed before 2 years of age, 10 were or became atopic, compared with 20 of the 23 children who wheezed at 11 years. These findings suggest that childhood asthma is a heterogeneous condition with atopy being strongly associated with the persistence of wheeze.

Longitudinal study of cholesterol values in 68 children from birth to 11 years of age.

Sixty eight children born in 1977 who were taking part in an unrelated study of childhood asthma were selected to have their serum cholesterol concentrations measured at birth, and at 4 months and 1, 2, 3, 4, 5, and 11 years of age. Concentrations of high density lipoprotein were measured at 5 and 11 years. Cholesterol values increased rapidly from birth and plateaued at 1 year. There was a further small rise just before puberty. Tracking of values was seen after the age of 1 year, but did not become established until 4 years of age. The cholesterol concentrations in girls were marginally higher than those in boys. The mean (SD) values of cholesterol (mmol/l) for boys were: at birth, 1.7 (0.4); at 1 year, 3.9 (0.9); at 5 years, 5.2 (1.9); and at 11 years, 5.0 (0.7). For girls the corresponding figures were; at birth, 1.9 (0.6); at 1 year, 4.7 (1.0); at 5 years, 4.6 (0.7); and at 11 years, 5.1 (0.7). The mean (SD) high density lipoprotein concentrations (mmol/l) for boys were: at 5, 1.16 (0.35) and at 11, 1.51 (0.23). For girls they were 1.28 (0.30) and 1.56 (0.27), respectively. The serum cholesterol concentrations in these children were high compared with published figures from north America.

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 child's mattress, bedroom floor and living room floor. Sixty-two (75%) children admitted had been exposed to > 10 microg Der p I/g. Sixty-seven (82%) children were sensitive to house dust mite (RAST > or = 1 +, or weal > or = 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 > 10 microg 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 child's 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 microg Der p I/g. In contrast, of the remaining 62 children who were not readmitted, only 19 were both sensitive and still exposed to > 10 microg 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.

Monitoring allergen exposure in asthma: new treatment strategies.

The development of monoclonal antibody-based enzyme-linked immunosorbent assay technology for measuring environmental allergen exposure has provided a benchmark for assessing the role of indoor allergens in causing asthma and other allergic diseases. Epidemiological studies from several parts of the world have shown that immunoglobulin E (IgE)-mediated sensitization to indoor allergens (mite, cat, dog and cockroach) is a risk factor for asthma attacks. A dose-response relationship between allergen exposure and sensitization has been demonstrated for mite allergens, and threshold values for exposure levels leading to sensitization or to exacerbations of symptoms have been defined. Comparative studies on airborne allergen levels have made it possible to determine the properties of aeroallergen particles, their concentration in indoor air, and the relationship to clinical symptoms. Together, these studies provide strong evidence that allergen exposure plays a causal role in the development of bronchial hyperreactivity and of the chronic inflammatory responses seen in patients with asthma. Logically, the primary preventive treatment should be allergen avoidance. Through knowledge of indoor allergen levels, both in dust and in the air, different avoidance strategies have been applied to the various indoor allergens, and there is increasing evidence of their clinical efficacy. Monitoring allergen levels in patients' houses should improve their understanding of the role of allergens in asthma and improve compliance with avoidance measures.

Dog and cat allergens and asthma among school children in Los Alamos, New Mexico, USA: altitude 7,200 feet.

A survey of the Middle School in Los Alamos, N.M., USA, identified 57 children with symptoms of asthma and 54 controls. Among these children, sensitization to cat and dog allergens was very strongly associated with bronchial reactivity and symptoms. In contrast, sensitization to mites, cockroach, or grass pollen allergens was not significantly associated with symptoms or bronchial reactivity. In keeping with these results, dust from houses in Los Alamos only contained high levels of cat or dog allergens.

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.

The role of domestic allergens.

The documented increase in asthma has been almost entirely in perennial asthma and a large proportion of the cases are allergic to one of the common allergens found all year round in houses, i.e. house dust mites, cats, dogs or cockroaches. In population and case-control studies sensitization to one of these allergens is the strongest risk factor for asthma (adjusted odds ratios > or = 4). Using monoclonal antibody-based assays for the major indoor allergens it has been shown that sensitization to house dust mites is directly related to the concentration of Group 1 mite allergen in dust. This led to the hypothesis that increases in mite allergen secondary to changes in houses were responsible for increases in asthma. However, asthma has also increased in areas of the world where mites do not flourish. In these dry areas sensitization to one of the other indoor allergens is the major risk factor for asthma. Although sensitization of asthmatics reflects the concentration of allergens in their houses, these measurements of exposure do not accurately predict severity of symptoms. Other factors that can contribute to the symptoms of asthma may also have increased. In particular, diesel particulates, ozone, beta 2-agonists, endotoxin and rhinovirus infection have each been shown to enhance the inflammatory response to inhaled allergens. Increases in asthma must relate to some aspect of our predominantly sedentary indoor lifestyle; this could be either increased exposure to allergens or an increase in factors that enhance the response of the lungs to foreign proteins.

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.

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.

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.

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.