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Background: Wheezing occurs in both atopic and non-atopic children. The characteristics of atopic and non-atopic wheeze in children at 10 years of age were assessed and attempts made to identify whether different mechanisms underlie these states., Methods: Children were seen at birth and at 1, 2, 4 and 10 years of age in a whole population birth cohort study (n = 1456; 1373 seen at 10 years). Information was collected prospectively on inherited and early life environmental risk factors for wheezing. Skin prick testing, spirometry, and methacholine bronchial challenge were conducted at 10 years. Wheezing at 10 years of age was considered atopic or non-atopic depending on the results of the skin prick test. Independent significant risk factors for atopic and non-atopic wheeze were determined by logistic regression., Results: Atopic (10.9%) and non-atopic (9.7%) wheeze were equally common at 10 years of age. Greater bronchial hyperresponsiveness (p<0.001) and airways obstruction (p = 0.011) occurred in children with atopic wheeze than in those with non-atopic wheeze at 10 years. Children with atopic wheeze more often received treatment (p<0.001) or an asthma diagnosis for their disorder, although current morbidity at 10 years differed little for these states. Maternal asthma and recurrent chest infections at 2 years were independently significant factors for developing non-atopic wheeze. For atopic wheeze, sibling asthma, eczema at 1 year, rhinitis at 4 years, and male sex were independently significant., Conclusions: Non-atopic wheeze is as common as atopic wheeze in children aged 10 years, but treatment is more frequent in those with atopic wheeze. Different risk factor profiles appear relevant to the presence of atopic and non-atopic wheeze at 10 years of age.

Background: Identifying the protective effect of a higher number of siblings is a significant finding in understanding the aetiology of allergic sensitization, asthma, eczema, and hayfever. Knowledge about causes behind the sibling effect may allow us to prevent atopic manifestations., Objective: We tested the hypothesis that rising order of live offspring increases maternal immune tolerance (immune non-reactivity) against allergens. To this end, we investigated whether maternal IgE levels are associated with the number of live offspring., Methods: In a cohort of 1456 newborns recruited between January 1989 and February 1990 on the Isle of Wight, UK, we determined maternal and cord serum IgE, and the order of live offspring. The data were analysed by means of linear and path analysis., Results: Maternal and cord serum IgE were available in 820 mother-infant pairs with birth order information. We found that the number of live offspring significantly reduces maternal IgE. The decline was more prominent in mothers with atopy (n=268). The geometric means of IgE after the first, second, and third or higher delivery were 74.4, 66.6, and 43.0 kU/L, respectively. Findings of path analysis suggest a significant direct effect of birth order on maternal IgE, but no direct effect of birth order on cord serum IgE., Conclusion: The findings support that maternal immune tolerance against allergens may increase with increasing order of live offspring and thus pass on a lower risk of developing atopy in children of higher birth order.

The role of primary prevention of allergic disease has been a matter of debate for the last 40 years. In order to shed some light into this issue a group of experts of the Section of Pediatrics EAACI critically reviewed the existing literature on the subject. The design of observational and interventional studies was evaluated with relevance to the important factors influencing outcome of studies on allergy development/prevention. in this analysis the statements of evidence as defined by WHO were applied. Best evidence of recommendations are those fulfilling the criteria for statements category 1 and 2 and grade of recommendations A and B as proposed by WHO. This survey include target group for dietary prevention and methods and diagnostic criteria of atopic dermatitis, asthma and food allergy for prevention studies., (Copyright 2004 Blackwell Munksgaard)

Purpose of Review: Recent increases in the prevalence of atopic disease argue strongly that environmental factors operating primarily in early life play a significant role. Exposure to food and inhalant allergens early in life may constitute a risk factor amenable to manipulation., Recent Findings: Recent observational and interventional studies have produced conflicting data regarding the effectiveness of allergen avoidance in primary and secondary prevention of atopic diseases., Summary: Exclusive breast feeding for 4-6 months may protect against the development of allergic diseases in early childhood and remains good advice. Convincing proof for the preventive effects of the delayed introduction of solid foods and hydrolyzed formula in formula-fed infants is lacking. There is some evidence to support a preventive effect of house dust mite allergen avoidance before sensitization occurs. The effect of exposure to animal allergen is uncertain, with some studies showing an increase in sensitization while others suggest a protective effect. Therefore, no evidence-based advice can be given at this stage regarding allergen avoidance measures to be adopted by families with infants at high risk of atopy, except perhaps to breast feed exclusively for at least 4 months. Data regarding the secondary prevention of allergic disease by allergen avoidance were more secure until the publication this year of two randomized controlled trials which suggest that mattress impermeable covers, the main dust mite allergen avoidance measure, may not work. Allergen avoidance, however, should remain an essential part of the management of allergic diseases, even if the benefit of mattress covers is in doubt.

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light into this issue, a group of experts of the Section of Pediatrics EAACI critically reviewed the existing literature on the subject. In this paper, the immunology of the fetus and newborn is reviewed as well as the post-natal development of the immune system. The influence of post-natal environment and breastfeeding on tolerance induction and sensitization are examined. Allergic diseases result from a strong relationship between genetic and environmental factors. Sensitization to food allergens occurs in the first year of life and cow's milk allergy is the first food allergy to appear in the susceptible infants. Hypoallergenicity of food formulas to be used is a critical issue both for treatment of cow's milk-allergic children and for prevention. Methods to document hypoallergenicity are discussed and evaluated in the preclinical and clinical steps.

Objective: We investigated the role of environmental and hereditary factors in determining whether persistent childhood wheezing phenotypes had an early or late onset., Methods: In a whole population birth cohort (n = 1456), children were seen at birth and at 1, 2, 4, and 10 years. At each visit, information was collected prospectively regarding wheeze prevalence and used to classify subjects into wheezing phenotypes. Information on genetic and environmental risk factors in early life was also obtained prospectively, and skin-prick testing to common allergens was performed at 4 years., Results: Early-onset persistent wheezers (n = 125) had wheeze onset in the first 4 years, still present at age 10, whereas late-onset persistent wheezers (n = 81) had wheeze onset after age 4 years that was still present at 10 years. Multivariate logistic regression analysis identified independent significance only for inherited factors (parental asthma, family history of rhinitis, eczema at 4 years, and atopic status at 4 years) in the development of late-onset persistent wheeze. However, low social class at birth, recurrent chest infections at 2 years, and parental smoking at 2 years plus inherited factors (eczema at 2 years; food allergy at 4 years; maternal asthma, sibling asthma, maternal urticaria, and atopic status at 4 years) demonstrated independent significance for early-onset persistent wheeze., Conclusion: Inheritance seems to be of prime significance in the cause of persistent childhood wheeze. Environmental exposure in early life may combine with this tendency to produce an early onset of persistent wheeze. Absence of these environmental factors might delay but not prevent the onset of wheeze in children with atopic heredity.

This study sought to determine factors influencing the persistence of early life wheezing up to the age of 10 yrs and to create a score identifying those with the highest risk of persistent disease. Children were seen at birth, 1, 2, 4 and 10 yrs in a whole population birth cohort study (n=1,456). Information was collected prospectively on wheeze prevalence and subjects were classified into wheezing phenotypes. Early life genetic and environmental risk factors were recorded and skin-prick testing (SPT) was performed at 4 yrs. Independently significant factors for persisting wheeze were identified at logistic regression and used to create a score for persistence. Wheezing persistence from the first 4 yrs to the age of 10 yrs occurred in 37% of early life wheezers. Independent significance for persistence was associated with asthmatic family history, atopic SPT at 4 yrs and recurrent chest infections at 2 yrs, whilst recurrent nasal symptoms at 1 yr conferred reduced risk. A cumulative risk score using these factors identified wheezing persistence in 83% scoring 4 and transience in 80% scoring 0. Thus, a combination of genetic predisposition, early life atopy and recurrent chest infections favours the persistence of early life wheezing. Risk scores using such knowledge could provide prognostic guidance on the outcome of early wheeze.

Background: The ability of an intact protein to reach the circulatory system may be a prerequisite to allergenicity and many allergens, particularly those from plant foods, have been found to be consistently more resistant to digestion by pepsin than other proteins., Objective: This study assessed the pepsinolytic stability of native 2S albumins from Brazil nut and sunflower seed and their recombinant versions produced in Pichia pastoris. The physicochemical stability of native and recombinant Brazil nut 2S albumins and recombinant sunflower seed 2S albumin was also assessed. The immunoreactivity of native Brazil nut 2S albumin and recombinant 2S albumins was compared using serum from patients allergic to Brazil nuts and animals immunized with native 2S albumins., Methods: Digestibility was measured in simulated gastric fluid followed by SDS-PAGE. Circular dichroism spectra were used to analyse unfolding, as proteins were denatured by temperature, pH and guanidinium chloride. Immunoreactivity was assessed by immunoblot, RAST and ELISA., Results: Brazil nut 2S albumin was significantly more resistant to proteolytic digestion than other Brazil nut proteins. It was also resistant to thermally and chemically induced denaturation. Equally high resistance to proteolytic digestion was observed with sunflower seed 2S albumin. The recombinant albumins mirrored their native counterparts in stability and immunoreactivity., Conclusion: The important food allergen Brazil nut 2S albumin is as stable to digestion as is sunflower seed 2S albumin, whose allergenicity has yet to be determined. The 2S albumins and their recombinant counterparts could not be easily denatured by physicochemical treatments. The results suggest that 2S albumin is the only Brazil nut protein to reach the gut immune system intact. The production of properly folded recombinant proteins will facilitate mechanistic studies as well as diagnostic testing and antigen-based therapies.

Objectives: We sought to identify factors associated with wheezing symptoms in children found to have bronchial hyperresponsiveness (BHR) at 10 years of age., Methods: Children were seen at birth, 1, 2, 4 and 10 years of age in an entire population birth cohort study (n = 1456). At each stage information was collected prospectively on genetic and environmental risk factors for BHR. Skin prick testing was performed at 4 and 10 years of age. Spirometry and methacholine bronchial challenge were conducted at 10 years of age when BHR was considered present if PC(20) FEV(1) was < 4.0 mg/mL. In children with BHR at 10 years of age, factors independently associated with current wheezing were determined by logistic regression., Results: BHR was identified in 169 10-year-olds at bronchial challenge, 55.6% of whom manifested current wheeze. In children with BHR, current wheezers had higher Log(10) total IgE and greater BHR than those who had never wheezed. Symptomatic BHR was independently associated with atopic sensitization (P <.001) and maternal asthma (P =.011) at 10 years of age. If only factors present in the first 4 years of life were considered, parental smoking at 4 years of age (P =.021), maternal asthma (P =.017), and atopic sensitization at 4 years of age (P =.004) were independently associated with symptomatic BHR at 10 years of age., Conclusions: Symptomatic BHR is associated with greater degrees of BHR and higher total IgE. Heredity, atopy, and environmental exposure might influence symptom expression in children with BHR.

Background: Recent increases in the prevalence of asthma and atopy emphasise the need for devising effective methods for primary prevention in children at high risk of atopy., Method: A birth cohort of genetically at risk infants was recruited in 1990 to a randomised controlled study. Allergen avoidance measures were instituted from birth in the prophylactic group (n=58). Infants were either breast fed with mother on a low allergen diet or given an extensively hydrolysed formula. Exposure to house dust mite was reduced by the use of an acaricide and mattress covers. The control group (n=62) followed standard advice as normally given by the health visitors. At age 8, all 120 children completed a questionnaire and 110 (92%) had all assessments (skin prick test, spirometry, and bronchial challenges)., Results: In the prophylactic group eight children (13.8%) had current wheeze compared with 17 (27.4%) in the control group (p=0.08). Respective figures were eight (13.8%) and 20 (32.3%) for nocturnal cough (p=0.02) and 11 of 55 (20.0%) and 29 of 62 (46.8%) for atopy (p=0.003). After adjusting for confounding variables, the prophylactic group was found to be at a significantly reduced risk for current wheeze (odds ratio (OR) 0.26 (95% confidence interval (CI) 0.07 to 0.96)), nocturnal cough (OR 0.22 (95% CI 0.06 to 0.83)), asthma as defined by wheeze and bronchial hyperresponsiveness (OR 0.11 (95% CI 0.01 to 1.02)), and atopy (OR 0.21 (95% CI 0.07 to 0.62))., Conclusion: Strict allergen avoidance in infancy in high risk children reduces the development of allergic sensitisation to house dust mite. Our results suggest that this may prevent some cases of childhood asthma.

Background: Childhood wheezing illnesses are characterized into different phenotypes. However, severity of the disease associated with these phenotypes has not been extensively studied., Objectives: To determine characteristics of childhood wheezing phenotypes in the first decade of life using health outcomes plus measurements of atopy, lung function and bronchial hyper-responsiveness., Methods: A whole population birth cohort (n = 1456) was prospectively studied to examine the natural history of childhood wheezing. Children were seen at 1, 2, 4 and 10 years for questionnaire completion and prospectively collected data used to define wheezing phenotypes. Assessment was made of adverse health outcomes plus spirometry, bronchial hyper-responsiveness, serum IgE measurement at 10 years and skin test sensitization at both 4 and 10 years for wheezing phenotypes., Results: Phenotypic analysis identified that 37% early life wheezers (symptom onset by age 4 years) still wheezed at 10 years. These persistent wheezers showed significantly more physician-diagnosed asthma in early life (P < 0.005 at 2 years) than early transient wheezers (wheezing transiently with onset by age 4 years). Overall they experienced greater multiple hospital admissions (P = 0.024), specialist referral (P = 0.009) and use of inhaled (P < 0.001) and oral steroids (P < 0.001) than early transient wheezers. They also demonstrated enhanced bronchial hyper-responsiveness compared with early transient wheezers (P < 0.001). However, both groups of early life wheezers showed impairment of baseline lung function at 10 years in comparison with non-wheezers: FEV1 (P < 0.029) and FEV1/FVC ratio (P < 0.001) with persistent wheeze and PEF (P = 0.036) with early transient wheeze. Late-onset wheezers (onset from 5 years onwards) had similar BHR to persistent wheezers but maintained normal lung function at age 10 and had lower cumulative prevalence of adverse health outcomes than persistent wheezers., Conclusions: Persistent wheezing with early childhood onset is associated with substantial morbidity in the first decade of life in association with high levels of atopy, bronchial hyper-responsiveness and impaired lung function at 10 years of age. Late-onset wheezing in the first decade of life could harbour potential for similarly significant disease subsequently.

The primary immune response to allergens is the prototypic T-helper cell type 2 (Th2) response. This occurs prenatally, favoured by the normal Th2-skewed immune response of pregnancy. The immune system matures during the early years of life. The immune responses, primarily determined by genetic susceptibility, are also influenced by exposure to allergens and infections, which may reverse their direction. Although wheezing is observed before 2 years of age, this is usually not attributable to allergy, and the majority of the wheezers do not develop asthma. The development of allergic asthma can be considered to be a two-stage process. The first stage involves the development of allergen-specific immunological memory against inhaled allergens. This happens in childhood and polarises the immune response towards a Th2 phenotype. These individuals are therefore more prone to developing allergic inflammation. Stage two involves the consolidation and maintenance of this polarised Th2 response, leading to a state of chronic airway inflammation. This second phase is influenced by various factors, for example respiratory viral infections, repeated indoor and outdoor allergen exposure, environmental tobacco smoke and air pollutants. The persistent airway inflammation leads to tissue remodelling and airway hyperresponsiveness, the clinical sine qua non of asthma., (Copyright 2003 Elsevier Science Ltd.)

Research evidence supports a causative relationship between indoor allergen exposure and the development of asthma. Epidemiologic studies demonstrate that exposure to indoor allergens, particularly house-dust mites and cockroaches and, to a lesser extent, animal allergens and mold, is a risk factor for the development of sensitization and perhaps respiratory symptoms. Sensitization to indoor allergen is clearly a major risk factor for the development of asthma and allergy. There is also epidemiologic and experimental evidence that, in sensitized subjects, higher exposure to indoor allergen causes morbidity. Most, but not all, prospective studies support the causative link between allergen exposure and asthma. Additional evidence comes from the prevention studies, in which reduction in indoor allergen exposure may lead to improvement in symptoms, pulmonary function, and bronchial hyperresponsiveness, and, if practiced, in early years of life, perhaps the development of asthma and allergy.

Background: Allergy to peanut is common. However, it is not known whether the prevalence of sensitization and clinical allergy to peanut is increasing., Objective: We sought to determine any change in the prevalence of peanut sensitization and reactivity in early childhood in 2 sequential cohorts in the same geographic area 6 years apart., Methods: Of 2878 children born between September 1, 1994, and August 31, 1996, living on the Isle of Wight, 1273 completed questionnaires, and 1246 had skin prick tests at the age of 3 to 4 years. Those with positive skin prick test responses to peanut were subjected to oral peanut challenges, unless there was a history of immediate systemic reaction. These data were compared with information on sensitization and clinical allergy to peanut available from a previous cohort born in 1989 in the same geographic area., Results: There was a 2-fold increase in reported peanut allergy (0.5 % [6/1218] to 1.0 % [13/1273]), but the difference was nonsignificant (P =.2). Peanut sensitization increased 3-fold, with 41 (3.3 %) of 1246 children sensitized in 1994 to 1996 compared with 11 (1.1 %) of 981 sensitized 6 years ago (P =.001). Of 41 sensitized children in the current study, 10 reported a convincing clinical reaction to peanut, and 8 had positive oral challenge results, giving an overall estimate of peanut allergy of 1.5% (18/1246)., Conclusions: Sensitization to peanut had increased between 1989 and 1994 to 1996. There was a strong but statistically nonsignificant trend for increase in reported peanut allergy.

Background: Sensitization to dust mites predisposes to asthma and allergic rhinitis, and prevention of this sensitization might reduce the rising prevalence of these disorders., Objective: To test the effectiveness of dust mite avoidance measures on the development of sensitization to dust mites in children., Methods: As part of a multicentre study (Study of Prevention of Allergy in Children of Europe), 242 children, aged 5-7 years, in three European countries (United Kingdom, Greece and Lithuania), were randomized to prophylactic group (n = 127) and control group (n = 115). At randomization these children were required to have a family history of atopy and positive skin test to an aeroallergen but not to house dust mite. Children in the prophylactic group were provided with dust mite impermeable mattress covers and advice on environmental measures to reduce exposure to dust-mite allergen. Control group children were given non-specific advice. After 12 months a standardized questionnaire was completed and skin prick tests were performed., Results: Ten children in the prophylactic group and 19 in the control group were lost to follow-up. Three of 117 (2.56%) children in the prophylactic group and nine of 96 (9.38%) in the control group developed sensitization to dust mites. Logistic regression analysis confirmed an independent effect of prophylactic measures (adjusted odds ratio (OR): 0.14, 95% confidence interval (CI): 0.03-0.79, P = 0.03). Fifteen children need to be treated to prevent sensitization in one child., Conclusion: Dust mite sensitization can be reduced in school age children with simple mite avoidance measures.

Asthma and wheezing illnesses carry a significant burden of disease during childhood. Prevalence studies have the capacity to provide invaluable insights into the nature of these common conditions. As part of the Isle of Wight Whole Population Birth Cohort Study (n=1456) we have examined wheezing and asthma development amongst 10-year-old children. At this age 1373 children completed ISAAC written questionnaires whilst 1043 children performed further testing including skin-prick testing, serum inhalant IgE antibody screening, spirometry and bronchial challenge. At 10-years, prevalence of current wheeze was 18.9%, current asthma (symptomatic bronchial hyper-responsiveness--BHR) 14.4% and currently diagnosed asthma (current wheeze and asthma ever--CDA) 13.0%. Both wheezing and asthma at 10 years were associated with average symptom onset at 3 years of age indicating an early life origin for such conditions. Current wheeze (P=0.011) and CDA (P=0.008) showed significant male predominance. Considerable disease morbidity was identified for these states that tended to be greatest amongst children defined asthmatic rather than simply current wheezers. Wheezing and asthma were significantly associated with both atopy (P<0.001) and allergic co-morbidity Children with these states, particularly current asthma, also demonstrated impaired lung function (FEV1, P<0.001 and FEV1/FVC, P=0.010) and increased BHR (inverse slope, P<0.001). In conclusion, Asthma and wheezing showed substantial prevalence at 10 years of age. Strong associations to male gender, atopy, impaired lung function and BHR were seen for both wheeze and asthma. In regard to prevalence and morbidity characteristics, a questionnaire-based definition of currently diagnosed asthma gave similar results to the use of symptomatic BHR in defining current asthma.

The incidence of allergic diseases is increasing to epidemic proportions both in the developed and developing world with increasing medical costs and lost productivity. The discovery of immunoglobulin (Ig) E heralded a new era in pathophysiological understanding of allergic disorders. Twenty-five years later, a humanised, non-anaphylactogenic antibody was developed against IgE that could provide a therapeutic alternative to the existing medications. RhuMAb-E25 (omalizumab, Xolair, Genetech, Inc.) is a novel anti-IgE antibody that is directed against the receptor-binding domain of IgE. This binding is specific towards free IgE thereby preventing it from attaching to the mast cell and its subsequent activation. Initial studies demonstrated attenuation of the early and late asthmatic responses when anti-IgE was administered to asthmatic subjects. Later this novel molecule was found to improve symptom scores, rescue medication use, quality of life scores and peak expiratory flows in patients with allergic asthma. Most importantly, omalizumab treatment reduced the corticosteroid use in asthmatic individuals. In patients with seasonal allergic rhinitis, there was a significant reduction in the nasal and ocular symptoms as well as the use of rescue medications. Omalizumab also demonstrated a high level of safety in adults, adolescents and children with a side effect profile no different from the placebo. Its development is an exciting milestone in the treatment of allergic diseases.

Background: Atopy is defined as the genetic propensity to develop immunoglobulin E antibodies in response to exposure to allergens and assessed by skin prick test responses to common allergens. Although it is generally agreed that atopy is an important risk factor for allergic diseases such as asthma, rhinitis, and eczema, the extent to which atopy accounts for these diseases is controversial., Objective: We aim to describe the prevalence of sensitization to common allergens and investigate the degree of association of atopy (as defined by positive skin prick test to 1 or more common allergens) to asthma, rhinitis, and eczema in a birth cohort at the age of 4 years., Methods: A birth cohort of 1456 children was recruited over a 14-month period (1989-1990). These children have been seen previously at 1 and 2 years of age. At 4 years, 1218 children were reviewed and an interview was administered or postal questionnaire was completed for the presence of allergic diseases (asthma, rhinitis, and eczema). Additionally, in 981 children, skin prick tests with a battery of 12 common allergens were performed. Allergens were house dust mite (Dermatophagoides pteronyssimus), grass pollen mix, cat, dog, Alternaria alternata, Cladosporium herbarum, cow's milk, hen's egg, soya, cod, wheat, and peanut. A mean wheal diameter of at least 3 mm greater than the negative control was taken as positive. This analysis is confined to the 981 (67% of the original population) who also had skin prick tests to the standard battery. chi(2) tests were used to test the univariate association between each allergic disease and positive skin test. Multiple logistic regression analysis was performed to obtain the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the independent effect of sensitization to each allergen on allergic disease, adjusting for the effect of sensitization to other allergens. To ascertain how much of allergic disease is attributable to atopy, we estimated the population-attributable risk. This was calculated with the formula: P(R - 1) where R is the OR for the allergic disease under consideration and P is the proportion of atopy in children with that disease., Results: Children who were skin prick-tested at 4 years were similar in most characteristics to the rest of the population, except that they had a higher prevalence of allergic disease. Allergic disorders (asthma, rhinitis, and eczema) were present in 276 (28.1%) of 981. One hundred ninety-two (19.6%) children were atopic (positive reaction to 1 or more allergens). Sensitization to inhalant allergens was relatively common (19.2%) as compared with food allergens (3.5%). House dust mite (11.9%), grass pollen (7.8%), and cat (5.8%) were the most common positive reactions. A test to the 4 most common allergens (house dust mite, grass pollen, cat, and A alternata) could detect 94% of the atopic children. Sensitization to the 4 most common allergens was strongly associated with the presence of allergic disorders. There was a graded effect with the potent allergens, such as house dust mite, having the greatest impact. For example, 50% of children sensitized to house dust mite had asthma as opposed to 44% sensitized to cat, 42% sensitized to grass pollen, and 32% sensitized to A alternata. Overall, 68.4% of children sensitized to house dust mite had asthma, eczema, and/or rhinitis. The respective figures for grass pollen, cat, and A alternata were 64.9%, 66.7%, and 57.4%. The proportion of children sensitized to cat was not higher in households with cat ownership (households with cats: 5.1% [19/374]; households without cats: 6.2% [36/580]; not significant [NS]). Similarly, no difference was seen in sensitization to dog in households with and without dogs (households with dogs: 1.8% [5/282]; households without dogs: 2.8% [19/673]; NS). Boys were atopic more often than girls at this age (male: 112 of 497 [22.5%] vs female: 80 of 484 [16.5%]; OR: 1.47, 95% CI: 1.07-2.02). Male preponderance was observed with most allergens, but this was statistically significant only for house dust mite (male: 75/497 [15.1%] vs female: 42/484 [8.7%]; OR: 1.87; CI: 1.25-2.79) and grass pollen (male: 51/497 [10.3%] vs female: 26/484 [5.4%]; OR: 2.01; CI: 1.23-3.29). An independent effect of allergen sensitization on asthma was observed only with house dust mite with an OR of 8.07 (CI: 4.60-14.14). The highest independent risk for rhinitis was sensitization to grass pollen (OR: 5.02; CI: 2.21-11.41), and for eczema, sensitization to peanut (OR: 4.65; CI: 1.02-21.34). The majority of children (98/192) were sensitized to >1 allergen. A graded effect was observed with the risk of allergic disease in the child increasing with the number of positive skin prick test reactions. This effect was consistent throughout the spectrum of allergic diseases (asthma, eczema, and rhinitis). (ABSTRACT TRUNCATED)

The pharmacokinetics of andolast, a new tetrazolyl-benzamido derivative with antiallergic, antiinflammatory, mucosal protective and antisecretive activities, have been investigated in patients suffering from mild asthma (FEV(1) > or =70% of predicted) in whom obstruction was reversible (FEV(1) increase > or =15% of initial) after the administration of 0.2 mg of salbutamol by inhalation. Twelve out-patients (seven males and five females) were enrolled in the present study and were treated with a single dose of andolast of 2, 4 and 8 mg by inhalation using the MIAT Monohaler device according to a randomised crossover design. Plasma samples were collected before drug administration and up to 540 min after dosing. Andolast plasma concentrations were determined using a validated LC-MS/MS method with a limit of quantitation of 0.2 ng ml(-1). Pharmacokinetic analysis was carried out using standard non-compartmental methods. In addition, andolast safety and tolerability were evaluated by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence of adverse events throughout the study period. Andolast was absorbed after inhalation and was available to the systemic circulation. The mean peak plasma concentrations were 6.3, 10.9 and 30.5 ng ml(-1) at the three doses, respectively, and occurred at 30, 52.5 and 30 min (median t(max)). The mean AUC(t) values were 1852, 2889 and 7677 ng min ml(-1). The apparent plasma clearance (CL/F) and volume of distribution (V(z)/F) were, respectively, 1168 ml min(-1) and 430 l at the dose of 2 mg, 1143 ml min(-1) and 468 l at the dose of 4 mg, and 1141 ml min(-1) and 486 l at the dose of 8 mg. The apparent elimination half-life averaged 4.5, 5.0 and 4.6 h at the three doses, respectively. Even though the small number of subjects participating in the present study reduced the power of the statistical test, there was no statistically significant evidence of non-proportionality for all the andolast pharmacokinetic parameters calculated at the three doses. Thus, the data obtained as a whole suggest that andolast pharmacokinetics are dose-independent in the dose range investigated. Finally, the safety and tolerabilty of the drug administered to mild asthmatic patients was good up to the maximum investigated dose of 8 mg., (Copyright 2001 John Wiley & Sons, Ltd.)

Approximately 5-10% of children suffer from allergy to one or more foods. Primary prevention through a hypoallergenic diet may reduce the prevalence of food allergy and associated co-morbidity, such as eczema and urticaria. Breastfeeding has many advantages and should be recommended for all children. Those with a history of atopy in the immediate family are at a higher risk and maternal diet during lactation, avoiding highly allergenic foods, may enhance the benefit. Cow's milk should be strictly avoided, and supplements, if required, should be with a hypoallergenic formula. Delayed introduction of egg, nuts, wheat and fish has also been suggested. Dietary restriction may have nutritional consequences for the mother and child and supervision by a dietician is essential. Maternal diet during pregnancy is not advisable as the benefit is minimal and there may be adverse effects on the foetal nutrition. In high risk infants, a combined approach, where breastfeeding with maternal avoidance of highly allergenic foods, supplemented by extensively hydrolysed formula during the first 6 months of life, in addition to the delayed introduction of solid foods, has been shown to reduce the development of food allergy in infants.

Background: Atopy is an important risk factor for asthma and allergic diseases. However, the relationship between atopy and allergic symptoms is not fully understood, and may not be the same for different allergy related symptoms and in differing environmental conditions., Objective: To study the differences in the association of allergy-related symptoms and atopy, in an adult population from five European countries., Methods: A prospective, multi-national study was conducted. Centres included Isle of Wight (UK), Vienna (Austria), Freiburg (Germany), Athens (Greece), and Kaunas (Lithuania). We used five questions derived from the ISAAC (International Study of Asthma and Allergy in Children) and other validated questionnaire, to evaluate the presence of allergic symptoms in a selected adult population. Atopy was assessed by SPT or IgE measurement to 3 core allergens (dust mite, cat and grass pollen) in all centres and 1-2 additional allergens relevant to each area (parietaria, olive, birch pollen, tree pollen mix, dog)., Results: Of 3985 subjects, 2478 (62%) responded positively to one or more core ISAAC questions. Sensitisation rate was high in Austria and UK and relatively low in Greece. Dust mite and cat were important allergens for asthma, odds ratio (OR): 2.24, 95% confidence interval (CI): 1.63-3.08 and OR: 2.31, CI: 1.69-3.14, respectively. Grass pollen was strongly associated with hay fever in all centres (OR: 3.62 CI: 2.81-4.66) and with birch pollen in Austria (OR: 3.57, CI: 2.09-6.09) and with parietaria in Greece (4.61 (2.99-7.12). In the comparative analysis, using UK as a reference, Lithuanians had a 10-20-fold reduced risk of asthma and hay fever, but were twice more likely to report chronic itching. The risk of dust mite allergy was 3- and 10-fold lower in Lithuania and Greece, respectively, whereas the risk of cat and grass pollen allergy was one and half times higher in Austria., Conclusion: The risk of allergic symptoms and sensitisation and their association vary widely in different European countries.

Background: Apart from heredity, several early life environmental factors are implicated in the development of childhood asthma. Maternal smoking is believed to increase asthmatic symptoms but its influence on the development of allergen sensitisation is debatable., Study Design: A whole population birth cohort was reviewed at ages 1, 2, and 4 years. Of 1218 children seen at 4 years, 981 (80.5%) were skin prick tested with a battery of common food and aeroallergens. Smoking history was recorded at birth and updated at each follow up and its impact on the development of asthma and allergen sensitisation in the children was assessed., Results: Two hundred and fifty mothers smoked during pregnancy (20.5%) and 307 (25.2%) after childbirth. Maternal smoking in pregnancy was associated with low birth weight (mean (SD): 3.3 (0.5) v. 3.5 (0.5) kg; p<0.001). Smoking mothers were more often from lower social classes (31.8% v. 16%, p<0. 001) and they breast fed their babies for a shorter duration (8.5 (11.4) v. 16.6 (15.2) weeks; p<0.001). The difference in breast feeding duration was partly due to a higher proportion of smoking mothers who never breast fed their babies. Although at age 2 years asthmatic symptoms were associated with exposure to maternal tobacco smoke (odds ratio 2.2, 95% confidence interval 1.5 to 3.4; p<0.001), this association was lost by 4 years. However, maternal smoking was a significant risk factor in a subgroup of children with asthmatic symptoms but negative skin prick test. Maternal smoking did not increase allergen sensitisation at age 4 years. No effect of paternal smoking on asthma was observed in the children.

Sensitization to hen's egg early in life has been proposed as a predictor for respiratory allergic disease during childhood. However, symptomatic egg allergy in infancy has not been studied in this context. In 1989, a cohort of consecutive births was recruited. Data on family history of atopy and environmental factors were collected. At 4 years of age, 1,218 children were seen of whom 981 were skin-prick tested with a range of food and aero-allergens. Of the 1,218 children, 29 (2.4%) had suffered symptomatic egg allergy (20 during infancy). Egg allergy in infancy was associated with increased respiratory (asthma, rhinitis) allergic disease (odds ratio [OR] 5.0, 95% confidence intervals [CI] 1.1-22.3; p < 0.05) at 4 years of age, with a positive predictive value (PPV) of 55.0%. The addition of infantile eczema to egg allergy increased the PPV to 80% whereas the addition of family history of atopy had no effect. Egg allergy also increased aero-allergen sensitization (OR 6.1, CI 1.1-37.5; PPV 61.1%; p < 0.05). As a predictor for respiratory allergic disease and aeroallergen sensitization, it carried a high specificity but poor sensitivity. Hence, egg allergy in infancy, especially when coexisting with eczema, increases respiratory allergic symptoms and aero-allergen sensitization in early childhood.

Background: Increasing prevalence of allergic disorders has focused attention on primary prevention. There is a need to improve the accuracy of early-life predictors of atopy so that the at-risk population can be accurately defined and preventive measures instituted., Objective: The predictive capacity of elevated cord IgE, with or without family history of atopy, to allergic symptoms and skin prick test (SPT) sensitization is evaluated in a birth cohort followed up prospectively for 4 years., Methods: A birth cohort of 1456 consecutively born children was recruited in 1989. Data were collected on family history of atopy and cord serum total IgE (cord IgE) was measured. Of these, 1218 children were seen in the clinic at 4 years to determine the development of symptoms and signs of allergic disease and 981 were skin tested to a range of common food and aeroallergens., Results: Of 1218 children reviewed at age 4 years, 218 (17.8%) had symptoms of respiratory allergy and, of those skin tested (n = 981), 192 (19.6%) reacted positively. Twice as many children with elevated cord IgE (>/= 0.5 kU/L) at birth became sensitized to aeroallergens by age 4 years (34.8% vs 17.3%, P < 0. 001). Positive predictive value (PPV) of elevated cord IgE for the development of aeroallergen sensitization was better than that of family history of atopy (34.8 vs 22.6%). Combining paternal atopy with elevated cord IgE substantially increased the predictive capacity (PPV 77.8%). Cord IgE levels did not correlate with clinical asthma or rhinitis at age 4 years and PPV for allergic respiratory symptoms remained poor at all cutoffs., Conclusion: Cord IgE is better than family history for predicting atopy as defined by allergen sensitization and this predictive value can be further increased by combining cord IgE with paternal atopy.

To improve our understanding of the pathophysiology of chronic allergic asthma, we mimicked natural allergen exposure by giving tiny doses of dust-mite extract (equivalent to estimated daily exposure in a typical bedroom) in three weekly sessions for 4 wk. Nine mild asthmatic adults who were highly sensitive to dust-mite allergen participated in the study. Serial assessments of bronchial reactivity by methacholine challenge, pulmonary function, symptoms, and bronchodilator requirements were obtained. Seven of nine subjects had a twofold or more (median: 6, range: 2.7 to 25) reduction (p = 0.008) in PC20, after which saline inhalations were substituted for dust-mite extract. Bronchial reactivity returned to normal within 2 to 3 wk after cessation of dust-mite inhalations in all but one subject. Predosing FEV1 dropped 10% over 4 wk of provocation (p = 0.001) and 7 of 9 returned to prestudy level within 2 wk after dosing was stopped. Late-phase responses were seen in 6 of 9 subjects. We conclude that repeated aerosol exposure to dust-mite allergen in doses comparable to natural bedroom exposure is sufficient to adversely affect pulmonary function and bronchial hyperractivity in sensitized individuals. These changes are rapidly reversible. This low-dose provocational strategy provides an attractive model for the experimental study of allergic asthma. Arshad SH, Hamilton RG, Adkinson NF, Jr. Repeated aerosol exposure to small doses of allergen: a model for chronic allergic asthma.

Objectives: A birth cohort was followed-up to age 4 years to record the development of allergic disorders and to study the influence of genetic and environmental factors., Methods: Information on family history and environmental factors was obtained at birth, and serum cord IgE was measured. At age 4 years, 1218 children were reviewed., Results: By age 4 years, 27% of the children had symptoms of allergic disease. Period prevalence of asthma increased from 8.7% in infancy to 14.9% at 4 years. Family history of atopy was the single most important risk factor for atopy in children. Sibling atopy was a stronger predictor of clinical disease than maternal or paternal atopy, whereas paternal atopy, male sex, and high cord IgE were significant for the development of allergen sensitization. Children of asthmatic mothers were three times more likely to have asthma (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.6-5.8) and rhinitis (OR: 2.9, CI: 1.1-7.4). Formula feeding before 3 months of age predisposed to asthma at age 4 years (OR: 1.8, CI: 1.2-2.6). The effect of maternal smoking on childhood wheeze seen at 1 and 2 years was lost by age 4, except for a subgroup with negative skin test responses (nonatopic asthma). Less than half (46%) of the infantile wheezers were still wheezing at 4 years of age., Conclusion: Family history of atopy remains the most important risk factor for atopy in children, but other markers can be identified with a potential for intervention at an early age.

In an attempt to prevent or reduce the manifestations of atopic disease, a group of infants considered to be genetically at high risk of atopy was entered in a prenatally randomized, controlled study. A prophylactic group (n = 58) was either breast-fed with their mothers excluding foods regarded as highly antigenic from their diets, or given an extensively hydrolysed formula. In addition, strenuous efforts were made to reduce exposure to the house-dust mite by application of acaricide to the bedroom and living room carpets and upholstered furniture. A control group (n = 62) was fed conventionally by breast or on formula, and no specific environmental measures were taken. The results (previously reported) after 1 year showed significantly less total allergy, asthma, and eczema in the prophylactic group. Similar results were obtained at 2 years although the reduction in asthma no longer achieved statistical significance. However, there was significantly less sensitization, as shown by a battery of skin prick tests (SPTs), to both dietary allergens and aeroallergens in the prophylactic group. All the children have now been reviewed at the age of 4 years, and SPTs to a wide range of dietary allergens and aeroallergens have been performed. The control group continues to show more total allergy (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.21-6.13, P < 0.02), definite allergy (allergic symptoms plus positive SPT) (OR 5.6, CI 1.8-17.9, P < 0.005), and eczema (OR 3.4, CI 1.2-10.1, P < 0.05). More control children have positive SPTs (OR 3.7, CI 1.3-10.0, P < 0.02). A dual approach to the prevention of allergic disease, avoiding as far as possible sensitization to food and aeroallergens, significantly reduces the risk of atopic disease. This should be reserved for infants considered at very high risk of atopy, and close medical and dietetic supervision must be available.

Background: One hundred twenty children, identified before birth as being at high risk for atopy, were prenatally assigned to prophylactic or control groups., Methods: The infants in the prophylactic group either received breast milk from mothers on an exclusion diet or an extensively hydrolyzed formula. Their bedrooms and living rooms were treated repeatedly with an acaricide, and they used polyvinyl-covered mattresses with vented head areas. The infants in the control group were fed conventionally, and no environmental control was recommended., Results: A significant advantage, first demonstrated at 1 year of age, persists for children in the prophylactic group. They have less of any allergy or eczema, but the reduced prevalence of asthma is no longer significant. Only three children in the prophylactic group had positive skin prick test results compared with 16 in the control group, suggesting a significant reduction in sensitization., Conclusion: A dual approach to allergen avoidance, focusing on foods and aeroallergens, appears to be beneficial in selected high-risk infants. Avoidance of potent allergens in early life increases the threshold for sensitization in these high-risk infants. Whether sensitization has been avoided or merely deferred has yet to be proved.

The effect of genetic and environmental factors on the prevalence of allergic disorders in early childhood was determined in a prospective follow-up study. Information was available on 1174 children at the age of 2 years. Two-hundred and seventy-five were considered to have an allergic disorder. The prevalence varied from 3.2% for rhinitis to 10.9% for asthma. At 2 years 60 children reacted positively on skin-prick test (SPT). Multivariate logistic regression analysis was used to obtain adjusted odds ratios (95% confidence interval) for each factor. For asthma, positive family history, male sex, low birth-weight, maternal smoking and season of birth were significant risk factors. For eczema, positive family history was the only significant risk factor. For rhinitis, lower socio-economic group and autumn birth were significant. Male sex and low birth-weight were significant for skin test positivity. Positive family history and low birth-weight were significant risk factors for any allergy. Low birth-weight was also a significant risk for skin test reactivity to house dust mite. Genetic and environmental factors have a profound effect on the development of allergic disorders in the first two years of life.

House dust mites are believed to be major triggers for allergic disease in atopic individuals. As part of a programme controlling dietary and aero-allergen exposure in high-risk infants, an acaricidal foam and powder (Acarosan) was applied to bedroom and main living room carpets, as well as upholstered furniture, on four occasions in the first year of life. Dust was assayed for mite antigen (Der p1) and these results compared with the semi-quantitative assay of guanine content (Acarex Test). After nine months mean Der p1 levels had decreased by 70% in the treatment group. Proportionally, the greatest fall occurred in those items that had the highest initial mite antigen content. The Acarex score does show a correlation with Der p1 levels, but cannot replace antigen assay when accurate data is required. A chemical acaricide may help reduce house dust mite antigen levels, but is not by itself sufficient to reduce levels below that considered critical for sensitisation.

A total of 1167 infants were followed for 1 year in a population-based prospective study to assess the effect of environmental factors on the development of allergic disorders. Some of these environmental factors are interdependent. Mothers who formula fed their infants smoked more often (p less than 0.001) and tended to belong to lower social classes (p less than 0.01). Logistic regression analysis was performed to adjust for these confounding variables. Maternal smoking adversely affected the prevalence of asthma (p = 0.003) defined as three or more separate episodes of wheezing and total allergy (p = 0.02). Infants in lower socioeconomic groups developed asthma significantly more often (p = 0.03) than infants born in higher socioeconomic groups. There was a nonsignificant trend for infants born in summer to develop asthma more than infants born in winter (p = 0.08). No effect of these factors was observed on eczema, food intolerance, or on the subgroup of infants with definite allergy (clinical disorder with positive skin prick test [SPT]). Exposure to animal dander did not influence the prevalence of clinical disorder, but positive SPT reaction to cat dander was more prevalent in infants who were exposed to cats and/or dogs (p = 0.04). Positive SPT to house dust mite occurred significantly more often in infants who were formula fed (p = 0.05). The environmental factors had a profound effect on the prevalence of asthma but not on other allergic disorders.

There is much evidence that the development of allergic disorders may be related to early exposure of allergens, including those in breastmilk. We have tried to find out whether avoidance of food and inhaled allergens in infancy protects against the development of allergic disorders in high-risk infants. In a prenatally randomised, controlled study 120 infants with family history of atopy and high (greater than 0.5 kU/l) cord-blood concentrations of total IgE were allocated randomly to prophylactic and control groups. In the prophylactic group (n = 58), lactating mothers avoided allergenic foods (milk, egg, fish, and nuts) and avoided feeding their infants these foods and soya, wheat, and orange up to the age of 12 months; the infants' bedrooms and living rooms were treated with an acaricidal powder and foam every 3 months, and concentrations of Dermatophagoides pteronyssinus antigen(Der p l) in dust samples were measured by enzyme-linked immunosorbent assay. In the control group (n = 62), the diet of mothers and infants was unrestricted; no acaricidal treatment was done and Der p l concentrations were measured at birth and at 9 months. A paediatric allergy specialist unaware of group assignment examined the infants for allergic disorders at 10-12 months. Odds ratios were calculated by logistic regression analysis for various factors with control for other confounding variables. At 12 months, allergic disorders had developed in 25 (40%) control infants and in 8 (13%) of the prophylactic group (odds ratio 6.34, 95% confidence intervals 2.0-20.1). The prevalences at 12 months of asthma (4.13, 1.1-15.5) and eczema (3.6, 1.0-12.5) were also significantly greater in the control group. Parental smoking was a significant risk factor for total allergy at 12 months whether only one parent smoked (3.97, 1.2-13.6) or both parents smoked (4.72, 1.2-18.2).

Cord total serum IgE has been advocated as a screening test to detect infants at high risk of allergy who would be suitable for preventive measures. In a population based prospective study to look at the predictive capacity of cord IgE and family history of atopy 1111 one-year-old infants were followed-up. Cord IgE was measured using the EIA ultra technique (Pharmacia, Uppsala, Sweden). Atopic symptoms developed in 255 (23%) at one year, 183 (16.5%) had probable atopy (clinical disorder but negative skin prick test (SPT)) and 72 (6.5%) had definite atopy (clinical disorder with positive SPT). There was no difference in the mean cord IgE levels in infants with or without atopic manifestations. The cut-off for IgE was taken at 0.6 ku/1. The specificity of the test was 92% but the sensitivity was only 8.5%. The positive and negative predictive values were 24% and 78% respectively. Family history of atopy is far more sensitive in detecting infants at risk of atopy and little is added by knowledge of cord IgE.

This population-based prospective study assessed the relationship between pets and atopic disorders in infancy. One or more pets were found in 61.4% of households. Pets were found in homes with a family member affected by asthma or rhinitis as often as in homes with no allergy in the family. The presence of pets was not shown to affect the development of atopic manifestations in the first 12 months of life. Infants exposed to cats developed skin prick test sensitivity to cat dander significantly more often (p = 0.01) than those infants who had had no such exposure.

Twelve cases of allergy to Brazil nut have been recorded in the last 8 years. The reaction is usually IgE mediated and most patients have other atopic diseases. There appear to be several proteins with potent antigenic components in Brazil nut.