Atopy in childhood. III. Relationship with pulmonary function and airway responsiveness

The relationship between atopy and pulmonary function in children, and how these relate directly or indirectly to airway hyperresponsiveness, is uncertain. We have examined these relationships in a sample of 13-year-old children. A questionnaire on respiratory symptoms, skin-prick tests to 11 common allergens, spirometry and an abbreviated methacholine challenge test were completed by 662 members (341 boys) of a birth cohort of New Zealand children followed longitudinally to age 13. There was a significant relationship between the presence and degree of atopy, and baseline pulmonary function. Low FEV1/VC ratios were associated with a greater likelihood of airway responsiveness, not only in subjects with diagnosed asthma, but also in the full cohort and in the sub-group of 426 children who denied asthma or current wheeze. The relationships between baseline FEV1/VC and airway responsiveness were stronger in atopic than in non-atopic children, with the strongest relationships in children sensitive to house dust mite and/or cat dander. In the presence of atopy, progressively lower levels of lung function were strongly associated with a higher prevalence of airway responsiveness (P<0.001). In non-atopic subjects, only those with the most impaired lung function (FEV1/VC < 75%) showed any substantive prevalence of airway responsiveness. The relationship between the degree of atopy and the FEV1/VC ratio, although significant in univariate analysis, became completely non-significant after accounting for airway responsiveness. In 13-year-old children, atopy, especially to house dust mite and cat dander, was correlated with pulmonary function expressed as FEV1/VC ratio. Airway responsiveness likewise correlated with impaired baseline lung function. The apparent relationship of lung function to atopy occurred primarily as a result of the relationship between atopy and airway responsiveness. Atopy and impaired lung function were additive factors predicting airway responsiveness.     

Atopy in childhood. I. Gender and allergen related risks for development of hay fever and asthma

Reasons for the gender differences in prevalence rates for asthma remain unclear. We have examined the relationships between allergen skin-test reactions and diagnoses of hay fever and asthma in New Zealand boys and girls examined at the age of 13 years. Information on current and past wheezing, diagnosed asthma, and hay fever was obtained for 662 subjects (341 boys) of a birth cohort followed longitudinally to the age of 13 years, using a physician-administered questionnaire. Atopic status was determined by skin-prick tests to 11 common allergens. The proportion of 13-year-old boys with current asthma was 1.6 times higher and of ever-diagnosed asthma 1.4 times higher than in girls, but the prevalence of recurrent wheeze (> or = three episodes per year) not diagnosed as asthma, or of hay fever, was not significantly different between the sexes. The prevalence of diagnosed asthma increased with increasing numbers of positive skin tests, but hay fever without asthma was little affected above one positive skin-test. Boys had a greater prevalence of any positive skin-test (50.1% vs 37.1%), two or more positive tests (29.3% vs 21.8%), and responses to house dust mite (34.0% vs 23.1%) and cat (14.7% vs 11.2%). Gender differences for asthma became insignificant when adjusted for skin-test responsiveness to house dust mite and/or cat. The proportion of children with diagnosed asthma increased with increasing size of weals to house dust mite and cat dander. Gender differences in allergen sensitivities partly explain the gender differences in diagnosed asthma in children. In both sexes, risk of asthma was primarily associated with sensitization to indoor allergens (house dust mite and cat), and was related to the magnitude of the skin-test response, while the risk of hay fever was primarily associated with grass pollen sensitivity.     

Pet-keeping in childhood and adult asthma and hay fever: European community respiratory health survey

BACKGROUND: Whether pet-keeping early in life protects against or promotes allergy remains unclear. OBJECTIVE: Our aim was to examine the effects of childhood pet-keeping on adult allergic disease in a large international population-based study, including information on sensitization, adult pet-keeping, and pet prevalence in the populations. METHODS: We used information from structured interviews (n = 18,530) and specific IgE to common aeroallergens in blood samples (n = 13,932) from participants in the European Community Respiratory Health Survey (ECRHS) to analyze the associations between keeping pets and adult asthma and hay fever. RESULTS: Keeping cats in childhood was associated with asthma only among atopic subjects, an association that varied between centers (P =.002) and was stronger where cats where less common (< 40% cats: odds ratio(wheeze) [OR(wheeze)] = 1.84, 95% CI = 1.31-2.57; 40%-60% cats: OR(wheeze) = 1.33, 95% CI = 1.10-1.61; > or =60% cats: OR(wheeze) = 0.98, 95% CI = 0.73-1.33). Dogs owned in childhood or adulthood were associated with asthma among nonatopic subjects (childhood: OR(wheeze) = 1.28, 95% CI = 1.13-1.46; adulthood: OR(wheeze) = 1.31, 95% CI = 1.14-1.51; both: OR(wheeze) = 1.69, 95% CI = 1.40-2.04). In atopic subjects, those who had owned dogs in childhood had less hay fever (OR = 0.85; 95% CI = 0.73-0.98) and no increased risk of asthma (OR(wheeze) = 1.01, 95% CI = 0.87-1.17). Respiratory symptoms were more common in subjects who had owned birds during childhood (OR(wheeze) = 1.12; 95% CI = 1.02-1.23) independent of sensitization. CONCLUSIONS: The effects of pet-keeping in childhood varied according to the type of pet, the allergic sensitization of the individual, and the wider environmental exposure to allergen. Cats owned in childhood were associated with more asthma in sensitized adults who grew up in areas with a low community prevalence of cats. Dogs owned in childhood seemed to protect against adult allergic disease but promote nonallergic asthma.     

Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood

BACKGROUND: The relationship between atopy, asthma, and eosinophilic inflammation is less clear in early childhood than later in life. OBJECTIVE: We sought to determine the relationships between asthma, atopy, and serum eosinophil cationic protein (ECP), a biomarker of eosinophil activation, in 6-year-old children. METHODS: Serum ECP levels were available from 968 six-year-old children who were part of a longitudinal birth cohort being assessed for asthma and atopy. Detailed clinical history and examination, lung function testing, methacholine challenge, and skin prick testing to 4 common allergens were undertaken. Subgroups of the children were compared by using t tests, ANOVA, chi 2 tests, and regression analysis. RESULTS: One hundred ninety-one (19.7%) children had current asthma, with 114 (59.7%) of these being atopic. The mean serum ECP level for the entire group was 18.0 mug/L (range, 2.0-146.0 mug/L), with no difference between male and female patients. Serum ECP was higher in atopic children (20.5 +/- 18.4), those with asthma (22.4 +/- 19.6), and those with asthma and atopy (26.6 +/- 22.4; all P < .001 compared with children with no asthma or atopy [16.1 +/- 15.9]). Serum ECP levels were highest in children with severe asthma ( P < .001), especially in those with concurrent atopy. Severity of atopy, judged on the basis of wheal size or derived variables combining wheal size and the number of positive skin tests, was a major determinant of serum ECP. Heightened methacholine responsiveness was not associated with increased serum ECP levels. CONCLUSION: The higher serum ECP levels seen in 6-year-old children with current asthma and more severe atopy suggest that atopy and eosinophilic inflammation are important in driving this clinical phenotype and that this might represent asthma that persists.     

Natural history of hay fever and pollen sensitization,and doctors' diagnosis of hay fever and pollen asthma in German schoolchildren

BACKGROUND: In order to prevent pollen asthma by immunotherapy it is mandatory to know the best time to initiate it. Children with hay fever complaints are at considerable risk of developing pollen asthma. Population-based data on their natural history is urgently needed. METHODS: A longitudinal cohort study was conducted over four years in six rural towns in Baden-Württemberg, Germany. A questionnaire with questions taken from the International Study of Asthma and Allergies in childhood (ISAAC) was filled in every spring and autumn. Hay fever complaints, asthma defining symptoms and new doctors' diagnosis of hay fever and asthma were recorded. Additionally a skin prick test with pollen allergens was performed every autumn. RESULTS: In 1996, 19.7% of 1101 elementary school children (age: 8.1-9.9 years (5-95%)) were found to be sensitized to pollen and 8.7% had already been diagnosed as having hay fever. In a pooled analysis of 2478 children-summers, children with positive pollen sensitization had a significantly higher risk of developing hay fever symptoms (2.63; 2.17-3.10 odds ratio (OR); 95% confidence interval (CI)) and of being diagnosed as suffering from hay fever (7.88; 4.70-13.20). Furthermore, although their OR for the development of asthma symptoms during the pollen season was 3.88 (2.48-6.07 CI), it was only 0.69 (0.24-2.01 CI) for doctors' diagnosis of pollen asthma. CONCLUSION: Children of elementary school age with pollen sensitization and a history of hay fever are at considerable risk of getting pollen asthma, but they are not quickly diagnosed as such. Specific immunotherapy might be a means of preventing asthma completely in such a situation. Our data helps to estimate the sample size for intervention studies of this kind.     

Change in airway responsiveness to inhaled house dust from childhood to adulthood.

Between 1966 and 1969, housedust (HD) inhalation provocation tests were performed in 119 children with asthma. Between 1984 and 1987, 101 of the 119 subjects (85%) were reinvestigated. Thirty-one of these 101 adults who participated in a study on the outcome of childhood asthma were rechallenged with HD after a mean interval of 16 years to establish the change in airway responsiveness to HD from childhood to adult life. In the childhood study in these 31 subjects, six had no response (NAR); six, an early response (EAR); eight, a late (LAR); and eleven subjects, an EAR followed by an LAR (dual asthmatic response [DAR]) to the inhalation of HD. In the second survey, two of the subjects with NAR in the first study had a bronchoconstrictor response to HD. Five subjects with an EAR or an LAR response in childhood had NAR as an adult. The eleven subjects with a DAR during childhood also had a response to HD as an adult; five had an EAR, and six adults again had a DAR. Eleven of the 13 adults (85%) with current respiratory symptoms had a response to HD during the second survey. Although they were symptom free, 11 of the other 18 adults (61%) responded on inhalation of HD. One of the 18 subjects without (6%), and six of the 13 subjects (46%) with current respiratory symptoms, had a provocative concentration of histamine in FEV1 10% of baseline less than or equal to 16 mg/ml. We conclude that, although respiratory symptoms disappear in one half the children with asthma and although adults may believe that they have outgrown their disease, adults still have the potency to respond to inhaled allergens. Most children do outgrow their respiratory symptoms but not the susceptibility of their airways to allergens.     

Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients

Background Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect airway inflammation more closely compared with AHR measured by stimuli that act directly on BSM. Methods Fifty‐three adult non‐smoking asthmatics (28 females, 18–56 years) who were not taking inhaled steroids were challenged with mannitol (up to 635 mg) and methacholine (up to 8 μmol). Induced sputum eosinophils, exhaled nitric oxide (eNO), peak flow variation and clinical severity of asthma according to the Global Initiative for Asthma guidelines were measured in addition to the health‐related quality‐of‐life score using the Juniper asthma quality‐of‐life questionnaire. Findings Both AHR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was >20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20 p.p.b., but none had sputum% eosinophils >1%. AHR to mannitol was more closely associated with the percentage of sputum eosinophils (PD₁₅ to mannitol vs. sputum% eosinophils: r: ?0.52, P<0.05), compared with AHR to methacholine (PD₂₀ to methacholine vs. sputum% eosinophils: r: ?0.28, NS). Furthermore, there was a stronger correlation between AHR to mannitol and the level of eNO [PD₁₅ to mannitol vs. eNO (p.p.b.): r: ?0.63, P<0.001], compared with AHR to methacholine [PD₂₀ to methacholine vs. eNO (p.p.b.): r: ?0.43, P<0.05]. Interpretation In asthma patients not being treated with steroids, AHR to mannitol and to methacholine indicated the presence of airway inflammation. AHR to mannitol reflected the degree of airway inflammation more closely when compared with methacholine.     

Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.

BACKGROUND: Although the role of eosinophils in airway inflammation in chronic asthma has been extensively studied, a role for neutrophils has not been well characterized. Furthermore, prior studies have not systematically sought or controlled for factors that might confound the relationship between cellular markers of inflammation and physiologic measures of airway function. OBJECTIVE: The purpose of this study was to determine whether eosinophilic and neutrophilic inflammation independently contribute to abnormalities of airway function in asthma. METHODS: Multivariate analysis of data collected during screening and enrollment of 205 asthmatic adults for clinical trials was conducted to examine the relationships between cellular inflammation in induced sputum and FEV(1) and methacholine responsiveness (PC(20)) while confounding factors were controlled for. RESULTS: We found that age, sex, ethnicity, and use of inhaled corticosteroids were important confounding factors of the relationship between cellular inflammation and airway function. When these factors were controlled for, multivariate analysis showed that eosinophil percentage in induced sputum is independently associated with lower FEV(1) and lower PC(20) (P = .005 and P = .005, respectively). In the same models, increased sputum neutrophil percentage is independently associated with lower FEV(1) (P = .038) but not with PC(20) (P = .49). CONCLUSIONS: These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV(1) in asthma. Therapies directed specifically at control of neutrophilic inflammation might be useful in improving airway caliber in patients with chronic asthma.     

Exposure to pets, and the association with hay fever, asthma, and atopic sensitization in rural children

BACKGROUND: An increasing number of studies report pet exposure to be associated with lower risk of asthma and allergies. This 'protective pet effect' has been suggested to result from a modified T-helper (Th)2-cell response, or because of increased microbial load in homes where pets are kept. We examined the associations between pet contact and the occurrence of asthma and allergies in children of the rural Allergy and Endotoxin (ALEX) population, taking farm animal contact, endotoxin and cat allergen levels in mattress dust into account. METHODS: Information about contact with pets and farm animals, asthma and allergy were collected for 812 children by a standardized parents' questionnaire and an interview. Mattress dust endotoxin and cat allergen levels as well as specific IgE and IgG4 antibodies to Fel d1 were determined. RESULTS: Current contact with dogs was inversely associated with diagnosed hay fever (OR 0.26, 95% CI 0.11-0.57), diagnosed asthma (OR 0.29, 95% CI 0.12-0.71), sensitization to cat allergen (OR 0.48, 95% CI 0.23-0.99) and to grass pollen (OR 0.55, 95% CI 0.33-0.94), but not with increased IgG4 levels. Early and current contact with cats were associated with reduced risk of wheezing (OR 0.48, 95% CI 0.23-1.00, and OR 0.49, 95% CI 0.26-0.92, respectively) and grass pollen sensitization. Adjustment for farm animal contact but not for endotoxin and cat allergen exposure attenuated these associations and the effect of pet was stronger among farmers' children. CONCLUSION: Although pet exposure was very frequent in this rural population, the inverse relation between current dog contact, asthma and allergy was mostly explained by simultaneously occurring exposure to stable animals or was restricted to farm children. In addition, a subtle form of pet avoidance may contribute to the protective effect of pet.     

Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing

BACKGROUND: Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. METHODS: We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. RESULTS: Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. CONCLUSIONS: Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.     

Mannitol challenge for assessment of airway responsiveness,airway inflammation and inflammatory phenotype in asthma

Background Assessment of airway inflammation in asthma is becoming increasingly important, as the inflammatory phenotype underpins the treatment response. Objective This study aimed to evaluate mannitol as a tool for assessing airway responsiveness and airway inflammation in asthma, compared with hypertonic saline. Methods Fifty‐five subjects with stable asthma completed a hypertonic (4.5%) saline challenge and a mannitol challenge at two separate visits, performed 48–72 h apart, in random order. Results Induced sputum was obtained from 49 (89%) subjects during the saline challenge and 42 (76%) subjects during the mannitol challenge (P>0.05). There was a significant correlation between the greatest percentage fall in forced expiratory volume in 1 s (FEV₁) (r=0.6, P<0.0001), the dose–response slope (r=0.73), cumulative dose (r=0.55) and PD15 (r=0.46) for mannitol and hypertonic saline. The greatest percentage fall in FEV₁ to mannitol was less in non‐eosinophilic asthma. There was a lower total cell count in mannitol vs. hypertonic‐saline‐induced sputum. However, sputum eosinophils and neutrophils were not significantly different. Using mannitol, a higher proportion of subjects were classified as having eosinophilic asthma. There were no differences in IL‐8, neutrophil elastase or matrix‐metalloproteinase 9 concentrations in sputum samples induced with mannitol or hypertonic saline. Conclusion We conclude that mannitol can be used to induce good‐quality sputum, useful for analysis of inflammatory mediators and for predicting the inflammatory phenotype in asthma. Cite this as: L. G. Wood, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2010 (40) 232–241.     

Atopy and asthma in migrants

Atopy and asthma result from the effects of environmental factors on genetically susceptible persons, and different prevalence rates have been documented worldwide. In developed and industrialized countries a higher prevalence of atopy and asthma is observed as compared with undeveloped and less affluent countries. Migration involves exposure to a new set of pollutants and allergens. In addition, it involves several socioeconomic and cultural issues such as housing conditions, diet and accessibility to medical services, all of which are likely to affect migrants' health. Migration studies provide information on the role of environmental factors in the development of atopy and asthma. Immigration to allergy-prevalent countries causes more allergies and asthma in immigrants as compared to the prevalence of atopy in their countries of origin. The increase in allergy and asthma is usually not related to ethnicity, but in certain populations may play an important role. Studies on migrants support the notion that lifestyle and environmental factors in western industrialized countries facilitate atopy and asthma. The effect is time-dependent. Acquiring allergy is influenced by the age at the time of immigration. Migrants, in general, are more prone to the development of allergies than the local population. Low hygiene prior to immigration does not seem to protect against the development of atopy or asthma. Vaccinations do not affect the development of atopy or asthma in the general population and in migrants. Migrants should be aware of the potential of developing allergies and/or asthma. Strategies for primary prevention in high-risk atopic individuals and secondary prevention guidelines should be developed both for populations in developing countries as well as for immigrants from such countries to atopy-prevalent developed countries.     

The i.v. infusion of mannitol decreases airway responsiveness to methacholine in asthma

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation and oedema. The oedema of the airway wall may contribute to airway narrowing and hyperresponsiveness by increasing airway wall thickness, by altering airway compliance, or by impairing the transmission of the lung elastic recoil to the airway smooth muscle (ASM). We hypothesized that the i.v. infusion of mannitol, an osmotic diuretic, would reduce the water content of the airway wall in asthma and COPD, thus decreasing airway responsiveness to methacholine (MCh). In eight asthmatic and in six COPD patients, airway responsiveness to MCh, lung volumes and lung mechanics were measured before and after infusion of mannitol. In the asthmatics, mannitol decreased airway responsiveness to MCh and lung elastic recoil. In the COPD patients, no differences were recorded after mannitol infusion. These data suggest that the airway wall oedema, in asthma, has an impact on airway responsiveness to MCh. The differential effect of mannitol in asthma versus COPD, may relate to the specific pathologic features of the diseases.     

HLA in eczema and hay fever.

The presumed HLA haplotype A1:B8 was more frequent and the combination of A3 and B7 was less frequent in allergic subjects presenting with eczema, than in those presenting with hayfever. A1:B8 was most frequent (36%) in eczema complicated by asthma and/or hay fever, and least frequent (5%) in hay fever alone, considerably above and below the frequency in the general population (17%).