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Background: Environmental factors may play important roles in asthma, but findings have been inconsistent., Objective: The goal of this study was to determine the associations between early life exposures, environmental factors, and asthma in urban and rural children in southeast China., Methods: A screening questionnaire survey was conducted in 7,164 children from urban Guangzhou and 6,087 from rural Conghua. In the second stage, subsamples of 854 children (419 from Guangzhou, 435 from Conghua) were recruited for a case-control study that included a detailed questionnaire enquiring on family history, early life environmental exposures, dietary habits, and laboratory tests (including histamine airway provocation testing, skin prick tests, and serum antibody analyses). House dust samples from 76 Guangzhou families and 80 Conghua families were obtained to analyze levels of endotoxins, house dust mites, and cockroach allergens., Results: According to the screening survey, the prevalence of physician-diagnosed asthma was lower in children from Conghua (3.4%) than in those from Guangzhou (6.9%) (P < .001). A lower percentage of asthma was reported in rural subjects compared with urban subjects (2.8% vs. 29.4%; P < .001) in the case-control study. Atopy (OR, 1.91 [95% CI, 1.58-2.29]), parental atopy (OR, 2.49 [95% CI, 1.55-4.01]), hospitalization before 3 years of age (OR, 2.54 [95% CI, 1.37-4.70]), high consumption of milk products (OR, 1.68 [95% CI, 1.03-2.73]), and dust Dermatophagoides farinae group 1 allergen (OR, 1.71 [95% CI, 1.34-2.19]) were positively associated with asthma. Living in a crop-farming family at < 1 year of age (OR, 0.15 [95% CI, 0.08-0.32]) and dust endotoxin levels (OR, 0.69 [95% CI, 0.50-0.95]) were negatively associated with asthma., Conclusions: Rural children from an agricultural background exhibited a reduced risk of asthma. Early life exposure to crop farming and high environmental endotoxin levels might protect the children from asthma in southern China., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objectives: To investigate the relationship between current and early life factors and airway responsiveness to inhaled methacholine in children with a median age of 7.0 years., Participants: Study subjects were a subset of a prospective birth cohort of children in the Boston area at high risk for atopy., Methods: One hundred thirty-one children underwent both skin-prick testing to a panel of aeroallergens and a methacholine challenge test between 6.5 years and 8.8 years of age. Telephone questionnaires were performed at set intervals, and home dust samples were collected in the first year of life., Results: Of the 131 participating children, 51% (67 patients) had at least one positive skin-prick test response and 28% (37 patients) had airway hyperresponsiveness (AHR) [provocative concentration of methacholine causing a 20% fall in FEV(1) of < 4 mg/mL]. After adjusting for relevant covariates, AHR was strongly associated with sensitization to at least four aeroallergens (odds ratio [OR], 13.41; 95% confidence interval [CI], 3.03 to 59.42). In separate adjusted models, sensitization to cat (OR, 14.73; 95% CI, 3.64 to 59.55), dust mite (OR, 5.13; 95% CI, 1.94 to 13.56), cockroach (OR, 4.00; 95% CI, 1.19 to 13.50), and ragweed (OR, 10.08; 95% CI, 2.31 to 44.10) were significant predictors of AHR. However, no relationship was found with early life exposure to perennial aeroallergens or other perinatal and first-year-of-life factors., Conclusions: Among young children at risk for atopy, sensitization to specific aeroallergens, but not early life exposures, is associated with increased airway responsiveness.

Background: Asthma development and prognosis have been studied extensively in at-risk populations, but knowledge of the natural history of asthma in the general population is limited., Objective: To describe the incidence and remission of asthma and its predictors, data from a 12-year follow-up study of a random population sample (n = 291; age range, 7 to 17 years) at enrollment, were analyzed., Methods: The sample was examined in 1986 and in 1998. A case history, including data on asthma, allergic diseases, and lifestyle factors, was obtained by questionnaire and interview. Airway hyperresponsiveness (AHR) to histamine, lung function, and skin-prick test reactivity to a standard panel of 10 aeroallergens were measured., Results: The point prevalence of asthma increased from 4.1% at the first survey to 11.7% at follow-up, at which point 19.6% of the sample had ever experienced asthma symptoms. Of the subjects with ever-asthma, 40% had remitted at follow-up. Asthma developed in 45 subjects (16.1%) during the follow-up period, which was predicted by the following factors: wheezing in childhood (odds ratio [OR], 3.61; 95% confidence interval [CI], 1.34 to 9.75), AHR (OR, 4.94; 95% CI, 2.42 to 10.08), allergic sensitization to house dust mites (OR, 3.23; 95% CI, 1.00 to 10.40), and dermatitis (OR, 2.94; 95% CI, 1.22 to 7.11). The simultaneous presence of more than one of these risk factors was associated with a high probability of developing asthma at follow-up (61.5%). In subjects without any risk factors, such as AHR, allergic sensitization, rhinitis, dermatitis or wheezing in childhood; paternal/maternal allergy, or asthma, asthma developed in only 4% during follow-up., Conclusion: The presence of AHR and concomitant atopic manifestations in childhood increase the risk of developing asthma in adulthood, and should be recognized as markers of prognostic significance, whereas the absence of these manifestations predicts a very low risk of future asthma.

Objective: Parental atopy and environmental exposures at home have been recognized risk factors for adulthood asthma. However, the relative contributions of specific risk factors and the overall contributions of heredity or home exposure remain unexplored. The purpose of this study was to identify predictors and estimate the population attributable risk (PAR) of each exposure for typical asthma symptoms among 26- to 50-year-old Taiwanese. We also investigated whether an interactive effect existed between parental atopy and home exposures on the occurrence of asthma symptoms in adulthood., Design: A cross-sectional study with retrospective components., Setting: Elementary and middle schools in Southern Taiwan., Subjects: Between March and October 2004, we conducted a cross-sectional survey among schoolchildren's parents from 94 elementary and middle schools in Southern Taiwan. The main outcome measure was typical asthma-like symptoms occurring within the preceding 5 years. Information on hereditary and home exposures was collected by using a self-administered questionnaire., Results: After excluding unqualified questionnaires, data from 24,784 subjects were left for analysis. New-onset asthma was reported for 0.83% of male (n = 80 of 9,662) and 1.36% of female subjects (n = 206 of 15,122). Besides parental atopic factors, environmental tobacco smoke or pet avoidance and visible mold on walls at home were independently associated with the occurrence of asthma symptoms. Mutually adjusted models produced statistically significant associations between any home exposure (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.08 to 3.23; PAR, 28.04%), parental atopy (OR, 4.47; 95% CI, 3.47 to 5.75; PAR, 31.38%), and new-onset asthma. However, there was no interaction between parental atopy and home exposures., Conclusions: Home exposures and parental atopy both increased the risks of new-onset asthma in adulthood but did not show an interactive effect. These two exposure categories approximately contributed equally to the adulthood asthma.

Objectives: To examine the relationship between ethnicity and sensitization to allergens among children with asthma living in urban and suburban areas of Connecticut., Study Design: Cross-sectional study., Study Population: A total of 791 children with mild-to-severe asthma who received their medical care in the city of Hartford., Results: Puerto Rican ethnicity was associated with skin test reactivity (STR) to cockroach (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.7 to 6.4), STR to dust mite (OR, 1.7; 95% CI, 1.2 to 2.4), STR to mixed grass pollen (OR, 1.7; 95% CI, 1.1 to 2.7), and STR to mugwort/sage (OR, 2.4; 95% CI, 1.4 to 4.1). African-American ethnicity was associated with STR to four outdoor allergens (ie, mixed tree pollen [OR, 2.3; 95% CI, 1.3 to 3.9], mixed grass pollen [OR, 2.7; 95% CI, 1.6 to 4.8], mugwort/sage [OR, 3.1; 95% CI, 1.6 to 6.0], and ragweed [OR, 2.1; 95% CI, 1.2 to 3.8]). Among all children, STR to outdoor allergens was strongly associated with the extent of allergen sensitization. As an example, children sensitized to mixed grass pollen had 34.7 times higher odds of having at least four positive skin tests to other allergens than nonsensitized children (95% CI for OR, 15.6 to 77.0)., Conclusions: Our findings suggest that Puerto Rican ethnicity is associated with an increased risk of sensitization to indoor and outdoor allergens among children with asthma, and that allergy skin testing should be performed more often as part of the management of asthma in African-American children and in Puerto Rican children in the United States.

Background: Respiratory syncytial virus (RSV) infection causes bronchiolitis in a minority of children. Using a guinea pig model to determine if an allergic predisposition in the host increases permissiveness to RSV infection or severity of experimental "bronchiolitis," we compared the effects of RSV inoculation between strain 2 (allergy-resistant) and strain 13 (allergy-susceptible) inbred animals., Methods: One month-old, juvenile guinea pigs were classified into four groups (eight guinea pigs per group): (group 1) strain 2, uninfected; (group 2) strain 13, uninfected; (group 3) strain 2, RSV infected; and (group 4) strain 13, RSV infected. Seven days after inoculation, the animals were studied by the following: viral plaque assays for quantification of intrapulmonary RSV; immunohistochemical localization of RSV antigens in lung tissue sections; physiologic assessment of airway obstruction and nonspecific bronchial hyperresponsiveness; quantitative histology of airway T lymphocytes, neutrophils, and eosinophils; and semiquantitative reverse transcriptase-polymerase chain reaction for levels of messenger RNA expression of a panel of proinflammatory cytokines and chemokines., Results: Significantly higher titers of replicating RSV were isolated from the lungs of strain 13 vs strain 2 animals (p < or = 0.001). The two guinea pig strains showed similar cell types with positive viral immunostaining; RSV-associated changes in airway obstruction and nonspecific bronchial hyperresponsiveness; airway T cells, neutrophils, and eosinophils; and messenger RNA expression of cytokines and chemokines., Conclusions: Strain 13 guinea pigs show increased pulmonary RSV replication than strain 2 animals, but this increased permissiveness to the virus is not reflected by more severe virus-induced changes in airway obstruction, nonspecific bronchial hyperresponsiveness, airway inflammation, or gene expression of proinflammatory cytokines and chemokines.

Study Objectives: To identify which tests would be useful in selecting patients for a specific inhalation challenge with bovine dander allergens (bSIC)., Design: A prospective study., Setting: A university hospital., Patients: Thirty-seven dairy farmers with a clinical suspicion of occupational asthma due to bovine allergens., Interventions: Each patient (n = 27) underwent histamine challenge, mannitol challenge, exhaled nitric oxide (NO) measurement, bovine-specific serum IgE measurement, and skin-prick test (SPT) with bovine allergens prior to undergoing a bSIC., Results: Eleven patients responded to the inhalation challenge with bovine allergens. The sensitivity and specificity of the tests, based on this response, were 82% and 65%, respectively, for the histamine challenge; 20% and 94%, respectively, for the mannitol challenge; 27% and 77%, respectively, for the NO measurement; 82% and 100%, respectively, for the bovine-specific serum IgE measurement; and 100% and 50%, respectively, for the SPT. Multiple regression analysis revealed that only IgE-mediated sensitivity to bovine allergens, but neither bronchial hyperreactivity nor exhaled NO concentration, contributed significantly to the response., Conclusion: Only the SPT with bovine allergens and bovine-specific serum IgE measurements were useful in selecting patients for the bSIC. This challenge should not be performed in SPT-negative subjects. A diagnosis of occupational asthma due to bovine dander allergens could be made without an inhalation challenge test in asthmatic patients with high bovine-specific serum IgE levels. This practice would eliminate the need for the majority of bSICs.

Background: Vitamin A plays an important role in airways epithelial repair and differentiation. Allergen challenge induces epithelial damage and shedding, which cause an increase in repair activity., Objective: To examine whether repeated allergen challenges could increase vitamin A consumption in a rat model., Design: Allergic bronchitis was induced in 12 animals, and 12 rats remained naive. After 14 days, repeated allergen inhalation challenges were performed in the sensitized rats for 2 weeks. On day 16, allergen challenge was performed and bronchoconstriction was measured in all 24 rats. On day 30, all rats were killed. BAL was performed and ex vivo tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production was measured in the lavage cells. Liver, lung tissue, and serum were collected for measurement of vitamin A concentration., Results: The study rats showed severe bronchoconstriction after allergen challenge compared to the naive rats, and ex vivo TNF-alpha and NO production was significantly higher in the sensitized rats. Serum and lung concentrations of vitamin A were not different among the two groups. However, the vitamin A liver concentration in the study rats was significantly lower compared to the naive rats., Conclusions: We conclude that vitamin A utilization is increased during repeated allergen challenge and allergic bronchitis, most probably due to increased demand for epithelial repair.

Background: None of the existing tests for the diagnosis of asthma are considered to be definitive. Certain circumstances require prompt diagnosis, and a test able to predict the absence of asthma would be very useful., Objective: To evaluate the contribution of a skin-prick test (SPT) to the diagnostic workup of subjects with suspected asthma., Patients and Methods: The study included three groups of subjects aged 18 to 24 years: group A, asthmatic patients (n = 175); group B, control subjects (n = 100); and group C, subjects with suspected asthma (n = 150) with normal spirometry findings and a negative exercise challenge test result. All underwent an SPT to a battery of common aeroallergens, and group C underwent a methacholine challenge test (MCT) in addition. The sensitivity, specificity, positive predictive value, and negative predictive values (NPV) of the SPT were calculated using provocative concentrations of methacholine causing a 20% fall in FEV(1) (PC(20)) of < 4 mg/mL and < 8 mg/mL as diagnostic cutoff values for asthma in the MCT. Bayes' formula was used to determine posttest probabilities of having asthma, both for positive and negative SPT results., Results: A positive SPT result to at least one allergen was found in 95.5%, 54%, and 69% of patients in the three groups, respectively. The sensitivity, specificity, and NPV of the SPT were 90.7%, 52.0%, and 84.8%, respectively, with a cutoff value of PC(20) < 8 mg/mL. The lower cutoff, PC(20) < 4 mg/mL, increased the sensitivity and NPV to 98.2% and 97.8%, respectively. A negative SPT result decreased the probability of having asthma by 10-fold to 20-fold in subjects whose pretest probability was low to moderate., Conclusions: Incorporating an SPT into the workup of subjects with suspected asthma can reduce the cost of this process significantly. The SPT may be used as a simple, fast, safe, inexpensive, and reliable method to predict the absence of asthma in young adults.

Background: The increase of work-related respiratory complaints in artificially ventilated buildings has multiple causes, and the role of allergen exposure and symptoms is still controversial., Study Objectives: To analyze the risk factors and the association of work-related symptoms with allergen exposure and different conditions of the same air conditioning system in São Paulo, Brazil., Design: Workers were classified according to characteristics of the air conditioning system: the first group (group 1) with ventilation machinery and ducts with > 20 years of use, the second group (group 2) with ventilation machinery with > 20 years of use and ventilation ducts with < 2 years of use, and the third group (group 3) with ventilation machinery and ducts with < 2 years of use. Logistic regression was performed to check the associations between air conditioning groups, allergen exposure (fungi, mites, animal dander, and cockroach), and symptoms., Results: There was a higher prevalence of building-related worsening of respiratory symptoms (p = 0.004; odds ratio [OR], 8.53) and symptoms of rhinoconjunctivitis (p = 0.01; OR, 8.49) in group 1. There was a lower relative humidity (p = 0.05) and nonsignificant lower temperature in group 1, when compared to the other groups. The viable mold spores totals were higher outdoors than in the indoor samples (n = 45, p = 0.017). There were higher levels of Der p 1 in group 2 (p = 0.032). All allergen levels were considered low., Conclusion: There was a strong association of building-related upper-airway symptoms with places having ventilation systems with > 20 years of use.

Background: Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma. It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens. Moreover, it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists., Methods: Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting beta(2)-agonist (SA; n = 48), a long-acting beta(2)-agonist (LA; n = 50), or placebo (n = 47), double blind, double dummy. The study covered three periods: (1) a 4-week run-in period, in which no changes took place; followed by (2) cessation of treatment with asthma medication including inhaled corticosteroids, introduction of allergen avoidance measures (active/placebo treatment) to lower HDM exposure in the active group, and an 8-week washout period to adjust patients to these changes; followed by (3) a 12-week study medication period. At the start of the 12-week medication period, and every 4 weeks thereafter, spirometric measurements (FEV(1) and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)]) were performed. Peak flow and asthma symptoms were recorded daily. Additionally, at the start and every 6 weeks thereafter, dust samples were collected from mattresses and living room and bedroom floors to assess HDM (der p 1) concentrations. Effects on FEV(1), PC(20), peak flow, and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens., Results: There were no significant differences among the three medication groups after 12 weeks for FEV(1). However, a significant decrease in mean FEV(1) percent predicted (95% confidence interval [CI]) was observed within the SA group: - 6.6 (- 10.4 to - 2.8) (p = 0.0002). A decrease in geometric mean PC(20) (95% CI) of - 1.2 (- 1.96 to - 0.44) doubling concentration was observed within the SA group (p = 0.05). No significant changes in FEV(1) and PC(20) were observed > 12 weeks within the LA group or the placebo group. There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups. Moreover, none of the parameters showed interactive effects with allergen exposure., Conclusion: There were no significant differences among the three medication groups for FEV(1) and PC(20). The within-treatment group comparison showed a significant small decline in FEV(1) for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV(1). This was not seen during regular use of LAS: No clear pathophysiologic mechanism can explain these findings at the moment. Relatively high or low exposure to allergens did not alter these findings.

Study Objective: To examine the baseline factors influencing the occurrence and magnitude of immediate- and late-phase responses in asthmatic patients after an allergen-induced bronchial provocation test (A-BPT)., Design: Cross-sectional analysis in a homogenous group of 31 mild, Dermatophagoides pteronyssinus-allergic patients with asthma., Setting: Allergy Department, Hospital Virgen del Camino, Pamplona, Spain., Interventions and Measurements: Patients completed an asthma symptom questionnaire and underwent skin tests, sputum induction, and methacholine bronchial provocation test. The A-BPT was performed on a separate day. Sputum cell profile and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin-5 levels were quantified in the entire sputum supernatant. Assays were done for eosinophils in blood, and/or ECP, and total and specific IgE levels in serum. Exposure to D pteronyssinus major allergens (Der p1 and Der 2) was measured by an assay based on monoclonal antibodies., Results: A-BPT findings were positive in all patients, and late-phase responses were detected in 29%. Late responders were exposed to higher levels of Der p1 (p = 0.028), had greater levels of ECP (p = 0.007) and albumin (p = 0.019) in sputum, and showed a trend toward higher lymphocyte numbers (p = 0.053) in sputum than isolated early responders. The allergen-induced provocative dose that induced a fall in FEV(1) values > or =20% from the postdiluent values correlated with bronchial hyperresponsiveness (r = 0.36). The late-phase response magnitude correlated with Der p1 exposure (r = 0.49) and showed a trend toward correlation with sputum ECP levels (r = 0.38)., Conclusion: Factors involved in the development of allergen-induced immediate- and late-phase responses are different. Allergen natural exposure might prime the infiltration of the airway by activated inflammatory cells enhancing the appearance and the severity of late-phase responses.

Background: Patients with chronic bird fancier's lung (BFL) can be classified into two types. One group of patients develops chronic disease with fluctuating acute episodes, including low-grade fever, mild exertional dyspnea, and cough (fluctuating chronic BFL; formerly termed recurrent and relapsing chronic BFL). The other group of patients shows no history of acute episodes (insidious chronic BFL). The diagnosis of chronic BFL is difficult, since the onset of chronic BFL may be insidious, with few if any symptoms during the early stages of the disease process., Study Objective: To attempt to diagnose the conditions of these patients more precisely, inhalation provocation tests were conducted using avian dropping extracts., Design: Retrospective chart review., Setting: The Tokyo Medical and Dental University Hospital in Japan., Patients: Eleven patients with chronic BFL (6 with fluctuating chronic BFL and 5 with insidious chronic BFL) and 6 control subjects (4 asymptomatic bird owners and 2 idiopathic pulmonary fibrosis patients) were evaluated., Measurements and Results: Inhalation provocation tests using avian dropping extracts were conducted. All BFL patients were evaluated as positive or probable by inhalation challenge, whereas control subjects were evaluated as negative. A peripheral leukocytosis, an increase of alveolar-arterial oxygen pressure difference, an increase of body temperature, and the development of respiratory symptoms including cough and dyspnea were more frequently observed in chronic BFL patients than in control subjects. All the BFL patients had an increase in neutrophils in BAL fluids following inhalation challenge., Conclusions: We validated the utility of inhalation challenge for the diagnosis of chronic BFL, including fluctuating and insidious BFL. We also demonstrated that neutrophilia in BAL fluids following inhalation challenge could be added to the diagnostic criteria for chronic BFL.

Study Objective: To examine whether atopy influences exhaled nitric oxide (NO) levels in adults with established asthma., Setting: Specialist respiratory unit in a university teaching hospital., Patients: Twenty-eight asthmatics (mean FEV(1), 85.7%) receiving short-acting inhaled bronchodilators and a range of inhaled steroids (0 to 4,000 microg/d)., Interventions: Subjects were studied on two occasions, 5 to 7 days apart, between September and March., Measurements and Results: On the first day, FEV(1), exhaled NO, and histamine challenge were performed. On the second day, exhaled NO, total IgE, and skin-prick testing to six common allergens were conducted. Exhaled NO was measured with the single exhalation method. We found exhaled NO levels to correlate positively with total IgE (r = 0.43, p = 0.02) and number of positive skin-prick tests (p = 0. 002). By contrast, there was no significant correlation between exhaled NO and FEV(1) or the provocative concentration causing a 20% fall in FEV(1). Subanalyses of steroid-treated and steroid-naive patients in this group revealed the same findings., Conclusion: Exhaled NO levels in asthmatics correlate more closely with atopy than with bronchial hyperreactivity and lung function.

Study Objectives: This study reports a classic case of hypersensitivity pneumonitis (HP) with classic histologic changes in lung tissue and the research used to identify the causative antigens., Design: A patient with clinical, radiographic, pulmonary function abnormalities and a lung biopsy consistent with HP had no identifiable antigen exposure., Setting: Evaluation of the patient's activities provided no suggestion of antigen exposure. Her home was evaluated. It was found that her humidifier ran continually without being cleaned but water was added periodically., Measurements: Serologic analysis demonstrated precipitating antibodies against her humidifier water and ten antigens in the hypersensitivity lung disease serologic panel., Conclusion: Removal of the humidifier, cleaning of the house, and a course of prednisone resulted in the return of the patient to a normal state.

Soybean asthma, which occurred as an epidemic among patients in Barcelona, Spain, is associated with specific IgE to soybean hull allergens. The purpose of this study was to investigate the possible role of specific IgG, IgG subclasses, IgA, and IgM in the pathogenesis of soybean asthma. We studied 3 groups of subjects from Barcelona: group 1, 12 asthmatic epidemic patients; group 2, 23 asthmatic nonepidemic patients; and group 3, 32 nonallergic subjects. Specific IgE was determined by radioimmunoassay and specific IgG, IgG subclasses (1, 2, 3, and 4), IgA, and IgM by amplified enzyme-linked immunosorbent assay. Cross-inhibition studies were performed for specific IgE and IgG4. We partially characterized the soybean hull allergens that bind specific IgE, IgG, and IgG4 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blot. Percentage of positive results for the assays of the 8 Igs are as follows: for group 1, 100% (IgE), 75% (IgG), 16.6% (IgG1), 8.3% (IgG2), 0% (IgG3), 66.6% (IgG4), 25% (IgA), and 25% (IgM); for group 2, 4.3% were positive for specific IgE only; and for group 3, 0% (IgE), 0% (IgG), 6.2% (IgG1), 9.4% (IgG2), 9.4% (IgG3), 9.4% (IgG4), 6.2% (IgA), and 6.2% (IgM). The correlation between the specific IgE and the other specific Igs was significant between IgE and IgG4 in group 1 only (r = 0.752, p < 0.01). Cross-inhibition studies demonstrated a higher inhibitory capacity for IgG4 than for IgE. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis/ Western blot demonstrates three low molecular weight protein bands that bind specific IgE, IgG, and IgG4. This study suggests that specific IgG4 to soybean hull allergens plays a role in the pathogenesis of soybean asthma and corroborates the role of specific IgE in the same disease.

Long-term treatment with inhaled beta 2-agonists may be associated with a deterioration in asthma control, potentially due to tolerance. Regular use of short-acting beta 2-agonists has been shown to induce tolerance to allergen or adenosine 5'-monophosphate challenge. The aim of the study was to detect the efficacy of a single dose and a short-term treatment with salmeterol, a long-acting beta 2-agonist, to protect against early asthmatic reaction (EAR) to allergen. Eight subjects with mild allergic asthma underwent two treatment periods in which subjects performed an allergen challenge (specific bronchial provocation test) protected by a single dose (50 micrograms) of salmeterol (Salm-1) followed by a second specific bronchial provocation test after regular treatment with salmeterol for 1 week (Salm-2), or a single dose of placebo (Plac-1) and regular treatment (1 week) with placebo (Plac-2). Each subject performed both treatments in a randomized order. Each time allergen challenge was performed 1 h after last drug inhalation and it was stopped when the same provocative dose of allergen of a previous screening allergen challenge was achieved. The maximum decrease in FEV1 and area under curve in the first hour after allergen inhalation were significantly lower in Salm-1 (max delta FEV1 %, median [range]: 4%[0 to 9]) with respect to Salm-2, Plac-1, Plac-2 (24%[13 to 38], 31%[19 to 50], 30%[6 to 44], respectively, p < 0.001); there was no difference among Salm-2, Plac-1 and Plac-2. In Salm-1, all subjects were protected against EAR, whereas in Salm-2 only 2 subjects showed a partial protection. In conclusion the protective effect of a single dose of salmeterol against allergen-induced EAR was lost after regular treatment with salmeterol for 1 week. The clinical relevance of this mechanism remains to be elucidated.

Study Objective: In search of a better universal marker of tissue inflammation in allergic reactions, we studied platelet activation and its relation to allergic asthma in sheep., Setting: University research laboratory., Subjects: Twenty-three allergic sheep., Design and Interventions: We serially measured plasma thrombospondin (TSP), a glycoprotein secreted from activated platelets, using enzyme-linked immunosorbent assay with a monoclonal antibody. We validated the assay by establishing a standard curve that closely matches that of humans., Measurements and Results: Of the 23 allergic sheep tested, 10 demonstrated early airway response (ER group) and 13 had early and late dual airway responses (DR group) to inhaled Ascaris suum antigen. TSP was measured before, and at 0, 1, 2, 3, 4, 6, 8, and 24 h postantigen challenge. Both groups showed an increase in plasma TSP level after antigen challenge, but only the DR group showed a significant increase in TSP at I h (threefold) and 8 h (sixfold) postchallenge. The two sheep that received carbachol challenge showed a slight rise in TSP at 8 h postchallenge. There was a significant correlation between the TSP level at I h and the peak early airway response in the DR group., Conclusions: These results suggest that the two groups of allergic sheep may have two distinct induction processes leading to airway obstruction. The dual peak rise in TSP level that coincided with the airway response also suggests that an early priming effect exists in the DR group, which might have led to the late response. We conclude that intravascular platelet activation often occurs in mast cell-mediated allergic disorders. Therefore, plasma TSP may be useful for monitoring the course of allergic disorders.

The past 15 years have seen a rise in mortality and morbidity resulting from asthma, despite a concurrent rise in general knowledge about the disease. The step-care strategy recognized these changes in its approach to asthma management; however, this approach should be used only with attempts to control environmental allergens. Step-care therapy requires that patients be categorized by the severity of illness. Step-one therapy is used for mild, infrequent symptoms and involves treatment based primarily on inhaled bronchodilators. Step-two therapy is instituted in all asthmatics except the mildest cases; it involves treatment by inhaled corticosteroids, cromolyn, or nedocromil. Step-three treatment targets cases of severe asthma through the use of oral corticosteroids. In all phases of treatment, however, it should be remembered that patient education is of critical importance. Education improves patient compliance and is critical to the successful treatment of asthma.

Previous studies have suggested that intercellular adhesion molecule 1 (ICAM-1, CD54) may be involved in the pathogenesis of asthma. In addition, a soluble form of ICAM-1 (sICAM-1) has been detected in increased concentrations in the sera of patients with certain inflammatory conditions. To determine whether bronchial asthma is associated with increased levels of sICAM-1 in serum and to assess the effects of therapy on these levels, the concentrations of sICAM-1 were measured in sera of healthy donors and asthmatic patients. The mean (+/- SD) level of serum sICAM-1 for 60 asthmatic patients (304.0 +/- 82.5 ng/mL) was significantly higher than that for 39 healthy volunteers (260.9 +/- 67.2 ng/mL; p = 0.004). Twenty-two patients considered to have atopic asthma and 24 patients with nonatopic asthma did not differ in their levels of sICAM-1. In 14 patients, serum concentrations of sICAM-1 were higher during asthma attacks than in the same patients during remission (p = 0.035). Serum sICAM-1 levels were lower in nine patients during treatment with oral prednisolone (2.5 to 40 mg/d) than during periods without systemic corticosteroid therapy (p = 0.002). Thus, active bronchial asthma is associated with the presence of increased levels of sICAM-1 in serum, and these levels may be modulated by corticosteroid therapy.

Three inhalation formulations of ICI 204,219 were compared for antagonism of antigen-induced bronchoconstriction in 16 subjects with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each subject received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204,219 until the forced expiratory volume in 1 s (FEV1) decreased by 20 percent or the maximum allergen concentration (100 micrograms/ml) was reached. The majority of subjects tolerated 100 micrograms/ml of allergen without a 20 percent decrease in FEV1. Inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.

To investigate the possible role of mast cell or basophil histamine release in mediating platelet-activating factor (PAF) airway obstruction, we studied the effect of inhaled PAF (30 micrograms, single dose) on plasma histamine, bronchial caliber, and leukocyte and platelet counts in six patients with mild or moderate allergic asthma (mean age, 27 +/- 1.3 years; mean FEV1, 95 +/- 5 percent of predicted; mean PC20 methacholine, 1.46 +/- 0.36 mg/ml). Specific conductance (SGaw) FEV1, FEF25-75 percent, differential leukocyte and platelet counts, and plasma histamine (radioimmunoassay) were measured before and 5, 10, 15, and 20 min after PAF inhalation. Mean basal plasma histamine level was 0.28 +/- 0.04 ng/ml. Inhalation of PAF caused a fall in SGaw peaking at 5 min (43 +/- 9 percent) and a fall in FEV1 and FEF25-75 peaking at 10 min (19 +/- 10 percent and 30 +/- 13 percent, respectively). There was also a rapid and transient fall in circulating neutrophils at 5 min (from 3,096 +/- 204/mm3 to 2,551 +/- 158/mm3, p < 0.05) followed by a rebound neutrophilia. In contrast, plasma histamine level did not change significantly at any time measured. Conversely in the same asthmatics, a rapid rise in plasma histamine level (from 0.29 +/- 0.03 ng/ml at baseline to 0.53 +/- 0.06 ng/ml at 5 min; p < 0.01) was observed after an allergenic challenge (Dermatophagoides pteronyssinus) causing a fall in FEV1 peaking at 10 min (22 +/- 4 percent). Thus, inhaled PAF may induce airway obstruction and neutropenia in asthmatics without any significant change of plasma histamine level. These results indicate that it is unlikely that lung mast cells or basophils degranulate during PAF-induced bronchoconstriction.

To study whether circadian variation of bronchial caliber participates in causing late asthmatic response (LAR), house-dust inhalation was made at 10 AM and 6 PM on separate days in 6 house-dust-sensitive asthmatic children aged 8 to 13 years. Bronchial obstruction was assessed through measurements of FEV1 at 4-h intervals from 24 h before to 24 h after the inhalation. The LAR, which is a 15 percent or greater decrease in FEV1 from the value at the same hour of the previous day, occurred 4 h or later after the inhalation in all challenges. The mean (+/- SD) time to the occurrence of the lowest FEV1 (maximum LAR) following the morning inhalation was 14.7 +/- 2.1 h versus 10.0 +/- 2.2 h following the evening inhalation (p < 0.05). Regardless of the hour of inhalation, FEV1 after the inhalation was lowest or near-lowest at 2 AM in all. Therefore, the maximum LAR was indistinguishable from the trough of further amplified circadian variation in FEV1 following the inhalation. These findings suggest that the downward arm of circadian variation may partially participate in causing the LAR.

To determine whether a link exists between the recruitment of inflammatory cells in the airways on a bronchial and bronchoalveolar level and the development of allergen-induced increase in bronchial hyperresponsiveness after allergen challenge, we used bronchial lavage and bronchoalveolar lavage to assess the airway responses to allergen. Twelve symptomatic atopic asthmatics were studied. In all patients bronchial and bronchoalveolar lavage was performed before, 3 h, and 24 h after allergen challenge. Monoclonal antibodies were used directed against T cells (CD3, CD4, CD8) and the eosinophil cationic protein (EG2). Eight patients showed a dual asthmatic response; four patients showed only an early asthmatic reaction after allergen challenge. Clear differences were found between bronchial and bronchoalveolar lavage. Activated eosinophils (EG2) were significantly increased both at 3 h (p = 0.01) and 24 h (p = 0.005). The number of activated eosinophils was significantly higher in the dual responders. A correlation was observed between the severity of the late asthmatic reaction (LAR) and the number of epithelial cells in the bronchial recovery at 3 h, but not at 24 h, in patients who clinically developed a LAR. No significant changes in the number of CD3, CD4, and CD8 cells 3 and 24 h after the challenge both in the bronchial and bronchoalveolar recovery were observed. We conclude that the number of activated eosinophils in bronchial lavage is associated with the development of the LAR and allergen-induced increase in bronchial hyperresponsiveness.

Study Objective: We previously described a closed-circuit system for exposure to particles in humans. This system has three components: a particle generator, an exposure chamber connected to an orofacial mask, and monitors. We describe results of challenges in 56 subjects who underwent challenges with the apparatus using occupational sensitizers in particles., Subjects: Fifty-six consecutive subjects referred for the investigation of occupational asthma to occupational sensitizers in particles were included. The agents were the following: flour and grains (n = 19), cedar (n = 10), psyllium (n = 9), guar gum (n = 9), drugs (n = 3), persulfate (n = 2), and miscellaneous (n = 4)., Intervention: The duration of exposure was progressive and varied from one breath to a maximum of 180 min depending on the reaction. When no significant fall in FEV1 occurred after exposure with the aerosolization device, the standard approach of tipping particles from one tray to another was used., Results: Twenty-nine subjects (52 percent) had a significant (greater than or equal to 20 percent) fall in FEV1 after exposure. This includes 18 subjects with isolated immediate reactions, four with dual asthmatic reactions, and two with atypical reactions. In 20/24 instances (83 percent), the percentage of fall in FEV1 did not exceed 30 percent, thus showing that dose-response curves can generally be obtained in a safe way. In all instances except one (26/27 cases), subsequent exposures using the traditional method did not result in significant falls in FEV1., Conclusion: This new procedure results in safe tests in terms of the percentage of changes in FEV1 during the immediate reactions and very rare false-negative challenges.

Nine asthmatic patients with an allergy to birch or timothy underwent bronchial allergen provocations on three different trial days, with intervals of 2 to 5 wk. Two weeks prior to one of the provocations, no medication was allowed. Before the other two provocations the patients had been on continuous treatment with oral terbutaline (7.5-mg slow-release pill bid) for 2 wk, which was discontinued 12 or 48 h before the allergen provocation. After allergen challenges, terbutaline was inhaled in increasing doses (0.5 mg, 1.0 mg, and 2.0 mg), and pulmonary function was measured after each dose. Before each allergen provocation, blood samples were drawn for measurements of catecholamine and terbutaline concentrations and for in vitro measurements of beta-adrenergic receptor function on lymphocytes (isoproterenol-induced accumulation of cyclic AMP). Beta-adrenergic receptor function on blood lymphocytes was impaired after the two treatment periods, compared with the drug-free period, and was significantly more depressed at 12 h than 48 h after dosing. The bronchial responsiveness to allergen, defined as PC20PEF (median values), was 1,700 biologic units (BU) after the period of no treatment and 220 BU and 445 BU at 12 and 48 h after discontinuation of the terbutaline treatment (p less than 0.1 after 48 h). Five of the nine patients exhibited increased bronchial responsiveness 48 h after treatment, compared to results without treatment. The responsiveness was similar on all occasions in three patients. The bronchodilator response to inhaled terbutaline after allergen-induced bronchoconstriction was attenuated (p less than 0.01) at both 12 and 48 h after terbutaline, compared to results without treatment, indicating desensitization also of the bronchial beta-adrenergic receptors. We conclude that the early bronchial responsiveness to allergen is increased following a period of continuous treatment with a beta-adrenergic receptor agonist in some asthmatic patients and that the capability of a beta-agonist to reverse allergen-induced bronchoconstriction is attenuated after beta-agonist treatment.

Among 154 referrals to a university hospital clinic for assessment of possible occupational asthma, the feasibility and results of different investigations were assessed using a consistent approach to all patients. A positive skin test to a workplace allergen (14 percent of all subjects), positive peak flow workplace changes (12 percent), improvement in methacholine response on holiday (9 percent), and/or positive specific challenge testing (14 percent) supported the diagnosis of occupational asthma in 61 subjects (39 percent of the total referrals). Fifty-one of these were related to a workplace sensitizer and ten to a presumed irritant. Occupational asthma was excluded in 48 subjects (31 percent) who had normal methacholine responsiveness within 24 hours of work (22 percent of the 154 subjects), peak flow readings no worse at work than on holidays (14 percent of the total referrals) and/or negative specific challenge testing (10 percent of the total referrals). Insufficient information could be obtained for a diagnosis in the remaining 45 subjects (28 percent). No single investigation was considered diagnostic in this study, as each could be positive or negative for other reasons.

Platelet-activating factor (PAF) is an inflammatory mediator capable of inducing protracted inflammation of the airways and bronchial hyperreactivity. Twenty-one asthmatic children were evenly divided into three groups and each group performed a double-blind, placebo-controlled and crossover study on the effect of aerosolized BN52021, a PAF antagonist, on the bronchoconstriction induced by PAF, methacholine, or specific allergen, respectively. One group of healthy children was included for comparison. Total WBC, neutrophils, and eosinophils were counted before and after PAF challenge. The results showed the following: (1) six of seven asthmatics and one of seven normal subjects gave a positive bronchial provocation with PAF; (2) in asthmatics, prior inhalation of BN52021 could inhibit the bronchoconstriction induced by PAF (6/6) and allergen (3/7), but not by methacholine; and (3) 5 min after inhalation of PAF, there was a marked decrease of peripheral blood eosinophils and neutrophils that could be inhibited by prior inhalation of BN52021 in normal subjects but not in asthmatics. These findings support the idea that PAF may be involved in the pathogenesis of bronchial asthma and PAF antagonist may have a role in the prevention and treatment of this disease.

Late inflammatory sequelae following allergen (and occupational low molecular weight sensitizing chemical) exposure, including the late asthmatic response and increased nonallergic airway responsiveness, are now felt to be more important in the pathogenesis of atopic allergic and occupational asthma than are the early bronchospastic responses. These late sequelae can be inhibited by sodium cromoglycate and by corticosteroids but not by bronchodilators. Recognition that allergic and occupational (and likely all forms of) asthma are inflammatory conditions underscores the rationale for the early use of anti-inflammatory therapeutic strategies in the management of asthma. Such "anti-inflammatory" therapeutic strategies include environmental control, sodium cromoglycate, and both inhaled and oral corticosteroids.

The serum concentration of angiotensin-converting enzyme is frequently elevated in individuals with active sarcoidosis. The enzyme is presumably actively synthesized by the epithelioid and giant cells of the granuloma. Hypersensitivity pneumonitis, resulting from the inhalation of antigens from pigeons by susceptible individuals, is associated with the development of a granulomatous interstitial and alveolar infiltrate in the pulmonary parenchyma. Because the clinical and pathologic presentation may mimic that of sarcoidosis, we compared the serum levels of angiotensin-converting enzyme in these two diseases. The concentration of angiotensin-converting enzyme is not elevated in individuals with active hypersensitivity pneumonitis, in contrast to its frequent elevation in sarcoidosis. We suggest that the granulomatous response in hypersensitivity pneumonitis may differ at a biochemical level from that of sarcoidosis, since the synthesis of angiotensin-converting enzyme does not appear to be increased.

Eight asthmatic patients who had no history of asthma before starting work in a hard-metal plant and eight control subjects (three atopic, three nonatopic asthmatic, and two normal volunteers) without a history of exposure to hard metal dust were subjected to provocation tests, skin tests, radioallergosorbent tests (RAST) and Farr test with cobalt. Four of the eight patients were atopic, and seven showed bronchial hyperresponsiveness to methacholine (BHR). Patch and intradermal skin tests with cobalt chloride (CoCl2) could not discriminate the patients from control subjects. All patients had positive reactions to CoCl2 in the provocation tests; two developed immediate asthmatic reaction (IAR), four late asthmatic reaction (LAR), and two dual asthmatic reaction (DAR), while the control subjects showed no reaction. Evidence of specific IgE antibodies to cobalt-conjugated human serum albumin (Co-HSA) was presented by four patients (RAST score greater than 2) based on comparison of serum samples from 60 asthmatic patients and 25 asymptomatic workers in the same plant. Positive serum samples selectively bound 57Co, and the test was blocked by nonlabled cobalt sulfate (CoSO4). These findings suggest the development of hard metal-induced asthma from cobalt sensitivity.

We examined airway responsiveness to allergen inhalation using a novel technique by which dynamic compliance (Cdyn) and pulmonary resistance (Rl) are simultaneously calculated by Fourier-series analysis of flow and transpulmonary pressure during tidal breathing. C0 and C0.5 (Cdyn at the frequency of zero and 0.5 Hz, respectively) were computed using the regression line of Cdyn versus frequency measured at the fundamental and first three harmonics in each breathing cycle. First, the validity of this system was tested by comparing Rl, C0 and C0.5 during five consecutive breaths with those obtained by the conventional method. A good correlation was seen in Rl, C0 and C0.5 between the two methods. Second, we studied airway response to allergen inhalation before and after oral administration of a long-acting beta 2-stimulant (procaterol, 50 micrograms or 100 micrograms) or placebo in a double-blind crossover trial in six atopic asthmatic subjects. In control allergen inhalation tests by administration of placebo, Rl increased progressively, and C0.5, expressed as percentage of control compliance at zero frequency (C0.5/COcont), decreased progressively. After 100 micrograms procaterol, Rl response to allergen was almost completely inhibited. However, a decrease in C0.5/C0cont was still observed. These findings suggest that pretreatment of asthmatic patients with procaterol can release allergen-induced bronchoconstriction of the central airways, but cannot release that of the peripheral airways.

Allergy prick skin testing was performed on 137 newly diagnosed patients with primary lung cancer and 137 age-(+/- 3 years) and sex-matched randomly selected control subjects. We also compared 38 patients with lung cancer and 38 of their closest in age, same-sex siblings. Demographic data, personal, medical, smoking and occupational histories were obtained by personal interview. We skin tested these individuals with a standard battery of seven common allergens and a diluent control. Fewer patients (35.8 percent) than control subjects (58.4 percent) responded with one or more positive skin reactions (p less than .005). There was no significant difference between patients (27.8 percent) and control subjects (37.2 percent) responding to more than one allergen. Fewer of the 38 sibling-matched patients had one or more positive skin tests (23.7 percent) than did their siblings (55.3 percent) (p less than .01). There were fewer patients with greater than one positive skin test (15.8 percent) than sibling control subjects (42.1 percent) (p less than .025). There were no differences in smoking pack-years between patients and siblings. Historic evidence of allergy was greater in both control groups compared to their matched cancer groups; p less than .05 for community controls, p less than .005 for sibling control subjects. These findings raise the possibility that atopy, by either immunologic or nonimmunologic means, protects against development of lung cancer, or alternately, that lung cancer affects immunologic status as gauged by (type 1) skin sensitivity.