Genome-wide association study reveals an association between the HLA-DPB1∗02:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

Distinct trajectories of treatment response to mepolizumab toward remission in patients with severe eosinophilic asthma.

Patients with severe eosinophilic asthma, characterised by a high disease burden, benefit from mepolizumab, which improves symptoms and reduces exacerbations, potentially leading to clinical remission in a subgroup. This study aimed to identify treatment response trajectories to mepolizumab for severe eosinophilic asthma and to assess the achievement of clinical remission.Data from the Australian Mepolizumab Registry were used to assess treatment responses at 3, 6, and 12 months. The treatment response trajectories were identified using a group-based trajectory model. The proportions achieving clinical remission at 12 months, which was defined as well-controlled symptoms, no exacerbations, and no oral corticosteroid (OCS) use for asthma management, were compared between trajectories, and baseline predictors of the trajectories were identified using logistic regression analysis.We identified three trajectory groups: group 1, responsive asthma with less OCS use (n=170); group 2, responsive late-onset asthma (n=58); and group 3, obstructed and less responsive asthma (n=70). Groups 1 and 2 demonstrated higher proportions achieving clinical remission at 36.5% and 25.9%, respectively, compared to group 3 with 5.7% (p <0.001). Baseline predictors for assigned groups included lower OCS dose in group 1; greater FEV1% predicted, higher Asthma Quality of Life Questionnaire score, higher OCS dose, and nasal polyps in group 2; with group 3 as the reference.Treatment response to mepolizumab in severe eosinophilic asthma follows 3 trajectories with varying proportions achieving clinical remission and differing baseline characteristics. Treatment response variability may influence the achievement of clinical remission with mepolizumab therapy.

Metagenomic gut microbiome analysis of Japanese patients with multiple chemical sensitivity/idiopathic environmental intolerance.

BACKGROUND: Although the pathology of multiple chemical sensitivity (MCS) is unknown, the central nervous system is reportedly involved. The gut microbiota is important in modifying central nervous system diseases. However, the relationship　between the gut microbiota and MCS remains unclear. This study aimed to identify gut microbiota variations associated with MCS using shotgun metagenomic sequencing of fecal samples. METHODS: We prospectively recruited 30 consecutive Japanese female patients with MCS and analyzed their gut microbiomes using shotgun metagenomic sequencing. The data were compared with metagenomic data obtained from 24 age- and sex-matched Japanese healthy controls (HC). RESULTS: We observed no significant difference in alpha and beta diversity of the gut microbiota between the MCS patients and HC. Focusing on the important changes in the literatures, at the genus level, Streptococcus, Veillonella, and Akkermansia were significantly more abundant in MCS patients than in HC (p < 0.01, p < 0.01, p = 0.01, respectively, fold change = 4.03, 1.53, 2.86, respectively). At the species level, Akkermansia muciniphila was significantly more abundant (p = 0.02, fold change = 3.3) and Faecalibacterium prausnitzii significantly less abundant in MCS patients than in HC (p = 0.03, fold change = 0.53). Functional analysis revealed that xylene and dioxin degradation pathways were significantly enriched (p < 0.01, p = 0.01, respectively, fold change = 1.54, 1.46, respectively), whereas pathways involved in amino acid metabolism and synthesis were significantly depleted in MCS (p < 0.01, fold change = 0.96). Pathways related to antimicrobial resistance, including the two-component system and cationic antimicrobial peptide resistance, were also significantly enriched in MCS (p < 0.01, p < 0.01, respectively, fold change = 1.1, 1.2, respectively). CONCLUSIONS: The gut microbiota of patients with MCS shows dysbiosis and alterations in bacterial functions related to exogenous chemicals and amino acid metabolism and synthesis. These findings may contribute to the further development of treatment for MCS. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Clinical Trials Registry as UMIN000031031. The date of first trial registration: 28/01/2018.

Computed tomography findings of paranasal sinuses in patients with eosinophilic granulomatosis with polyangiitis: Comparison with other eosinophilic sinus diseases and clinical relevance of their severity.

BACKGROUND: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. METHODS: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund-Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. RESULTS: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. CONCLUSIONS: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.

Identification of asthma cases in Japan using health insurance claims data: Positive and negative predictive values of proposed discrimination criteria: A single-center study.

BACKGROUND: Asthma cases have been increasingly investigated using claims data. However, the validity of defining asthma cases using health insurance claims in Japan is unclear. This study aims to assess the positive and negative predictive values of our proposed discrimination criteria for asthma. METHODS: We developed discrimination criteria for asthma based on both the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 disease codes for asthma and health insurance claims data for prescriptions and the treatment of asthma. Inclusion criteria were patients aged ≥16 years with at least one health insurance claim from April 2018 to March 2019 in all departments of our hospital. Physician-diagnosed asthma documented in the charts was used as the reference standard. Positive and negative predictive values of the discrimination criteria for physician-diagnosed asthma were estimated and compared with those estimated from discrimination criteria based solely on ICD-10 codes. RESULTS: The new discrimination criteria had a high positive predictive value (PPV) of 86.0%, which was significantly higher than the PPV for the criteria defined solely by the ICD-10 codes (61.5%) (P < 0.01). The negative predictive values for both criteria were 100%. Allergic rhinitis and chronic cough were frequently misclassified as asthma using the discrimination criteria based solely on ICD-10 codes but were more likely to be appropriately classified using our proposed criteria. CONCLUSIONS: Our proposed criteria adequately identified asthma subjects using health insurance claims data in Japan with a high PPV. Further studies are needed for external validation of these criteria.

Longitudinal changes in the prevalence of adult asthma: An epidemiological survey among Japanese salaried employees and their dependents using healthcare insurance claim from 1999 to 2019.

BACKGROUND: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. METHODS: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20-59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. RESULTS: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. CONCLUSIONS: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults.

Frailty and muscle weakness in elderly patients with asthma and their association with cumulative lifetime oral corticosteroid exposure.

BACKGROUND: Frailty is a geriatric syndrome of age-related physiological decline, which is associated with higher mortality and decreased healthy life expectancy, and muscle weakness is one of the presentations of frailty. We investigated an association between lifetime oral corticosteroid (OCS) exposure with frailty and muscle weakness among elderly patients with asthma. METHODS: We studied 203 consecutive elderly outpatients with asthma aged ≥60 years old. They were classified into three groups according to their cumulative lifetime OCS dose (lifetime non-users, lower-dose users, and higher-dose users), which was retrospectively estimated from the response to a structured questionnaire. The prevalence of frailty determined by the Kihon Checklist was compared between the three groups. Hand-grip strength, and lean mass index were also measured as markers of muscle strength. RESULTS: Thirty-seven percent of the patients studied were considered frail. Higher cumulative lifetime OCS exposure was associated with a significantly higher prevalence of frailty (33% in lifetime non-users, 59% in lower-dose users, and 68% in higher-dose users; P for trend <0.005). This was also associated with lower hand-grip strength in both sexes (P for trend; 0.012 in men, and 0.020 in women), and lower lean mass index in men (P for trend 0.002). However, current doses of OCS were not significantly associated with these outcomes. CONCLUSIONS: Cumulative lifetime OCS exposure was associated with a higher prevalence of frailty and muscle weakness. These findings emphasize the importance of minimizing lifetime OCS exposure for the prolongation of healthy life expectancy in patients with asthma.

Prevalence of inhaled allergen-specific IgE antibody positivity in the healthy Japanese population.

BACKGROUND: Measurement of allergen-specific IgE antibodies to inhaled allergens is important for the diagnosis and risk evaluation of allergic diseases such as asthma and allergic rhinitis. This study aimed to elucidate the prevalence of allergen sensitization among the healthy population in Japan using serum samples stocked in the Japanese Red Cross for blood donation. METHODS: Age- and gender-stratified serum samples (n = 800) from residents in Tokyo aged 20-59 years were randomly selected from the stocked serum obtained for blood donation in 2005. Total and specific IgE antibodies to 17 inhaled allergens were measured by the ImmunoCAP method. Individuals with positive (≥0.35 UA/mL) specific IgE antibodies to at least one inhaled allergen were defined as atopic. Stocked serums from donors aged 20-29 years in Sapporo, Osaka, Fukuoka, and Okinawa (n = 200 each) were also obtained for the measurement of IgE to six common inhaled allergens, to evaluate regional differences in the rate of positivity. RESULTS: Among residents in Tokyo, the prevalence of atopy was 78.0% and highest in men aged 20-29 years (94.0%), which decreased with age. The prevalence of specific IgE antibodies was highest for Japanese cedar pollen (66.8%), followed by cypress pollen (46.8%), Dermatophagoides pteronyssinus (38.3%), and moths (30.1%). Examination of IgE to Japanese cedar pollen, D. pteronyssinus, and moths identified 97.6% of atopic subjects in Tokyo. There were substantial regional differences in the prevalence of pollen IgE positivity. CONCLUSIONS: This study demonstrated an extremely high prevalence of positivity in inhaled allergen-specific IgE antibodies among healthy adults in Japan.

Low-dose mepolizumab is effective as an add-on therapy for treating long-lasting peripheral neuropathy in patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: To assess the effectiveness of low-dose mepolizumab as an add-on therapy for treating peripheral neurological symptoms in eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: We prospectively studied 13 EGPA patients with conventional treatment-resistant peripheral neuropathy. Their symptoms (pain, numbness, and muscle weakness) were assessed on a visual analogue scale (VAS) before and after 12 months of mepolizumab therapy (100 mg every 4 weeks). Peripheral eosinophil levels and several biomarkers including urinary levels of eosinophil-derived neurotoxin (EDN) were measured before and after therapy. RESULTS: VAS scores for pain and numbness significantly improved after 12 months of mepolizumab therapy (from 67.0 to 48.0, P = 0.012, and from 67.0 to 51.0, P = 0.017, respectively). However, the VAS score for muscle weakness did not improve (P = 0.36). There were significant correlations between treatment-related changes in urinary EDN levels from baseline to 6 months later and percent changes in the VAS scores of pain and numbness (r = 0.75, P = 0.020; r = 0.88, P = 0.002). CONCLUSIONS: Treatment-resistant peripheral neuropathy in EGPA was significantly improved by low-dose mepolizumab, and effectiveness was correlated with decreased urinary EDN. Because the possibility of a placebo effect cannot be formally excluded, placebo-controlled studies will be required in the future.

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Optimal Aspergillus fumigatus and Asp f 1 serum IgG cut-offs for the diagnosis of allergic bronchopulmonary aspergillosis.

BACKGROUND: The presence of IgG antibodies (Abs) to Aspergillus fumigatus (Af) is a crucial diagnostic criterion for allergic bronchopulmonary aspergillosis (ABPA). Although precipitation is traditionally used to document IgG Abs, anti-Af serum IgG levels can also be measured by enzyme immunoassay (EIA). However, there are insufficient data on the optimal cut-offs to assess diagnostic performance of the EIA method. This study aimed to determine cut-off levels of IgG binding crude Af extracts or recombinant Asp f 1 (by ImmunoCAP®) and to compare their efficacy for ABPA diagnosis with Af-precipitating Abs. METHODS: The age distribution of levels of IgG to crude extracts of Af (Af-IgG) and recombinant Asp f 1 (Asp f 1-IgG) was established using sera from 694 healthy controls (HC). Receiver operating characteristic analysis for Af-IgG and Asp f 1-IgG levels for the purpose of ABPA diagnosis was performed in 306 Af-sensitized asthma patients (including 49 ABPA), and cut-offs were determined. RESULTS: An age-dependent decline in the levels of Af-IgG was observed in HC. Thus, cut-offs for Af-IgG levels were determined separately by age as 60 mg/L for patients aged <55 years, and 45 mg/L for those aged ≥55 years. For Asp f 1-IgG, 6.6 mg/L was set as the cut-off regardless of age. Although such IgG testing by EIA allowed a sufficiently good diagnostic performance, Af-precipitating Abs had better diagnostic applicability for ABPA. CONCLUSIONS: We determined cut-offs for Af-IgG and Asp f 1-IgG measured by EIA, which can be useful in clinical settings where precipitating Abs are unavailable.

[Characterization of Small Volume Plastic Scintillation Detector].

Some radiation detectors are used for quality assurance and measured to radiation dose for high precision external beam radiotherapy. Recently, plastic scintillation detectors for MeV X-ray measurement are commercially released. The purpose of this study was to evaluate the performance of a commercial plastic scintillation detector with respect to the dose linearity, dose rate dependence, and the output coefficient compared the ionization chamber and the semiconductor detector using each different X-ray energy with or without flattening filter. The result that the dose linearity of each detector showed a linear response in any detectors. Dose rate dependence of plastic scintillation detector was increased when setting dose rate was changed, especially setting to low dose rate. The output coefficient of plastic scintillation detector was equivalent as that of the semiconductor detector even in smallest irradiation field. In conclusion, it was suggested that the plastic scintillation detector is a suitable detector in dose verification measurements for high precision external beam radiotherapy, although we must be with care to low dose rate measurements.

[PULMONARY TUBERCULOSIS AND TUBERCULOUS PLEURISY COMPLICATED WITH RIFAMPICIN-INDUCED HYPOTHYROIDISM: A CASE REPORT].

Rifampicin can induce hypothyroidism. We report a case of pulmonary tuberculosis and tuberculous pleurisy that was complicated by rifampicin-induced hypothyroidism. The patient received rifampicin-based tuberculosis treatment and experienced persistent appetite loss, which led us to pro- vide concomitant hypothyroidism treatment. An 85-year-old woman with no underlying thyroid-related disease presented to her local hospital with a 3-month history of appetite and weight loss. A chest radiograph revealed pleural effusions and infiltrative shadows in the lower fields of both lungs, and we also detected high levels of lympho- cytes and adenosine deaminase levels (49.6 IU/1) in the pleu- ral effusion, with positive results from a polymerase chain reaction assay of a sputum sample. Thus, we diagnosed the patient with pulmonary tuberculosis and tuberculous pleurisy, and initiated treatment using isoniazid, rifampicin, etham- butol, and pyrazinamide. Her clinical course was good and her anorexia was improved. However, she subsequently experienced recurrent appetite loss, malaise, and bilateral lower-leg edema. Follow-up laboratory testing revealed that she had developed hypothyroidism. We started treatment using levothyroxine without interrupting the tuberculosis treatment. The loss of appetite and other thyroid-related symptoms were improved. The patient's thyroid function had been normal at her admission, and there were no findings of Hashimoto's thyroiditis or other thyroid conditions. Based on the clinical course, we conclude that the rifampicin induced the hypothyroidism. Therefore, rifampicin-induced hypothyroidism should be considered in cases with persistent appetite loss, even if the patient appears to be experiencing anorexia as an adverse drug reaction.

DIFFERENCES IN FRACTION OF EXHALED NITRIC OXIDE VALUES MEASURED BY TWO HAND-HELDED ANALYZERS (NObreath® AND NIOX Vero®).

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is a useful marker of asthma control. The FENO measurement with two hand-helded analyzers (NObreath® and NIOX Vero®) may be more affordable, no studies have examined the differences in FENO values measured with those methods in adult. METHODS: The study population comprised 44 subjects at our outpatient clinic. FeNO values (FENOb and FENOv) were measured by two methods (NObreath® and NIOX Vero®). RESULTS: FENOb values were significantly correlated with FENOv (r = 0.911, p < 0.001). However, FENOv values were high compared with FENOb (FENOv = 1.40 × FENOb). CONCLUSION: Differences exist in the values of FENO measured by two hand-helded analyzers: conversion equations are needed to compare the FENO values between these methods.

A CASE OF BRONCHIAL ASTHMA WITH HYPEREOSINOPHILIA WITH EFFECTIVE SAIBOKUTOU THERAPY.

A 42 year old woman visited on our hospital because of cough, sputum, pruritus and erythema. She showed peripheral blood eosinophilia, high level of FENO, bronchial hyperresponsiveness. Diagnosis of bronchial asthma and atopic dermatitis was made, but she rejected therapy except for Saibokutou, a Kampo herbal medicine. After 1 year, her symptoms and her laboratory data were improved.

THE FRACTION OF EXHALED NITRIC OXIDE (FENO) AND FORCED OSCILLATION TECHNIQUE (FOT) CAN PREDICT BRONCHIAL HYPERRESPONSIVENESS AGAINST ACETYLCHOLINE IN TREATED ASTHMATICS.

BACKGROUND: The bronchial hyperresponsiveness (BHR) test is useful to diagnose or evaluate effect of therapy in asthmatics, but invasive. On the other hands, the fraction of exhaled nitric oxide (FENO) is a useful noninvasive marker of eosinophilic airway inflammation in asthmatics. And also, the forced oscillation technique (FOT) is a noninvasive method that is used to measure respiratory mechanics, including respiratory resistance and reactance at multiple frequencies. AIM: To evaluate the complementary roles of FENO and FOT to predict bronchial hyperresponsiveness in adult stable asthmatic patients taking inhaled corticosteroids. METHODS: From our outpatient clinic, we recruited 115 stable asthmatics that were being treated with inhaled corticosteroids at the time of the study. For each subject, we measured FENO by using an offline methods (CEIS' method); and we measured resistance at 5Hz (R5), resistance at 20Hz (R20), R5-R20, reactance at 5Hz (X5), frequency of resonance (Fres), and low-frequency reactance area (ALX), by using a MostGraph FOT machine. We also used spirometry to test BHR to acetylcholine (PC20Ach). RESULTS: LogPC20Ach was significantly correlated with FENO, R5, R20, R5-R20 and %FEV1. The ROC curve decided that the cutoff point of FENO was 37.8ppb (AUC=0.647, sensitivity 83.3%, specificity 55.6%, p=0.007) and that of R5 was 3.03cmH2O/L/S (AUC=0.684, sensitivity 72.2%, specificity 52.8%, p=0.001) and that of R20 was 2.77cmH2O/L/S (AUC=0.684, sensitivity 74.5%, specificity 59.4%, p=0.001). When R5 was >3.03 and FENO was >37.8ppb, 25 of 38 subjects (65.7%) had bronchial hyperresponsiveness. If R5 was <3.03 and FENO was <37.8 ppb, only 5 of 29 (17.2%) subjects had. When R20 was >2.77 and FENO was >37.8ppb, 29 of 43 subjects (67.4%) had bronchial hyperresponsiveness. If R20 was <3.03 and FENO was <37.8ppb, only 2 of 18 (11.1%) subjects had. CONCLUSION: Combining R5 or R20 and FENO can predict the level of bronchial hyperresponsiveness in adult stable asthmatics.