Relation of Airway Reactivity and Sensitivity with Bronchial Pathology in Asthma

Airway hyperresponsiveness in asthmatics, which may result from inflammation or remodeling, is expressed as the concentration of methacholine that causes a 20% fall in FEV₁ in the concentration–response curve (PC₂₀). A decrease in PC₂₀ may be due to a steeper curve (hyperreactivity) and/or a curve shift to the left (hypersensitivity). Our purpose was to analyze the relation of airway sensitivity and reactivity to airway pathological changes. The PC₆, as sensitivity parameter, and the slope between PC₂₀ and PC₄₀ as reactivity parameter, were calculated. Total and differential cell counts in the bronchoalveolar lavage fluid, and percentage of epithelial shedding, basement membrane thickness, and submucosal thickness on bronchial biopsy, were measured. The PC₆ showed a correlation with the baseline FEV₁%. The slope was significantly correlated with the basement membrane thickness, and also demonstrated a strong association with submucosal thickness. The PC₂₀ showed a correlation with the baseline FEV₁% and the degree of epithelial shedding. These results suggest that the airway sensitivity and reactivity measurements reflect the degree of airway caliber and remodeling, respectively.     

Comparison of Δ FVC (% Decrease in FVC at the PC20) Between Cough-Variant Asthma and Classic Asthma

The percentage decrease in forced vital capacity (FVC) at the methacholine PC₂₀ (Δ FVC) has been proposed as a surrogate marker of maximal airway response. The aim of this study was to compare the Δ FVC between patients with cough-variant asthma (CVA) and those with classic asthma (CA). We performed a retrospective analysis of methacholine challenge test data from 47 children who were diagnosed as having CVA and from 75 children who had CA of mild severity. The mean (± SD) Δ FVC was significantly (p = 0.001) lower in the CVA group (14.7 ± 3.4%) compared with the CA group (17.1 ± 4.4%), whereas PC₂₀ was not different between the two groups. Our results suggest that CVA is associated with a lower level of maximal airway response than CA.     

Obesity is not Associated with Mild Asthma Diagnosis in a Population of Spanish Adults

Background. Several studies have suggested a relationship between asthma and obesity. Moreover, atopy is an important risk factor for asthma, but the relationship between obesity and atopy is uncertain. Methods. A cross-sectional multicenter study was conducted in a population of Spanish adults between November 2007 and July 2008. The subjects included had experienced asthma symptoms in the last year but had a forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) > 70%. Mild asthma diagnosis was confirmed by measuring airway hyperresponsiveness to methacholine. Body mass index in kg/m² was used as measure of obesity. Subjects were considered atopic when they had at least one positive skin prick test to common aeroallergens. Adjusted odd ratios (OR) were obtained by logistic regression. Results. A total of 662 subjects were included and 234 subjects (35.3%) were diagnosed with asthma (consistent symptoms and positive methacholine test). After adjusting the model for age, gender, atopy, baseline FEV₁, and FEV₁/FVC ratio, there was no association between overweight or obesity with asthma diagnosis, with OR of 0.889 (95% CI, 0.60–1.38) and 0.925 (95% CI, 0.577–1.48), respectively. A multivariable logistic regression analysis confirmed that atopy increases the risk of asthma (p = 0.008). The non-atopic obese group had an increased risk of asthma compared to the non-atopic group with normal weight or overweight (p = 0.0032). Conclusions. In this study obesity was not associated with a diagnosis of asthma. The presence of atopy was a risk factor for asthma, independent of obesity. Obesity, however, may be a risk factor for the development of asthma among non-atopic subjects.     

Low Attenuation Area Is Associated with Airflow Limitation and Airway Hyperresponsiveness

Background. Asthma is a chronic inflammatory disorder of the airways characterized by airflow limitation and airway hyperresponsiveness. Lung density indices on quantitative computed tomography (QCT) are assumed to reflect the degree of air trapping originated from airflow limitation in airway diseases. Purpose. The present study investigated the availability of lung density indices on QCT in clinical evaluation of asthma. Methods. Eleven asthmatic patients and 48 healthy control subjects were prospectively evaluated by QCT, pulmonary function testing, and a methacholine challenge test. High-resolution computed tomography scans were performed at full-inspiratory and full-expiratory phases, and percentage of lung field occupied by low attenuation area (LAA%) and mean lung density (MLD) at both inspiratory and expiratory phases were measured. Results. MLD values at inspiratory phase were significantly increased in asthmatic patients compared with those in healthy control subjects. Inspiratory LAA% values were significantly decreased in asthmatics compared with the values in control subjects. On expiratory scans, MLD values of asthmatics were significantly lower than the values of control subjects. Expiratory LAA% values of asthmatics were significantly higher than the values of control subjects. The LAA% in the expiratory phase showed significant negative correlation with forced expiratory volume in 1 second (FEV₁), FEV₁/forced vital capacity, and the provocative dose of methacholine causing a 20% decrease in FEV₁ in asthmatic patients. Conclusion. These results suggest that lung density indices on QCT may be useful for clinical evaluation of asthmatic patients and increased LAA% in the expiratory phase is associated with airflow limitation and airway hyperresponsiveness in asthma.     

Body Mass Index-Percentile and Diagnostic Accuracy of Childhood Asthma

Objective. To determine whether high BMI-percentile is associated with misdiagnosis of asthma among children referred to an asthma specialist. Methods. We queried the electronic records of children 8 to 18 years of age seen by a Nemours pediatric pulmonologist. All visits during a 6-year period with the chief complaint of asthma, or an asthma-like symptom such as wheeze, cough, or dyspnea, were included. We collected spirometry, blood counts, and immunoglobulin E (IgE) if available. We determined whether the child had referring physician-diagnosed asthma, specialist-diagnosed asthma, or both. Specialist-diagnosed asthmatics who met additional objective “gold-standard” criterion were labeled strict-criterion asthma. Results. Prevalence of high BMI-percentile was extremely common in all defined asthma groups, even those meeting strict criteria for diagnosis. Referring physician-diagnosed asthmatics did not have higher rates of obesity, and referring physician-diagnosed asthmatics had objective indicators of asthma that were the same as asthmatics diagnosed by a specialist. There was good diagnostic correlation between referring physicians and asthma specialists that was not affected by BMI. Among specialist-diagnosed asthmatics, increased BMI-percentile associated with significantly reduced forced expiratory volume in 1 second (FEV₁), forced expiratory flow during the middle half of the forced vital capacity (FEF_{25 ? 75}), and FEV₁/forced vital capacity (FVC); and significantly increased total blood leukocytes, neutrophils, and platelets compared to leans. For all 2,258 referrals, the estimated odds ratio of receiving a specialist-diagnosis of asthma increased by 0.4% with each increasing BMI percentile. Conclusions. Referring physicians do not appear to erroneously diagnose children with asthma due to overweight status. Our data confirm that overweight status is extremely high in children with true asthma and likely increases the risk for true asthma. Although these data cannot discern causality, high BMI-percentile is associated with greater airflow obstruction and elevated markers of systemic inflammation that could contribute to underlying mechanisms of asthma.     

Usefulness of Exhaled Nitric Oxide for Diagnosing Asthma

Rationale. A standard asthma diagnosis is made based on clinical history, reversibility of airway obstruction, and bronchial hyperresponsiveness. Fractional exhaled nitric oxide (FeNO) is a noninvasive airway inflammatory marker that has been suggested as a diagnostic tool for asthma. The aim of this study was to establish a FeNO cut-off value for asthma diagnosis. Methods. One hundred and fourteen consecutive adult patients (mean age 34 ± 13 years) reporting symptoms consistent with asthma, with normal spirometric parameters and a negative bronchodilator test, were included in the study. All underwent a methacholine challenge test following the five-breath dosimeter protocol. FeNO was measured with a portable device (NioxMino, Aerocrine AB, Sweden) just before the methacholine challenge. The sensitivity, specificity, and diagnostic performance of FeNO measurement were calculated. Results. Thirty-five out of the 114 patients (30.7%) were diagnosed with asthma. A positive methacholine challenge was associated with higher FeNO levels and with lower forced expiratory volume in one second (FEV₁) at baseline. No correlation was found between methacholine provocative concentration causing a decrease of 20% in FEV₁ (PC₂₀) and FeNO levels. A receiver-operating characteristic curve was constructed for FeNO levels (area under the curve [AUC]: 0.762; 95% confidence interval [CI]: 0.667-0.857; p < .001). The FeNO cut-off point with maximal specificity and sensitivity for asthma diagnosis was 40 ppb. Conclusions. Patients with confirmed asthma showed higher FeNO levels. A cut-off value of 40 ppb was calculated as the most efficient for asthma diagnosis in our population. The use of FeNO measurement may be a helpful tool to rule out a diagnosis of asthma, especially in patients in whom a methacholine challenge is not feasible or available.     

Adipokines,asymmetrical dimethylarginine,and pulmonary function in adolescents with asthma and obesity

Objective: This study was to investigate whether the metabolic abnormalities of adipokines and asymmetrical dimethylarginine (ADMA) associate with pulmonary function deficits in adolescents with obesity and asthma. Methods: This study enrolled 28 obese adolescents with asthma, 46 obese adolescents without asthma, 58 normal-weight adolescents with asthma, and 63 healthy control subjects. Serum levels of leptin, high-molecule-weight (HMW) adiponectin, retinol binding protein 4 (RBP4), asymmetrical dimethylarginine (ADMA), and pulmonary function were qualified. Results: The obese subjects had higher levels of leptin and ADMA but lower levels of HMW adiponectin than the normal-weight subjects with or without asthma. The subjects with asthma had higher levels of RBP4 than those without asthma. The obese adolescents with asthma had lowest forced expiratory lung volume in the first second (FEV₁)/forced vital capacity (FVC) ratio among the four study groups. In all the study subjects and in the subjects with asthma alone, the FEV₁/FVC ratio associated negatively with leptin, however, such association was rendered non-significant when adjusted for BMI. The pulmonary function deficits associated inversely with BMI percentile in the subjects with asthma. However, the decreased FEV₁/FVC ratio was not correlated with HMW adiponectin, RBP4 or ADMA. Conclusions: Our present study confirmed obstructive pattern of pulmonary function characterized by the reduced FEV₁/FVC ratio in the obese adolescents with asthma. These pulmonary deficits were associated inversely with the increased BMI percentile.     

Relationship Between Lung Function and Asthma Symptoms in Patients with Difficult to Control Asthma

Several studies have demonstrated a poor relationship between measures of asthma control and lung function in patients with asthma. We sought to examine this relationship in a cohort of difficult to control asthmatics attending a hospital outpatient clinic. FEV₁% and asthma control scores (ACSs) were measured at the first clinic visit and at a follow-up visit. A total of 59 patients took part in the study. At the initial visit, FEV₁% correlated with limitation of activity (p = 0.002), shortness of breath (p = 0.02), wheezing (p = 0.029), and ACS (p = 0.014). However, at follow-up, there was no correlation between FEV₁% and any measured index of asthma control. When patients with severe fixed airflow obstruction were excluded from the analysis (n = 16), FEV₁% at follow-up became significantly correlated with night waking (p = 0.02), wheezing (p = 0.05), and ACS (p = 0.036). The improvement in asthma control score at follow-up was significantly and strongly associated (r = 0.51 for total asthma control, p < 0.001) with the improvement in lung function in patients without severe fixed airflow obstruction. Lung function was not associated with any measure of asthma control in patients with severe fixed airflow obstruction. FEV₁% correlates well with asthma symptoms in difficult asthma patients with poor control but not when control improves. This loss of relationship is due to subjects with severe fixed airflow obstruction where good subjective control does not exclude the presence of significant obstruction. How severe fixed airflow obstruction should be prevented, delayed, or managed in asthma requires further research.     

Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics

Objective: Periostin, a matricellular protein, is produced from airway epithelial cells and lung fibroblasts by IL-13. It has been suggested that periostin is involved in allergic inflammation and fibrosis. However, the usefulness of serum periostin measurement in the assessment of airway inflammation and remodeling and management of asthmatic patients is still debated. We aimed to determine whether serum periostin levels reflect eosinophilic airway inflammation and airway remodeling in asthma. Methods: We examined the relationship of serum periostin levels with clinical features, biomarkers for eosinophilic airway inflammation, fraction of exhaled nitric oxide (FeNO) levels and blood eosinophil counts, and pulmonary functions in 235 well-controlled asthmatic patients on inhaled corticosteroids (ICS) treatment. Results: Serum periostin levels were positively correlated with blood eosinophil counts (%) and age (r = 0.36 and 0.23, respectively), and were negatively correlated with body weight and FEV₁/FVC (%) (r = ?0.24 and ? 0.23, respectively) in well-controlled asthmatic patients on ICS treatment (daily dose of 453 µg equivalent to fluticasone propionate). Blood eosinophil counts and serum periostin levels were similarly associated with increased FeNO levels (≥40 ppb) in the asthmatics. Serum periostin levels were better associated with fixed airflow limitation (FEV₁/FVC ratio <70%) than FeNO levels, blood eosinophil counts or total IgE levels in the asthmatics. Multivariate analysis showed that fixed airflow limitation was significantly associated with high serum periostin levels (≥97 ng/ml) (Odds ratio 3.2). Conclusions: Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics on ICS treatment.     

Airway Hyperresponsiveness: A Comparative Study of Methacholine and Exercise Challenges in Seasonal Allergic Rhinitis with or without Asthma

Background. Asymptomatic airway hyperreactivity in allergic rhinitis is a risk factor for later development of asthma. Although non-specific bronchial hyperresponsiveness (BHR) has been measured by several stimuli, the most appropriate measurement technique still remains unclear. Objective. To investigate whether an exercise challenge can be used to predict BHR in seasonal allergic rhinitis patients with or without asthma and to compare this bronchial reactivity with a methacholine challenge technique. Methods. Forty-six consecutive patients with seasonal allergic rhinitis only (n = 31) and with both seasonal allergic rhinitis and asthma (n = 15) were included in the study during the pollination period. Subjects underwent first methacholine (mch) and then exercise challenge testing (ECT). There was a 1-week interval between the tests. ECT was performed on a bicycle ergometer. Positive result was defined as a 15% decrease in forced expiratory volume in 1 second (FEV₁) post-exercise. A patient's bronchial reactivity to methacholine was considered as hyperresponsive if PC₂₀ was less than 8 mg/mL. Results. Mch PC₂₀ values were significantly lower in patients with both rhinitis and asthma (p < 0.062). Among the 46 patients, mch PC₂₀ values were significantly different between patients who had positive and negative exercise challenge tests (p = 0.007). All patients with rhinitis alone had a negative ECT and 10 had a positive mch challenge. Change in FEV₁ values after ECT was significantly higher in patients with both rhinitis and asthma compared to those with rhinitis alone (p = 0.009). There was a significant relation between positivity of mch and exercise challenges (p = 0.025). ECT positivity was found to be a significant confounding factor in the diagnosis of asthma (p = 0.001). Specificity and sensitivity values were 100% and 24% for ECT and 68% and 100% for mch, respectively. Conclusion. Exercise challenge presents poor diagnostic value for detecting bronchial responsiveness in individuals with allergic rhinitis alone during the pollen season.     

Gender differences in effects of obesity and asthma on adolescent lung function: Results from a population-based study

Objective: To investigate lung function associated with asthma and body mass index (BMI) among adolescents at 96 northern Taiwan junior high schools participating in an asthma screening program. Methods: The questionnaires and lung function test results measured for 3669 boys and 3523 girls were included in this study for data analysis. Measures of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁) and FEV₁/FVC ratio were compared by sex, asthma status and BMI. Results: Overall mean FVC levels were similar between students with and without asthma, 3.71 L vs. 3.71 L for boys (p = 0.991) and 2.79 vs. 2.78 for girls (p = 0.517). The overall mean FEV₁ levels were also similar between girls with and without asthma. Asthmatic boys had lower FEV₁ than non-asthmatic boys. Mean FEV₁/FVC was significantly lower in students with asthma than those without asthma. Mean FVC and FEV₁ increased with BMI in both sexes. A lower mean FEV₁/FVC was observed among students with asthma and high BMI, and was more pronounced in boys than in girls. Multivariable regression analysis also showed that FEV₁/FVC ratios were negatively associated with asthma and high BMI, stronger in boys than in girls for asthma (β = ?2.176 (standard errors (SE) = 0.268) vs. ?1.085 (SE = 0.258) and for BMI (β = ?0.309 (SE = 0.025) vs. ?0.218 (SE = 0.029)). Conclusion: This northern Taiwan study suggests that FEV₁/FVC is negatively associated with asthma and high BMI in adolescents, stronger for boys than for girls.     

Relationship Among Pulmonary Function, Bronchial Hyperresponsiveness, and Atopy in Children with Clinically Stable Asthma

Pulmonary function testing plays a key role in the diagnosis and management of asthma in children. However, the literature does not clearly show whether children with clinically stable asthma have significantly reduced lung function when compared with normal children. We compared the lung function of 242 clinically stable asthmatic children who were initially diagnosed with mild intermittent or mild persistent asthma with the lung function of 100 nonasthmatic controls. The lung function was assessed using FEV₁, FEV₁/FVC, FEF_25–75 and PEF. In addition, we measured bronchial hyperresponsiveness (BHR) using the provocation concentration of methacholine needed to produce a 20% fall in FEV₁. All measures of pulmonary function were significantly decreased in the children with asthma. Pulmonary function was not influenced by atopy, serum IgE, or total eosinophil count (TEC). However, the likelihood ratio for trends revealed a significant association between our pulmonary parameters and the degree of BHR. Children with mild-to-severe BHR had greatly decreased lung function compared with those with normal BHR, the control group. In addition, a direct correlation was found between PC₂₀ and our pulmonary parameters in asthmatic children. However, only atopic children with asthma had a significant correlation between PC₂₀ and TEC. We found children with clinically stable asthma to have pulmonary obstruction, which associated strongly with their degree of BHR.     

Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics

Introduction: Testing for airway hyperresponsiveness with indirect stimuli as exercise or mannitol has been proposed to better reflect underlying airway inflammation, as compared with methacholine (MCh), believed to act directly on airway smooth muscle cells. Objective: To investigate whether different direct and indirect stimuli induces different patterns of obstruction, recorded as central and peripheral resistance, and to see whether baseline resistance could predict a positive response to direct or indirect provocation. Methods: Thirty‐four mild asthmatics and 15 controls underwent MCh, mannitol and eucapnic voluntary hyperventilation (EVH) challenge tests. The response was evaluated with spirometry and impulse oscillometry (IOS). Results: Twenty‐three out of 34 asthmatics were positive to either EVH (22) or mannitol (13). Those positive to mannitol had a significant increased baseline value of IOS parameters such as ΔR5‐R20 and AX. Twelve of the asthmatics had a 10% fall or more in forced expiratory volume in 1 s (FEV₁) in all three challenge tests. However, the response pattern measured by IOS did not differ between the tests. When the limit for a positive mannitol provocation was set to 10% fall in FEV₁, 16 out of 19 mannitol‐positive patients were also positive to EVH. Conclusion: Even in mild asthmatics, a substantial number had a positive indirect test. Mannitol FEV₁ provocative dose to decrease FEV₁ by 10% from baseline (PD10) was closely associated to EVH10%. No difference in bronchoconstrictive pattern could be seen between the different provocation tests, but those positive to mannitol had more peripheral airway involvement at baseline. This supports the idea that peripheral airway involvement is an important predictor of asthma airway reactivity. Please cite this paper as: Aronsson D, Tufvesson E, Bjermer L. Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics. Clin Respir J 2011; 5: 10–18.     

Comparison of airway reactivity induced by cold air and methacholine challenges in asthmatic children

Bronchial responsiveness to isocapnic hyperventilation with cold air (CAH) and to inhaled methacholine (MCH) was compared in 17 children with bronchial asthma. The response to cold air was expressed as the percent drop in FEV₁ from baseline at 4 min. after the challenge (Δ% FEV₁ CAH), and the response to methacholine as the provocative concentration required to reduce the FEV₁ by 20% from baseline (PC₂₀MCH). Both tests were sensitive (94%) for detecting airway hyperreactivity. There was no statistically significant relationship between A% FEV, CAH and the log PC₂₀MCH (r = 0.39; P = 0.12). In clinical practice, methacholine test is easier to perform, but in the research field cold air challenge may be preferable because it avoids potential drug effects. © 1995 Wiley-Liss, Inc.     

Airway Responsiveness Measured by Forced Oscillation Technique in Severely Obese Patients,before and after Bariatric Surgery

Background. The influence of obesity on airway responsiveness remains controversial. Objective. This study was designed to investigate airway responsiveness, airway inflammation, and the influence of sleep apnea syndrome (SAS), in severely obese subjects, before and after bariatric surgery. Methods. A total of 120 non-asthmatic obese patients were referred consecutively for pre-bariatric surgery evaluation. Lung function, airway responsiveness to methacholine, exhaled nitric oxide measurement, and sleep studies were performed. Airway hyperresponsiveness (AHR) was defined as a 50% or greater increase in respiratory resistance measured using the forced oscillation technique in response to a methacholine dose ≤2000 μg. Forced expiratory volume in 1 second (FEV₁) was measured after the last methacholine dose. Airway responsiveness was reevaluated after weight loss in patients with a pre-surgery AHR. Results. AHR was found in 16 patients. The percent FEV₁ decrease or percent respiratory resistance increase in response to methacholine was related to baseline expiratory airflow (forced expiratory flow at 50%) (r = 0.26, p < .006 and r = 0.315, p = .0005, respectively) but not to body mass index (BMI) or exhaled nitric oxide. Both airway responsiveness parameters were significantly related to forced expiratory flow at 25–75%/forced vital capacity, a measure of airway size relative to lung size (r = 0.27, p < .005 and r = 0.25, p < .007, respectively). Sleep apnea was not significantly associated with AHR or airway inflammation. About 11 patients with AHR were reevaluated 18 months to 2 years after surgery, with no change in AHR associated with weight loss. Conclusion. Airway responsiveness is not related to BMI or to SAS. AHR in severely obese patients might be related to distal airway obstruction or low relative airway size.     

Gender Differences in Asthma Management and Quality of Life

Background. Objective assessment of airway function is important in epidemiologic studies of asthma to facilitate comparison between studies. Airway hyperresponsiveness (AHR), peak expiratory flow (PEF) variability, and bronchodilator reversibility (BR) are widely used as markers of airway lability in such studies. Data from a survey of a population sample of adolescents and young adults (n = 609; 288 males), aged 13–23 years, were analyzed to investigate whether AHR, PEF variability, and BR can be used interchangeably as markers of asthma in an epidemiological setting. Methods. Case history, including self-reported and doctor-diagnosed asthma, smoking habits, and use of asthma medication, was obtained by interview and questionnaire. Lung function, airway responsiveness (positive test: PC₂₀ FEV₁< 16 mg/mL histamine), PEF variability (positive test: amplitude percentage mean > 20%), BR (positive test: ΔFEV₁ [(FEV₁max ? FEV₁min)/FEV₁max) 100]> 10%), blood eosinophil count, and skin prick test reactivity were measured by using standard techniques. Results. The prevalence of a positive test was AHR 16.4%, PEFpos 13.3%, and BRpos 7.2%, respectively; 73.5% of the sample had three negative tests. Among the 74 participants with current self-reported asthma (12.2%), 34 subjects (46%) had more than one positive test. Using AHR as the only objective marker of asthma identified 93% of the participants with current asthma, whereas PEF and BR identified 45% and 10%, respectively. Confining the analysis to participants with only one positive test revealed that 61% of the subjects with isolated AHR had current asthma, whereas none of the subjects with isolated BRpos had asthma, and only one participant with isolated PEFpos had current asthma. Degree of histamine responsiveness was closer associated with other asthma-related factors, including self-reported asthma, use of asthma medication, and level of lung function, than PEF variability and bronchodilator responsiveness. Conclusions. Airway responsiveness to histamine, diurnal peak-flow variability, and bronchodilator reversibility cannot be used interchangeably as objective markers of asthma in epidemiologic studies. On the basis of the present findings, airway hyperresponsiveness to a nonspecific bronchoconstrictor is recommended as the objective marker of asthma-related airway lability.     

Underrecognition of the Severity of Asthma and Undertreatment of Asthma in a Rural Area of Japan

Background and Aim. Revised guidelines were released in Japan in 2003 for the assessment, treatment, and management of adult asthmatics, and similar guidelines for child asthmatics were released in 2002. We reassessed the severity and possible undertreatment of asthma according to these guidelines in stable asthmatics. Methods. We reviewed medical records of 861 well-controlled asthmatic patients who, in April through June 2004 were cared for by 47 pulmonologists at 29 medical centers and 13 asthma clinics in a rural community in the San-in area of Japan. The physician obtained completed medical records about their symptoms and current treatment of the subjects, 726 adult and 135 children (aged 6 years or older) who were in stable condition and had had no exacerbations in the previous 3 months. The severity of asthma and current treatment for each patient were assessed according to the newly revised Japanese guidelines for the assessment, treatment, and management of adult and child asthmatics. Results. In adult and child asthmatics, the percentage of predicted forced expiratory volume at 1 second (FEV_1.0) was smaller and has a narrower distribution range than the percentage of predicted peak expiratory flow (PEF). When the severity of asthma was classified according to symptoms alone, 50% and 35% of those classified as mildly asthmatics patients with adults and children, respectively, had moderate to severe airflow limitation. Inhaled corticosteroids were prescribed to 90.6% of adult and 14.9% of child patients. When we compared the treatments that patients were actually receiving against the optimal treatments indexed according to a combined symptoms-FEV_1.0 classification, we found that 49% of adult asthmatics were overtreated, 21% were properly treated, and 30% were undertreated. Among children, the respective percentages were 35%, 25%, and 40%. Conclusion. In well-controlled adult and child asthmatics, the severity of asthma is poorly judged when symptoms alone are considered. We suggest that the severity of asthma should be assessed through a combination of symptoms and the measurement of FEV_1.0 during office visits. We also suggest that the proper dose of inhaled steroid needed to maintain stable conditions should be judged according to this combined symptoms-FEV_1.0 classification.     

Airway Responsiveness to Beta‐Adrenergic Agonist (Salbutamol) in Asthma

Despite the controversy of airway responsiveness to β₂‐agonist drugs in asthma, in a previous study we showed increased responsiveness of asthmatic airways to isoprenaline. Therefore, in the present study of airway sensitivity to other β₂‐agonists, salbutamol and its relationship to histamine responsiveness was reexamined. The threshold bronchodilator concentrations of inhaled salbutamol required for a 20% increase in forced expiratory flow in 1 sec (FEV₁), (PC₂₀) was measured in 20 normal and 19 asthmatic adults. Airway responsiveness to histamine, as the concentration that caused a 20% decrease in FEV₁, was also measured in 11 normal and 12 asthmatic subjects; and the correlation between PC₂₀ salbutamol and PC₂₀ histamine was evaluated. Sensitivity to salbutamol was greater in asthmatics (PC₂₀ = 7.24 mg/L) than in non‐asthmatics (PC₂₀ = 124.25 mg/L, p < 0.001). Airway responsiveness to histamine in asthmatics (PC₂₀ = 0.18 g/L) was also significantly greater than in normal subjects (PC₂₀ = 19.46 g/L, p < 0.001). There was a significant correlation between PC₂₀ salbutamol and histamine (Rs = 0.6052, p < 0.005). Maximum response to both salbutamol and histamine and slope of concentration‐response curves of both agents were significantly greater in patients with asthma than in normal subjects (p < 0.001 and p < 0.005 for maximum response and slope, respectively). The increased sensitivity of asthmatics to inhaled salbutamol suggests that they also may be more sensitive to their endogenous adrenaline, which may thus dilate and stabilize their airways.     

Obesity in aspirin-tolerant and aspirin-intolerant asthmatics

Background and objective: Obesity is an important factor in the development of asthma. Aspirin hypersensitivity affects 5–10% of asthmatics. The association between obesity and aspirin hypersensitivity in asthma is unclear. This study evaluated the association of BMI and asthma in patients with aspirin-tolerant asthma (ATA) and aspirin-intolerant asthma (AIA). Methods: Aspirin provocation tests were performed in 667 asthmatic patients and changes in FEV₁ were used to categorize patients as ATA or AIA. The BMI of asthmatics was graded using the percentile BMI of 406 normal controls. Results: Aspirin-induced changes in FEV₁% ranged from 15% to 68%. Compared with the controls, the ATA group had a higher BMI (24.5 ± 0.1 vs 23.8 ± 0.2 kg/m², P = 0.001). The AIA group had a lower BMI. The aspirin-induced percentage fall in FEV₁ was inversely correlated with BMI in asthmatic patients (r = −0.094, P = 0.016). BMI was correlated with age and PC20, but not with FEV₁ in asthmatic patients. In a logistic regression adjusted for age, gender, and smoking status, FEV₁ and PC20 were associated with AIA with odds ratios of 0.986 and 0.586, respectively. BMI was associated with AIA with an odds ratio of 0.916. Conclusions: Aspirin intolerance in asthmatics explains the lesser association with obesity. Obesity is not a risk factor in the development of asthma in patients with AIA.     

Steroid-Naive Adolescents with Mild Intermittent Allergic Asthma Have Airway Hyperresponsiveness and Elevated Exhaled Nitric Oxide Levels

Although atopic asthma symptoms often seem to disappear around puberty, subjects in this age group may experience unexpected, often severe, asthma attacks. This may be related to persistence of untreated airway hyperresponsiveness/inflammation in a life period characterized by low perceptiveness of disease-related symptoms. This study was designed to evaluate the prevalence and the severity of bronchial hyperreactivity and the exhaled nitric oxide (FE_NO) levels in a group of steroid-naive asthmatic adolescents. Fifty-two patients with mild-intermittent asthma were studied, ages 12 to 16, sensitized to house dust mites; 22 age-matched controls, were also studied. Asthma patients showed FEV₁, FEF_25–75%, and FVC values not significantly different from controls, (p>0.05, each comparison). By contrast, although none of the control subjects showed bronchial hyperreactivity, increased airway responsiveness to methacholine (MCh) was demonstrated in the majority of the patients and found to be severe in 36.5% (MCh PD₂₀ ≥ 400 µg or accumulative dose ≤1220 µg) and moderate in 32.7% (MCh PD₂₀ 400–1400 µg or accumulative dose 1220–4620 µg). In addition, FE_NO concentrations were significantly higher in asthmatics, as compared with controls (20.4 ± 5.3 ppb and 4.4 ± 0.7 ppb, respectively; p<0.01) and 83% of the patients had FE_NO levels higher than 8.9 ppb (i.e., >2 standard deviations of the mean in control subjects). A positive, statistically significant correlation was found between FEF_25–75% values and MCh PD₂₀ (r = 0.358; p<0.01) or MCh accumulative dose (r = 0.355; p<0.05). No correlations were demonstrated between MCh responsiveness and FVC or FEV₁ values or FE_NO levels and between FE_NO levels and pulmonary function parameters (p>0.05). The high incidence of bronchial hyperresponsiveness to MCh and of airway inflammation (as demonstrated by the elevated FE_NO levels) in adolescents with mild asthma suggests the need for more accurate evaluation and, possibly, for early intervention with antiinflammatory drugs in a significant proportion of patients in this age group.