Recognition of asthma in adolescents and young adults: which objective measure is best?

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: deltaFEV1 [(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.     

Relationship of non-specific airway hyper-responsiveness (AHR) to measures of peak expiratory flow (PEF) variability

Background: The relationship between airway hyper-responsiveness (AHR) and clinical asthma remains controversial and unclear. Aims: To test the hypothesis that serial measures of variability of peak expiratory flow rate (PEF) correlate with serial measures of AHR, and to determine which mathematical expression of variability provides the best correlation. Methods: A longitudinal study over 180 days of 20 atopic, moderately severe asthmatics was undertaken. A diary of medication use and morning and evening PEFR before and after (3 agonist was kept and AHR (PD₂₀ histamine) was measured at three-weekly intervals. Using group data (128 sets) In PD₂₀ was correlated with various measures of PEF variability over 9 days. Results: Within the group there was a weak but highly statistically significant correlation between AHR and measures of PEF variability - the strongest correlation being with mean morning PEF. Within individual subjects, however, the correlation was not a consistent finding and only four patients had a statistically significant relationship (p<0.05) between AHR and mean morning PEF. Conclusions: These results suggest that while PEF variability may reflect AHR for the purposes of epidemiologic studies, it is unlikely to be useful as a simple ‘non-invasive’ means of assessing AHR in individual patients. More complex measures of PEF variability do not have an advantage over simpler measures such as mean morning PEF.     

Excessive bronchoconstriction induced by histamine and effects of volume history in patients with bronchial asthma

Abstract The aim of this study was to examine the inter-relationships between the different effects of deep breaths and histamine provocation on airway function in patients with bronchial asthma. Group 1 consisted of 38 consecutive out-patients with newly diagnosed mild asthma, group 2 consisted of 20 patients with bronchial asthma of varying severity who were studied during clinical remission. We measured bronchial responsiveness (BR) to histamine inhalation as the dose of histamine which provoked a 20% fall in FEV₁ (PD₂₀). The fall in forced vital capacity (FVC) after inhaling the highest dose of histamine during each BR test was calculated and expressed as percentage of the value measured at baseline (δFVC in percentage). We studied the effects of deep breaths on airway caliber in group 2 patients by comparing isovolumic flow rates on partial (P) and maximal (M) forced expiratory flow volumes curves expressed as the M/P ratio. The changes in residual volume (RV) after deep breaths (δRV) were expressed as a percentage of the largest VC measured on the composite M and P curves. The patients in group 1 had significantly higher PD₂₀ and lower δFVC than patients in group 2. There was, however, no significant correlation between PD₂₀ and δFVC measurements in individual patients (r<0.1, P>0.05). The M/P ratio was significantly related to δFVC (r=?0.6, P<0.006). There was also a significant positive relation between the magnitude of increase in residual volume following deep breaths (δRV) and the degree of fall in FVC following histamine inhalation (δFVC) (r= 0.65, P= 0.001). This significant relationship between the degree of airway closure after a deep breath and airway closure after histamine challenge is a new finding. In patients with bronchial asthma, the effects of a deep breath on airway function may be indicative of the tendency for airway closure during BR testing.     

The prevalence and predictors of airway hyperresponsiveness in sarcoidosis

Background and objective: Obstructive airflow limitation is the most common physiological impairment in sarcoidosis. This study determined the prevalence of airway hyperresponsiveness (AHR) in sarcoidosis, the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge, and the clinical, physiological and radiological predictors of AHR. Methods: Subjects with sarcoidosis and a baseline forced expiratory volume in 1 s (FEV₁) >35% predicted underwent hypertonic and histamine challenge, lung function testing and high resolution computed tomography (HRCT) of the chest. AHR was defined as a 15% fall in FEV₁ to hypertonic saline and a 20% fall in FEV₁ to histamine. Results: The 52 subjects had well‐preserved lung function (FEV₁ = 2.8 ± 0.7 L, 87% predicted). AHR was detected in 5/47 (11%) to hypertonic saline and 19/43 (44%) to histamine challenge. On univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (P = 0.02) and reticular pattern (P = 0.03) on HRCT. The baseline % predicted forced expiratory volume in 1 s was significantly inversely associated with AHR on univariate (P = 0.004) and multivariate analysis (P = 0.01) when adjusted by HRCT patterns. Conclusions: The higher prevalence of AHR using histamine challenge than hypertonic saline challenge and the association with baseline % predicted FEV₁ suggest that the AHR in sarcoidosis may reflect the consequences of airway remodelling following inflammation.     

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.     

Acute Bronchodilator Response Has Limited Value in Differentiating Bronchial Asthma from COPD

Background. Acute responsiveness to inhaled bronchodilators is often used to differentiate between bronchial asthma and chronic obstructive pulmonary disease (COPD). The response can be expressed in terms of a change in FEV₁ and FVC in several ways—as absolute change, change as percent of baseline value, or as percent of predicted value with different thresholds for a positive test. A comprehensive evaluation of the diagnostic value of these different methods of expressing the acute bronchodilator response has not been carried out. Methodology. Response to inhaled salbutamol was measured by spirometry in 200 asthmatics and 154 patients with COPD. The sensitivity, specificity, and positive and negative predictive values of different methods of expressing responsiveness were calculated. Receiver operative characteristic curves were obtained. Results. None of the expressions of response gave a clear-cut separation between the two diseases. A ΔFEV₁≥ 0.2 L gave the most satisfactory combination of sensitivity (73%) and specificity (80%) and the highest positive (82%) and negative predictive values (69%) for diagnosing asthma. These values were superior to those obtained for the ERS or the ATS criteria for reversibility (ΔFEV₁%predicted ≥ 9% and ΔFEV₁ of ≥ than 12% and 0.2 L over the baseline, respectively), which had almost similar diagnostic characteristics. This was confirmed by the area under curve of the ROC plots. Expressions of response in terms of changes in FVC were unsatisfactory in separating the two diseases. Conclusions. It was concluded that the test of acute bronchodilator responsiveness has limited diagnostic value in separating asthma and COPD.     

Inspiratory flow limitation in children with bronchopulmonary dysplasia

The objective of this study was to compare pulmonary function tests of children with bronchopulmonary dysplasia (BPD) and asthma, and to evaluate children with BPD for evidence of upper airway obstruction. This is a case-control retrospective study of pulmonary function tests (PFTs) of 11 children with BPD between 5 and 8 years of age who were followed by pediatric pulmonologists, and of 32 age- and height-matched children with asthma. The median forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), and peak expiratory flow (PEF) were significantly lower in the BPD group (0.86 L, 0.79 L, 120 L/min) than in the asthmatic group (1.34 L, 1.21 L, 155 L/min; P = 0.002, P = 0.007, P = 0.004, respectively). Both groups were equally hyperinflated (median thoracic gas volume 155% of predicted values in the BPD compared to 152% predicted in the asthma group; P = 0.67), and both groups showed decreases in air-trapping after a bronchodilator. The ratios of forced expiratory flow at 50% of the FVC to forced inspiratory flow at 50% of the FVC (FEF_50%/FIF_50%) and FEV₁ to PEF (FEV₁/PEF) were used to assess upper airway obstruction and were higher in children with BPD than asthma (P = 0.0001 and P = 0.035, respectively). We conclude that pulmonary function of children with BPD who are still symptomatic after 5 years of age is different from age-matched children with asthma, and the children with BPD demonstrate significant inspiratory flow limitations. Pediatr Pulmonol. 1998;26:167–172. © 1998 Wiley-Liss, Inc.     

Testing airway responsiveness using inhaled methacholine or histamine

Abstract Airway responsiveness assessed using histamine and methacholine is safe, reproducible and relatively easily undertaken in adults and children. Results are similar for methacholine and histamine although methacholine is better tolerated. Responsiveness is increased in children and the elderly, and in women compared to men, possibly due to body size effects. Baseline lung function confounds the interpretation of airway responsiveness and may explain the effect of smoking in most studies. Results are most usefully expressed as the provocative dose producing a 20% fall in FEV₁ (PD₂₀FEV₁) or the dose-response slope (DRS). When technical factors are controlled the reproducibility of the test is from one to two doubling doses. Measurements of airway responsiveness have been widely used in clinical and research practice. However, assessing their value in diagnosing asthma is limited by the lack of a gold standard for the definition of asthma. Using a cut-off value of 8 mg/mL or 8 μmol for PD₂₀, the tests will discriminate asthmatic from non-asthmatic subjects (based on questionnaire definitions of asthma) with a sensitivity of around 60% and a specificity of around 90%. These properties of the test result in positive and negative predictive values of 86% and 69% when the prevalence of asthma is high (50%– as in the clinical setting) and 40% and 95% when the prevalence of asthma is low (10%, as in general population studies). In the usual clinical setting, assessing the significance of atypical or non-specific symptoms, the tests are of intermediate value in predicting the presence of asthma and less useful in excluding asthma. The additional benefit of testing airway responsiveness to measuring peak flows or to a trial of therapy has yet to be fully assessed. Testing of airway responsiveness may be of value in assessing occupational asthma, asthma severity and the effects of potential sensitizers or treatments. In research, tests of airway responsiveness are more useful for excluding cases of asthma. In population studies, they serve as an objective marker of abnormal airway function which may be genetically determined and, like allergy, are strongly associated with asthma. The predictive value of airway hyperresponsiveness for the development of airway disease is yet to be clearly established. In epidemiology the benefits of measuring airway responses must be weighed against the added inconvenience and cost that is incurred.     

Specific airway resistance is a better outcome parameter in bronchial provocation testing compared to FEV1 in patients with bronchial asthma

Objectives: Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR). A bronchial provocation test (BPT) is used to test for AHR. However forced expiratory volume in one second (FEV₁), used as outcome parameter is effort-related, in contrast to specific airway resistance (sRaw). This research was conducted to provide insight in the usefulness of sRaw as an outcome parameter in BPT. Methods: A total of 85 patients performing a BPT were included in the study. Bronchial reactivity was defined as the provocative dosage or provocative concentration causing a 20% decrease in FEV1 (PC-20) or a 100% increase in sRaw (PC+100). Results: No significant response in either FEV₁ or sRaw was found in 20 patients (24%). Twenty-nine patients (34%) only had a positive response for sRaw; 24 out of these 29 patients recognized their symptoms. 36 patients (42%) showed a positive response for both PC-20 and PC + 100. Conclusions: Twenty-nine patients (34%) showed a significant increase in sRaw without a fall in FEV₁. As performing sRaw is not a routine investigation, these patients are at risk of being excluded from a diagnosis of asthma. We suggest performing sRaw for patients without a fall in FEV₁ during BPT when they report recognizable symptoms.     

Effect of Obesity on Asthma Phenotype is Dependent upon Asthma Severity

Background. We recently reported that obese and non-obese patients with asthma have similar airflow limitation and bronchodilator responsiveness, but obese patients have more symptoms overall. There is limited information on the effect of obesity on asthmatics of varying severity measured by objective physiological parameters. Understanding how obesity affects asthmatics of differing severity can provide insights into the pathogenesis of asthma in the obese and a rationale for the therapeutic approach to such patients. Methods. Participants with asthma from two American Lung Association—Asthma Clinical Research Center (ALA-ACRC) studies were grouped by tertiles of airflow obstruction (forced expiratory volume in one second (FEV₁%) predicted, FEV₁/forced vital capacity (FVC)) and methacholine reactivity (PC₂₀FEV₁). Within each tertile, we examined the independent effect of body mass index (BMI), divided into normal weight, overweight, and obese categories, on lung function, airway reactivity, and symptoms. Results. Overall, both FEV₁ and FVC decreased and symptoms worsened with increasing BMI; airway reactivity was unchanged. When stratified by the degree of airflow obstruction, higher BMI was not associated with greater airway reactivity to methacholine. Higher BMI was associated with more asthma symptoms only in the least obstructed FEV₁/FVC tertile. When stratified by degree of airway reactivity, BMI was inversely associated with FVC in all PC₂₀FEV₁ tertiles. BMI was directly associated with asthma symptoms only in those with the least airway reactivity. Conclusions. Obesity does not influence airway reactivity in patients with asthma and it is associated with more symptoms only in those with less severe disease.     

Chronic mucus hypersecretion: a marker of asthma in young adults?

OBJECTIVE: To investigate if chronic mucus hypersecretion (CMH) can be used as a marker of asthma in young adults. STUDY DESIGN AND SETTING: Cross-sectional study of a population sample of young Danish adults (n=624, 279 males), aged 19-29 years. Case history, including tobacco exposure and respiratory symptoms, was obtained by questionnaire. Pulmonary function, histamine responsiveness, bronchodilator reversibility, skin test reactivity, and leukocyte count were measured using standard techniques. RESULTS: The overall prevalence of CMH was 7.7%, 8.4% in females and 6.9% in males, respectively, of whom more than 70% were current smokers. The presence of CMH was significantly associated with self-reported asthma, dyspnea at exertion, number of pack-years, lower FEV1/FVC ratio, and lower BMI. However, no significant association was found between CMH and the following asthma-related factors: airway responsiveness to inhaled histamine, bronchodilator reversibility, self-reported rhinitis or eczema, atopy, FEV1 (%pred), and B-eosinophil count. CONCLUSIONS: CMH is a common finding in young adults, primarily in smokers. CMH was related to respiratory symptoms suggesting asthma, but no significant association was observed between CMH and objective signs of asthmatic airway lability. The present findings therefore may suggest that CMH is likely to be an early marker of smoking-related lung disease in young adults, instead of a marker of reversible obstructive lung disease, which may have important implications for the approach to young people presenting with respiratory symptoms suggesting asthma.     

Airway Reactivity Is a Determinant of Bronchodilator Responsiveness After Methacholine‐induced Bronchoconstriction

Airway hyperresponsiveness (AHR) is one of the characteristics of asthma and a risk factor for persistent airflow limitation. Poor response to bronchodilator may be a cause of persistent airflow limitation. Multiple factors may determine bronchodilator responsiveness, including airway reactivity to nonspecific bronchoconstrictive agents. If patients with AHR have poor bronchodilator responsiveness, then it could be a potential mechanism for asthma and persistent airflow limitation in these patients. The objective of this study is to assess the relationship between airway reactivity to methacholine and responsiveness to beta‐agonist and beta‐agonist/anticholinergic combination in a large subject population. A retrospective data analysis was undertaken of 764 consecutive subjects with ≥ 20% reduction in forced expiratory volume during the first second of exhalation from total lung capacity (FEV1) after ≤ 189 cumulative units of methacholine. The first 382 subjects received 3 inhalations of metaproterenol and the second 382 subjects received 3 inhalations of albuterol and ipratropium combination after ≥ 20% reduction in FEV1. Bronchodilator responsiveness was measured as the percent increase in FEV1 after the treatment. Airway reactivity was assessed as the log10 of methacholine dose response slope. In a simple linear regression model, airway reactivity was significantly related to bronchodilator responsiveness. The coefficient of determination (r²) was 0.15 for the whole groups; 0.14 for metaproterenol group and 0.18 for albuterol/ipratropium combination group (all p < 0.0001). The regression coefficient (β) was 14.0 for the whole group; 14.8 and 13.2, respectively, for the two bronchodilator groups. Airway reactivity to methacholine is a determinant of airway responsiveness to both beta‐agonist and beta‐agonist/anticholinergic combination. Subjects with higher airway reactivity have higher bronchodilator responsiveness.     

Metabolic Acidosis Improves Airway Conductance in Patients with Asthma

The objective was to investigate whether acute metabolic acidosis could cause bronchodilation in patients with asthma. Twelve patients with asthma (8 females, mean age 39 (± SD 12) years, forced expiratory volume in 1 second [FEV₁] 93 [±9] % predicted, PC₂₀ 1.9 (±1.0) mg/mL) participated in a double-blind, placebo-controlled trial. Subjects ingested calculated amounts of ammonium chloride to induce acidosis or saline as placebo, in random order, each on a separate day. Airway resistance (R_aw), specific airway conductance (sG_aw), FEV₁, and PEF were measured as primary variables. To evaluate the consequences of alterations in bronchial contractility on the airway responsiveness, the histamine provocation test (PC₂₀) was measured as secondary variable.

The intervention resulted in a mean (SD) decrease in base excess from –0.5 (±1.4) to –3.9 (±1.1) mmol/L (p < 0.01) and a decrease in pH from 7.41 (±0.02) to 7.36 (±0.02) (p < 0.01). This caused a statistically significant increase in sG_aw from 1.15 (±0.16) to 1.26 (±0.13) 1/kPa.s) (p < 0.05). Tendencies towards increase were found in PEF (7.79 (±2.2) versus 8.09 (±1.9) (NS, p = 0.10) and in FEV₁ (2.98 (±0.9) versus 3.06 (±0.9) (NS, p = 0.15). PC₂₀ did not change significantly.

It was concluded that acute metabolic acidosis has a modest bronchodilating effect in patients with asthma.     

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.     

Serial Lung Function Variability Using Four Portable Logging Meters

Objective. Portable lung function logging meters that allow measurement of peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV₁) are useful for the diagnosis and exclusion of asthma. The aim of this study was to investigate the within and between-session variability of PEF and FEV₁ for four logging meters and to determine the sensitivity of meters to detect FEV₁ and PEF diurnal changes. Methods. Thirteen assessors (all hospital staff members) were asked to record 1 week of 2-hour PEF and FEV₁ measurements using four portable lung function meters. Within-session variability of PEF and FEV₁ were compared for each meter using a coefficient of variation (COV). Between-session variability was quantified using parameter estimates from a cosinor analysis which modeled diurnal change for both lung function measures and also allowed for variation between days for individual sessions. Results. The mean within-session COV for FEV₁ was consistently lower than that for PEF (p < 0.001). PEF showed a higher but not significantly different (p = 0.068) sensitivity for detecting diurnal variation than FEV₁. PEF was also slightly more variable between days, but not significantly different than FEV₁ (p = 0.409). PEF and FEV₁ diurnal variability did not differ between the 4 meters (p = 0.154 and 0.882 respectively), but within-session FEV₁ COV differed between meters (p = 0.009). Conclusion. PEF was marginally more sensitive to within-day variability than FEV₁ but was less repeatable. Overall, differences between the 4 meters were small, suggesting that all meters are clinically useful.     

Airway responsiveness as a direct factor contributing to the dyspnoea perception in asthma.

It is not clear whether airway responsiveness is directly related to the perception of bronchoconstriction in asthma. The purpose of this study is to directly compare the perception of induced bronchoconstriction among the groups classified according to the degree of airway responsiveness. Two hundred and twenty-seven patients with the definitive or suspected asthma underwent a methacholine provocation test. During the test, the degree of dyspnoea was assessed by a modified Borg scale. The perception of induced bronchoconstriction was indicated by the slope in the linear regression analysis between changes in Borg score and the reduction in forced expiratory volume in 1 sec (FEV1) as a percentage of baseline value. The provocative concentration of methacholine resulting in 20% fall in FEV1 (PC20) was calculated. The degree of airway responsiveness to methacholine was categorized as moderate to severe airway hyper-responsiveness (AHR) if PC20 was < 1 mgml(-1), mild AHR if PC20 was > or =1 but < or =4 mgml(-1), borderline AHR if PC20 was >4 but < or =16 mgml(-1), and normal airway responsiveness (negative AHR) if PC20 was > 16 mgml(-1). Positive AHR was defined as PC20< or =4 mgml(-1). Another index of bronchial responsiveness (BR index) was calculated as the log [(% decline in FEV1/log final methacholine concentration as mg dl(-1)+10]. We found that the geometric mean of the slope was lower in subjects with positive AHR (0.12, n=115) than in subjects with negative AHR (0.17, n=72; P<0.01). The geometric mean of the slope in subjects with borderline AHR (0.14, n=40) was between the two groups. Furthermore, the slope was decreased in asthmatics with moderate to severe AHR compared with mild AHR (P <0.05), although the baseline FEV1 did not differ between the two groups. In multiple regression analysis, airway responsiveness expressed as BR index had a significant effect on the perception of bronchoconstriction. We conclude that the perception of bronchoconstriction is diminished in patients with AHR and the degree of airway responsiveness may be directly related to the perception of bronchoconstriction in asthmatic subjects.     

Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing

Background and Objective

Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV₁) (PC₂₀) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC₄₀) < 8 mg/ml corresponds to a clinical diagnosis of asthma.

Methods

We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.

Results

The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV₁ = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15–0.23) L/s/cm H₂O/L, (median, 25–75 IQR). There were many more patients who responded by PC₄₀ only (n = 120) than who responded by PC₂₀ (n = 52). There was no significant difference in asthma diagnosis between the PC₂₀ (98%) and PC₄₀ (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV₁ criterion was used.

Conclusion

Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.     

Association between β‐adrenoceptor gene polymorphisms and relative response to β2‐agonists and anticholinergic drugs in Japanese asthmatic patients

Background and objective: Whether β₂‐adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to β₂‐agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to β₂‐agonists. Methods: The increases in FEV₁ after inhalation of procaterol hydrochloride (ΔFEV₁ procaterol) or oxitropium bromide (ΔFEV₁ oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5′‐flanking regions of ADRB2 were genotyped by direct sequencing and PCR‐restriction fragment length polymorphism assay. Results: The mean age of the participants was 54 years, and 38 (47%) were smokers. Although ΔFEV₁ procaterol and ΔFEV₁ oxitropium adjusted for predicted FEV₁ were not associated with ADRB2 polymorphisms, the ratio of ΔFEV₁ procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that ΔFEV₁ procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). Conclusions: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to β₂‐agonists even in elderly asthmatic patients and smokers.     

Comparison of 4 AM and 4 PM Bronchial Responsiveness to Hypertonic Saline in Asthma

Bronchial responsiveness to methacholine or histamine increases at night and may contribute to the mechanisms of nocturnal asthma. Hypertonic saline (HS) is a more clinically relevant stimulus for the diagnosis and assessment of the severity of asthma, but the circadian variation in bronchial responsiveness to hypertonic challenges has not been addressed. The aim of this study was to compare the responsiveness to hypertonic saline at 4:00 AM and at 4:00 PM. Eighteen diurnally active patients (11 women) with asthma, 31 ± 9 years of age (mean ± SD) and with a forced expiratory volume in 1 s (FEV₁) of 79.11% ± 12.85%, underwent two challenge tests (4:00 AM and 4:00 PM) in random sequence separated by an interval of 7 days. The challenge test consisted of inhalations of 4.5% saline with increasing doses by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min). The inhalation continued until a drop of 20% in FEV₁ was achieved or total time of 15.5 min. The provocative dose that caused the 20% drop in FEV₁ (PD₂₀) was calculated. Differences were found between 4:00 PM and 4:00 AM values for inhalation times [3.80 ± 3.57 min and 2.19 ± 2.42 min (p = 0.001), respectively] and for PD₂₀ [4.94 ± 6.77 ml and 2.93 ± 4.74 ml (p = 0.002), respectively]. Eight patients with a home-assessed nocturnal peak expiratory flow (PEF) drop of more than 15% formed the nocturnal asthma group. The behavior of these patients was similar to that of the non-nocturnal asthma group. We conclude that the bronchial responsiveness to HS increases at night.     

Prevalence and features of asthma–chronic obstructive pulmonary disease overlap in Northern Italy general population

Objective: There is controversy about the diagnostic criteria, prevalence, symptoms, and spirometry characteristics of asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO). Recent data indicate that the fixed method for diagnosing airway obstruction (AO) may overestimate ACO prevalence in the elderly, and a variable method may be more accurate. We aimed at estimating ACO prevalence in a general population sample and comparing patient and clinical features in subjects with ACO, COPD, and asthma. Methods: We analyzed data from a cross-sectional study estimating COPD prevalence in randomly selected adults aged 20–79 years in Verona, Italy, and estimated prevalence and analyzed characteristics of asthma, COPD, and ACO. ACO was defined as AO (Forced Expiratory Volume in one second–FEV₁/ Forced Vital Capacity–FVC < Lower Limit of Normal–LLN), highly positive bronchodilator test (≥15% increase in FEV₁ and FVC ≥400 mL), and personal self-reported history of physician diagnosed asthma and atopy. Results: One thousand two hundred and thirty-six patients were included; 207 (16.7%) had asthma, COPD, or ACO (mean ages: 61.2, 59.7, and 57.2 years, respectively). The 3 groups had similar clinical and demographic variables; however, spirometry revealed differences between ACO and COPD patients, particularly post-bronchodilator FEV₁ reversibility, which was detected in ACO and asthma patients but not in those with COPD. Conclusion: ACO prevalence in Northern Italy was estimated at 2.1%, in the range of values reported by previous studies. Marked differences between ACO and COPD revealed by spirometry may have important clinical implications in terms of treatment for patients with ACO.