Methacholine Dose-response Slope Research Articles

Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study

BackgroundIt has been debated, but not yet established, whether increased airway responsiveness can predict COPD. Recognising this link may help in identifying subjects at risk.ObjectiveWe studied prospectively whether airway responsiveness...

Reduced forced expiratory flow but not increased exhaled nitric oxide or airway responsiveness to methacholine characterises paediatric sickle cell airway disease

BackgroundAsthma and airway hyper-responsiveness are reportedly more common in children with sickle cell disease (SCD).AimTo determine airway responsiveness, airway inflammation and clinical features of asthma in SCD.MethodsA prospective, single-centre study...

Can an airway challenge test predict respiratory diseases? A population-based international study

Evidence on the longitudinal association of airway responsiveness with respiratory diseases is scarce. The best indicator of responsiveness is still undetermined. We investigated the association of airway responsiveness with the incidence of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. We studied 3851 subjects who underwent spirometry and methacholine challenge tests both at baseline (1991-1993), when they were 20 to 44 years old, and at follow-up (1999-2002) in the European Community Respiratory Health Survey. Airway responsiveness was defined based on the methacholine dose-response slope on both occasions. Incidence rate ratios for the association of airway responsiveness with disease occurrence were computed by using Poisson regression. With respect to reference (slope of the fourth quintile or greater), subjects with the greatest degree of airway responsiveness (slope less than the first quintile) showed the greatest risk of developing asthma, COPD, and allergic rhinitis (incidence rate ratios of 10.82, 5.53, and 4.84, respectively; all P < .01). A low slope predicted disease occurrence, even in subjects who did not reach a 20% decrease in FEV1 at the cumulative dose of 1 mg of methacholine (PD20 >1 mg). A decrease in slope over time was an independent predictor of disease risk. Airway responsiveness predicted new-onset asthma, COPD, and allergic rhinitis. Our study supports the use of a continuous noncensored indicator of airway responsiveness, such as the slope of the methacholine dose-response curve, in clinical practice and research because it showed clear advantages over PD20.

Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma

Altered deposition of extracellular matrix (ECM) in the airway smooth muscle (ASM) layer as observed in asthma may influence ASM mechanical properties. We hypothesized that ECM in ASM is associated with airway function in asthma. First, we investigated the difference in ECM expression in ASM between asthma and controls. Second, we examined whether ECM expression is associated with bronchoconstriction and bronchodilation in vivo. Our cross-sectional study comprised 19 atopic mild asthma patients, 15 atopic and 12 nonatopic healthy subjects. Spirometry, methacholine responsiveness, deep-breath-induced bronchodilation (ΔR(rs) ) and bronchoscopy with endobronchial biopsies were performed. Positive staining of elastin, collagen I, III and IV, decorin, versican, fibronectin, laminin and tenascin in ASM was quantified as fractional area and mean density. Data were analysed using Pearson's or Spearman's correlation coefficient. Extracellular matrix expression in ASM was not different between asthma and controls. In asthmatics, fractional area and mean density of collagen I and III were correlated with methacholine dose-response slope and ΔR(rs) , respectively (r=0.71, P<0.01; r=0.60, P=0.02). Furthermore, ASM collagen III and laminin in asthma were correlated with FEV(1) reversibility (r=-0.65, P=0.01; r=-0.54, P=0.04). In asthma, ECM in ASM is related to the dynamics of airway function in the absence of differences in ECM expression between asthma and controls. This indicates that the ASM layer in its full composition is a major structural component in determining variable airways obstruction in asthma.

Hypertonicity of the challenge solution may increase the diagnostic accuracy of histamine challenge

There is significant overlap in the responsiveness to direct airway challenges, such as the histamine challenge, between asthmatic and non-asthmatic subjects, which decreases their accuracy in the diagnosis of asthma. To minimise this overlap, a new test, hypertonic histamine challenge, was developed. Fifteen healthy subjects, 16 subjects with steroid-naive asthma, and 16 asthmatic subjects undergoing inhaled corticosteroid treatment underwent inhalation challenges with hypertonic saline, isotonic histamine, and hypertonic histamine, using an ultrasonic nebuliser and 2-min tidal breathing method. The increase in histamine solution tonicity decreased the histamine PC20 values only in the steroid-naive asthmatic subjects (1.1 (0.5-2.7) vs. 0.5 (0.2-1.2) mg/ml, P = 0.047). Using 1mg/ml as the cut-off value, the sensitivity, specificity, and accuracy of the hypertonic histamine challenge to detect steroid-naive asthma was 81%, 100%, and 90%. The respective values for the isotonic histamine challenge were 56%, 100%, and 77%. Furthermore, there was a statistically significant difference in the hypertonic histamine PC20 between steroid-naive and steroid-treated asthmatic subjects, which could not be detected in the isotonic histamine PC20. The hypertonic histamine PC20 was highly repeatable, with a single determination 95% range of +/-1.35 doubling concentrations. The hypertonic histamine challenge was safe but provoked more cough and throat irritation than the other two challenges. In conclusion, compared with a conventional, isotonic histamine challenge, hypertonic histamine challenge may be more accurate in the diagnosis of asthma and also, more capable to detect the effects of inhaled corticosteroid treatment.

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.

Discriminant analysis in allergic rhinitis and asthma: methacholine dose–response slope allows a good differentiation between mild asthma and rhinitis

Asthma and rhinitis frequently coexist in allergic patients, but nasal symptoms may predominate, leading to asthma underdiagnosis and undertreatment. Discriminant analysis obtains the best differentiation between groups using one or one set of variables. Our aim was to identify the laboratory test [allergen exposure, total and specific serum IgE, lung function, blood eosinophils and, bronchial response and sensitivity to methacholine (Mth) and allergen] or combination of them that allowed the best differentiation between mild asthma and allergic rhinitis. A cross-sectional analysis was performed in 86 Dermatophagoides pteronyssinus allergic rhinitis patients, who were classified according to clinical data as rhinitis plus mild asthma ( n =62) or “pure” rhinitis ( n =24). Bronchial symptoms had been exhaustively evaluated during a 2-years pre-inclusion period. Patients underwent skin tests and bronchial challenge with Mth and allergen. The exposure to D. pteronyssinus allergen (Der p1) was quantified in dust samples. Dose–response curves with Mth [until the FEV 1 fell by 40% or the maximal dose (200mg/ml) was inhaled] were attained. We developed multiple models of discriminant analysis in order to evaluate the capacity of the above variables to differentiate groups. Asthma patients had higher total and specific IgE levels and a greater sensitivity (PD 20 values) and response [dose–response slope (DRS)] to both Mth and allergen. The model entering these variables was the one that correctly classified more patients (79.2%). The discriminative power of the model that only included Mth-DRS values was similar to the above (78.8%). Bronchial response to Mth is quantitatively different in allergic rhinitis patients who display mild asthma symptoms when compared to those that only report rhinitis, suggesting a distinct bronchial intrinsic behavior. The utilization of complete dose–response curves with Mth allows a good separation between mild asthma and “pure” rhinitis patients and might be useful in the diagnosis of mild asthma. Whether the early detection and treatment of these patients prevents the development of symptomatic asthma needs further evaluation.

Objective assessment of ocular and respiratory alterations in employees in a sick building.

Sick building syndrome (SBS) is a constellation of diffuse, "irritative" symptoms predominantly involving the eyes and the respiratory tract. To date, the effects of working in a "sick building" have not been adequately assessed using objective measures. We undertook the present study to determine whether objective alterations could be found in the eyes and respiratory' tracts of employees working in an office building in which a high rate of SBS had been reported in the preceding year. We studied 163 office workers: 87 workers from a modern, air-conditioned building (the sick building), and 76 employees employed in three traditional-style office buildings (the comparison buildings). After being surveyed for SBS symptoms, all subjects underwent a series of objective tests, including spirometry, a methacholine test, prick tests for aeroallergens, and submitted tear samples. In addition, Schirmer's test and the break-up time test were used to explore for potential ocular effects of sick building exposure. Employees in the sick building complained more frequently of ocular symptoms, upper-airway disturbances, and general and respiratory' symptoms than did employees in the comparison buildings; prick tests were positive in 20% and 17.4%, respectively. Groups did not differ significantly on spirometry measures. Bronchial hyperreactivity to methacholine (PD15 = 16.348 mumol) was present in 20.5% of the sick building workers and in 16.2% of comparison buildings workers. Methacholine dose-response slope values were similar. Stability of tear film was significantly reduced (P < 0.01) in the employees in the sick building compared with employees in the comparison buildings. Our results indicate that (1) atopy does not seem to influence the prevalence of SBS symptoms, and (2) the lower respiratory tract seems unaffected by exposure to a "sick building," but (3) alterations in tear film stability do exist after such exposure.

Cross-sectional assessment of workers with repeated exposure to chlorine over a three year period

Airflow obstruction has been described in workers who experienced symptoms after acute exposure to chlorine. Persistent bronchial hyperresponsiveness has also been assessed, but mainly in case studies. In this cross-sectional study, we have assessed the relationship between inhalational accidents ("puffs") involving chlorine and persistent symptoms as well as hyperresponsiveness in 239 out of 255 at-risk workers (94%). No relationship was found between persistent symptoms and the exposure variables studied. Forced vital capacity (FVC) was higher in subjects who had had no symptoms after a "puff", compared with those who had experienced mild symptoms. Forced expiratory volume in one second (FEV1) and FVC were significantly lower in subjects who experienced more than 10 puffs with mild symptoms than in subjects who reported no symptomatic puff. The presence of bronchial hyperresponsiveness was not related to exposure, but the methacholine dose-response slope showed a tendency to increased bronchial responsiveness with increased exposure. A significant difference was shown in subjects who experienced more than 10 puffs with mild symptoms. In this group of workers, repeated exposure to chlorine with acute respiratory symptoms was associated with a slight but significant reduction in expiratory flow rates, together with an increase in bronchial responsiveness, without long-term symptoms.

Evaluation of peak expiratory flow variability in an adolescent population sample. The Odense Schoolchild Study.

The validity of peak expiratory flow (PEF) recordings and the sensitivity of PEF variability indices in asthma and asthma-like conditions were examined in an adolescent population. Recordings from 245 randomly selected subjects and from an additional 181 subjects reporting or considered at risk for developing asthma were analyzed. Subjects recorded PEF twice daily for 2 wk using Mini-Wright meters, completed a symptoms questionnaire, and were tested for airway responsiveness to methacholine. The first three recording days showed significant accumulation of lowest PEF values recorded (41%) and were excluded from further analysis. Among nine PEF variability indices, the Two-lowest%mean (the mean of the two lowest PEF values as a percentage of the period mean) had the best sensitivity for physician-diagnosed asthma (28%). The sensitivity of the methacholine dose-response slope (DRS) was 69%. Combining these indices, a sensitivity of 77% for diagnosed asthma was obtained. Among subjects with asthma-like symptoms but no diagnosis of asthma, 14% had increased Two-lowest%mean and the DRS was increased in 17%, but only 3% were identified by both tests. In conclusion, inhomogeneity of PEF data could be corrected by disregarding the first three recording days. PEF variability indices identified some diagnosed asthmatics, and particularly some symptomatic "nonasthmatics," not identified by the DRS, suggesting that the combined use of these indices might be helpful.

Predictors of longitudinal change in methacholine airway responsiveness among middle-aged and older men: the Normative Aging Study.

Increasing nonspecific airway responsiveness during aging may precede and predispose to the development of asthma in later life. Characteristics potentially related to longitudinal change in methacholine airway responsiveness were examined over a 3-yr follow-up interval among 435 middle-aged and older men. Initial and follow-up evaluation included spirometry, allergy skin testing with common aeroallergens, measurement of the serum concentration of total IgE, and blood cell counts (total leukocytes and eosinophils, basophils, and neutrophils as a percentage of total leukocytes). The initial values and annual rates of change of these characteristics were examined by multiple linear regression as potential predictors of annual change in methacholine dose-response slope. Annual change in basophil count was directly related to change in dose-response slope (p = 0.02). Initial values and annual rates of change of other cell counts, pulmonary function, allergy skin test reactivity, and serum total IgE concentration were not significantly related to change in dose-response slope. Cigarette smoking history was also not significantly related to longitudinal change in dose-response slope. These data suggest that inflammatory mechanisms involving the basophil may be important in the development of increasing nonspecific airway responsiveness during aging.

Methacholine Airway Responsiveness and 24-Hour Urine Excretion of Sodium and Potassium: The Normative Aging Study

Prior studies have suggested a direct relationship between dietary sodium intake and nonspecific airway responsiveness. The relationship of dietary sodium and potassium intake to methacholine airway responsiveness was examined among 273 male participants of the Normative Aging Study (age range 44 to 82 yr) using 24-h urinary excretion of these cations as a surrogate for intake. Methacholine airway responsiveness was analyzed as dose-response slope, a continuous measure of responsiveness that represents the slope of a line connecting the origin to the last point of the dose-response plot. Greater airway responsiveness to methacholine was associated with greater potassium excretion. A significant relationship between methacholine dose-response slope and potassium excretion (p = 0.014) was observed in multivariate analysis that took into account other covariates, including age, percentage of predicted FEV1, cigarette smoking, and skin test reactivity. In contrast, methacholine airway responsiveness did not appear related to urinary sodium excretion. These data suggest that dietary potassium may have an influence on airway responsiveness of middle-aged and older men.

Smoking, atopy, and methacholine airway responsiveness among middle-aged and elderly men. The Normative Aging Study.

The interrelationships between smoking history, objective markers of allergy and inflammation, and methacholine responsiveness were examined among 778 middle-aged and elderly men (age range 41 to 86 yr). Methacholine responsiveness was analyzed using dose-response slope to describe each subject's responsiveness. Current smokers were observed to have significantly greater total serum IgE concentration ([IgE]), blood total leukocyte count, and blood eosinophil count than nonsmokers. Current smokers with at least one positive skin test reaction to common aeroallergens displayed significantly greater methacholine dose-response slope than smokers with negative skin test results (p less than 0.01). Among nonsmokers, skin test positivity was associated with slightly but not significantly greater methacholine responsiveness. Among subjects with negative skin test results, smoking was not associated with greater methacholine responsiveness. Blood eosinophil count and serum total [IgE] displayed weak but statistically significant direct relationships to methacholine dose-response slope (p less than 0.01), and these relationships were not significantly modified by smoking status. In a multivariate model, the cigarette smoking/skin test positivity interaction, total serum [IgE], and blood eosinophil count displayed significant, independent relationships to methacholine dose-response slope, although only a small portion of the variance of dose-response slope was accounted for by these covariates. These data suggest that smoking and atopy may act synergistically to increase the degree of nonspecific airway responsiveness displayed by middle-aged and elderly individuals. Allergic airway inflammation, as reflected by total serum [IgE] and blood eosinophil count, may also influence nonspecific airway responsiveness in this age group.