Cumulative Dose Of Methacholine Research Articles

Bronchial hyperresponsiveness and asthma during oral immunotherapy for egg or peanut allergy in children.

BackgroundBronchial hyperresponsiveness (BHR) and asthma are frequently present in children with food allergy. We assessed BHR in children receiving oral immunotherapy (OIT) for persistent egg or peanut allergy and examined whether OIT affects asthma control.MethodsMethacholine challenge testing was performed in 89 children with persistent egg or peanut allergy diagnosed by double‐blind, placebo‐controlled food challenge and 80 control children without food allergy. Of the 89 food‐allergic children, 50 started OIT for egg allergy and 39 for peanut allergy. Sensitization to aeroallergens was evaluated by skin prick testing. Forty of the 89 children with regular controller treatment for asthma underwent methacholine challenge testing and 34 measurement of exhaled nitric oxide (FeNO) at baseline and after 6–12 months of OIT.ResultsMethacholine challenge testing revealed significant BHR in 29/50 children (58%) with egg allergy, 15/39 children (38%) with peanut allergy, and 6/80 controls (7.5%). The mean cumulative dose of methacholine causing a 20% fall in FEV1 differed significantly between the egg and peanut‐allergic versus the control children (1009 μg, 1104 μg, and 2068 μg, respectively, p < 0.001). Egg or peanut OIT did not affect lung function, the degree of BHR or FeNO levels in children with asthma and had no adverse effect on asthma control. Lung function or BHR did not associate with the OIT outcome.ConclusionBHR was significantly more frequent in children with persistent egg or peanut allergy than in children without food allergy. Oral immunotherapy did not increase BHR and was safe for children on regular asthma medication.

Obesity in women with asthma: Baseline disadvantage plus greater small-airway responsiveness.

Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small-airway responsiveness. The objective of this study was therefore to compare small-airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLDe/i , as determined by computed tomography [CT]) throughout methacholine testing in obese versus non-obese women with asthma. Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n=18 non-obese and n=13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLDe/i response and compared between groups. Obesity-associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non-obese (82.19 ± 8.78; p=0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLDe/i slopes (group×ln(1 + % PD20 interaction; p=0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p=0.004 and p=0.021). Significant obesity effects (p=0.035 and p=0.008) indicating lower forced vital capacity and greater % change in MLDe/I (respectively) throughout methacholine testing, were also observed. In addition to baseline differences, small-airway responsiveness (as represented by the change in MLDe/i ) during methacholine challenge is greater in obese women with asthma as compared to the non-obese.

Bronchial provocation test measured by using the forced oscillation technique to assess airway responsiveness.

Background: The bronchial provocation test (BPT) performed by using the forced oscillation technique (FOT) is cooperated without forced expiratory effort. However, a comparison of the application value and safety of BPTs measured by using the FOT and the standardized dosimeter method is lacking, which limits its clinical practice. Objective: We aimed to analyze the diagnostic value and safety of the BPT as measured by the FOT in patients with asthma and in healthy subjects. Methods: This was a randomized cross-over clinical study. Airway responsiveness was measured by using the FOT and the aerosol provocation system (APS) dosimeter method in all the participants. The between-test interval was 24 hours. The diagnostic value and safety of the two tests were analyzed. Results: Asthma control status was assessed based on ACT scores, and patients with asthma (including 27 uncontrolled, 34 partially controlled, and 32 controlled) were collected, and 69 healthy subjects were recruited. Receiver operating characteristic curves revealed slightly superior screening capability of cumulative dose of methacholine causing a 20% decrease (PD20)-forced expiratory volume in the first second of expiration when measured by using the APS-dosimeter method (area under the curve [AUC] 0.981 [95% confidence interval {CI}, 0.952-1.000]) over that of cumulative dose of inhaled methacholine at the inflection point when respiratory resistance began to increase continuously (Dmin) by using the FOT (AUC 0.959 [95% CI, 0.924-0.994]). The sensitivity and specificity were 98.9% and 98.6%, respectively, with the APS-dosimeter method, and 100% and 87.0%, respectively, with the FOT. It took an average of 9.0 minutes (range, 6.0-11.0 minutes) when using the FOT and an average of 17.0 minutes (range, 14.0-25.0 minutes) when using APS-dosimeter method (p < 0.01) in all the participants. The measurement time for the FOT was reduced by 47.1% than the APS-dosimeter. The incidence rate of the adverse events with the FOT was slightly higher than that with the APS-dosimeter method (p < 0.05). Both tests were well tolerated. No serious adverse event was found. Conclusion: The FOT, characterized as being simple, safe, and time saving, could be used to assess airway hyperresponsiveness in patients with asthma and worthy of clinical application.

In Vitro Study of Bronchial Relaxation Mechanism of Coptosapelta Flavescens Korth Root’s Methanol Extract On Receptors

Objective: To evaluate the bronchorelaxation effect of methanol extract of Coptosapelta flavescens Korth. ischolar_main (MECFR) on cholinergic, histamine receptors and beta2-adrenoceptors, in vitro. Method: The research design was experimental in which a 4-mm long guinea pig’s bronchus was kept in an isolated organ bath containing Kreb’s-Henseleit solution at 37°C, pH 7.4 and flooded with carbogen gas. The study was divided into 3 groups: in Group 1 and 2, the bronchial rings were incubated in 3 concentrations of MECFR, and then contracted with cumulative doses of methacholine and histamine, respectively; in Group 3, the bronchial ring was incubated in 3 concentrations of propranolol, contracted with a single dose of methacholine, and then the MECFR was administered in cumulative doses. Results: In both Group 1 and Group 2, the dose-response curves of all 3 doses of MECFR shifted to the right with lower E max (P&lt;0.05) as compared to the negative control. In Group 3, the dose-response curves showed MECFR has bronchorelaxation effect on bronchial rings both in the presence of propranolol andwithout, with similar E max (P&gt;0.05). Conclusion: MECFR exhibits bronchorelaxation effects by acting as non-competitive antagonist at the cholinergic and histamine1 receptors, and also by acting as beta 2 -adrenoceptor agonist.

Variable ventilation decreases airway responsiveness and improves ventilation efficiency in a rat model of asthma

The optimal ventilation strategy in patients receiving mechanical ventilation for severe asthma remains unclear. The effect of conventional ventilation (with constant tidal volume and respiratory rate) and variable ventilation (with the same average but variable tidal volume and respiratory rate) on peak airway pressure and airway exacerbation induced by increasing doses of methacholine was compared in a rat model of asthma. The respiratory rate and tidal volume data were obtained from a spontaneously breathing intact rat during immobility using a whole-body plethysmograph. Peak airway pressure and airway responsiveness to cumulative doses of methacholine were significantly affected by ventilation mode and they were lower in variable ventilation group than in the conventional ventilation group. Also, variable ventilation improved oxygen saturation compared to conventional ventilation. Our results indicate that variable ventilation decreases airway responsiveness and enhances ventilation efficiency in a rat model of asthma. We suggest further investigations on beneficial effects of variable ventilation strategy in mechanically ventilated patients with severe asthma.

Simultaneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity

We have previously described that fraction of exhaled nitric oxide (Feno) levels and blood eosinophil counts offer additive information in relation to asthma and asthma exacerbations when analyzing data from a large population study. We sought to investigate increased Feno levels and blood eosinophil counts in relation to lung function, bronchial hyperresponsiveness (BHR), and asthma control in a cohort of young asthmatic patients. Measurements of Feno levels and blood eosinophil counts were available in 406 subjects (208 women) aged 10 to 35years. Asthma control was assessed through the Asthma Control Test. Moderate-to-severe BHR was defined as a cumulative dose of methacholine of less than 0.3 mg causing an FEV1 decrease of 20%. Subjects with simultaneously increased Feno levels (≥20-25ppb) and blood eosinophil counts (≥0.3×109/L) had a higher prevalence of uncontrolled asthma (Asthma Control Test score, <20) than subjects with singly increased blood eosinophil counts (40.5% vs 21.1%, P=.01). This difference remained significant (P=.006), and a significant difference was also found between subjects with both increased Feno levels and blood eosinophil counts and subjects with normal Feno levels and blood eosinophil counts (P=.02) after adjusting for confounders. Having increased Feno levels and blood eosinophil counts related to a higher prevalence of moderate-to-severe BHR than having normal Feno levels and blood eosinophil counts or singly increased Feno levels or blood eosinophil counts (85.7% vs 35.8% or 63.3% or 60%, P<.05 all comparisons). We have shown that simultaneously increased local (Feno) and systemic (blood eosinophil) markers of type 2 inflammation related to a higher likelihood of BHR and uncontrolled asthma in a large cohort of young asthmatic patients.

Bronchial hyperresponsiveness, airway inflammation, and reversibility in patients with chronic obstructive pulmonary disease.

BackgroundBronchial hyperresponsiveness (BHR), sputum eosinophilia, and bronchial reversibility are often thought to be a hallmark of asthma, yet it has been shown to occur in COPD as well.ObjectivesTo evaluate the relationship between BHR, lung function, and airway inflammation in COPD patients.MethodsThirty-one, steroid-free patients with stable, mild and moderate COPD were studied. The following tests were carried out: baseline lung function, reversibility, provocative dose of methacholine causing a 20% fall in forced expiratory volume in 1 second, a COPD symptom score, and sputum induction.ResultsTwenty-nine patients completed the procedures. About 41.4% had BHR, 31.0% had increased sputum eosinophils, and 37.9% had bronchial reversibility. Some of the patients had only one of these characteristics while others had two or the three of them. Patients with BHR had higher sputum eosinophils than patients without BHR (P=0.046) and those with sputum eosinophils ≥3% had more exacerbations in the previous year and a higher COPD symptom score than patients with sputum eosinophils <3% (P=0.019 and P=0.031, respectively). In patients with BHR, the cumulative dose of methacholine was negatively related to the symptom score and the number of exacerbations in the previous year. When patients with bronchial reversibility were considered, bronchodilation was positively related to sputum eosinophils.ConclusionOur study showed that BHR, sputum eosinophilia, and bronchial reversibility were not clustered in one single phenotype of COPD but could be present alone or together. Of interest, BHR and airway eosinophilia were associated with clinical data in terms of exacerbations and symptoms. Further investigation is needed to clarify this topic.

The gain of smooth muscle's contractile capacity induced by tone on in vivo airway responsiveness in mice

Airway hyperresponsiveness to a spasmogenic challenge such as methacholine, and an increased baseline tone measured by the reversibility of airway obstruction with a bronchodilator, are two common features of asthma. However, whether the increased tone influences the degree of airway responsiveness to a spasmogen is unclear. Herein, we hypothesized that increased tone augments airway responsiveness in vivo by increasing the contractile capacity of airway smooth muscle (ASM). Anesthetized, tracheotomized, paralyzed, and mechanically ventilated mice were either exposed (experimental group) or not (control group) to tone for 20 min, which was elicited by nebulizing serial small doses of methacholine. Respiratory system resistance was monitored during this period and the peak response to a large cumulative dose of methacholine was then measured at the end of 20 min to assess and compare the level of airway responsiveness between groups. To confirm direct ASM involvement, the contractile capacity of excised murine tracheas was measured with and without preexposure to tone elicited by either methacholine or a thromboxane A2 mimetic (U46619). Distinct spasmogens were tested because the spasmogens liable for increased tone in asthma are likely to differ. The results indicate that preexposure to tone increases airway responsiveness in vivo by 126 ± 37% and increases the contractile capacity of excised tracheas ex vivo by 23 ± 4% for methacholine and 160 ± 63% for U46619. We conclude that an increased tone, regardless of whether it is elicited by a muscarinic agonist or a thromboxane A2 mimetic, may contribute to airway hyperresponsiveness by increasing the contractile capacity of ASM.

Bronchial hyperresponsiveness decreases through childhood

Limited knowledge exists about development of bronchial hyperresponsiveness (BHR) through adolescence. We aimed to assess changes in and risk factors for BHR in adolescence. From a Norwegian birth cohort 517 subjects underwent clinical examinations, structured interviews and methacholine challenges at age 10 and 16. BHR was divided into four categories: no BHR (cumulative methacholine dose required to reduce FEV(1) by 20% (PD(20)) >16 μmol), borderline BHR (PD(20) ≤16 and >8 μmol), mild to moderate BHR (PD(20) ≤8 and >1 μmol), and severe BHR (PD(20) ≤ 1 μmol). Logistic regression analysis was used to assess risk factors and possible confounders. The number of children with PD(20) ≤ 8 decreased from 172 (33%) to 79 (15%) from age 10-16 (p < 0.001). Most children (n = 295, 57%) remained in the same BHR (category) from age 10-16 (50% with no BHR), whereas the majority 182 (82%) of the 222 children who changed BHR category, had decreased severity at age 16. PD(20) ≤ 8 at age 10 was the major risk factor for PD(20) ≤ 8 6 years later (odds ratio 6.3), without significant confounding effect (>25% change) of gender, active rhinitis, active asthma, height, FEV(1)/FVC, or allergic sensitization. BHR decreased overall in severity through adolescence, was stable for the majority of children and only a minority (8%) had increased BHR from age 10 to 16. Mild to moderate and severe BHR at age 10 were major risk factors for PD(20) ≤ 8 at 16 years and not modified by asthma or body size.

Cystic fibrosis and the relationship between mucin and chloride secretion by cultures of human airway gland mucous cells.

We investigated how cystic fibrosis (CF) alters the relationship between Cl(-) and mucin secretion in cultures of non-CF and CF human tracheobronchial gland mucous (HTGM and CFTGM, respectively) cells. Biochemical studies showed that HTMG cells secreted typical airway mucins, and immunohistochemical studies showed that these cells expressed MUC1, MUC4, MUC5B, MUC8, MUC13, MUC16, and MUC20. Effects of cumulative doses of methacholine (MCh), phenylephrine (Phe), isoproterenol (Iso), and ATP on mucin and Cl(-) secretion were studied on HTGM and CFTGM cultures. Baseline mucin secretion was not significantly altered in CFTGM cells, and the increases in mucin secretion induced by mediators were unaltered (Iso, Phe) or slightly decreased (MCh, ATP). Across mediators, there was no correlation between the maximal increases in Cl(-) secretion and mucin secretion. In HTGM cells, the Cl(-) channel blocker, diphenylamine-2-carboxylic acid, greatly inhibited Cl(-) secretion but did not alter mucin release. In HTGM cells, mediators (10(-5) M) increased mucin secretion in the rank order ATP > Phe = Iso > MCh. They increased Cl(-) secretion in the sequence ATP > MCh ≈ Iso > Phe. The responses in Cl(-) secretion to MCh, ATP, and Phe were unaltered by CF, but the response to Iso was greatly reduced. We conclude that mucin secretion by cultures of human tracheobronchial gland cells is independent of Cl(-) secretion, at baseline, and is unaltered in CF; that the ratio of Cl(-) secretion to mucus secretion varies markedly depending on mediator; and that secretions induced by stimulation of β-adrenergic receptors will be abnormally concentrated in CF.

Methacholine challenge – Comparison of an ATS protocol to a new rapid single concentration technique

Bronchial methacholine challenge is well established in asthma diagnostics and research. ATS guidelines propose a five step standard dosimeter (SDM) protocol with incremental concentrations of methacholine to calculate the concentration causing a 20% drop in FEV(1) in an individual (PC(20)FEV(1)). In contrast, the aerosol provocation system (APS) by Viasys automatically determines the administered dose of methacholine by measuring the effective nebulisation time and referring it to drug concentration and nebuliser power. Therefore, it offers a feasible and less time-consuming provocation procedure by applying incremental doses (PD(20)) of methacholine using a single concentration (16mg/mL methacholine, APS-SC). In this study we compared these two methods in 52 young adults (25+/-5.8 years). Following a screening visit, subjects were randomly assigned to undergo either SDM or APS-SC followed by the other method within 1 week. A close correlation between concentration and dosage causing a 20% fall of FEV(1) was found (r=0.69, p<0.001). Using the ATS categorisation of bronchial responsiveness we interpreted the results of the APS-SC method as follows: PD(20) methacholine<0.3mg as "moderate to severe BHR", 0.3 - 0.6mg as "mild BHR", 0.6 - 1.0mg as "borderline BHR", and>1.0mg as "normal bronchial response". We conclude that the five-step APS-SC is a suitable method, providing reliable results. In clinical practice the APS-SC is a timesaving procedure and less prone to errors since only one dilution of methacholine is necessary compared to the SDM.

Evaluation of Bronchial Hyperresponsiveness by Monitoring of Transcutaneous Oxygen Tension and Arterial Oxygen Saturation during Methacholine Challenge in Asthmatic Children

Background. Bronchial hyperresponsiveness (BHR) is a key feature of asthma, but the measurement of BHR is hampered by the fact that most tests of airway caliber are difficult to conduct at a young age. Methacholine-induced bronchoconstriction is associated with significant hypoxemia, which can be assessed noninvasively by transcutaneous oxygen pressure (tcPO2) and pulse oximetry. Evaluating BHR by monitoring tcPO2 instead of respiratory resistance (Rrs) has been used over a wide age range in childhood.Objective. To investigate whether there is a consistent relationship between changes in arterial oxygen saturation (SaO2) and respiratory resistance (Rrs) similar to the relationship between tcPO2 and Rrs during methacholine challenge in young children and to assess the usefulness of SaO2 as a parameter for the indirect measurement of BHR.Method. We performed methacholine inhalation challenge by monitoring SaO2, tcPO2 and Rrs in 37 asthmatic children 5 to 7 years of age. Consecutive doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. We recorded the cumulative dose of methacholine (Dmin) at the inflection point of tcPO2 (Dmin-tcPO2), SaO2 (Dmin-SaO2), and Rrs(Dmin-Rrs).Results. The mean value of Dmin-Rrs was 4.27 ± 2.02 units, the mean value of Dmin-tcPO2 was 4.48 ± 2.01 units, and the mean value of Dmin-SaO2 was 4.57 ± 0.20 units. Inhalation of increasing doses of methacholine raised Rrs curvilinearly and depressed tcPO2 and SaO2. There were no significant differences between any of the parameters. There were significant relationships between Dmin-tcPO2 and Dmin-Rrs (r = 0.914, p < 0.001) and between Dmin-SaO2 and Dmin-Rrs (r = 0.905, p < 0.001) and a relationship between Dmin-tcPO2 and Dmin-SaO2 (r = 0.949, p < 0.001).Conclusion. We concluded that measurement of SaO2 and/or tcPO2 during methacholine inhalation challenge may be used to assess bronchial hyperresponsiveness. This study showed that both SaO2 and tcPO2 monitoring are safe, useful, and tolerable for use in children who are too young to cooperate with lung function tests.

Bronchial Sensitivity and Bronchial Reactivity in Children With Cough Variant Asthma

Cough variant asthma (CVA) is diagnosed in some children with chronic cough who do not have wheezing. However, the precise mechanism of CVA in children is unclear. To evaluate the physiologic differences in the airways of children with classic asthma and CVA, the methacholine dose-response curves of respiratory resistance (Rrs) were studied. CVA was diagnosed in 31 children with chronic cough (age range, 5 to 14 years; 19 boys and 12 girls; mean age, 8.5 years) on the basis of methacholine inhalation challenge using an oscillation method. For comparison, the study included 86 age-matched children with classic asthma (age range, 5 to 15 years; 42 boys and 44 girls; mean age, 9.5 years), 25 age-matched children with cough (age range, 5 to 15 years; 17 boys and 8 girls; mean age, 8.8 years), and 23 age-matched control subjects (8 boys and 15 girls; mean age, 9.2 years). Consecutive doses of methacholine were doubled until a 200% increase in Rrs from baseline was reached. The cumulative dose of methacholine at the inflection point of Rrs was considered to represent the bronchial sensitivity to inhaled methacholine (minimum dose of methacholine [Dmin]). The slope of the methacholine dose-response curve (SRrs), which was considered to represent bronchial reactivity, was measured from the increasing Rrs curve. The values of Dmin in classic asthma patients and in CVA patients were significantly lower than those for cough patients and control subjects. There was no significant difference in the values of Dmin between the classic asthma and CVA patients. The value of SRrs in CVA patients was significantly lower than that in classic asthma patients, cough patients, and control subjects (p < 0.05, p < 0.01, and p < 0.01, respectively). There was no significant difference in the value of SRrs between classic asthma patients, cough patients, and control subjects. These data show that bronchial reactivity in the children with CVA was significantly lower than that in the children with classic asthma, and this specificity has an effect on prolonged cough without wheezing in children with CVA.

Alveolar Nitric Oxide and Effect of Deep Inspiration During Methacholine Challenge

To assess whether the dual anatomic origin of exhaled nitric oxide (NO), namely alveolar and bronchial, could explain the link between exhaled NO and airway responsiveness, and could participate in the bronchodilatory effect of deep inspiration (DI) that may be evidenced during methacholine challenge. Prospective study in a laboratory performing pulmonary function tests of an academic hospital. Patients underwent multiple flow analysis of exhaled NO, allowing calculation of total maximum airway NO flux (J'awno) and NO concentration of expansible compartment (CAno), and received a cumulative methacholine dose of 2,000 microg. DI effect was assessed by continuous measurement of the resistance of respiratory system using the forced oscillation technique before and after DI. In a first phase involving 23 patients, a positive correlation between log values of J'awno and CAno was demonstrated with the degree of airway responsiveness (percentage of FEV(1) decrease). In a second phase involving 38 patients, only log CAno was correlated with responsiveness, and no significant relationship was demonstrated between J'awno or CAno and the effect of DI. Patients with smaller airways and/or distal airflow limitation exhibited a constrictive response to DI. Airway responsiveness is mainly associated with an increase in distal origin of NO output, and no relationship between exhaled NO and the effect of DI was evidenced.

Methacholine bronchial responsiveness and variations in lung function among workers exposed to flour

Methacholine bronchial responsiveness and variations in the pulmonary function of workers exposed to wheat flour and a reference group were compared. Each subject [140 men exposed to flour (bakers and pastry makers) and 77 controls] completed a standardized questionnaire. Bronchial responsiveness was quantified by measuring the slope between percentage decrements in forced expiratory volume in 1 second (FEV1) and cumulative methacholine dose. FEV1 and peak expiratory flow (PEF) were recorded four times a day for 15 days using a handheld electronic spirometer. The variability in the FEV1 and PEF readings was expressed as variation coefficients (100 x standard deviation/mean). The mean duration of exposure to flour was 14 (SD 9) years. Rhinitis was significantly more common in the exposed group than in the control group (30.7% versus 11.7%, P = 0.001). The mean FEV1 and PEF did not significantly differ between the two groups. The slope of the dose-response to methacholine and the variation coefficients were lower among the unexposed nonsmokers than among the exposed workers and smokers. The differences were significant for the exposed smokers. The two variation coefficients correlated with each other (r = 0.82) but not with the slope of the methacholine challenge. Conclusions Occupational exposure to flour and smoking increase bronchial responsiveness, as measured by the slope of the dose-response to methacholine and the variation coefficients of airflow. However, methacholine bronchial responsiveness and the variability of lung function do not measure exactly the same aspect of airway behavior.

Geographic and Gender Variability in the Prevalence of Bronchial Responsiveness in Canada

Geographic variability in reported prevalences of asthma worldwide could in part relate to interpretation of symptoms and diagnostic biases. Bronchial responsiveness measurements provide objective evidence of a common physiologic characteristic of asthma. We measured bronchial responsiveness using the standardized protocol of the European Community Respiratory Health Survey (ECRHS) in six sites in Canada, and compared prevalences across Canada with international sites. Samples of 3,000 to 4,000 adults aged 20 to 44 years were randomly selected in Vancouver, Winnipeg, Hamilton, Montreal, Halifax, and Prince Edward Island, and a mail questionnaire was completed by 18,616 individuals (86.5%). Preselected random subsamples (n = 2,962) attended a research laboratory for examination including more detailed questionnaires, lung function testing including methacholine challenge, and skin testing with 14 allergens. Prevalences of bronchial hyperresponsiveness, measured as cumulative dose of methacholine required to produce a 20% fall from the post-saline solution FEV1 < or = 1 mg, ranged from 4.9% (95% confidence interval [CI], 1.6 to 8.5) in Halifax to 22.0% (95% CI, 18.1 to 26.0) in Hamilton (median, 10.7%). In all Canadian sites, bronchial hyperresponsiveness was more prevalent in women than in men. Neither the geographic nor gender differences were accounted for by differences in age, smoking, skin test reactivity, or baseline FEV1. Geographic- and gender-related variability changed little when only bronchial hyperresponsiveness associated with asthma-like symptoms was considered. A wide variability in bronchial responsiveness can occur within one country, almost as wide as the range found across all international sites participating in the ECRHS study and not explained by differences in gender, smoking, skin test reactivity, and FEV1. While gender variability in the prevalence of bronchial responsiveness is likely due to hormonal and immunologic factors, geographic variability is likely to result from environmental factors.

Ratio Between Forced Expiratory Flow Between 25% and 75% of Vital Capacity and FVC Is a Determinant of Airway Reactivity and Sensitivity to Methacholine

The ratio between forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) and FVC is thought to reflect dysanapsis between airway size and lung size. A low FEF(25-75)/FVC ratio is associated with airway responsiveness to methacholine in middle-aged and older men. The current study was designed to assess this relationship in both male and female subjects over a broader range of ages. Data analysis of consecutive subjects who had a >or= 20% reduction in FEV(1) after <or= 189 cumulative units of methacholine over a 7-year period. Pulmonary function laboratory in a university-affiliated hospital. A total of 764 consecutive subjects aged 4 to 91 years (mean +/- SD age, 40.8 +/- 19.6 years). There were 223 male (29.3%) and 540 female (70.7%) subjects. Airway reactivity was assessed as the dose-response slope of the reduction in FEV(1) from baseline vs the cumulative dose of inhaled methacholine. The cumulative dose of methacholine causing 20% reduction in FEV(1) (PD(20)) was used as the indicator of airway sensitivity. In a linear regression model that included age, height, and percentage of predicted FEV(1), the FEF(25-75)/FVC ratio accounted for 7.6% of variability in airway reactivity (p < 0.0001, r(2) = 0.076). Subjects with higher airway sensitivity, indicated by lower PD(20), also had a lower FEF(25-75)/FVC ratio. A low FEF(25-75)/FVC ratio, indicating small airway size relative to lung size, is associated with higher airway sensitivity and reactivity to methacholine in susceptible subjects.

Childhood cough variant asthma and its relationship to classic asthma

In pediatrics, some patients with chronic cough who have no evidence of a causative disease are diagnosed as having cough variant asthma (CVA). The precise prognosis of infants and children with CVA, however, is still unclear. To evaluate the relationship between CVA and classic asthma in childhood. To diagnose CVA, we performed a methacholine inhalation challenge with use of a transcutaneous oxygen pressure (tcPO2) monitoring system in 100 children with chronic cough, and 75 children (45 boys and 30 girls; mean age, 5.7 years) were diagnosed as having CVA. These patients underwent follow-up monitoring for more than 3 years to ascertain whether classic asthma developed. For comparison, 53 age-matched children with classic asthma (30 boys and 23 girls; mean age, 5.6 years) and 30 age-matched control subjects (12 boys and 18 girls; mean age, 5.5 years) also participated in this study. Consecutive doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO2 (Dmin-PO2) was considered to represent the sensitivity of tcPO2 to inhaled methacholine. After 3 years or more of follow-up assessments, 52 of the 75 patients answered our questionnaire. Of the responding patients, 28 had been diagnosed as having classic asthma. A significant difference was noted in the age at onset of CVA between the children in whom classic asthma developed (the asthma-developed group) and those in whom classic asthma did not develop (the asthma-free group). No statistically significant differences in Dmin-PO2 between the asthma-developed group and the asthma-free group or between the girls and the boys, however, were foun This study showed that 75% of children with chronic cough had CVA, that classic asthma developed in 54% of the children with CVA, and that it is not the severity of bronchial hyperresponsiveness in CVA but the age at onset of CVA that is a risk factor for the development of classic asthma in childhood CVA.

Predictors of Methacholine Responsiveness in a General Population

Methacholine responsiveness is an end point widely used in epidemiologic studies of asthma. This study aims to quantify the relative importance of different predictors of responsiveness such as age, sex, airway caliber, smoking and atopic status, and potential interactions deserving further investigation. Methacholine challenge was performed in 7,126 participants (aged 18 to 60 years) of the Swiss Study on Air Pollution and Lung Diseases in Adults according to the European Respiratory Health Survey protocol. Responsiveness was quantified by the slope between percentage decrements in FEV(1) and cumulative methacholine dose. Variation of slopes according to sex, smoking, and atopy was then examined separately by multivariate regression models that controlled for baseline FEV(1). We found a nonlinear relationship between methacholine slope and baseline FEV(1) for both sexes, which could be well described by a quadratic function. The corresponding curves were almost identical in the region of overlap for male and female neversmokers. Methacholine responsiveness declined with age. The slope of this decline was less steep among nonatopic persons and nonsmokers compared with atopic neversmokers. Methacholine responsiveness increased with the number of cigarettes smoked per day and with the number of positive skin-prick test results (except among heavy smokers). Our multiple regression results show that bronchial responsiveness (BR) varies with age, FEV(1), and smoking and atopic status. They suggest that there is a physiologic basis for the univariate sex difference in BR. Secondly, they show that while smaller airways are more responsive than larger ones, the reduction of responsiveness diminishes with each increase of lung size. The quantification of the relative influence of the different factors examined should help in the interpretation of BR.

Age-dependent relationship between bronchial hyperresponsiveness to methacholine and total serum IgE level in asthmatic children

A relationship between nonspecific bronchial hyperresponsiveness and allergic airway inflammation has been reported in children and in adults with asthma, but the relationship in infants with asthma is still unclear. To evaluate the relationship between bronchial hyperresponsiveness and total serum IgE level throughout childhood. Bronchial reactivity to methacholine from the age of 1 to 16 years was studied by methacholine inhalation challenge using transcutaneous oxygen pressure (tcPO2) monitoring. Two hundred one asthmatic children (boys:girls = 132:69; 7.3+/-4.0 years of age, mean +/- SD) were enrolled in this study. The tcPO2 was measured using a tcPO2 monitor. Serial doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO2 was considered to represent the bronchial reactivity to methacholine. There was no relationship between the cumulative dose of methacholine at the inflection point of tcPO2 and total serum IgE level in the group of children aged 1 to 4 years (P = 0.212), but significant correlations were found in the groups aged 5 to 10 years and 11 to 16 years (P = 0.044 and P = 0.014, respectively). We conclude that there is an age-dependent relationship between bronchial reactivity to methacholine and the total serum IgE level and that inhaled allergens, which were more common allergens in older children, may have some effects on the degree of bronchial reactivity to methacholine in children with asthma.