Methacholine Provocation Research Articles

Pulmonary Function and Airway Hyperresponsiveness in Adults with Sickle Cell Disease

Pulmonary involvement is a major cause of morbidity and mortality in patients with sickle cell disease (SCD). Although a high prevalence of airway hyperresponsiveness (AHR) has been reported, there are no studies demonstrating the relationship between AHR and acute chest syndrome (ACS) in adults with SCD. We investigated AHR prevalence, lung function abnormalities, and the relationships of these variables with ACS in SCD patients. Thirty-one adult patients without asthmatic symptoms were compared with 31 matched controls. Expiratory flow rates, lung volumes, carbon monoxide diffusion capacity (DLCO), and methacholine provocation test (MPT) results were assessed. Forced vital capacity (FVC), forced expiratory volume in one second, forced expiratory flow rate at 25% to 75% of FVC (FEF(25%-75%)), peak expiratory flow rate, total lung capacity, and DLCO values were significantly lower in the patient group than in the controls. No significant difference in pulmonary function test results was found between patients with and without a history of ACS. Fifteen patients with SCD (48%) and only 5 controls (16%) had AHR (p = 0.007). A significant correlation was found between the number of ACS episodes and MPT positivity (r = 0.379, p = 0.035). The FEF(25%-75%) values were significantly lower in patients with positive MPT results than in patients with negative MPT results (p = 0.027). The prevalence of AHR was high in adult patients with SCD. A significant correlation was found between AHR and recurrent ACS episodes. Anti-inflammatory controller agents can be used routinely to decrease pulmonary morbidity associated with SCD, even in the absence of asthmatic symptoms.

Role of Methacholine PC20 in FEF25-75% for the Diagnosis of Bronchial Asthma

Background: The methacholine bronchial provocation test is a useful tool for evaluating asthma in patients with normal or near normal baseline lung function. However, the sensitivity of this test is 82~92% at most. The purpose of this study is to evaluate the clinical usefulness of in identification of airway hyperresponsiveness in patients with suspected asthmatic symptoms. Methods: One hundred twenty-five patients who experienced cough and wheezing within one week prior to their visiting the clinic were enrolled. Results: Sixty-four subjects showed no significant reduction of or on the methacholine bronchial provocation test (Group I). In 24 patients, fell more than 20% from baseline without a 20% fall of during methacholine challenge (Group II). All patients who had more than 20% fall of (n=37) also showed more than 20% of reduction in (Group III). Baseline /FVC (%) and (L) were higher in group II than group III (81.511.56% vs. 75.021.60%, p0.21 L vs. 2.450.21 L, p=0.013, respectively). Group II had greater reductions of both and than group I at 25 mg/mL of methacholine (p in group II was about three-fold higher than that in group III. Conclusion: A 20% fall of by methacholine provocation can be more sensitive indicator for detecting a milder form of airway hyperresponsiveness than criteria.

The Effect of Thoracosopic Thoracic Sympathetomy on Pulmonary Function and Bronchial Hyperresponsiveness

Background. Endoscopic thoracic sympathectic denervation (ESD) is a procedure used in primary hyperhidrosis and upper extremity ischemia. Bronchial tone is affected by the sympathetic and parasympathetic nervous systems and bronchial asthma is associated with an imbalance between them. The aim of this study was to evaluate the effects of ESD on pulmonary function and bronchial hyperresponsiveness (BHR). Patients and methods. Fifty-eight patients with primary hyperhidrosis (n = 54) or upper limb ischemia (n = 4) were included. Spirometry and bronchial provocation test with methacholine was performed before and 4 weeks after ESD. Results. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were significantly decreased early after ESD (from 4.67 ± 0.84 L and 4.36 ± 0.85 L to 4.12 ± 0.78 L and 3.84 ± 0.82 L, respectively), although no patient complained of an aggravation of respiratory symptoms. Twelve patients (21%) had a positive response to methacholine provocation preoperatively, and all remained positive post surgery. The provocative concentration of methacholine, which brought about a 20% decrease in the FEV1 in the patients, was not significantly changed after surgery (from 5.1 ± 4.3 to 4.6 ± 4.6). Of 46 patients who had a negative result for methacholine challenge preoperatively, 12 (26%) became positive after surgery. In terms of the level of sympathectomy, T3 sympathectomy significantly increased the ratio of patients exhibiting a positive response to methacholine (from 19% to 34%, respectively) (p < 0.005). Conclusions. Thoracic sympathectomy can adversely affect lung function early after surgery, although the clinical significance is uncertain. It may also exert an influence on the development of bronchial hyperresponsiveness, especially when performed at the T3 level.

Relationships Between Airway Inflammation And Response To Methacoline Or Eucapnic Voluntary Hyperventilation In Athletes Training In Cold Air

Background : In asthma, airway hyperresponsiveness may be associated with an eosinophilic airway inflammatory process. High-level exercise may induce a systemic and/or airway neutrophilic response. In athletes, the prevalence of exercise-induced bronchoconstriction is higher than that of symptomatic asthma. Purpose : To examine the relationships between responses to EVH (% fall in FEV1), methacholine (PC20) and eosinophilic airway inflammation in athletes training in cold air. Methods : Thirty-one athletes (cross-country skiing, biathlon and speed skating-long track) had a medical examination, a questionnaire on respiratory symptoms, a spirometry, a methacholine provocation test, skin prick tests for common respiratory allergens, EVH test and induced sputum analysis. Results : IS analysis revealed a low eosinophilic count (mean % cells ± SEM: 0.82 ± 1.9 %) and a mild neutrophilia (46.8 ± 21.3 %). PC20 was positively correlated with the fall in FEV1 after EVH (r = 0.41, p = 0.02) and with the % of eosinophils (r = 0.58, p = 0.01) in sputum. The fall in FEV1 after EVH was also positively correlated with eosinophil count (r = 0.72, p = 0.001). There was no relationships between these parameters and IS neutrophil count. Conclusion :Response to methacholine and EVH in athletes correlates with the degree of eosinophilic airway inflammation, although this last is small.

Blood Lead Levels and Increased Bronchial Responsiveness

The immune system is one of the targets most sensitive to lead toxicity, and the association between lead exposure and serum immunoglobulin E (IgE) has been published. Recent studies also reported that lead caused the development of IgE-mediated allergy. To investigate whether blood lead levels contribute to other allergic conditions, we examined the effect of blood lead on bronchial responsiveness (BR) in the general population. We performed a cross-sectional study with adults aged 19 to 58 years in a Korean community. Blood lead level and the methacholine provocation test were performed. The overall mean blood lead level was 2.9 microg/dl, and the mean BR index was 1.14. The percent of subjects with clinically diagnosed asthma was 21 (4%) and there was no difference in blood lead level with and without asthma. In the multiple regression model, the elevation of blood lead level was related to the increase of BR after adjusting for age, sex, height, smoking status, and the presence of asthma. Blood lead level was significantly associated with increased BR that came from the elevation of the IgE level with lead exposure. Lead may contribute to the increase of asthma and other allergic conditions.

Alterations of the Beneficial Effect of Deep Inspiration in Scleroderma: Relationships between Lung Function and Imaging

Background: It has been postulated that the beneficial effects of deep inspiration are dependent on the magnitude of airway distension by virtue of airway to parenchyma interdependence. Objective: This study was designed to examine whether the changes that occur in pulmonary fibrosis affect the beneficial effect of deep inspiration. Methods: Thirty-one subjects with scleroderma underwent lung volume and diffusion capacity assessment as well as high-resolution computed tomography. To assess the effect of deep inspiration, each subject underwent methacholine provocations in the absence of deep breaths. When the targeted change in lung function was achieved, subjects were asked to take 4 consecutive deep inspirations after which lung function measurements were repeated. The inspiratory vital capacity (IVC) was used as primary outcome. Results: Only 19 subjects attained the desired reduction in IVC in the absence of deep breaths. In those subjects, deep inspiration reversed the effect of methacholine on IVC by 48 ± 8.4%. The effect of deep inspiration correlated with DLCO% predicted (r = 0.55, p = 0.01), but not with high-resolution computed tomography abnormalities or baseline lung function measurements. When all subjects were considered, responsiveness to methacholine in the absence of deep inspiration was progressively lower with decreasing DLCO% predicted values (r = 0.51, p = 0.003). Conclusions: In systemic scleroderma, pulmonary abnormalities resulting in mild to moderate reduction in the diffusion capacity are associated with reduced ability of deep inspiration to reverse methacholine-induced early airway closure and bronchoconstriction. When diffusion capacity is severely affected, methacholine fails to produce obstructive airway changes.

Bronchial Hyperresponsiveness in Skiers: Field Test versus Methacholine Provocation?

Bronchial Hyperresponsiveness in Skiers: Field Test versus Methacholine Provocation?

Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage–derived cytokines

Asthma is a heterogeneous clinical disorder. Methods for objective identification of disease subtypes will focus on clinical interventions and help identify causative pathways. Few studies have explored phenotypes at a molecular level. We sought to discriminate asthma phenotypes on the basis of cytokine profiles in bronchoalveolar lavage (BAL) samples from patients with mild-moderate and severe asthma. Twenty-five cytokines were measured in BAL samples of 84 patients (41 severe, 43 mild-moderate) using bead-based multiplex immunoassays. The normalized data were subjected to statistical and informatics analysis. Four groups of asthmatic profiles could be identified on the basis of unsupervised analysis (hierarchical clustering) that were independent of treatment. One group, enriched in patients with severe asthma, showed differences in BAL cellular content, reductions in baseline pulmonary function, and enhanced response to methacholine provocation. Ten cytokines were identified that accurately predicted this group. Classification methods for predicting methacholine sensitivity were developed. The best model analysis predicted hyperresponders with 88% accuracy in 10 trials by using a 10-fold cross-validation. The cytokines that contributed to this model were IL-2, IL-4, and IL-5. On the basis of this classifier, 3 distinct hyperresponder classes were identified that varied in BAL eosinophil count and PC20 methacholine. Cytokine expression patterns in BAL can be used to identify distinct types of asthma and identify distinct subsets of methacholine hyperresponders. Further biomarker discovery in BAL may be informative.

An in vivo and in vitro comparison of inhaled steroid delivery via a novel vortex actuator and a conventional valved holding chamber

Valved holding chambers improve delivery of inhaled corticosteroids to the lung but are bulky in design. A novel compact vortex actuator device has therefore been developed. To compare the in vitro and in vivo performance of a novel compact vortex actuator (the Neohaler [NH]) vs a conventional small-volume valve holding chamber (the AeroChamber Plus [AP]. Seventeen asthmatic patients completed the study per protocol, receiving 4 weeks each of 100 microg/d (50-microg formulation) or 400 microg/d (100-microg formulation) of hydrofluoroalkane beclomethasone dipropionate via the NH or AP devices in a randomized crossover, double-blind, double-dummy, placebo-controlled design. The doubling dilution (dd) shift in methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (primary outcome) was used to evaluate anti-inflammatory effects and adrenal function to measure systemic exposure. The fine particle (<4.7 tm) dose was evaluated using an Andersen Cascade Impactor. A total of 100 microg of hydrofluoroalkane beclomethasone dipropionate via the NH and AP produced 0.95-dd (95% confidence interval [CI], 0.44-1.45; P = .006) and 0.45-dd (95% CI, -0.16 to 1.06; P = .83) improvements from baseline in methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%, respectively, with no statistically significant difference between devices: 0.50 dd (95% CI, -0.25 to 1.24; P = .18). At 400 microg/d, 1.08-dd (95% CI, 0.49-1.67; P = .006) and 0.85-dd (95% CI, 0.32-1.39; P = .02) improvements were found for the NH and AP, respectively, with a 0.23-dd difference (95% CI, -0.28 to 0.74; P = .36) between devices. No adrenal suppression occurred with either device. The in vitro fine particle dose was 39.1 microg for the NH and 39.0 microg for the AP with the 100-microg formulation and 26.0 g and 25.2 microg, respectively, with the 50-microg formulation. Delivering hydrofluoroalkane beclomethasone dipropionate via the NH and AP attenuates asthmatic airway inflammation to a comparable degree and produces a similar in vitro fine particle dose profile.

Adrenergic Responsiveness: FEV1 and Symptom Differences in Whites and African Americans with Mild Asthma

Decision-making about inhaler use is, in part, determined by the ability of asthmatic patients to compare their symptoms over time and to recall the previous response to the bronchodilator during an episode of asthma. The perception of airway symptoms across varied ethnic and cultural groups are poorly understood. Study purpose was (1) to determine if African Americans and Whites with mild asthma could accurately perceive bronchodilation and (2) to identify the word descriptors they used to describe their breathing. Sixteen African American and 16 White patients (34.5 ± 9.7 years old, mean±SD) with mild atopic asthma (FEV1 ≥70% predicted normal) were given increasing doses of an inhaled bronchodilator (Albuterol) after a methacholine challenge. Albuterol (180 μ g) was given, by spacer, at 15 min intervals until the FEV1 increased < 5%. Borg, VAS, and Word Descriptors were collected at baseline and after each dose of Albuterol. Baseline FEV1 after Methacholine provocation was 1.94 ±. 39 L for African Americans and 2.13 ±. 70 L for Whites. After 180 μ g and again after 360 μ g Albuterol, FEV1 increased to 2.88 ± 0.48 L for African Americans and 3.37 ± 0.91 L for Whites. But after 540 μ g Albuterol, FEV1 decreased significantly (16%) to 2.42 ± 1.19 L for African Americans while increasing only slightly to 3.47 ± 0.95 L for Whites. After this dose, 10/16 African Americans felt “tight at the base of throat” (p < 0.01); 7/16 felt “speech-voice-tight” (p < 0.03) suggesting persistent airway discomfort despite marked improvement in FEV1, Borg and VAS scores compared with baseline values. Word descriptors by African Americans' are a more reliable measure of airway symptoms compared to FEV1, Borg or VAS.

Effects of Personal Exposure to Nitrogen Dioxide on Peak Expiratory Flow in Asthmatic Patients

Nitrogen dioxide (NO2) has been inconsistently associated with gradual decreases in lung function. Here, we studied the effects of NO2 exposure in asthmatics by examining the association between changes in lung function and concentrations of NO2 which were personally measured. Peak expiratory flow (PEF) and daily personal exposures to NO2 were recorded on 28 patients with asthma (confirmed by methacholine provocation test) over 4 weeks. We used generalized estimating equations to assess the relationship between personal NO2 exposure and PEF, adjusting for potential confounders such as age, gender, outdoor particulate matter, temperature, humidity, and exposure to environmental tobacco smoke. The personal NO2 exposures were higher than the corresponding ambient levels. The mean personal: ambient ratio for NO2 was 1.48. The personal NO2 exposures were not associated with the morning PEF, evening PEF, or the diurnal PEF variability. However, environmental tobacco smoke was negatively associated with both the morning and evening PEF. Among the asthmatic adults who participated in this study, we found no apparent impact of personal NO2 exposures on the peak expiratory flow.

Onset of relief of dyspnoea with budesonide/formoterol or salbutamol following methacholine-induced severe bronchoconstriction in adults with asthma: a double-blind, placebo-controlled study.

BackgroundThe long-acting β2-agonist (LABA) formoterol has an onset of effect comparable to that of salbutamol. Consequently, the combination of formoterol and budesonide in one inhaler, approved for maintenance use, can potentially be used for reliever therapy. This study compared the onset of relief from induced bronchospasm with a single dose of budesonide/formoterol versus standard salbutamol therapy in patients with asthma.MethodsIn this randomised, double-blind, placebo-controlled, cross-over study, 32 patients with asthma underwent a methacholine provocation test leading to a fall in forced expiratory volume in 1 second (FEV1) of ≥30% at enrolment (Visit 1) and three subsequent study visits (Visits 2–4). Immediately after each provocation at Visits 2–4, patients received one of three test treatments: one inhalation of budesonide/formoterol 160/4.5 μg (via Turbuhaler®), two inhalations of salbutamol 100 μg (via a pressurised metered-dose inhaler [pMDI]) or placebo. All patients received each of the test treatments in a randomised order, after separate methacholine provocations. The effect of treatment on FEV1 and breathlessness (using the Borg scale) was measured at 1, 3, 5, 10, 15, 20, 25 and 30 minutes after test treatment.ResultsFollowing methacholine provocation, Borg score increased from a baseline value of below 0.5 to 3.03, 3.31 and 3.50 before treatment with budesonide/formoterol, salbutamol and placebo, respectively. Budesonide/formoterol and salbutamol reversed methacholine-induced dyspnoea (breathlessness) rapidly. At 1 minute after inhalation, statistically significant decreases in Borg score were observed for budesonide/formoterol and salbutamol (p = 0.0233 and p < 0.0001, respectively, versus placebo), with similar rapid increases in FEV1 (both active treatments p < 0.0001 versus placebo). The median time to 50% recovery in Borg score after methacholine provocation was 3 minutes with budesonide/formoterol, 2 minutes with salbutamol and 10 minutes with placebo. All treatments and procedures were well tolerated.ConclusionSingle doses of budesonide/formoterol and salbutamol both provided rapid relief of dyspnoea and reversal of severe airway obstruction in patients with asthma with experimentally induced bronchoconstriction. The perception of relief, as confirmed by objective lung function assessment, provides evidence that budesonide/formoterol can be used as reliever medication in asthma.

Effect of challenge method on sensitivity, reactivity, and maximal response to methacholine

Recent data suggest that the tidal breathing method may produce methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) values significantly lower than the dosimeter method; however, the effect of the challenge method on the shape of the concentration-response curve has not been investigated. To determine the effect of the challenge method on sensitivity, reactivity, and maximal response to methacholine. We measured airway responsiveness to methacholine using dosimeter and tidal breathing methods in 30 individuals with suspected asthma. Concentration-response curves were characterized by their PC20 (sensitivity), slope (reactivity), and, if possible, level of plateau. Dosimeter PC20 values were significantly higher than tidal breathing values (geometric mean, 8.9 and 5.2 mg/mL, respectively); the mean difference in PC20 values obtained using each method was 0.78 doubling concentrations (P = .01). The mean slopes were 22.7%/log mg/mL using the tidal breathing method and 24.9%/log mg/mL using the dosimeter method; the mean difference in the slopes obtained using each method was -2.17%/log mg/mL (P = .18). In 10 individuals who showed a plateau with the 2 methacholine challenge tests, the mean level of plateau was 19.8% using the tidal breathing method and 19.5% using the dosimeter method; the mean difference in the plateau values obtained with each method was 0.3% (P = .87). Although the tidal breathing method produces methacholine PC20 values significantly lower than the dosimeter method, both methods provide similar values for slope and level of plateau. These results suggest that the technical factors that affect methacholine sensitivity and the shape of the curve are different.

Effect of body mass index on response to methacholine bronchial provocation in healthy and asthmatic adolescents

A linkage between airway hyperreactivity and obesity could partly explain the prevalence of obesity in asthmatics. To test for such a linkage, we analyzed body mass index (BMI), pulmonary function, methacholine bronchial provocation, and asthma severity scores in 216 adolescents (aged 12-18 years), of whom 82 were healthy and 134 were asthmatic. Methacholine provocations in a subgroup of 36 subjects (healthy and asthmatic) enabled us to examine the effects of BMI on dynamic hyperinflation and ventilatory indices during induced bronchospasm. Age- and gender-specific BMI was higher in asthmatics (74 +/- 24%) compared to healthy subjects (61 +/- 28%, P < 0.002). General linear model analysis, in which baseline spirometric results were adjusted for gender, age, race, and height, showed opposing effects of BMI on expiratory flow in controls and asthmatics (P < 0.05), i.e., forced expired volume in 1 sec increased with BMI in controls (P < 0.02), but forced expiratory flow (FEF)(25-75%) decreased with BMI in asthmatics (P < 0.05). However, linear regression analysis showed no effect of BMI on the provocation dose for methacholine (PD(20)) in either controls or asthmatics, and there was no effect of BMI on asthma severity scores. Overweight (BMI >85th percentile) and nonoverweight subjects had similar degrees of dynamic hyperinflation during positive provocations, but overweight subjects had greater decreases in mean inspiratory flow (mean, 28% vs. 9%, P < 0.05). We conclude that our measurements support a relationship between overweight and baseline flow limitation, rather than a relationship between overweight and airways hyperreactivity, in the linkage between overweight and asthma during adolescence.

Effect of whey protein to modulate immune response in children with atopic asthma

Background Levels of glutathione (GSH) in antigen-presenting cells promote a T-helper type 2 (Th2) cytokine response in mice. We have previously demonstrated that we can increase intracellular GSH levels in healthy young adults using a whey-based oral supplement (HMS90™). We hypothesized that such supplementation in children with atopic asthma, a Th2 cytokine disease, would improve lung function and decrease atopy.Methods Eleven children (six females, five males; mean±standard deviation age, 12.6±3.6 years; baseline forced expired volume in 1 sec (FEV1), 82.4±15.4%predicted), underwent spirometry, methacholine provocation testing, and blood analysis for serum IgE and lymphocyte GSH before and after 1 month of supplementation (10 g twice daily).Results Initially the IgE was 1689±1596 µg/l (normal range ≤240 µg/l) and lymphocyte GSH was 1.75±0.48 µM (normal range 1.55±0.33 µM). IgE significantly decreased to 1379±1329 µg/l (P < 0.05) following supplementation. Although no significant changes in lymphocyte GSH or FEV1 were found for the group as a whole, the two patients with significant increases in lymphocyte GSH concentrations were the only two to demonstrate reductions in methacholine provocation doses (provocative concentration causing a 20% fall in FEV1).Conclusions These results suggest a modest impact of whey protein supplementation on the cytokine response in atopic asthma. Supplementation for longer periods, or with more potent whey-based supplements, currently under development, may prove more beneficial.

The Role of Inhaled Corticosteroid in the Management of Chronic Cough

Background : Cough may be a consequence of bronchial hyperresponsiveness or inflammation. Empirical treatment is important in this context because it difficult to verify the obvious cause of cough using laboratory tests, Corticosteroid has a nonspecific anti-inflammatory effect, and can be used for cough management. However, its response rate has not yet been fully elucidated. This study investigated the short- term effects of inhaled corticosteroid on chronic cough Methods : Patients with chronic cough with a normal chest radiograph and a pulmonary function test were enrolled. Cases with a prior respiratory infection within 8 weeks, a history of bronchial asthma, objective wheezing on examination, subjective symptoms of gastroesophageal reflux or taking an ACE inhibitor were excluded. On the first visit, a methacholine bronchial provocation test, spontaneous sputum eosinophil count performed twice and a paranasal sinus radiograph were checked, and the patients were treated with budesonide turbuhaler for ten days. The primary outcome measure was a decrease in the cough score after treatment. Results : Sixty nine chronic coughers were finally analyzed. The final diagnoses by the routine tests were as follows: bronchial asthma 13.0%, eosinophilic bronchitis 18.8%, paranasal sinusitis 23.2% and non-diagnostic cases 53.6%. The following responses to the inhaled corticosteroid were observed: definite responders, 76.8%, possible responders, 2.9% and non-responders, 20.3%. The response rate was not affected by the final diagnosis even in the non-diagnostic cases. There were minimal adverse drug related effects during the empirical treatment. Conclusion : Routine objective tests such as methacholine provocation, sputum eosinophil count and simple radiographs were notare not suitable for diagnosing chronic cough Therefore, empirical treatment is important. Short term inhaled corticosteroid is effective and can guide a further treatment plan for chronic cough.

Effect of fluticasone propionate–salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma

There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens, resulting in increased airway responsiveness. To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids. Forty-two asthmatic patients sensitized to pollen allergens were randomly allocated to treatment with fluticasone propionate-salmeterol (n=21) or fluticasone propionate alone (n=21). Spirometry, the methacholine provocation concentration causing a 20% decline in forced expiratory volume in 1 second (PC20), the adenosine 5'-monophosphate (AMP) PC20, and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment. Changes in the methacholine PC20, the AMP PC20, and ENO levels were not significantly different between treatment groups. No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure. However, a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group (P = .03) and in the fluticasone propionate group (P = .04); ENO concentrations decreased significantly in both groups during natural allergen exposure (P = .009 and .005). In patients with pollen-induced asthma, treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations, even during natural pollen exposure. Furthermore, at least in patients with mild asthma, natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone.

A case–control study of bronchial asthma associated with ulcerative colitis: role of airway microvascular permeability

Recent attention has been devoted to the respiratory manifestations that may be associated with diseases of distant organs. The most prevalent and distinctive pattern of respiratory involvement in ulcerative colitis (UC) is airway inflammation. This study was designed to examine the contribution of airway microvascular permeability to the pathophysiological association of asthma with UC. Sputum induction and methacholine provocation test were performed in 27 asthmatic patients (15 without UC and 12 with UC), nine patients with UC and 15 normal controls. Inflammatory indexes, vascular endothelial growth factor (VEGF) levels in induced sputum, airway vascular permeability index and exhaled nitric oxide (NO) levels were examined in all subjects. The percentage of eosinophils and concentration of eosinophil cationic protein in induced sputum were similar in all four groups. Though exhaled NO levels were significantly higher in asthmatics with or without UC than in normal controls or UC patients, these levels were comparable in asthmatics with and without UC. VEGF levels in induced sputum and airway vascular permeability index were significantly higher in asthmatics without UC (VEGF: 1920 (990) pg/mL; airway vascular permeability index: 0.018 (0.008)) and asthmatics with UC (6570 (1000) pg/mL; 0.040 (0.006)) than in normal controls (950 (700) pg/mL; 0.009 (0.003)), whose levels were comparable to those of UC patients (900 (600) pg/mL; 0.011 (0.003)). In particular, these parameters were markedly increased in asthmatics with UC than in asthmatics without UC. VEGF level was significantly correlated with airway vascular permeability index in asthmatics with UC. Moreover, VEGF level and airway vascular permeability index was inversely correlated with degree of airway obstruction and airway hyper-reactivity to methacholine in these asthmatics. Airway microvascular hyper-permeability induced by VEGF may have a profound effect on airway function and can explain the heightened airway hyper-responsiveness characteristic of asthma associated with UC.

Salmeterol Does Not Alter Increased Bronchial Responsiveness Caused by Organic Dust Exposure

Exposure in a swine house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. The aim was to investigate whether a long-acting beta2-agonist, salmeterol, alters the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust in a swine barn. The study includes three separate parts. In the first part (part 1), healthy subjects inhaled salmeterol (50 microg bid, n = 8) or placebo (n = 8) over 2 weeks. In part 2, healthy subjects inhaled one single dose of salmeterol (100 microg, n = 6) or placebo (n = 6) 1 h prior to exposure in a swine barn, which was followed by a bronchial methacholine challenge. In part 3, eight healthy individuals inhaled placebo or salmeterol (100 microg), 2 h or 8 h prior to a bronchial methacholine provocation, without being exposed in the swine barn. Exposure caused an increase of bronchial responsiveness to methacholine by 3.2 doubling concentration steps (25 to 75th percentiles, 2.8 to 4.1) and 2.6 doubling concentration steps (25 to 75th percentiles, 1.4 to 3.7) in the placebo and salmeterol groups (2 weeks), respectively, with no significant differences between the groups (p = 0.3; part 1). Similar results were obtained when salmeterol was administered as a single dose (part 2) prior to exposure. However, salmeterol significantly attenuated the bronchial responsiveness to methacholine by 1.2 doubling concentration steps (0.8 to 1.7) 8 h after inhalation (part 3). Salmeterol inhalation did not protect against the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust when administered for 2 weeks or as a single dose prior to exposure. This lack of protection cannot be explained by homologous beta2-adrenoceptor desensitization. We hypothesize that exposure to organic material may alter the airway response to beta2-agonists.

Bronchoprotection with formoterol via dry powder and metered-dose inhalers in patients with asthma

Determination of device comparability for new inhaled medications is essential. To evaluate the methacholine bronchoprotection afforded by formoterol, 12 microg, delivered via Clickhaler and Aerolizer dry powder inhalers and a pressurized metered-dose inhaler (pMDI) in mild-to-moderate asthmatic patients. Two separate randomized, double-blind, double-dummy, crossover studies were performed. Peak bronchoprotection (30 minutes) was measured after administration of a single dose in a placebo-controlled study (n = 16). First-dose (8 hours) and trough (12 hours) protection were evaluated after 2 weeks (n = 28). Doubling dilution differences (DDD) in the methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% from baseline were compared, with equivalence defined if the 95% confidence interval was within the predefined equivalence limits of +/- 1.5 DDD (peak) and +/- 1.0 DDD (trough). For peak single-dose effects, DDD (95% confidence interval) data showed significant protection vs placebo for all devices but no significant differences among active inhalers. For trough first-dose effects, there was significant protection vs baseline for all devices and equivalence for Clickhaler vs Aerolizer (-0.41; -0.85 to 0.04) and Aerolizer vs pMDI (-0.27; -0.66 to 0.13) but not for Clickhaler vs pMDI (-0.68; -1.12 to -0.23). For trough effects after 2 weeks, there was significant residual protection from baseline and equivalence for Clickhaler vs Aerolizer (-0.32; -0.94 to 0.30), Clickhaler vs pMDI (0.34; -0.96 to 0.27), and Aerolizer vs pMDI (-0.02; -0.57 to 0.52). Formoterol delivered by 3 different inhalers exhibited a significant degree of peak and trough bronchoprotection after single and repeated dosing, with most comparisons being within predefined equivalence limits.