Provocative Concentration Of Methacholine Research Articles

Airway hyperresponsiveness in chronic obstructive pulmonary disease: A marker of asthma-chronic obstructive pulmonary disease overlap syndrome?

The impact of airway hyperreactivity (AHR) on respiratory mortality and systemic inflammation among patients with chronic obstructive pulmonary disease (COPD) is largely unknown. We used data from 2 large studies to determine the relationship between AHR and FEV1 decline, respiratory mortality, and systemic inflammation. We sought to determine the relationship of AHR with FEV1 decline, respiratory mortality, and systemic inflammatory burden in patients with COPD in the Lung Health Study (LHS) and the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study. The LHS enrolled current smokers with mild-to-moderate COPD (n=5887), and the GLUCOLD study enrolled former and current smokers with moderate-to-severe COPD (n=51). For the primary analysis, we defined AHR by a methacholine provocation concentration of 4mg/mL or less, which led to a 20% reduction in FEV1 (PC20). The primary outcomes were FEV1 decline, respiratory mortality, and biomarkers of systemic inflammation. Approximately 24% of LHS participants had AHR. Compared with patients without AHR, patients with AHR had a 2-fold increased risk of respiratory mortality (hazard ratio, 2.38; 95% CI, 1.38-4.11; P=.002) and experienced an accelerated FEV1 decline by 13.2mL/y in the LHS (P=.007) and by 12.4mL/y in the much smaller GLUCOLD study (P=.079). Patients with AHR had generally reduced burden of systemic inflammatory biomarkers than did those without AHR. AHR is common in patients with mild-to-moderate COPD, affecting 1 in 4 patients and identifies a distinct subset of patients who have increased risk of disease progression and mortality. AHR may represent a spectrum of the asthma-COPD overlap phenotype that urgently requires disease modification.

Risk factors, lung function and bronchial hyperresponsiveness in current dust mite-induced allergic rhinitis

Purpose: We analyzed the pulmonary function and risk factors of allergic rhinitis (AR) in dust mite-sensitized children with current AR and no history of asthma. Methods: In this cross-sectional study, demographic and disease-related information was obtained from 1,792 Korean children aged 9?12 years using a questionnaire, skin-prick testing, spirometric analysis, and methacholine challenge testing. Results: A total of 672 children were analyzed. The control group consisted of 583 children without any allergic diseases who were not sensitized to 16 common allergens. The group with current AR and dust mite sensitization consisted of 89 children. Binary logistic regression analysis showed that helminth infection (adjusted odds ratio [aOR], 2.88; 95% confidence interval [CI], 1.23?6.77) and antibiotic use during infancy (aOR, 1.89; 95% CI, 1.10?3.25) were the risk factors. Pet ownership (aOR, 0.32; 95% CI, 0.15?0.69) and older siblings (aOR, 0.58; 95% CI, 0.35?0.96) were protective factors. Spirometry results did not differ between the control and dust mite-induced AR groups. None of the children showed a bronchodilator response. However, 8.5%, 7.1%, and 2.1% of the control-group children and 28.7%, 23.0%, and 8.0% of the dust mite-induced AR-group children showed methacholine PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second) values of ≤25 mg/mL, ≤16 mg/mL, and ≤8 mg/mL, respectively (P<0.01). Conclusion: The prevalence of current dust mite-induced AR may be reduced by controlling environmental factors. Even though the spirometry results seemed to be normal, bronchial hyperresponsiveness occurred more frequently in children with dust mite-induced AR than in normal children.

Comparison between exhaled nitric oxide and bronchial challenge with methacholine or adenosine-5'-monophosphate in the diagnosis of childhood asthma

Purpose: Asthma is a chronic airway inflammatory disease characterized by bronchial hyperresponsiveness and reversible airway obstruction. Bronchial challenge with methacholine or adenosine-5`-monophosphate (AMP) has been used to diagnose asthma. Recently, measurement of exhaled nitric oxide (eNO) can also be used for the diagnosis of asthma. The aim of this study was to compare the diagnostic value for asthma between challenge with methacholine or AMP and eNO in children with chronic nonspecific respiratory symptoms. Methods: One hundred thirty-three children who have chronic nonspecific respiratory symptoms were enrolled. Bronchial challenge with methacholin and AMP were performed, and eNO was measured in all subjects. Subjects were defined as asthma based on the clinical symptoms and bronchodilator response during follow-up of at least 3 months after test. Results: Thirty-three subjects (34%) were finally diagnosed as asthma among 97 patients after 3-month follow-up. The area under the receiver operating characteristic curves for the diagnosis of asthma were 0.903 (95% confidence interval [CI], 0.838-0.969; P<0.001) for methacholline challenge, 0.867 (95% CI, 0.783-0.950; P<0.001) for AMP challenge, and 0.588 (95% CI, 0.467-0.709, P=0.156) for eNO measurement. The cutoff values of these tests were methacholine PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second) 12.0 mg/mL (sensitivity, 87.9%; specificity, 82.8%), AMP PC20 566.2 mg/mL (sensitivity, 84.8%; specificity, 85.9%), and eNO 18.5 ppb (sensitivity, 45.5%; specificity, 71.9%). Conclusion: Measurement of eNO may be inferior to challenge with methacholine and AMP for the diagnosis of asthma in children. (Allergy Asthma Respir Dis 2016;4:100-106)

Ventilation Heterogeneity and Airway Hyperreactivity in Children with Well Controlled Asthma

Rationale: In asthma, airway inflammation, obstruction and reactivity may lead to ventilation heterogeneity; our understanding of this process is limited in asthmatic children. Objectives and Methods: The study’s objective was to measure ventilation heterogeneity, by the lung clearance index (LCI), in children with well controlled asthma and assess the association of LCI with airway reactivity through methacholine challenge tests. LCI and spirometry were measured in 24 children with asthma and 21 healthy controls between 4 and 10 years of age. Sixteen children with asthma and 11 healthy controls also performed methacholine challenge tests. Results: LCI was higher in children with asthma compared to healthy controls (7.58 vs 6.79, p=0.004); no differences in FEV1 or FEF25-75 were noted between groups. Ages were similar (p=0.54); however, the slope of LCI versus age differed between groups (p=0.001). The LCI slope increased with age in asthmatics. Further, higher LCI values were associated with decreasing PC20 (provocative concentration of methacholine to decrease baseline FEV1 by 20%) values in children with asthma (p=0.02), but not healthy controls (p=0.16). Conclusions: Ventilation heterogeneity is present from preschool age in children with well controlled asthma. The relationship between ventilation heterogeneity and airway reactivity suggests that normalizing ventilation heterogeneity may be an important therapeutic target for treating children with asthma.

Bioassay of salmeterol in children using methacholine challenge with impulse oscillometry.

Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4-11 years. None were taking a long-acting β-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 μg salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 μg salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40 R5 ) was calculated. The reduction in R5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 μg, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95%CI) PC40 R5 (mg/ml) was 2.4 (1.3-4.4) during screening, 22.9 (8.5-61.6) after 50 μg SM and 47.0 (25.2-87.8) after 100 μg SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. Pediatr Pulmonol. 2016;51:570-575. © 2015 Wiley Periodicals, Inc.

Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma

BackgroundImpulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. ObjectiveTo ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. MethodsPatients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 μg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. ResultsThe magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4–57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7–27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. ConclusionThe potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. Trial Registrationwww.clinicaltrials.gov (NCT01074853).

Effects of Weight Loss on Airway Responsiveness in Obese Adults With Asthma: Does Weight Loss Lead to Reversibility of Asthma?

The growing epidemics of obesity and asthma are major public health concerns. Although asthma-obesity links are widely studied, the effects of weight loss on asthma severity measured by airway hyperresponsiveness (AHR) have received limited attention. The main study objective was to examine whether weight reduction reduces asthma severity in obese adults with asthma. In a prospective, controlled, parallel-group study, we followed 22 obese participants with asthma aged 18 to 75 years with a BMI ≥ 32.5 kg/m2 and AHR (provocative concentration of methacholine causing a 20% fall in FEV1 [PC20] < 16 mg/mL). Sixteen participants followed a behavioral weight reduction program for 3 months, and six served as control subjects. The primary outcome was change in AHR over 3 months. Changes in lung function, asthma control, and quality of life were secondary outcomes. At study entry, participant mean ± SD age was 44 ± 9 years, 95% were women, and mean BMI was 45.7 ± 9.2 kg/m2. After 3 months, mean weight loss was 16.5 ± 9.9 kg in the intervention group, and the control group had a mean weight gain of 0.6 ± 2.6 kg. There were significant improvements in PC20 (P = .009), FEV1 (P = .009), FVC (P = .010), asthma control (P < .001), and asthma quality of life (P = .003) in the intervention group, but these parameters remained unchanged in the control group. Physical activity levels also increased significantly in the intervention group but not in the control group. Weight loss in obese adults with asthma can improve asthma severity, AHR, asthma control, lung function, and quality of life. These findings support the need to actively pursue healthy weight-loss measures in this population.

Association between asthma control test, pulmonary function tests and non-specific bronchial hyperresponsiveness in assessing the level of asthma control.

Global Initiative for Asthma (GINA) reports emphasize the use of validated and simple tools in order to assess the level of asthma control, as the Asthma Control Test (ACT). However, an ACT does not include assessment of airway inflammation, which is better reflected when measuring nonspecific bronchial hyperresponsiveness (BHR). The authors aimed to find out if the level of asthma control quantified by an ACT correlates with BHR and pulmonary function tests. 118 asthmatics participated in the study. All patients completed an ACT. The scores of the ACTs were compared with pulmonary function tests and BHR assessed with the methacholine challenge test and expressed as a provocative concentration of methacholine, inducing a 20% decline in the FEV1 (PC20 M in mg/ml). Patients with controlled asthma amounted to 52 (44%) while those with uncontrolled asthma amounted to 66 (56%). In patients with controlled asthma (ACT score ≥ 20) the mean geometric value of PC20M was 2.72 mg/ml (range from 0.25 to > 8.0), whereas 0.94 mg/ml (range from 0.28 to 8.0) (p = 0.02) was observed in patients with uncontrolled asthma (ACT score < 20). Almost 64% (21/33) of uncontrolled asthmatics achieved normal lung function (FEV1 > 80% pred. value) while 19% (5/26) patients with controlled asthma presented an FEV1 < 80% predicted value. Asthma duration in years in controlled asthmatics was significantly shorter than in uncontrolled patients (6.2 ± 8.9 vs. 12.0 ± 11.4, p = 0.005) CONCLUSION: In determining the most accurate level of asthma control it is reasonable to use an ACT in conjunction with BHR, which provides more accurate assessment of bronchial inflammation than ventilatory parameters alone.

Clinical characteristics related to onset age of wheeze in school-age children and adolescents with asthma

Purpose: We aimed to investigate the clinical characteristics and their relationship with the onset age of wheeze in school-age children and adolescents with asthma. Methods: Three hundred twenty-six patients, aged 6 to 19 years, diagnosed with asthma at 6 hospitals from Seoul, Gyeonggi, Daegu, and Busan were enrolled. They were categorized into 3 groups by the onset age of wheeze: group A, early onset (age <3 years); group B, preschool onset (age 3-6 years); group C, late onset (age ≥6 years). Clinical characteristics including atopic sensitization, family history, combined allergic diseases, severity of asthma, and influence of asthma on daily life were examined. A history of hospitalization for early lower respiratory infection (LRI) and environmental tobacco smoking were studied and lung function tests were also performed. Results: There was no difference in demographics, prevalence of atopy, combined allergic diseases, and family history of allergy between 3 groups. A history of sever LRI in early life was more common in groups A and B compared with group C. Sensitization to Dermatophagoides pteronyssinus was more prevalent in groups A and B than in group C. Forced expiratory flow between 25% to 75% (FEF25%-75%) was lower in groups A and B than in group C, and methacholine PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second) was lowest in group B. Significantly lower FEF25%-75% and methacholine PC20 were observed in the patients who had been hospitalized with LRI in early life. Conclusion: Our study shows significant difference in lung function and atopic sensitization in relation to the onset age of wheeze in school-age children and adolescents with asthma, and suggests that early LRI might contribute to the development of asthma in early life. (Allergy Asthma Respir Dis 2015;3:326-333)

Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma.

To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma. The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured. Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo. ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.

Relationships of bronchodilator response with asthma control and fractional exhaled nitric oxide in children with atopic asthma

Purpose: Because bronchodilator response (BDR) is variable among asthmatic patients, there are practical limitations in using BDR to assess asthma control. We investigated the relationships of BDR with asthma control status and fractional exhaled nitric oxide (FeNO) in children with atopic asthma. Methods: One hundred ninety-one patients aged 8 to 16 years with atopic asthma were enrolled. Pulmonary function tests including BDR and FeNO were serially measured 10 times or more over 2 years when subjects were not receiving controller medications. During the last year of follow-up, the loss of asthma control was assessed in all participants. Results: We identified 114 children (60%) with at least 1 positive BDR (≥12%) over the 2-year observation period. Higher levels of BDRs and higher rates of positive BDRs were associated with lower lung function and lower methacholine PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second). The loss of asthma control occurred in 106 of individuals (93%) who had positive BDRs, as compared to 52 of 77 (68%) with negative BDRs (P 21 parts per billion than those who maintained asthma control (all P<0.001). Conclusion: Positive BDRs are linked to a higher probability of asthma control loss in children with atopic asthma. In addition, high FeNO is associated with asthma control loss in asthmatic children with negative BDRs.

Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma

BackgroundThe methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose–response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established. ObjectiveTo determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20. MethodsA randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 μg/d) vs low-dose (250 μg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval. ResultsBecause there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements. ConclusionThe effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 μg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20.

Randomised placebo-controlled study of the effect of paracetamol on asthma severity in adults

ObjectiveTo investigate the effect of regular paracetamol on bronchial hyper-responsiveness (BHR) and asthma control in adult asthma.SettingSingle research-based outpatient clinic.Participants94 adults with mild-to-moderate asthma received randomised treatment; 85 completed the...

Heterogeneity of asthma according to systemic inflammatory pattern in children

Purpose: Asthma is a chronic airway inflammation. We evaluated whether systemic inflammatory patterns could reflect the nature of airway inflammation. We assessed characteristics of asthma according to systemic inflammatory patterns. Methods: A total of 413 children with asthma were enrolled in the study. Four systemic inflammatory patterns were classified according to eosinophil and neutrophil counts in peripheral blood. Children with neutrophil count≥5,000/μL were defined as the NEUhi group, those with neutrophil count <2,720/μL as the NEUlo group. The intermediate group with neutrophil count between 2,720/μL and 5,000/uL was excluded from the study. Children with eosinophil≥650/μL were defined as the EOShi group, those with eosinophil count<240/μL as the EOSlo group. The remaining patients were excluded from the study. The characteristics of asthma include pulmonary function test results, bronchodilator response, airway hyperresponsiveness, and atopy. Results: The EOShi group had a lower PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1]), a lower FEV1, and a higher immunoglobulin E level rather than the EOSlo groups, although there were no significant differences between the NEUhi and NEUlo groups. The eosinophil percentages of the induced sputum samples were higher in the EOShi group than the EOSlo group and correlated with blood eosinophil counts. Conclusion: Eosinophilic inflammation was related to characteristics of asthma and sputum eosinophils. However, neutrophilic inflammation reflected neither asthma features, sputum neutrophils, nor eosinophilic inflammation. Further studies on blood neutrophils involving asthma phenotypes in terms of more specific characteristics of asthma should be needed in children.

Risk factors influencing bronchial hyperresponsiveness to methacholine in school age and adolescence of atopic dermatitis

Purpose: Many studies have shown the importance for bronchial hyperresponsiveness (BHR) in children with bronchial asthma and allergic rhinitis. However, studies have not been done in BHR in school age and adolescence with atopic dermatitis (AD). Methods: The patients with history of bronchial asthma were excluded and methacholine challenge test (MCT) was performed in 103 children with atopic dermatitis. The positive of MCT result is defined as provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (PC20)≤8 mg/mL. According of the level of PC20, the patients were divided into two groups. Results: The group 1 (BHR+) was observed in 43 of all patients (41.7%). Of two groups, significant differences were observed in age, body mass index. No significant differences were observed in the number of male, SCORing Atopic Dermatitis (SCORAD) index, admission history, smoking exposure history, other allergic disease, parental allergic disease. The group 1 (BHR+) have higher levels of total eosinophil count compared with the group 2 (BHR-) (629.8±360.5/μL vs. 470.2±253.9/μL, P=0.01). But no significant association was found between severity of BHR and SCORAD score, total immunoglobulin E, total eosin ophil count and eosinophil cationic protein (r=0.008, P=0.961; r=-0.217, P=0.162; r=0.225, P=0.147; r=-0.032, P=0.841). The list of allergen is that the house dust mite, tree, weed, food, animal hair, and fungus. The house dust mite has correlation with bronchial hypersensitivity statistically and the any of allergen groups, either. Conclusion: No significant relationship was observed between degree of BHR and allergy laboratory finding, severity of AD.

The prevalence of bronchial hyperresponsiveness in elementary school children and its associated factors

Purpose: We investigated the prevalence of bronchial hyperresponsiveness (BHR) and its associated factors in population-based elementary school children. Methods: Methacholine bronchial provocation tests were performed on 1,151 elementary school children and BHR was defined as PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1]) ≤8 mg/mL. We analyzed the prevalence of BHR according to age and sex. The Korean version of International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, skin prick test, pulmonary function test, and blood tests were performed to determine associated factors for BHR. Results: A total of 1,106 students eligible for provocation tests were included in the analysis. The overall prevalence of PC20 ≤8 mg/mL was 11.5% (95% confidence interval, 10.6-13.4) and BHR decreased with age (P-value for trend <0.001). Younger age (adjusted odds ratio [aOR], 0.860; P=0.032), higher blood eosinophil % (aOR, 1.151; P=0.001), lower predictive % of FEV1 (aOR, 0.977; P=0.029), fraction of exhaled nitric oxide (FeNO) ≥25 ppb (aOR, 2.118; P=0.025), and sensitization to mites (aOR, 1.705; P=0.034) were associated with BHR. Preterm birth (aOR, 2.056; P=0.068) showed borderline significance. The associated factors for BHR with atopy were lower body mass index (aOR, 0.838; P=0.005), preterm birth (aOR, 4.361; P=0.003), and FeNO ≥25 ppb (aOR, 2.161; P=0.043). Younger age (aOR, 0.810; P=0.037) and higher blood eosinophil % (aOR, 1.296; P<0.001) were associated with BHR without atopy. Conclusion: The prevalence of BHR decreased with age in elementary school children. Younger age, preterm birth, eosinophilia, sensitization to mites, lower lung function, and higher FeNO level were independently associated with BHR.(Allergy Asthma Respir Dis 2014;2:171-178)

Disconnect between sputum neutrophils and other measures of airway inflammation in asthma

To the Editor: Asthma heterogeneity has been described by the nature and intensity of granulocytic infiltration into the airways [1, 2]. Sputum, endobronchial biopsies and bronchoalveolar lavage (BAL) sample different anatomical regions of the airways. Few studies have directly compared the inflammatory cell infiltrates in these regions within a large cohort of moderate–severe asthma patients using standard techniques. In the BOBCAT (Bronchoscopic exploratory research study Of Biomarkers in Corticosteroid-refractory AsThma) study, we sampled multiple airway compartments concurrently, enabling us to evaluate relationships between granulocytic infiltrates within and between compartments in a large cohort of moderate–severe adult asthma patients. This prospective multicentre observational study was conducted in four visits over a 4–6 week period, as described previously [3]. The patients included had moderate–severe persistent asthma (forced expiratory volume in 1 s (FEV1) 40–80% predicted and Asthma Control Questionnaire (ACQ) [4] score >1.5) and, within the past 5 years, evidence of >12% post-bronchodilator reversibility or a provocative concentration of methacholine causing a 20% decline in FEV1 ≤8 mg·mL−1 despite high-dose inhaled corticosteroid (ICS) (≥1000 μg·day−1 fluticasone propionate equivalent) with or without long-acting β2-adrenergic agonist therapy. Key exclusion criteria included initiation or increase in systemic steroid use 30 days prior to screening, chronic or recent (within the past 30 days) use of immunosuppressive therapies, or other active lung disease. Patients had a prior established diagnosis of moderate–severe asthma for ≥6 months prior to screening while receiving a stable dose regimen (>6 weeks) of a high-dose ICS. Allowed concomitant medications included leukotriene receptor antagonists and oral corticosteroids. 78 patients with confirmed moderate–severe asthma were enrolled at 18 sites; 67 (86%) completed the study. All patients had persistently impaired …

Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials

Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug. Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34. Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV1) and provocative concentration of methacholine causing a 20% fall in FEV1 (PC20MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL (95% CI 320-720; p<0·0001), which was a 14% increase from placebo, and increased the PC20MCh by 1·5 doubling doses (95% CI 0·63-2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 (555 mL, 95% CI 442-668), day 3 (505 mL, 392-618), and day 6 (485 mL, 371-598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference -3·9%, 95% CI -9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree. In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma. Verona Pharma.

Refractoriness to inhaled mannitol 3 hours after allergen challenge

BackgroundA positive response to indirect airway challenges (eg, mannitol) that cause release of mast cell mediators causes refractoriness to a repeat exposure to the same or different indirect stimulus that lasts for at least several hours. Allergen challenge causes increased response to methacholine measured at 3 hours. ObjectiveTo compare allergen-induced changes in airway response to methacholine and mannitol 3 hours after completion of an allergen challenge. MethodsTen atopic patients with asthma completed a randomized clinical trial. The provocation concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 second (FEV1) was measured 24 hours before and 3 hours after a standard allergen challenge. The provocation dose of mannitol causing a 15% decrease in FEV1 was also measured 24 hours before and 3 hours after allergen challenge. The allergen challenges were separated by 7 to 14 days. ResultsThe allergen-induced early responses, expressed as the maximum (SD) percent decrease in FEV1, were 29.7% (11.1%) and 27.8% (7.6%) on the methacholine and mannitol days, respectively. Airway response to methacholine increased significantly after allergen challenge (P = .02). By contrast, the airway response to mannitol was reduced by almost a doubling dose (P = .02) after allergen. ConclusionThree hours after allergen challenge at a time when the airways are more responsive to methacholine, there is a significant refractoriness to the indirect stimulus mannitol. Trial Registrationclinicaltrials.gov Identifier: NCT01699594

Glucocorticoid-induced Changes in Gene Expression of Airway Smooth Muscle in Patients with Asthma

Glucocorticoids are the mainstay of asthma therapy. However, it is unclear whether the benefits of glucocorticoids in asthma are merely based on antiinflammatory properties. Glucocorticoids may also alter gene expression of airway smooth muscle (ASM). We hypothesized that the gene expression profile of the ASM layer in endobronchial biopsies of patients with asthma is altered by oral glucocorticoid therapy as compared with placebo. First, we investigated the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral glucocorticoid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and lung function. Twelve steroid-free patients with atopic asthma were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolone (n = 6) or placebo (n = 6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using GS FLX+ (454/Roche). Gene networks were identified by Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. Fifteen genes were significantly changed by 14 days of oral prednisolone. Two of these genes (FAM129A, SYNPO2) were associated with airway hyperresponsiveness (provocative concentration of methacholine causing a 20% drop in FEV1: r = -0.740, P < 0.01; r = -0.746, P < 0.01). Pathway analysis revealed three gene networks that were associated with cellular functions including cellular growth, proliferation, and development. Oral prednisolone changes the transcriptomic profile of the ASM layer in asthma. This indicates that in parallel to antiinflammatory properties, glucocorticoids also exert effects on gene expression of ASM, which is correlated with improved airway function.