Hypodense eosinophil number relates to clinical severity, airway hyperresponsiveness and response to inhaled corticosteroids in asthmatic subjects
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The phenotypically distinct low-density eosinophil, with its greater inflammatory potential, is increased in asthma. However, the role of hypodense eosinophils in the development of asthma is still unclear. We conducted a double-blind, placebo-controlled study to examine the effect of inhaled corticosteroids on the number of hypodense eosinophils in 27 asthmatic subjects and its relationship with clinical severity. The density profile of eosinophils in the peripheral blood was determined using Percoll density gradient fractionation. Eosinophils recovered from asthmatics were mainly in the lower density fractions (< 1.095 g.ml-1) (63 +/- 3%; n = 27), significantly different from those of normal subjects (27 +/- 2%; n = 7). The proportion of hypodense eosinophils was inversely related to the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) value (r = -0.75). Patients with mild asthma had a lower percentage of hypodense eosinophils (45 +/- 4%; n = 14) than those with moderate asthma (67 +/- 3%; n = 13). Inhalation of budesonide (800 micrograms.day-1) (n = 15) for 4 weeks, but not placebo, significantly improved the PC20 values by 0.97 doubling dose, forced expiratory volume in one second (FEV1) % predicted by 17%, and peak expiratory flow rate (PEFR) by 15%, and decreased PEFR diurnal variability by 5.4%. The percentage of hypodense eosinophils was significantly decreased from 68 +/- 4 to 47 +/- 4% in the budesonide group (n = 15), but not in the placebo group (n = 12) (63 +/- 4 to 65 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)Keywords:
Methacholine
Bronchial hyperresponsiveness
Thirty-nine subjects were included in this double-blind, placebo-controlled study of bronchial hyperresponsiveness (BHR) in patients with mild to moderate asthma. The time-courses of change of FEV1, PEFR%, bronchial reactivity, and daily measures of asthma control were determined during 8 weeks of treatment after a run-in period of 2 weeks. Bronchial hyperresponsiveness was assessed by the methacholine provocation method, defined as the dose of methacholine causing a 20% fall of FEV1 compared with baseline values. The trends of FEV1 and the percentage change in PEFR from baseline were significantly different between groups, in favor of budesonide (P < .05). Patient assessments of the effect of treatment showed that PEF improved significantly in the budesonide group only. The budesonide group increased their tolerability for methacholine provocation by 1.8 DD (doubling dose), which tended to be higher compared with the 0.8 DD of the placebo group. It is evident from this study and previous studies that more data are needed to establish the dose-effect relationship with time and severity of the disease.
Methacholine
Bronchial hyperresponsiveness
Tolerability
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Methacholine
Toluene diisocyanate
Bronchial hyperresponsiveness
Airway hyperresponsiveness
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Cough in the patients with cough variant asthma is triggered by bronchoconstriction, which responds to bronchodilator therapy. Following airway narrowing induced by inhaled methacholine, deep inspiration (DI) causes dilation of the airways in both asthmatic and non-asthmatic subjects. The aim of the present study was to investigate the relationship between bronchodilator effect of DI and bronchoconstriction-triggered cough. We measured airway responsiveness to methacholine using partial and full flow-volume curves in 28 healthy adults. The expiratory flow at 40% above residual volume from the full forced vital capacity (MEF40) was obtained and the volume was used as the reference volume to determine the isovolume flow from the partial curve (PEF40). Coughs were counted for 32 min during and following the inhalation of methacholine at the provocative concentration which produced a 20% fall or more in FEV1from the post-saline value (PC20-FEV1). The bronchodilator effect of DI on bronchoconstriction induced by methacholine at the PC20-FEV1 concentration was expressed as the ratio of (MEF40-PEF40)/PEF40 (DI index). The number of coughs for 32 min during and following the inhalation of PC20-FEV1 concentration of methacholine was 39.3 ± 29.7 (mean ± SD)/32 min. The number of coughs during and following the inhalation was correlated with DI index (r = 0.57, p = 0.0015), but not with PC20-FEV1 or change in FEV1 or PEF40 by inhalation of the PC20-FEV1 concentration of methacholine. We found that methacholine-induced cough was associated with the bronchodilator effect of DI on methacholine induced-bronchoconstriction in normal subjects.
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The relationship between gastroesophageal reflux (GER) and asthma has been widely studied in the last years. GER may interfere with airway reactivity and aggravate or even induce asthma.To assess the prevalence of bronchial hyperresponsiveness (BHR) in patients with GER disease with a view to judging the potential influence of GER on BHR.30 patients with GER disease and no clinical evidence of asthma and 30 normal subjects underwent a methacholine bronchial challenge. The methacholine concentration that caused a 20% fall in the FEV(1) (PC20) was used to assess bronchial responsiveness.In the GER group 11 subjects of the 30 studied showed a PC20 methacholine equal to or less than 8 mg/ml while in the control group only 2 subjects had a PC20 methacholine equal to or less than 8 mg/ml (p < 0.01; ANOVA test).Subjects with GER had a greater increase in airway reactivity when inhaling methacholine compared to disease-free normal subjects.
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Bronchial hyperresponsiveness
Airway hyperresponsiveness
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The effects of ipratropium bromide (80 and 200 micrograms) and placebo on the basal bronchial tone and on methacholine-induced bronchoconstriction were investigated in 10 asthmatic patients in a placebo-controlled double-blind manner. Bronchial hyperreactivity to methacholine was confirmed at a pretrial bronchial challenge. The patients were randomly allocated to two groups in which the drug was inhaled from either metered-dose inhalers (MDI) or powder capsules. With the high dosage, the bronchodilation resulting from powder capsules was somewhat more pronounced than that achieved with the MDI. Otherwise the bronchodilator effect of ipratropium bromide and the protection afforded by the drug against methacholine-induced bronchoconstriction were similar in the two groups. In five patients the bronchodilator effect was better and in four patients the tolerance to methacholine was greater after the higher ipratropium dosage than after the lower one. In two patients ipratropium bromide had no bronchodilator effect but gave good protection against methacholine-induced bronchoconstriction. It is concluded that some patients benefit from a dosage of ipratropium bromide higher than that usually recommended and that an anticholinergic effect on the bronchi is possible even in the absence of the bronchodilator effect in the basal state.
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The aim of the present study was to determine the relationship between bronchodilator response, assessed by interrupter resistance (Rint), and bronchial reactivity in preschool children with chronic cough. Thirty-eight children coughers (median age 5.0 years, range 2.8-6.4) were tested. Bronchodilator response was recorded within 4 months before methacholine challenge. Response to the latter was assessed using transcutaneous partial pressure of oxygen and Rint. Children were considered responders if a 20% fall in transcutaneous partial pressure of oxygen occurred during the bronchial challenge. Bronchodilator response was not different between responders (n = 24) and nonresponders (n = 14) [median (range) -0.11 (-0.44-0.09) vs. -0.08 (-0.21-0.10) kPa L(-1) sec; respectively]. However, none of the nonresponders had a bronchodilator response larger than -0.21 kPa L(-1) sec, this cutoff had a 100% positive and a 44% negative predictive value to predict a positive methacholine challenge. The relationship between bronchodilator response and bronchial methacholine responsiveness reached the limit of significance (P = 0.048). Furthermore, the magnitude of the bronchodilator response was correlated to the level of methacholine-induced level of bronchoconstriction (P = 0.01), and to the postchallenge bronchodilation (P = 0.04), all values expressed as % predicted. Moreover, the postbronchodilator Rint value obtained with preceding methacholine challenge was lower than the postbronchodilator value without preceding methacholine challenge in 71.4% (10/14) of the nonresponders and in only 33.3% (8/24) of the responders. Conclusions in preschool coughers bronchodilator response, assessed by the interrupter technique, was correlated to the bronchial responsiveness to methacholine. Non responders had a bronchodilator response not larger than -0.21 kPa L(-1) sec.
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Bronchodilation
Bronchodilator Agents
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Current asthma is often excluded by the presence of normal bronchial hyperresponsiveness. We report two asthmatic patients with normal bronchial hyperresponsiveness and one asthmatic patient with mild bronchial hyperresponsiveness (methacholine PC20; 24 mg/ml) which was presumed to be caused by sensitization and exposure to Black GR, the most frequent sensitizer among reactive dyes. They all complained of lower respiratory symptoms after work as well as at the workstation. The bronchoprovocation test with Black GR revealed isolated immediate bronchoconstrictions in all 3 patients and all had high specific IgE antibodies to Black GR-human serum albumin conjugate. After one worker continued at work for 3 days, he experienced a marked drop of methacholine PC20, and it returned to the pre-exposure level during 1 week. The other patient whose initial methacholine challenge was negative developed bronchial hyperresponsiveness on the first day after the dye bronchoprovocation, and returned to normal bronchial hyperresponsiveness on the third day. These findings suggested that patients with occupational asthma caused by reactive dye may not always have bronchial hyperresponsiveness to methacholine, and the screening program utilizing methacholine challenges may not always identify these patients.
Methacholine
Bronchial hyperresponsiveness
Bronchial hyperreactivity
Occupational Asthma
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Bronchial hyperresponsiveness (BHR) is a hallmark of asthma. BHR to methacholine is used for diagnosis, but the role in monitoring treated asthma is not established. In the present study we assessed the relation between BHR to methacholine, airways inflammation, asthma control and symptoms. Methacholine challenge and FeNO measurements were done in 371 asthmatics (aged 10-35 years) with inhaled corticosteroids prescribed. PD 20 1.0 mg normal response (Schulze et al. Resp Med 2009). Well-controlled asthma (≥20 in Asthma Control Test) was found in 68% of children ( Moderate-severe BHR was found in 61% of children and 44% of adults. FeNO increased with more severe BHR in both children and adults, with a higher explanatory value in children (R 2 =0.15 vs 0.06). Well-controlled asthma was less prevalent in the moderate-severe BHR group than the other two BHR groups in adults (66% vs 83% and 82%, p In conclusion, bronchial hyperresponsiveness to methacholine was common in this treated asthma population and related both to airways inflammation and clinical aspects of asthma. BHR appears to be stronger related to poorer asthma control and exercise-induced dyspnea in adults than children.
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Bronchodilator response (BDR) is assessed to estimate the reversibility of airflow obstruction. Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma and is usually measured by means of bronchial challenges using direct or indirect stimuli. The aim of the present study was to compare BHR to methacholine (direct) and that to adenosine 5’-monophosphate (AMP) (indirect) with regard to their relationships to BDR in asthmatic children. Methacholine and AMP challenge tests were performed on 138 children with mild-to-moderate asthma, and the provocative concentration causing a 20% decline in forced expiratory volume in 1 s (FEV 1 ) (PC 20 ) was determined for each challenge. BDR was calculated as the change in FEV 1 , expressed as a percentage of the initial value, after inhalation of 400 μg salbutamol. Methacholine PC 20 correlated significantly but weakly with BDR (r = -0.254; p = 0.003). However, there was a significant and strong correlation between AMP PC 20 and BDR (r = -0.489; p = 0.000). For AMP PC 20 , the relationship was closer than for methacholine PC 20 (p = 0.024 for comparison between correlation coefficients). The same figures were observed when BDR was expressed as a percentage of the predicted value. A stronger correlation of BDR with AMP PC 20 than with methacholine PC 20 suggests that BDR may be better reflected by BHR as assessed by AMP challenge than by methacholine challenge.
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Bronchodilator Agents
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The bronchodilator agent is an important drug for patients with chronic obstructive pulmonary disease. Methacholine is a popular bronchial provocative agent. Although the major acting site of bronchodilator, methacholine and upper respiratory tract infection (URI) has been evaluated in some studies, the sites are still in debate. This study investigated the exact major acting sites.Thirty subjects participated in this study. Episodes of URI were identified by a questionnaire. Spirometry, bronchial provocative test with methacholine, and five minutes' inhalation of a mixture of helium and oxygen (HeO2) were done on day one. Spirometry, bronchodilator test, with five minutes' inhalation of HeO2 and expiratory flow-volume (F-V) curve were performed on another day. The change of pre- and post-HeO2 VEMax50 was calculated as delta VEMax50. The pre- and post-bronchodilator VEMax50 and delta VEMax50 differences were counted to decide the acting site of bronchodilator. After bronchial provocative test with methacholine, the volume of isoflow (VisoV) was estimated from pre- and post-HeO2 F-V curve to establish the acting site of methacholine.This study indicated that small airways are the major acting sites of bronchodilators, large airways are the major acting sites of methacholine and URI affects mainly large airways. Although airway hyperresponsiveness is more severe in subjects with positive methacholine response, the recovery of spirometry values is not significantly different between the methacholine-positive and -negative groups.The major acting sites of the bronchodilator, methacholine, and URI are the small, large and large airways, respectively. Bronchial hyperresponsiveness is not a cause of quick restoration of spirometry values in subjects with positive methacholine response.
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Respiratory tract
Bronchial hyperresponsiveness
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