Provocative Concentration Of Methacholine Research Articles

Does the Methacholine Test Reproduce Symptoms?

The interpretation of methacholine test results do not usually consider the symptoms for which the subject was referred and those that occur during the test. To assess the association between methacholine test results and symptoms, and to examine variables that may affect this association. METHODS A total of 400 prospectively chosen subjects who underwent methacholine testing for possible asthma were investigated. The subjects answered a short questionnaire regarding the symptoms for which they had been referred and those that were encountered during the methacholine test. The positive predictive value for the reproduction of symptoms during the test compared with symptoms for which subjects had been referred were 84% for dyspnea, 87% for cough, 81% for wheezing and 72% for chest tightness. The positive predictive value among the values obtained by measuring the provocative concentration of methacholine causing a 20% fall (PC20) in forced expiratory volume in 1 s on the one hand, and specific symptoms on the other, varied by up to approximately 50%; negative predictive values were higher. Forty-eight per cent of subjects with a PC20 of 16 mg⁄mL or lower reported that the test had globally reproduced their symptoms. This association was significantly stronger in women, young subjects and those taking inhaled steroids. The methacholine test generally reproduced the symptoms for which the subjects were referred. The absence of a specific symptom (eg, dyspnea, cough, wheezing or chest tightness), either in daily life or at the time of methacholine testing, was more generally associated with a negative test than the reverse. The global impression that the test had reproduced what the patient had experienced in daily life was significantly associated with a positive test (ie, a PC20 of 16 mg⁄mL or lower), with the association being stronger in young subjects and women.

Inflammatory biomarkers in airways of patients with severe asthma compared with non‐severe asthma

About 5-10% of patients with asthma suffer from poorly-controlled disease despite corticosteroid (CS) therapy. We determined whether there were any differences in inflammatory biomarkers between severe and non-severe asthma patients. Nineteen severe and 20 non-severe asthma patients were recruited and underwent collection of induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies. Biopsy results showed no differences in eosinophils (major basic protein positive), neutrophils, macrophages, T cells and mast cells in the bronchial submucosa. However, subbasement membrane (SBM) thickness and smooth muscle area were increased in the biopsies. No significant differences were observed in the induced sputum inflammatory cells. In BAL fluid, there was a significant increase in neutrophils but a significant decrease in macrophages. Eosinophil counts were non-significantly increased threefold in both sputum and BAL in severe asthma. Levels of IL-8 and IL-13 in sputum supernatants were similar in both groups of asthma patients. There was a significant inverse correlation between post-bronchodilator forced expiratory volume in 1 s and provocative concentration of methacholine causing a 20% fall in FEV(1) with SBM thickness. Differences in inflammatory cells were observed mainly in terms of increased neutrophils and reduction in macrophage numbers in BAL fluid with a trend towards increased eosinophils in severe asthma compared with non-severe asthma. However, the most notable features are the increase in features of airway wall remodelling of SBM thickness and smooth muscle area.

Relationship Between Amphiregulin and Airway Inflammation in Children With Asthma and Eosinophilic Bronchitis

Amphiregulin, a member of the epidermal growth factor family, has been shown to promote the growth of fibroblasts, to be associated with the T-helper type 2 cell adaptive immune response, and to up-regulate mucin gene expression. We aimed to determine whether sputum amphiregulin is expressed at elevated levels in patients with asthma or eosinophilic bronchitis (EB), and whether it is associated with eosinophilic inflammation, pulmonary function, and bronchial hyperresponsiveness in children. A total of 117 children with asthma, 77 with EB, and 84 control subjects were enrolled in this study. Amphiregulin and eosinophil cationic protein (ECP) levels were measured in sputum supernatants. We performed pulmonary function and methacholine challenge tests while measuring total eosinophil count, and serum levels of total IgE and ECP in all children. The children with asthma had significantly higher levels of sputum amphiregulin (mean, 10.80 pg/mL; range, 4.07 to 38.75 pg/mL) than both the children with EB (mean, 5.76 pg/mL; range, 0.61 to 21.65 pg/mL; p = 0.013) and the control subjects (mean, 6.56 pg/mL; range, 0.51 to 17.98 pg/mL; p = 0.003). Sputum amphiregulin levels positively correlated with levels of sputum eosinophils (gamma = 0.221; p = 0.007) and sputum ECP (gamma = 0.601; p < 0.0001). Negative significant correlations were found between sputum amphiregulin and FEV(1) (gamma = -0.181; p = 0.006) or post-bronchodilator therapy FEV(1) (gamma = -0.233; p = 0.002). In children with asthma who were not receiving any controller medications, sputum amphiregulin level was negatively correlated with the provocative concentration of methacholine causing a 20% fall in FEV(1) (r = -0.398; p = 0.008). Our findings suggest that childhood asthma is associated with sputum amphiregulin, whereas EB is not, and that sputum amphiregulin would be a supportive marker of airway inflammation in asthma.

Evaluation of airway hyperresponsiveness and exhaled nitric oxide as risk factors for airway remodeling in patients with stable asthma

Chronic eosinophilic airway inflammation, airflow limitation, and airway hyperresponsiveness (AHR) are distinctive features of bronchial asthma. Exhaled nitric oxide (eNO) is a marker of eosinophilic airway inflammation. Airway remodeling due to chronic airway inflammation results in fixed airway obstruction. Asthmatic patients have been reported to have greater declines in forced expiratory volume in 1 second (FEV(1)) over time than nonasthmatic patients. This longitudinal observational study aimed to elucidate outcomes and risk factors for the decline in FEV(1) in patients with stable asthma. Postbronchodilator FEV(1) was measured in 30 outpatients with stable asthma every 6 months for 5 years. We calculated the rate of decline in postbronchodilator FEV(1) (deltaFEV(1)/year) in each subject and adjusted deltaFEV(1)/year with predictive FEV(1). Patients were examined while their asthma was well controlled. In the first observation period, we measured AHR to methacholine (the provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]). In the second observation period (defined as the period over 2 years from start of observation), we measured methacholine PC(20) and eNO. The mean deltaFEV(1)/year (SEM) was -36 +/- 4 mL/year and the adjusted deltaFEV(1)/year (SEM) was -0.015 +/- 0.001/year. Adjusted deltaFEV(1)/year did not correlate with eNO measured during the second observation period or methacholine PC(20) measured during the first observation period. On the other hand, methacholine PC(20) measured during the latter period was correlated significantly with adjusted deltaFEV(1)/year. Persistent AHR may be a risk factor for longitudinal decline in FEV(1) in asthma patients even if their asthma is stable and well controlled by inhaled corticosteroid.

S-Nitrosoglutathione Reductase

Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model. We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity. We recruited 36 subjects with mild asthma with FEV(1) 88.5 +/- 2.3% predicted and 34 healthy control subjects with FEV(1) 100.7 +/- 2.5% predicted. Bronchoalveolar lavage (BAL) was performed in all subjects. Cell counts, differentials, GSNOR activity, and SNO levels were determined in BAL. SNO content was decreased in asthmatic BAL compared with control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in subjects with asthma compared with control subjects and correlated inversely with the provocative concentration of methacholine causing a 20% decrease in FEV(1). These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma.

Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of β-adrenergic bronchodilators and corticosteroids

Fluticasone affects airway bronchial hyperresponsiveness (BHR) and enhances bronchodilation and bronchoprotection induced by beta-adrenergic agonists. Interleukin 13 (IL-13), however, induces BHR. To test the hypotheses that fluticasone inhibits BHR after either allergen sensitization or IL-13 administration and that fluticasone restores the bronchodilation and bronchoprotective effects of beta-agonists. The BHR to methacholine induced by IL-13 or ovalbumin was determined in BALB/c mice, and the provocation concentration of methacholine that caused an increase in enhanced pause in expiration of 200% (PC200) was calculated. We compared this response to methacholine in control mice with the response after treatment with IL-13 receptor alpha 2-IgGFc fusion protein (IL-13R alpha 2) (an IL-13 blocker), fluticasone, albuterol, salmeterol, fluticasone-albuterol, and fluticasone-salmeterol. IL-13R alpha 2 (PC200, 17.59) completely blocks the BHR-induced effects of IL-13 (PC200, 7.28; P < .005). After IL-13 therapy (PC200, 5.90; P < .005), 1 mg/mL of albuterol (PC200, 3.38; P = .33), fluticasone (PC200, 4.59; P = .40), or fluticasone plus 50 microg/mL of salmeterol (PC200, 5.59; P = .11) showed no significant bronchoprotection. In nonsensitized mice, fluticasone plus 0.25 microg/mL of salmeterol (PC200, 25.90; P < .005) showed significantly greater bronchoprotection than did salmeterol alone (PC200, 11.08; P = .26). Fluticasone plus 0.3 mg/mL of albuterol and fluticasone plus 1 mg/mL of albuterol were significantly more protective than was fluticasone or albuterol alone in ovalbumin-sensitized mice. The protective effects of fluticasone, beta-agonists, and fluticasone plus beta-agonists are significantly less in IL-13-treated mice than in nonsensitized or ovalbumin-sensitized mice.

A proof-of-concept study to evaluate the anti-inflammatory effects of a novel soluble cyclodextrin formulation of nebulized budesonide in patients with mild to moderate asthma

A cyclodextrin solution formulation of budesonide has been developed. To assess the anti-inflammatory effect of a novel soluble formulation of nebulized budesonide compared with the present suspension formulation based on a 1:4 nominal dose ratio. Seventeen mild to moderate asthmatic patients were randomized to receive 120 microg of Capsitol-Enabled Budesonide Inhalation Solution (CBIS) twice daily or 500 microg of budesonide suspension (Pulmicort Respules) twice daily via nebulizer for 2 weeks in a crossover manner. Methacholine challenge, fractionated exhaled nitric oxide (NO) measurement, spirometry, and 10-hour overnight urinary creatinine-corrected cortisol measurement were conducted at baseline and after each treatment. Neither CBIS nor Pulmicort significantly improved the provocation concentration of methacholine that caused a decrease in FEV1 of 10% as change from baseline (doubling dilution changes, 0.82; 95% confidence interval [CI], -0.08 to 1.72; P = .08; and 0.86; 95% CI, -0.61 to 2.32; P = .41, respectively). Both CBIS and Pulmicort suppressed exhaled NO from baseline (geometric mean fold ratios: for tidal NO, 0.70; 95% CI, 0.55-0.90; P = .006; and 0.62; 95% CI, 0.50-0.76; P < .001, respectively; for bronchial flux, 0.73; 95% CI, 0.56-0.95; P = .02; and 0.54; 95% CI, 0.39-0.74; P < .001, respectively). Alveolar NO was significantly suppressed by CBIS (geometric mean fold ratio, 0.33; 95% CI, 0.13-0.85; P = .02) but not by Pulmicort (0.66; 95% CI, 0.25-1.76; P = .81). The mean (SEM) nebulization time for CBIS was 84 (3.0) seconds and for Pulmicort was 303 (19) seconds (P < .001). There were no differences between CBIS and Pulmicort for any other outcome. There are no significant differences between formulations for any inflammatory outcome. CBIS has a shorter nebulization time and is given at a quarter of the nominal dose of Pulmicort.

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.

The Effects of Inhaled Fluticasone and Pranlukast on Bronchial Hyperreactivity in Children with Asthma

Background: Guidelines recommend inhaled corticosteroids and leukotriene modifiers as daily therapies to control asthma in children. However, few studies have compared the effects of these drugs on bronchial hyperreactivity in children with asthma.Methods: The effects of inhaled fluticasone and pranlukast on bronchial hyperreactivity in 42 patients aged 7–15 years with mild persistent asthma (24 treated with inhaled fluticasone and 18 with pranlukast), who had experienced no asthma exacerbations after these treatments started, were studied. At the start of and after 6 and 18 months of treatment, bronchial hyperreactivity (PC20: provocative concentration of methacholine causing a 20% fall in FEV1) was assessed with methacholine.Results: Geometric averages of PC20 in patients treated with inhaled fluticasone were 385.2 μg/mL at the start, 2271.8 μg/mL after 6 months, and 4181.0 μg/mL after 18 months of treatment, whereas those patients treated with pranlukast were 415.8 μg/mL, 792.2 μg/mL, and 2105.1 μg/mL,...

Differences in the Response to Methacholine Between the Tidal Breathing and Dosimeter Methods: Influence of the Dose of Bronchoconstrictor Agent Delivered to the Mouth

Background It has been postulated that differences in provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ) values between the dosimeter method and tidal breathing method might be due to differences in the dose of agonist delivered to the mouth. The aim of the present study was to determine the influence of the dose of aerosol delivered to the mouth on differences in the response obtained with each challenge method. Methods This study measured airway responsiveness to methacholine by dosimeter method and tidal breathing method in 27 subjects with suspected asthma. The dosimeter was modified to deliver an identical volume to that obtained with the tidal breathing method. Concentration-response curves were characterized by the PC 20 . Results The dosimeter method PC 20 was significantly higher than the tidal breathing method PC 20 , with geometric mean values of 4.03 (95% confidence interval [CI], 1.86 to 8.78 mg/mL) and 2.19 (95% CI, 1.32 to 3.64 mg/mL; p=0.04), respectively. The mean difference in the PC 20 value detected with each method was similar in subjects with tidal breathing method PC 20 values ≥ 2 mg/mL (0.77 doubling concentrations) and in those with PC 20 values Conclusions The tidal breathing method produces PC 20 values significantly lower than a modified dosimeter method, which delivers the same volume of aerosol. These results suggest that the discordant PC 20 values obtained with the two methods are not due to differences in the dose of agonist delivered to the mouth.

Effect of specific immunotherapy on serum levels of tumor necrosis factor alpha in asthmatic children

There is no general agreement among investigators regarding the effect of specific immunotherapy (SIT) on T-cell reactivity. The aim of this study was to investigate the serum levels of IL-1beta, IL-6, and TNF-alpha of children with allergic asthma before and after 3 and 12 months of SIT. Additionally, after 12 months of SIT, we investigated the bronchial hyperresponsiveness. The secondary end points were clinical parameters. Thirty-two children with moderate asthma allergic to house-dust mites (study group) and 10 healthy children (control group) participated in this trial. At each visit blood samples were drawn from all asthmatic patients and at the prestudy visit in controls for determination of parameters. All asthmatic patients received SIT. At the second study visit, baseline spirometry and methacholine challenge tests were performed. Serum TNF-alpha during SIT tended to increase after 3 months with respect to baseline, whereas after 12 months of SIT, serum TNF-alpha decreased. The correlation coefficient (r) between the changes in TNF-alpha values between 3 and 12 months of SIT and provocative concentrations of methacholine to cause a 20% fall in FEV(1) (PC20M) after 12 months of SIT was positive (r = 0.76; p < 0.0001); the greater the changes in TNF-alpha level, the higher the PC20. No modification of IL-1beta and IL-6 was observed. Clinical symptoms also improved after 12 months of SIT in children with asthma. In summary, our results showed the variations in serum levels of TNF-alpha during SIT in asthmatic children and confirm anti-inflammatory properties of SIT.

Sputum Eosinophilia, Airway Hyperresponsiveness and Airway Narrowing in Young Adults with Former Asthma

30-80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma. 326 never-smoking young adults (mean age 24.0 years) were interviewed with special emphasis on history of asthma. Diagnosis of asthma was based on GINA guidelines. Former asthma subjects consisted of ones with a history of physician-diagnosed childhood asthma, who had been free of asthma symptoms without the use of medication for at least 10 years prior to the study. Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV(1))(PC(20)) and eosinophil percentage in induced sputum were measured. 31 subjects were former asthma subjects (FBA), 11 subjects were current asthma subjects (CBA) and 284 subjects had no history of asthma (non-BA). PC(20) and FEV(1)/FVC ratio were significantly lower in the FBA group than in the non-BA group (P < 0.01). Maximal mid-expiratory flow (MMF) was significantly lower in the FBA group than in the non-BA group (P < 0.05). Sputum eosinophil percentage was significantly increased in the FBA group compared with the non-BA group (P < 0.01). PC(20) was significantly lower in the CBA group than in the FBA and non-BA groups (P < 0.01). FEV(1), FEV(1)/FVC ratio and MMF were significantly lower in the CBA group than in the FBA group (P < 0.05, P < 0.05 and P < 0.05, respectively) and the non-BA group (P < 0.01, P < 0.01 and P < 0.05, respectively). Sputum eosinophils were significantly higher in the CBA group than in the FBA and non-BA groups (P < 0.01). This study shows that subjects with long-term outgrown asthma continue to have airway eosinophilic inflammation, airway hyperresponsiveness and airway narrowing.

Bronchodilator response in patients with persistent allergic asthma could not predict airway hyperresponsiveness.

Anticholinergics, or specific antimuscarinic agents, by inhibition of muscarinic receptors cause bronchodilatation, which might correlate with activation of these receptors by the muscarinic agonist methacholine. The aim of this study was to determine whether a positive bronchodilator response to the anticholinergic ipratropium bromide could predict airway hyperresponsiveness in patients with persistent allergic asthma. The study comprised 40 patients with mild and moderate persistent allergic asthma. Diagnosis was established by clinical and functional follow-up (skin-prick test, spirometry, bronchodilator tests with salbutamol and ipratropium bromide, and methacholine challenge testing). The bronchodilator response was positive to both bronchodilator drugs in all patients. After salbutamol inhalation, forced expiratory volume in 1 second (FEV1) increased by 18.39 ± 6.18%, p < .01, whereas after ipratropium bromide, FEV1 increased by 19.14 ± 6.74%, p < .01. The mean value of FEV1 decreased by 25.75 ± 5.16%, p < .01 after methacholine (PC20 FEV1 [provocative concentration of methacholine that results in a 20% fall in FEV1] from 0.026 to 1.914 mg/mL). Using linear regression, between methacholine challenge testing and bronchodilator response to salbutamol, a positive, weak, and stastistically significant correlation for FEV1 was found (p < .05). Correlations between methacholine challenge testing and the bronchodilator response to ipratropium bromide were positive and weak but not statistically significant. The positive bronchodilator response to ipratropium bromide could not predict airway hyperresponsiveness.

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.

Increased Leukotriene E4 in the Exhaled Breath Condensate of Children With Mild Asthma

Chronic airway inflammation is a feature of asthma. Increased levels of cysteinyl leukotrienes (cys-LTs; leukotriene [LT]C(4), LTD(4), LTE(4)) have been shown in the exhaled breath condensate (EBC) of children with moderate-to-severe asthma. The aim of this study was to examine the relationship between EBC cys-LTs (LTE(4)) levels and bronchial hyperreactivity in children with mild asthma in order to evaluate the clinical utility of measuring EBC cys-LTs levels. We measured LTE(4) levels in the EBC of children aged 8 to 18 years, including healthy nonasthmatic children (n = 6) and children with mild asthma (n = 37). Patients with mild asthma were classified into the following three groups: group 1, participants who had been asymptomatic (no wheezing/symptoms of asthma) for > 6 months prior to examination (n = 12); group 2, participants who were asymptomatic but had had wheezing/symptoms of asthma within 6 months before examination (n = 18); and group 3, patients with current wheeze and/or mild symptoms of asthma exacerbation at the time of examination. Exhaled LTE(4) levels were increased in all children with mild asthma compared with nonasthmatic control subjects (5.69 +/- 9.62 pg/20 min vs 0.74 +/- 0.79 pg/20 min, p < 0.05) [mean +/- SD]. In particular, the EBC LTE(4) levels in group 2 (4.99 +/- 6.70 pg/20 min) and group 3 (14.66 +/- 17.11 pg/20 min) were increased compared with control subjects and group 1 (1.50 +/- 1.69 pg/20 min). The EBC LTE(4) levels negatively correlated with the provocative concentration of methacholine causing a 15% fall in FEV(1) (r = - 0.454, p = 0.012). EBC cys-LTs may be useful as a noninvasive marker assessing airway inflammation and hyperreactivity in children with asthma.

Restrained whole body plethysmography for measure of strain-specific and allergen-induced airway responsiveness in conscious mice

The mouse is the most extensively studied animal species in respiratory research, yet the technologies available to assess airway function in conscious mice are not universally accepted. We hypothesized that whole body plethysmography employing noninvasive restraint (RWBP) could be used to quantify specific airway resistance (sRaw-RWBP) and airway responsiveness in conscious mice. Methacholine responses were compared using sRaw-RWBP vs. airway resistance by the forced oscillation technique (Raw-FOT) in groups of C57, A/J, and BALB/c mice. sRaw-RWBP was also compared with sRaw derived from double chamber plethysmography (sRaw-DCP) in BALB/c. Finally, airway responsiveness following allergen challenge in BALB/c was measured using RWBP. sRaw-RWBP in C57, A/J, and BALB/c mice was 0.51 +/- 0.03, 0.68 +/- 0.03, and 0.63 +/- 0.05 cm/s, respectively. sRaw derived from Raw-FOT and functional residual capacity (Raw*functional residual capacity) was 0.095 cm/s, approximately one-fifth of sRaw-RWBP in C57 mice. The intra- and interanimal coefficients of variations were similar between sRaw-RWBP (6.8 and 20.1%) and Raw-FOT (3.4 and 20.1%, respectively). The order of airway responsiveness employing sRaw-RWBP was AJ > BALBc > C57 and for Raw-FOT was AJ > BALB/c = C57. There was no difference between the airway responsiveness assessed by RWBP vs. DCP; however, baseline sRaw-RWBP was significantly lower than sRaw-DCP. Allergen challenge caused a progressive decrease in the provocative concentration of methacholine that increased sRaw to 175% postsaline values based on sRaw-RWBP. In conclusion, the technique of RWBP was rapid, reproducible, and easy to perform. Airway responsiveness measured using RWBP, DCP, and FOT was equivalent. Allergen responses could be followed longitudinally, which may provide greater insight into the pathogenesis of chronic airway disease.

Longitudinal changes of pulmonary function and bronchial responsiveness in cough-variant asthma treated with bronchodilators alone

Cough due to cough-variant asthma (CVA) responds well to bronchodilators such as beta 2 adrenergic agonists. The aim of this study was to assess longitudinal changes of pulmonary function and bronchial responsiveness in CVA, which was treated with bronchodilators alone. Seventeen CVA patients recorded intensity and frequency of cough every day. Spirometry and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (PC20) were measured in the run-in period and after cough almost completely relieved on therapy. Cough score had improved within 2 weeks after the initiation of bronchodilator therapy. Forced expiratory volume in one second (FEV1) was significantly increased from 2.7 +/-0.7 L in the run-in period to 2.8+/-0.7 L after improvement of cough. However, the geometric mean (GSEM) PC20 value did not change from the run-in period [1542 (GSEM 1.29) microg/mL] to the time of improvement [2600 (GSEM 1.43) microg/mL]. Mildly increased bronchial responsiveness in CVA does not improve when only bronchodilator therapy is carried out. Because bronchial hyperresponsiveness has been shown to be a risk factor for typical asthma onset from CVA, the effect of inhaled corticosteroids on the longitudinal changes in bronchial responsiveness should be examined.

Early MR imaging and spectroscopy appearance of eIF2B-related leukoencephalopathy

Interleukin (IL)-4, IL-5 and interferon (IFN)-gamma are thought to play an important role in chronic airway inflammation in asthmatic subjects. Increased airways responsiveness and nocturnal airway obstruction are important clinical manifestations of asthma. The aim of this study was to investigate whether IL-4, IL-5 and IFN-gamma values are elevated in atopic asthma and correlate with its clinical manifestations. Serum IL-4, IL-5 and IFN-gamma levels of 17 atopic asthmatics and eight nonatopic healthy subjects were determined at 16:00 and 04:00 h by a chemiluminescence enzyme-linked immunosorbent assay (ELISA) method. The clinical manifestation of asthma was determined by assessment of the degree of airway obstruction, airways responsiveness to methacholine and severity of nocturnal airway obstruction, defined as the mean circadian (16:00-04:00 h) peak expiratory flow (PEF) variation. Serum IL-4, IL-5 and IFN-gamma levels were significantly higher in asthmatic subjects as compared to healthy controls, both at 16:00 and 04:00 h. In asthmatic subjects serum IFN-gamma at both time points correlated significantly with the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20,meth) (rho= - 0.55) and with the mean 16:00-04:00 h PEF variation (rho = 0.53). In contrast, no relationship was found between the levels of IL-4 and IL-5 and the parameters of clinical manifestation of asthma. The results suggest that the serum interferon-gamma level is a reflection of the severity of airway inflammation in atopic asthma. More studies are needed to detect the cellular sources and to clarify the exact roles of interferon-gamma and other pro-inflammatory cytokines 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.

Commentary on “Restrained whole body plethysmography for measure of strain-specific and allergen-induced airway responsiveness in conscious mice”

The mouse is the most extensively studied animal species in respiratory research, yet the technologies available to assess airway function in conscious mice are not universally accepted. We hypothesized that whole body plethysmography employing noninvasive restraint (RWBP) could be used to quantify specific airway resistance (sRaw-RWBP) and airway responsiveness in conscious mice. Methacholine responses were compared using sRaw-RWBP vs. airway resistance by the forced oscillation technique (Raw-FOT) in groups of C57, A/J, and BALB/c mice. sRaw-RWBP was also compared with sRaw derived from double chamber plethysmography (sRaw-DCP) in BALB/c. Finally, airway responsiveness following allergen challenge in BALB/c was measured using RWBP. sRaw-RWBP in C57, A/J, and BALB/c mice was 0.51 ± 0.03, 0.68 ± 0.03, and 0.63 ± 0.05 cm/s, respectively. sRaw derived from Raw-FOT and functional residual capacity (Raw*functional residual capacity) was 0.095 cm/s, approximately one-fifth of sRaw-RWBP in C57 mice. The intra- and interanimal coefficients of variations were similar between sRaw-RWBP (6.8 and 20.1%) and Raw-FOT (3.4 and 20.1%, respectively). The order of airway responsiveness employing sRaw-RWBP was AJ > BALBc > C57 and for Raw-FOT was AJ > BALB/c = C57. There was no difference between the airway responsiveness assessed by RWBP vs. DCP; however, baseline sRaw-RWBP was significantly lower than sRaw-DCP. Allergen challenge caused a progressive decrease in the provocative concentration of methacholine that increased sRaw to 175% postsaline values based on sRaw-RWBP. In conclusion, the technique of RWBP was rapid, reproducible, and easy to perform. Airway responsiveness measured using RWBP, DCP, and FOT was equivalent. Allergen responses could be followed longitudinally, which may provide greater insight into the pathogenesis of chronic airway disease.