Effect of zafirlukast on methacholine and ultrasonically nebulized distilled water challenge in patients with mild asthma

BACKGROUND: Bronchial asthma is a chronic inflammatory disease characterized by airway inflammation and hyperresponsiveness due to the release of multiple mediators, such as cysteinyl-leukotrienes (cys-LTs). OBJECTIVE: Our study was designed to investigate whether oral pretreatment with zafirlukast (a cys-LTs receptor antagonist) reduces bronchoconstriction against methacholine (MC) and ultrasonically nebulized distilled water (UNDW) challenge in patients with mild asthma. METHODS: Fourteen non-atopic patients (8 males, 20-42 years, forced expiratory volume in 1 s (FEV(1)) 97% SD +/- 0.4) with mild, intermittent bronchial asthma performed a sequential weekly pulmonary function test following challenge with MC or UNDW 2 h after zafirlukast or placebo administration, according to a single-blind method. RESULTS: We found that pretreatment with zafirlukast significantly decreased bronchoconstriction MC (maximum FEV(1) drop -10.75% SD +/- 1.89, p < 0.001) and UNDW induced (maximum FEV(1) drop -12% SD +/- 0.15, p < 0.001), while pretreatment with placebo did not protect patients against FEV(1) drop following MC (maximum FEV(1) drop -33.22% SD +/- 1.42, p < 0.001) and UNDW challenge (maximum FEV(1) drop -30.02% SD +/- 0.4, p < 0.001). CONCLUSIONS: Pretreatment with zafirlukast significantly reduced bronchoconstriction against MC and UNDW challenge in individuals with mild intermittent asthma, indicating that cys-LTs receptor antagonists might be useful as preventive therapy in these patients population.     

Reduction of bronchial responsiveness to methacholine after mitral valve replacement

Sixteen patients with mitral valve disease, in whom bronchial hyperresponsiveness to methacholine had been detected shortly before mitral valve replacement (MVR), were reevaluated 35 +/- 1.5 months after MVR. In 9/16 patients there was a significant (greater than 1.5 fold) increase in bronchial provocation dose of methacholine (PD20FEV1) after MVR. In the same patients there was a significant increase in vital capacity (from 69.6 +/- 5 to 75.8 +/- 5.2% of predicted, p less than 0.01), a significant decrease in cardiothoracic ratio and in radiologic score for lung edema (from 64.3 +/- 2.9 to 56 +/- 2.1, p less than 0.01 and from 38 +/- 4.5 to 14.6 +/- 2, p less than 0.001, respectively). In all the patients the increase in PD20FEV1 was not related to any change in spirometric values but it was related to the decrease in cardiothoracic index (r = 0.72, p less than 0.01) and in radiologic score for lung edema (r = 0.61, p less than 0.05) observed after cardiosurgery.     

Response to inhaled bronchodilators and nonspecific airway hyperreactivity in children with cystic fibrosis.

We tested the hypothesis that children with CF who have a significant response to bronchodilator (BD) would respond positively to standard methacholine (Mch) challenge. Our objective was to correlate the response to BD with the concentration that produced a 20% fall (PC20) in forced expiratory volume in 1 second (FEV1). We studied 22 patients (12 males), aged 10.5 +/- 0.7 years (mean +/- SE), with a Shwachman-Kulczycki score 82 +/- 2.6 and baseline FEV1 of 80 +/- 4.5% predicted. Baseline expiratory flows, static lung volumes, and airway resistance were measured before and 30 min after inhaled salbutamol. On a separate day, within 2 weeks, a Mch challenge was given, with doubling concentrations from 0.03 to 8.0 mg/mL. A positive challenge was defined as a PC20 less than or equal to 2.0 mg/mL, and a positive response to BD as a greater than 6% of FEV1 increase. Mch challenge yielded 17 responders (R) with a PC20 of 0.5 +/- 0.1 mg/mL, and 5 nonresponders (NR) with a PC20 of 8.8 +/- 2.9 mg/mL. Baseline FEV1 was 77 +/- 5.3% predicted in R compared to 89 +/- 6.3% in NR (P = less than 0.001). History of springtime rhinitis was positive in 9/17 R and 2/5 NR. No significant correlation was found between baseline FEV1 and PC20, or between change in FEV1 post-BD and PC20. A greater than 6% increase in FEV1 was seen in 14/17 R (83% sensitivity) and in none of the 5 NR (100% specificity). In R, 8/17 patients had baseline FEV1 less than 80% predicted, compared to 1/5 in NR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peak expiratory flow variability and exercise responsiveness in methacholine-hyperresponsive adolescents with asthma remission.

The aim of this study was to investigate whether bronchial hyperresponsiveness in adolescents with long-term asthma remission is associated with increased peak expiratory flow (PEF) variability and/or increased bronchial response to exercise (BRE). Twenty-nine adolescents with asthma remission (neither symptoms nor any medication used during the previous two years), but with persistent methacholine hyperresponsiveness (PC20 < 18 mg/mL; remission group), 29 methacholine PC20-matched adolescents with symptomatic asthma (symptomatic group), and 20 healthy subjects (control group) were studied. Subjects recorded PEF twice daily for 14 days and PEF variability, expressed as amplitude % mean, was calculated. Subjects also underwent a standardized exercise challenge; BRE was defined as a maximal % fall in FEV1 within 30 min after exercise. The mean (+/- SD) PEF variations in the symptomatic group and in the remission group were 12.10 +/- 6.35% and 10.02 +/- 4.73%, respectively, which were significantly higher than that (5.94 +/- 2.44%) of the control group. On the other hand, the degree of BRE (7.36 +/- 3.85%) in the remission group was significantly lower than that (22.31 +/- 10.50%) of the symptomatic group, and similar to that (5.98 +/- 2.70%) of the control group. Methacholine hyperresponsiveness in asthma remission during adolescence is associated with increased PEF variability but not with increased BRE.     

Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects

Gastroesophageal reflux (GER) has been shown to be more frequent in people with asthma, but the mechanism by which it might aggravate asthmatic symptoms remains unclear. We compared the effects on maximal expiratory flow at 50% of VC (MEF50) of esophageal perfusion of hydrochloric acid (HCl) and of normal saline (NaCl) in 12 asthmatic subjects chosen at random. In all subjects, HCl perfusion did not change MEF50 but potentiated the bronchoconstriction induced by isocapnic hyperventilation of dry air (maximal decrease in MEF50 = 44 +/- 7% with HCl versus 22 +/- 5% with NaCl; p less than 0.001) or methacholine (provocative dose producing a 20% decrease in FEV1 = 349 +/- 99 micrograms with HCl versus 496 +/- 119 micrograms with NaCl; p less than 0.01). Seven of the asthmatic subjects were found to have GER on esophageal pH monitoring. In these subjects, HCl alone decreased MEF50 slightly but significantly (-17.5 +/- 5.5%; p less than 0.05), possibly reflecting the higher degree of basal bronchial hyperreactivity observed in this group. Thus, perfusion of acid into the distal esophagus caused slight but significant bronchoconstriction in asthmatic subjects with GER and increased the bronchoconstriction produced by isocapnic hyperventilation and by methacholine in asthmatic subjects without regard for the presence of GER.     

Bronchial hyperresponsiveness in a patient with systemic mastocytosis

In order to investigate the possible involvement of airway mast cells in bronchial hyperresponsiveness (BHR), we examined whether a patient with systemic mastocytosis would demonstrate BHR against ultrasonically nebulized distilled water (UNDW) and histamine inhalation challenge. A 56-year-old man with systemic mastocytosis underwent both UNDW and histamine inhalation challenge. We also evaluated the effect of beclomethasone dipropionate inhalation (BDI) treatment on the histamine inhalation challenge. The results showed that UNDW inhalation caused no changes in forced expiratory volume in 1 s (FEV1) for this patient. The provocative dose causing a 20% fall (PC20) in FEV1 in the histamine inhalation challenge was 625 microg/mL. After BDI treatment for 8 weeks, the histamine PC20 was still 625 microg/mL. These data suggest that UNDW-induced bronchoconstriction may be independent of airway mast cells and that the mechanism of histamine-induced bronchoconstriction in systemic mastocytosis may be independent of airway inflammation, which is often present in asthmatics.     

Airway responsiveness to exercise and ultrasonically nebulized distilled water in children: relationship to clinical and functional characteristics

We studied the bronchial response to exercise and ultrasonically nebulized distilled water (UNDW) challenge in 19 normal controls (3 females and 16 males; age 6-13 years) and in 44 asthmatic children (12 females and 32 males; age 6-13 years) in order (1) to determine the sensitivity and specificity of the two challenges and (2) to evaluate the relationship between bronchial responses and clinical and functional characteristics. A 20% fall in FEV1 was regarded as a significant bronchial response. The specificity of both challenges was high (100%), whereas the sensitivity of exercise (77.3%) was twice that of UNDW (38.6%). The combination of the two challenges increased the sensitivity to 81.8%. There was no correlation between the magnitude of bronchial response to exercise and UNDW (rs = -0.03; p greater than 0.05). Exercise responders were not different from nonresponders in regard to gender, age, resting lung function, length of asthmatic history and treatment requirement to control symptoms. However, the UNDW responders were different from nonresponders in regard to age (p less than 0.05) and length of asthmatic history (p less than 0.001). Children younger than 9 years old are unlikely to show a bronchial response to UNDW inhalation, since only 9.5% of them developed a significant bronchoconstriction. We suggest that the two stimuli recognize some different pathways or subjects have basic biological differences.     

Comparison of dynamic lung function indices during forced and quiet breathing in upper airway obstruction, asthma, and emphysema

We compared the dynamic lung function indices in patients with asthma (n = 27), emphysema (n = 20), and UAO (n = 18), with the purpose being to examine whether different patterns of abnormalities could be found and which tests were most discriminative among the three groups. Forced expiratory indices were measured (FEV1; PEF; MEF50%), as well as indices obtained during quiet breathing (Raw; Gaw; Gaw/VL). The three groups were comparable as far as PEF was concerned (about 60 +/- 20 percent of predicted, yet the group with UAO showed significantly larger FEV1 (84 percent of predicted vs 55 percent and 57 percent of predicted in asthma and emphysema respectively), and larger MEF50% (71 percent of predicted vs 25 percent and 23 percent of predicted in the other groups), and the group with asthma had the largest Raw (0.37 +/- 0.18 kPa.s.L-1 vs 0.24 +/- 0.13 in UAO and 0.22 +/- 0.10 in emphysema). From these functional tests, several ratios were derived which were discriminative among the three groups. Upper airway obstruction could be recognized by a significantly lower PEF/MEF50% ratio and higher FEV1/PEF ratio than in the other conditions. Furthermore, a distinction between asthma and emphysema could be made by comparing airway patency during forced and quiet breathing, ie, the MEF50%/Gaw ratio. This ratio was, in fact, significantly different for all three groups, having the lowest value in emphysema (0.19 +/- 0.08 kPa vs 0.44 +/- 0.23 kPa and 0.63 +/- 0.34 kPa in asthma and UAO, respectively). Within the group with UAO, those with variable intrathoracic obstruction showed the least difference from asthma and emphysema for the measured indices.     

Increase in alveolar nitric oxide in the presence of symptoms in childhood asthma

STUDY OBJECTIVES: To determine respective contributions of alveolar and proximal airway compartments in exhaled nitric oxide (NO) output (QNO) in pediatric patients with asthma and to correlate their variations with mild symptoms or bronchial obstruction. PATIENTS AND DESIGN: In 15 asthmatic children with recent mild symptoms, 30 asymptomatic asthmatic children, and 15 healthy children, exhaled NO concentration was measured at multiple expiratory flow (V) rates allowing the calculation of alveolar and proximal airway contributions in QNO, using two approaches, ie, linear and nonlinear models. MEASUREMENTS AND RESULTS: Asymptomatic and recently symptomatic patients were not significantly different regarding FEV(1) and maximum V between 25% and 75% of FVC (MEF(25-75)): FEV(1), 93.3 +/- 13.4% vs 90 +/- 7.5%; MEF(25-75), 70 +/- 22% vs 68 +/- 28% of predicted values, respectively (mean +/- SD). Maximal airway QNO output was significantly higher in recently symptomatic vs asymptomatic patients (p < 0.0001), and in asymptomatic patients vs healthy children (p < 0.02): 134 +/- 7 nl/min, 55 +/- 43 nl/min, and 19 +/- 8 nl/min, respectively. In a multiple regression analysis, variables that influenced airway QNO output were symptoms (p < 0.0001) and distal airway obstruction as assessed by MEF(25-75) (p < 0.05). Alveolar NO concentration (FANO) was significantly (p < 0.03) higher in recently symptomatic than in patients without symptoms, whereas it was not significantly different between asymptomatic patients and healthy children: 7.2 +/- 2.4 parts per billion (ppb), 5.5 +/- 2.7 ppb, and 4.2 +/- 2.0 ppb, respectively. CONCLUSIONS: An increase in FANO was observed in the presence of symptoms, and proximal airway NO output was correlated with distal obstruction during asthma.     

Significance of bronchospasm in the development of bronchial obstruction in lung diseases

VC, FVC, FEV1/VC%, PEF, MEF25, MEF50, MEF75 were studied in 254 patients with lung diseases with bronchial obstruction before and after berotec and antrovent inhalation. Bronchospasm was detected in most patients with bronchial asthma, in a half with exogenous allergic alveolitis, in more than a third with chronic bronchitis and pulmonary tuberculosis, and in a fifth with pulmonary sarcoidosis. In most examinees with bronchospasm, the proportion of the latter in bronchial obstruction amounted to 61-100%.     

An isoflow-volume technique for assessing airway dynamics in children and adults

BACKGROUND: We propose a new approach to the measurement of small airway function as an alternative to recordings of maximal expiratory flow-volume (MEFV) curves. OBJECTIVES: A newly developed technique to record isoflow-volume (IFV) curves to be tested against maximal respiratory flow curves. METHODS: An isoflow whistle (IFW; Iflopen) measures the length of a constant expiration after full inspiration. The note of the whistle enables a subject to generate an even expiration, and the isoflow maintenance times at 1 l x s(-1) (IFMT1) and 2 l x s(-1) (IFMT2) are recorded. The accuracy and reproducibility of the IFV technique were evaluated in 17 healthy adults (age 17-55 years) and in 14 asthmatic children (age 6-14 years). Comparisons with standard lung function parameters, such as forced expiratory volume in 1 s (FEV1), maximal expiratory flow at 50% (MEF50) and 25% (MEF25) vital capacity and peak expiratory flow (PEF), obtained with a Wright Peakflow Meter were undertaken in 102 healthy (aged 8-14 years) and 101 asthmatic children (aged 6-17 years). A bronchial challenge test was performed in 13 asthmatic children. RESULTS: The expired volume measured by the IFW showed an acceptable agreement with that of a pneumotachograph (mean error of 4.32% for IFMT1 and 5.93% for IFMT2). In healthy and in asthmatic children, the correlations between FEV1 and IFMT1 or IFMT2 (r = 0.92 and 0.94, respectively) were found to be greater than that between FEV1 and PEF (r = 0.68). During bronchial challenge tests in 13 asthmatic children, the FEV1 decreased to 69% of baseline and IFMT1 to 58% of baseline. CONCLUSIONS: The IFV technique accurately measured airway obstruction and closely followed changes in standard parameters of the MEFV curve.     

Comparison of bronchial responses to ultrasonically nebulized distilled water, exercise, and methacholine in asthma

We compared the responses to inhaled methacholine, ultrasonically nebulized distilled water, and exercise in 25 subjects with atopic asthma. The methacholine inhalation test and challenges with distilled water and exercise were performed on three separate days 48 hours apart. Bronchial responsiveness to methacholine and ultrasonically nebulized distilled water was measured as the concentration of methacholine (PC20M) and the volume output of the ultrasonic nebulizer (PO20 UNDW) producing a 20 percent fall in the forced expiratory volume in one second (FEV1). The response to exercise was expressed as the percentage of fall in FEV1 from the value before exercise. Seventeen subjects showed a fall in FEV1 of more than 20 percent after exercise. Eight subjects had a stimulus-response curve to distilled water that was flat up to the maximal volume output from the nebulizer, but only four of them also showed no significant response to exercise. The response to exercise correlated better with PO20 UNDW (r = -0.66; p less than 0.01) than with PC20M (r = -0.19; p greater than 0.5) in those responding to distilled water. In all of the tested subjects, exercise-induced bronchoconstriction correlated with PC20M (r = -0.61; p less than 0.01). The mean PC20M was significantly lower in the subjects with a significant response to distilled water and exercise (p less than 0.001 and p less than 0.0001, respectively). We concluded that ultrasonically nebulized distilled water and exercise provoke significant bronchoconstriction in the subjects with more severe nonspecific bronchial hyperresponsiveness. The correlation found between the two stimuli supports the hypothesis that they act by similar mechanisms.     

Bronchial reactivity in patients with chronic renal failure undergoing haemodialysis

We hypothesized that patients with chronic renal failure may present nonspecific bronchial hyperreactivity due to subclinical interstitial lung oedema. To assess lung function disturbances and methacholine (MTH) bronchial responsiveness in this condition, we studied 12 patients (9 men and 3 women; 41.8 +/- 13.3 yrs (SD] with chronic renal failure undergoing regular haemodialysis (HD). Before HD, mean results of conventional lung function tests were within the normal range: forced expiratory volume in one second (FEV1), 89 +/- 12.9% predicted; forced mid-expiratory flow (FEF25-75), 81 +/- 36.7% predicted; total lung capacity (TLC), 94 +/- 14.6% predicted, but 3 subjects presented mild reduction in lung volumes and 5 individuals showed mild obstructive ventilatory impairment. After HD, maximal expiratory flow rates increased significantly (FEV1, + 8.2 +/- 5.1% (p less than 0.005); FEF25-75, +26.2 +/- 25.9% (p less than 0.005]. Interestingly, these increases in FEV1 after HD correlated with body weight loss during HD (r = 0.74, p less than 0.01). In contrast, pre-HD bronchial reactivity was within the normal range (mean % change in FEV1 after MTH, -3.7 +/- 4.5%; range, +1- -14%) without significant changes in methacholine bronchial responsiveness after HD. We speculate that interstitial lung oedema may play a significant role in lung function impairment observed in patients with chronic renal failure. This study shows that nonspecific bronchial hyperreactivity is not present in clinically stable patients with this disorder.     

Usefulness of bronchial reactivity analysis in the diagnosis of bronchial asthma in patients with bronchial hyperresponsiveness

We examined the usefulness of some bronchial reactivity indices to identify bronchial asthma in patients with airway hyperresponsiveness. Eighty-eight consecutive patients with positive response to histamine bronchial challenge (> or = 20% fall in FEV1) were included in the study. Dose-response curves were characterised by their sensitivity (PD20) and reactivity. Dose-response slope, continuous index of responsiveness (CIR) and bronchial reactivity index (BRI) with respect to baseline and post-diluent baseline values were determined as reactivity indices. The clinical diagnosis remaining in the case history 2 years after the bronchial challenge was considered the definitive diagnosis. Asthmatic patients had higher baseline BRI (12.121+/-0.412 vs. 11.615+/-0.201; P<0.001) and post-diluent baseline BRI (12.054+/-0.368 vs. 11.563+/-0.531; P = 0.003) than other subjects. Area beneath their receiver operating characteristic (ROC) curve was 82.68% (standard error: 0.77) for the baseline BRI and 81.73 (standard error: 0.76). By multiple logistic regression analysis, baseline BRI was the only independent variable identified as a predictor for diagnosis of bronchial asthma (r = 0.387, P = 0.0007). A cut-off of 11.76 for baseline BRI reached an 87.2% sensitivity and an 80% specificity for bronchial asthma diagnosis. In conclusion, BRI calculated with respect to baseline FEV1 should be useful in identifying asthmatic patients among subjects with airway hyperresponsiveness.     

Impairment of nitric oxide output of conducting airways in primary ciliary dyskinesia

Nasal nitric oxide (NO) concentration is dramatically reduced in primary ciliary dyskinesia (PCD). The aims of this study were to apply a multiple-flow NO analysis to investigate whether NO output from the bronchial tree was affected in a similar way to nasal NO output, and to search for a relationship between flow-independent exchange parameters and airflow limitation. Multiple flow rate analysis of exhaled NO, allowing the calculation of maximum airway wall flux and alveolar NO concentration, was performed in 17 PCD patients (median age, 25-75th percentiles: 13.5, 12.1-17.6) with documented ultrastructural cilia abnormalities and 28 healthy subjects (16.0, 11.0-21.0). Median maximum airway wall flux and median alveolar NO concentration were significantly reduced in PCD patients compared to healthy subjects: 16.0, 7.5-29.5, vs. 25.0, 15.0-32.5 nl/min (P<0.05) and 2.5, 1.6-3.3, vs. 5.0, 3.6-6.5 ppb (P<0.01), respectively. Significant correlations between maximum airway wall flux and airflow limitation were found, i.e., resistance of respiratory system (rho=0.74, P<0.005), forced expiratory volume in one second (FEV(1))/VC (rho= -0.61, P<0.05), FEV(1) (rho=-0.52, P< 0.05), mid expiratory flow between 25 and 75% of forced vital capacity (MEF(25-75)) (rho=-0.54, P<0.05), and maximal instantaneous expiratory flow at 50% of the vital capacity (MEF(50)) (rho=-0.55, P<0.05). In conclusion, the impairment of NO output is less pronounced in the lower than in the upper (nasal) respiratory tract in PCD. A decrease in maximal NO output from conducting airways is associated with limited airflow impairment.     

Bronchial hyperresponsiveness, airway inflammation, and airflow limitation in endurance athletes

BACKGROUND: Whereas a high prevalence of bronchial abnormalities has been reported in endurance athletes, its underlying mechanisms and consequences during exercise are still unclear. STUDY OBJECTIVES: The purpose of this study was to assess the following: (1) bronchial responsiveness to methacholine and to exercise; (2) airway inflammation; and (3) airflow limitation during intense exercise in endurance athletes with respiratory symptoms. DESIGN: Cross-sectional observational study. SETTING: Lung function and exercise laboratory at a university hospital. PATIENTS AND MEASUREMENTS: Thirty-nine endurance athletes and 13 sedentary control subjects were explored for the following: (1) self-reported respiratory symptoms; (2) bronchial hyperresponsiveness (BHR) to methacholine and exercise; (3) airflow limitation during intense exercise; and (4) bronchial inflammation using induced sputum and nitric oxide (NO) exhalation. RESULTS: Fifteen athletes (38%) showed BHR to methacholine and/or exercise in association with bronchial eosinophilia (mean [+/- SD] eosinophil count, 4.1 +/- 8.5% vs 0.3 +/- 0.9% vs 0%, respectively), higher NO concentrations (19 +/- 10 vs 14 +/- 4 vs 13 +/- 4 parts per billion, respectively), a higher prevalence of atopy, and more exercise-induced symptoms compared with non-hyperresponsive athletes and control subjects (p < 0.05). Furthermore, airflow limitation during intense exercise was observed in eight athletes, among whom five had BHR. Athletes with airflow limitation reported more symptoms and had FEV1, FEV1/FVC ratio, and forced expiratory flow at midexpiratory phase values of 14%, 9%, and 29%, respectively, lower compared with those of nonlimited athletes (p < 0.05). CONCLUSION: BHR in endurance athletes was associated with the criteria of eosinophilic airway inflammation and atopy, whereas airflow limitation during exercise was primarily a consequence of decreased resting spirometric values. Both BHR and bronchial obstruction at rest with subsequent expiratory flow limitation during exercise may promote respiratory symptoms during exercise in athletes.     

Changes in FVC during methacholine-induced bronchoconstriction in elderly patients with asthma: bronchial hyperresponsiveness and aging

STUDY OBJECTIVE: We evaluated whether aging may produce changes in bronchial hyperresponsiveness, risk of enhanced bronchoconstriction, and changes of bronchoconstriction perception. SETTING: Each subject underwent a methacholine bronchial challenge. Methacholine challenge was stopped when one of the following conditions occurred: (1) plateau of bronchoconstriction; (2) decrease of FEV(1) > 40%; (3) FEV(1) drop below 1 L; or (4) excessive respiratory discomfort. Methacholine dose-response curves were plotted both for FVC and FEV(1). The provocative dose of methacholine causing a 20% decrease in FEV(1) with respect to baseline (PD(20)) and the fall in FVC (DeltaFVC) at PD(20) were computed. The Borg scale was used for scoring the perception of respiratory discomfort. PATIENTS: We compared 17 young asthmatic patients (aged 22 to 45 years) with 17 older asthmatic patients (aged 63 to 78 years) selected on the basis of similar baseline pulmonary function and disease duration. RESULTS: No significant between-group difference was found in PD(20) and in plateau development. Conversely, DeltaFVC was significantly higher in the older group (mean +/- SD, 15.5 +/- 3.9% vs 11.6 +/- 5.5% in younger patients). In addition, DeltaFVC showed a positive linear relationship with age (p = 0.0026). Elderly subjects were less aware of bronchoconstriction during the methacholine challenge (p = 0.04). CONCLUSIONS: In elderly patients with asthma having comparable pulmonary function and disease duration, bronchial responsiveness is not different from that observed in younger asthmatic patients. Nevertheless, in such patients, an age-related tendency to an enhanced bronchoconstriction and a reduced perception of the degree of bronchoconstriction exist.     

Bronchial responsiveness after human heart-lung transplantation

We evaluated bronchial responsiveness to inhaled albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol in eight heart-lung transplant (HLT) recipients 2.3 +/- 1.5 months (mean +/- SD) (range, 1 to 4.5 months) after HLT. All patients had a restrictive ventilatory defect but none had airflow limitation (FEV1/FVC = 0.93 +/- 0.05) (range, 0.86 to 0.97). Specific airway conductance (sGaw) improved significantly with both albuterol (p less than 0.01) and ipratropium bromide (p less than 0.01) but FEV1 did not. Only one HLT patient had bronchoconstriction with propranolol, whereas all but one were hyperresponsive to methacholine. Prior inhalation of ipratropium bromide blocked the response to methacholine (p less than 0.005). Serial methacholine provocation tests performed in seven long-term survivors of HLT 24.6 +/- 16.0 months (range, 12 to 51 months) after HLT revealed no time-dependent evolution of bronchial hyperresponsiveness to methacholine. Limited maximal airway narrowing to methacholine was seen in five HLT recipients who showed a 29 +/- 4 percent (range, 23 to 35 percent) fall in FEV1 compared with two patients who did not achieve a plateau with a 47 percent and 63 percent fall in FEV1, respectively. These results further our understanding of bronchial responsiveness in the denervated transplanted lung. The findings of stable hyperresponsiveness to methacholine over a prolonged time interval, limited maximal airway narrowing to methacholine, and blockade of methacholine hyperresponsiveness by ipratropium bromide support the concept of denervation hypersensitivity of muscarinic receptors.     

Peak expiratory flow variability and bronchial responsiveness to methacholine. An epidemiologic study in 117 workers.

We studied the relationships between peak expiratory flow (PEF) variability and bronchial responsiveness to methacholine in 117 workers attending the annual compulsory examination (mean age, 38.7 yr +/- 9.5; men, 86.3%). Subjects recorded their highest PEF out of three, every 3 waking hours (i.e., five times a day) for 7 days, each using a newly purchased Vitalograph peak flow meter, and underwent methacholine challenge tests with a maximal cumulative dose of 1,200 micrograms. Those with a FEV1 fall of 15% or more were considered as reactors. The variability of PEF was expressed as the amplitude percent mean, calculated from daily amplitude (highest-lowest reading/mean reading of the day x 100), averaged over 6 days, from the second to the seventh. This index had a continuous distribution, skewed towards the greatest amplitudes, and correlated negatively with FEV1 (r = -0.25, p = 0.01). Subjects with asthma (n = 8) had greater variations. In the 109 nonasthmatics, greater variability was observed in subjects with wheeze apart from colds, breathlessness, or hay fever; the average amplitude was greater in reactors than in nonreactors to methacholine (16.9% versus 9.3%, p less than 0.001). The subjects with excessive PEF variability were all methacholine reactors, but they were only a subgroup of the reactors. These results provide evidence that excessive PEF variability is an indicator of bronchial hyperresponsiveness to methacholine in a population sample.     

Inhaled furosemide prevents both the bronchoconstriction and the increase in neutrophil chemotactic activity induced by ultrasonic "fog" of distilled water in asthmatics

Inhaled furosemide has been shown to prevent bronchoconstriction induced by inhalation of ultrasonic nebulization of distilled water (UNDW) in bronchial asthma. To evaluate whether inhaled furosemide also prevents the increase in serum neutrophil chemotactic activity (NCA) observed during UNDW bronchoconstriction, we measured NCA during UNDW challenge without (control) and immediately after inhalation of furosemide (40 mg) or placebo (saline) in 10 asthmatics responsive to UNDW, in a randomized, double-blind study. NCA was assessed by measuring the maximal distance reached by neutrophils in a filter when challenged with the subject serum in a Boyden chamber ("leading front"). UNDW inhalation produced a significant increase in NCA in each subject. Gel filtration chromatography on S400 column indicated that the NCA released were 600 to 700 kD. Saline had no effect on bronchoconstriction nor on NCA increase induced by UNDW in nine patients. Furosemide did not change baseline FEV1, but it prevented bronchoconstriction and NCA increase in nine patients. In the whole group the maximal decrease in FEV1 after UNDW was -31.1%, SEM 4.7 after saline and -7.5%, SEM 5.2 after furosemide, p less than 0.001, the maximal increase in NCA after UNDW was +52.9%, SEM 9.2 after saline and +3.8%, SEM 3.1 after furosemide, p = 0.001. These results indicate that inhaled furosemide prevents both the bronchoconstriction and the NCA increase induced by UNDW inhalation in most asthmatic patients. This finding adds support to the suggestion that furosemide acts on mast cells.