Predictors of early- and late-phase reactions to bronchial allergen challenge

The influence of inhaled steroids and predictive factors on the response to bronchial allergen challenge (BCA) was evaluated in 80 asthmatics allergic to Dermatophagoides pteronyssinus (Der p). All underwent BCA with Der p and measurement of early (EAR) and late asthmatic reaction (LAR). The cumulative dose of allergen producing 20% fall in FEV1 in the EAR (PD20) was calculated. Bronchial histamine provocation, conjunctival provocation test (CPT), and skin prick test with Der p extract were performed. Specific IgE to Der p in serum (RAST), blood eosinophil (EOS) count, serum eosinophil cationic protein, and eosinophil protein X were measured. Thirty patients (38%) were treated with inhaled steroids. All patients had at least a 20% fall in FEV1 in EAR. Some 42% of nonsteroid- and 33% of steroid-treated patients had LAR with fall in peak flow of at least 20%. For patients not treated with steroid, 35% of variation in PD20 was explained by RAST and histamine reactivity, and 53% of variation of observed PD20 could be predicted. The baseline FEV1, EOS, and EAR explained 28% of variation in LAR, and 28% of variation in observed LAR could be predicted. For patients treated with steroids, 38% of variation in PD20 was explained by EOS and histamine reactivity, and only 18% of variation of observed PD20 could be predicted. For patients treated with steroids, it was impossible to predict LAR. We conclude that to achieve a quantitative estimation of allergen-specific EAR and LAR, BCA cannot be replaced by the tests used in this study. Treatment with inhaled steroids modifies the response to BCA, making quantitative prediction of EAR less accurate and prediction of the magnitude of LAR impossible.     

Antibody detection after antepartal rhesus prophylaxis: normal values or sensitization

Although poorly reproducible spirometric tests, "test failures," are associated with respiratory morbidity, it is not clear what causes them. Bronchial responsiveness was examined in relation to test failure for forced expiratory volume in 1 s (FEV1.0) (1979 definition of the American Thoracic Society) in 249 bakers, 165 chemical industry workers, and 204 office workers. The first two groups were studied by the same methods and were combined. Test failure was observed in 4%, and for 38% the provocative dose of inhaled methacholine causing a 20% fall in FEV1.0 relative to FEV1.0 after the inhalation of normal saline (PD20) was < or = 120 mumol (7% with a PD20 of < or = 8 mumol). Test failure was not related to the level of PD20. Of the office workers, 3% had test failure, 11% a PD20 of < or = 8 mumol of histamine, and no significant relation was observed. The study does not exclude the possibility that bronchial responsiveness might be related to test failure in patients with airway disease or that a clearer relation might be demonstrable in a larger study, but it does suggest that it is not a major determinant of test failure.     

Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction

BACKGROUND: The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS: A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS: Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS: High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment.     

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects

BACKGROUND: It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS: Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS: Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS: Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

The detection of cytochrome P450 2E1 and its catalytic activity in rat testis

The aim of this study was to compare the efficacy of 100 micrograms of salbutamol inhaled from a new metered-dose powder inhaler (MDPI, Leiras Taifun, Finland) with that of a same dose of salbutamol inhaled from a conventional pressurized metered-dose inhaler with a large volume spacer (pMDI + S) in protecting against methacholine (Mch) induced bronchoconstriction. This was a 3 day, randomized, cross-over, partly blinded, placebo-controlled multicentre study where the pMDI + S was used as an open control. Twenty-six asthmatic outpatients with a baseline FEV1 > or = 60% of predicted and with bronchial hyperreactivity (PD20 FEV1 < or = 890 micrograms of Mch) were studied. On each study day the patients underwent an Mch provocation 30 min after inhaling placebo from the MDPI or a dose of 100 micrograms of salbutamol from the MDPI and from the pMDI + S. PD20 FEV1 and dose-response slope [DRS; maximal change in FEV1 (%)/dose of Mch (mumol)] were used to evaluate efficacy. The median values of PD20 FEV1 were 250, 622 and 1737 micrograms after placebo MDPI, salbutamol pMDI + S and salbutamol MDPI, respectively. The corresponding DRS values were -11.0%, -4.5% and -2.0% mumol-1. With both parameters, all differences were statistically significant (P < 0.05). In conclusion, 100 micrograms of salbutamol inhaled from Leiras Taifun MDPI offers better protection against Mch-induced bronchoconstriction than 100 micrograms of salbutamol from a pMDI connected to a large volume spacer device.     

Bronchodilator response to salbutamol after spontaneous recovery from nonspecific bronchial provocation tests in asthma

Assessment of airway responsiveness by bronchoprovocation and bronchodilatation tests is important in the diagnostic work-up protocol of bronchial asthma and it would be convenient to undertake both tests on the same occasion. However, it is not known whether this can be done accurately. Therefore, this study evaluated the effect of a prior bronchial provocation test on the bronchodilator response to salbutamol after spontaneous recovery of the forced expiratory volume in one second (FEV1) in a group of asthmatic subjects. On two separate occasions at the same time of day, concentration-response studies with inhaled histamine or methacholine, or a sham challenge with normal saline were carried out in a blinded, randomized manner. Changes in airway calibre were followed as FEV1 and agonist responsiveness expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). After either spontaneous recovery or a fixed-duration wait of 45 min (when appropriate), the subjects received 2x100 microg of salbutamol from a metered dose inhaler with a spacer. The bronchodilator response to salbutamol was expressed as a percentage of initial FEV1 (deltaFEV1% init). Bronchial challenge with both agonists failed to alter significantly the airway response to salbutamol, with the deltaFEV1% init mean value (range) being 16.9% (9.0-31.9) and 17.5% (11.6-31.2) on the sham and histamine/methacholine challenge day respectively. It was shown that the degree of bronchodilatation achieved after salbutamol 200 microg is not affected by prior bronchoprovocation testing when enough time is allowed for the airways to recover spontaneously to baseline forced expiratory volume in one second. Thus evaluation of airway responsiveness by both bronchial provocation tests and bronchodilator testing can be assessed reliably within a few hours in asthmatic patients.     

The inhibition of yohimbine injected intrathecally on electroacupuncture-induced analgesia and release of beta-endorphin from rat brain

No study has investigated the effects of ethanol on bronchial responsiveness in patients with alcohol-induced asthma, although acetaldehyde, which is a metabolite of ethanol and is thought to be a main factor in alcohol-induced asthma, causes both bronchoconstriction and bronchial hyperresponsiveness. The purpose of this study was to investigate the direct action of ethanol on the airway in patients with alcohol-induced asthma. First, we investigated the bronchial response to inhalation of ascending doses (5, 10, and 20%) of ethanol in nine patients with alcohol-induced asthma. Then, the bronchial responsiveness to methacholine was measured in 14 patients who were pretreated with saline or 20% ethanol in a double-blind, randomized, placebo-controlled, crossover fashion. Ascending doses of inhaled ethanol caused no significant changes in FEV1. The methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) after 20% ethanol (0.769 mg/ml, GSEM 1.514) were significantly (P = 0.0357) higher than those after saline (0.493 mg/ml, GSEM 1.368). This indicates that ethanol has a reducing effect on nonspecific bronchial responsiveness in patients with alcohol-induced asthma; this paper is the first report on the effects of ethanol on bronchial responsiveness.     

Anti-inflammatory effects of inhaled beclomethasone dipropionate in nonatopic asthmatics

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.     

Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids

The aim of the present study was to examine the efficacy of low-dose inhaled budesonide (BUD) administered via Turbuhaler once or twice daily on symptoms, lung function and bronchial hyperreactivity in children with mild asthma. One hundred and sixty-three children (mean age 9.9 yrs, 56 females/107 males) with mild asthma (forced expiratory volume in one second (FEV1) 103% of predicted, morning peak expiratory flow (PEF) 87% pred, reversibility in FEV1 3%, fall in FEV1 after exercise 10.4% from pre-exercise value) and not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. After a two-week run-in period, the children received inhaled BUD 100 microg or 200 microg once daily in the morning, 100 microg twice daily or placebo for 12 weeks. Exercise and methacholine challenges were performed before and at the end of treatment. After 12 weeks of therapy, the fall in FEV1 after an exercise test was significantly less in all three BUD groups (43-5.1%) than in the placebo group (8.6%). Bronchial hyperreactivity to methacholine with the provocative dose causing a 20% fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo (ratio at the end of treatment 156%). Changes in baseline lung function (FEV1 and PEF) were less marked than changes in bronchial responsiveness. In conclusion, low doses of inhaled budesonide, given once or twice daily, provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function.     

Bronchial hyperresponsiveness and toluene diisocyanate. Long-term change in sensitized asthmatic subjects

Long-term change in nonspecific and specific bronchial hyperresponsiveness was studied in 16 subjects with asthma induced by toluene diisocyanate (TDI). A significant positive correlation between months of follow-up and provocative dose inducing a 20 percent fall in FEV1 (PD20FEV1) methacholine was observed in 5 of 16 subjects. In 4 of these 5 subjects, a PD20FEV1 > 1 mg of methacholine was observed 30 to 48 months after the end of TDI exposure. In most subjects, nonspecific bronchial hyperresponsiveness did not change. Nine of 16 subjects became nonresponsive to TDI at follow-up examination, but only 3 of these showed a significant increase in PD20FEV1 methacholine. Seven subjects were still responsive to TDI. Recovery from TDI-induced asthma can occur and only after long-term work cessation. Nonspecific bronchial hyperresponsiveness to methacholine can persist even in the absence of bronchial hyperresponsiveness to TDI, suggesting permanent chronic damage to mechanisms controlling airway tone.     

Metered-dose inhaler to deliver methacholine in bronchial provocation testing: a pilot study

BACKGROUND: Nonspecific bronchial provocation tests may be simplified by the use of hand-held devices to deliver methacholine. OBJECTIVE: To study the feasibility of using a metered-dose inhaler (MDI) to administer methacholine in bronchial provocation tests, and the ability of such a device to diagnose bronchial hyperresponsiveness (BHR) accurately. METHODS: In an open randomized crossover pilot study, we compared the provocative dose that induces a 20% fall in FEV1 (PD20 FEV1) obtained with the methacholine MDI with that obtained using a conventional nebulizer in 20 hyperresponsive and 20 nonhyperresponsive subjects. The MDI delivers 400 doses of 100 microg of methacholine, and was used via a spacer. Bronchial hyperresponsiveness (BHR) was defined as a PD20 FEV1 <2,000 microg with the conventional test using the nebulizer. The tests were performed in each subject in a randomized order, 1 to 7 days apart. RESULTS: Of the subjects who had a nebulizer PD20 FEV1 <2,000 microg, all but one had an MDI PD20 FEV1 <800 microg. When 800 microg was taken as the threshold for the diagnosis of BHR with the MDI test, the accuracy of this test to diagnose BHR was 97.5%, and the two tests were highly concordant for the diagnosis of BHR (Pearson chi2, 36.19; p<0.0001). CONCLUSION: A hand-held device may be suitable for delivery of methacholine during bronchial provocation tests, if these results are confirmed in large samples.     

Dose equivalence and bronchoprotective effects of salmeterol and salbutamol in asthma

BACKGROUND: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. METHODS: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. RESULTS: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. CONCLUSIONS: The data are compatible with a weight-for-weight dose ratio for salmeterol:salbutamol of < or = 1:4.     

Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study

Hyperosmolar aerosols are used to assess airway responsiveness in subjects with asthma. Using a 10% NaCl aerosol, we investigated airway responsiveness in 23 cystic fibrosis (CF) subjects (12 females, 11 males; 19.1 +/- 3.3 years) who had asthma-like symptoms. The pre-challenge predicted forced expiratory volume in 1 second (FEV1) was 74.7 +/- 21.5. The aerosol was generated by a MistO2gen 143A ultrasonic nebulizer and inhaled for 0.5, 1, 2, 4, 8, 8, and 8 minutes or part thereof. Spirometry was performed before and 1 minute after each inhalation period. The challenge was stopped when a > or = 20% fall from the baseline FEV1 was recorded, after the last inhalation period, or when requested by the subject. We recorded different responses to 10% NaCl among subjects. In 7, the FEV1 fell progressively throughout the challenge in a manner similar to asthmatics. By contrast, in 15 subjects the FEV1 was higher at the completion of challenge compared to during challenge, i.e., the fall in FEV1 was transient. In 7 of these subjects, the final FEV1 at the end of the challenge was higher than the pre-challenge FEV1. We conclude that inhaled 10% hyperosmolar saline causes either progressive and sustained or transient airway narrowing during challenge in the majority of CF subjects. The cause of the transient airway narrowing requires further investigation.     

Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

Preparing nurse leaders for the future: views from Canada

Airway responsiveness assessed using histamine and methacholine is safe, reproducible and relatively easily undertaken in adults and children. Results are similar for methacholine and histamine although methacholine is better tolerated. Responsiveness is increased in children and the elderly, and in women compared to men, possibly due to body size effects. Baseline lung function confounds the interpretation of airway responsiveness and may explain the effect of smoking in most studies. Results are most usefully expressed as the provocative dose producing a 20% fall in FEV1 (PD20FEV1) or the dose-response slope (DRS). When technical factors are controlled the reproducibility of the test is from one to two doubling doses. Measurements of airway responsiveness have been widely used in clinical and research practice. However, assessing their value in diagnosing asthma is limited by the lack of a gold standard for the definition of asthma. Using a cut-off value of 8 mg/mL or 8 mumol for PD20, the tests will discriminate asthmatic from non-asthmatic subjects (based on questionnaire definitions of asthma) with a sensitivity of around 60% and a specificity of around 90%. These properties of the test result in positive and negative predictive values of 86% and 69% when the prevalence of asthma is high (50%-as in the clinical setting) and 40% and 95% when the prevalence of asthma is low (10%, as in general population studies). In the usual clinical setting, assessing the significance of atypical or non-specific symptoms, the tests are of intermediate value in predicting the presence of asthma and less useful in excluding asthma. The additional benefit of testing airway responsiveness to measuring peak flows or to a trial of therapy has yet to be fully assessed. Testing of airway responsiveness may be of value in assessing occupational asthma, asthma severity and the effects of potential sensitizers or treatments. In research, tests of airway responsiveness are more useful for excluding cases of asthma. In population studies, they serve as an objective marker of abnormal airway function which may be genetically determined and, like allergy, are strongly associated with asthma. The predictive value of airway hyperresponsiveness for the development of airway disease is yet to be clearly established. In epidemiology the benefits of measuring airway responses must be weighed against the added inconvenience and cost that is incurred.     

Guidelines for reporting results of quality of life assessments in clinical trials

BACKGROUND: Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. METHODS: Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) > or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of beta 2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. RESULTS: There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1+, and EG2+ cells, mast cells, CD8+, and CD45RO+ cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. CONCLUSIONS: Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating leucocytes such as mast cells, (activated) eosinophils, CD8+, and CD45RO+ cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma.     

Comparison of bronchial reactivity to ultrasonically nebulized distilled water, exercise and methacholine challenge test in asthmatic children

We studied the responses to ultrasonically nebulized distilled water (UNDW) challenge, exercise challenge and methacholine challenge in asthmatic children. Fifty-four asthmatic and fourteen nonasthmatic control children participated in this study. The UNDW inhalation test was by the methodology described by Anderson. The average output of water was approximately 3.0 mL/min (SD = .1) and inhalation times were 30 seconds, one minute, two minutes and four minutes. Some subjects performed exercise challenge on a bicycle ergometer and methacholine challenge by an Astrograph technique. Twenty-three of 54 asthmatic patients (42.6%) and none of the controls showed a fall in FEV1 greater than 20% with UNDW challenge. The fall in FEV1 with UNDW correlated with that induced by exercise challenge (r = .89) and Log Dmin, which may reflect bronchial sensitivity (r = .70). Our method is not sensitive enough for detecting bronchial hyperresponsiveness in all asthmatic children. Bronchoconstriction induced by UNDW has a similar mechanism of action as exercise and methacholine.     

The effect of nedocromil sodium on the clinical course, ventilatory parameters and nonspecific bronchial hyperreactivity in patients with nonatopic bronchial asthma treated with beclomethasone dipropionate

The efficacy of nedocromil sodium (NED) (8mg twice daily) in controlling the clinical symptoms of asthma (score symptoms), the pulmonary parameters (FEV1, FVC) and bronchial hyperreactivity to histamine was assessed. The study was performed in double-blind, cross-over and placebo-controlled way in 16 patients suffering from nonatopic, stable, moderate asthma treated with beclomethasone dipropionate (from 400 micrograms to 800 micrograms). NED and placebo were administered in a randomized way with 8-week wash-out period. Bronchial reactivity to histamine, was measured as the amount of histamine causing a 20% fall in FEV1 (PC20H in mg/ml). Treatment with NED did not change asthma symptom scores, FVC and FEV1. Decreased usage of beta 2-agonist was observed. NED did not influence bronchial hyperreactivity to histamine (xg PC20H was respectively 0.09 and 0.11 mg/ml after placebo and 0.06 and 0.08 after NED). The authors conclude that studies with NED in nonatopic asthmatics should be continued, but the dosage of the drug ought to be bigger and the time of treatment ought to be longer.     

Effect of inhaled atrial natriuretic peptide and a neutral endopeptidase inhibitor on histamine-induced bronchoconstriction

The reduced ability of inhaled compared with intravenous atrial natriuretic peptide (ANP) to modify bronchial reactivity and tone may be due to degradation of the peptide by neutral endopeptidase (NEP) within the airways. To test this hypothesis, we have examined the effect of thiorphan, an NEP inhibitor, on the protection afforded by inhaled ANP against histamine-induced bronchoconstriction in 10 mildly asthmatic patients. Pretreatment with ANP alone attenuated the bronchoconstrictor response to histamine with a mean (SEM) maximum percent fall in FEV1 after histamine of 15.9 (2.9) (p < 0.05) compared with 24 (2.9) after placebo and 24 (4) after pretreatment with thiorphan alone. Prior inhalation of thiorphan greatly enhanced the ANP effect: the mean maximum percent fall after this combination was 5.1 (2.3) (p < 0.01, compared with ANP alone). Our results suggest that airway NEP is important in modulating the effect of inhaled ANP. It may be possible to exploit the guanylyl cyclase pathway, by which ANP acts, in the treatment of asthma by the administration of ANP analogues stable to neutral endopeptidase.