Cromolyn sodium inhibits the increased responsiveness to methacholine that follows ultrasonically nebulized water challenge in patients with asthma

We have previously reported that airway responsiveness to inhaled methacholine in subjects with asthma is increased 40 to 60 minutes after challenge with ultrasonically nebulized water. This study reveals that increased responsiveness to methacholine is abolished by administration of cromolyn sodium before the water challenge. The mean dose of methacholine (95% confidence limits) inducing a 20% fall in FEV1 (PD20) was 1.10 mumol (0.43 to 2.80). The PD20 after water challenge was 0.42 mumol (0.17 to 1.01) that was significantly lower (p less than 0.005) than that observed for the initial challenge. Administration of cromolyn before the water challenge abolished this increased responsiveness to methacholine. The mean PD20 was 1.32 mumol (0.47 to 3.68) that was not significantly different from that measured for the initial methacholine challenge. Methacholine responsiveness was unchanged when challenge was performed 40 to 60 minutes after cromolyn alone or after methacholine itself. We conclude that cromolyn abolishes the increased responsiveness to methacholine and probably does so by inhibiting the release of mediators.     

Incorporation and analysis of ultrasonically nebulized distilled water challenges in an epidemiologic study of asthma and bronchial reactivity

The usefulness of an ultrasonically nebulized distilled water (UNDW) challenge as a screening procedure was tested in an on-going epidemiologic study of asthma and bronchial reactivity. Sixty-six individuals underwent a methacholine challenge, an UNDW challenge, and were administered a standardized respiratory disease questionnaire. To perform the UNDW challenge, subjects inhaled increasing volumes of nebulized distilled water while breathing tidally. Thirty-eight asthmatics, two former asthmatics, 14 normal, and 12 allergic subjects, were included. Sixty-six percent of the asthmatics dropped 20% from their baseline FEV1 during the UNDW challenge. Only one allergic or normal subject had a similar drop. The Pearson's correlation coefficient between methacholine and UNDW challenges was 0.60. If positive, an UNDW seems to be highly specific in supporting a diagnosis of asthma, while methacholine challenges are more useful in verifying the presence of non-specific bronchial reactivity.     

The effect of indomethacin on the refractory period occurring after the inhalation of ultrasonically nebulized distilled water

We examined the involvement of inhibitory prostaglandins in refractoriness induced by repeated ultrasonically nebulized distilled water (UNDW) challenge. Six male subjects with asthma who developed both UNDW-induced bronchoconstriction and refractoriness after UNDW were studied on 3 separate days, 1 week apart. On each study day, subjects had an initial UNDW challenge. UNDW responsiveness was assessed with dose-response curves of UNDW volume output versus the percent fall in FEV1. The output provoking a 20% fall in FEV1 (PO20 UNDW) was calculated. FEV1 was measured again at 5-minute intervals until it returned to within 5% of baseline value. UNDW challenge was then repeated. On day 1, the two successive UNDW challenges were performed in absence of any treatment (control day). Before days 2 and 3, subjects received placebo capsules or indomethacin, 100 mg per day, in a double-blind, randomized fashion for 3 days. On both the control and placebo days, repeated UNDW inhalation provoked a significant increase in PO20 UNDW (p less than 0.01), indicating refractoriness. On the indomethacin day, the mean PO20 UNDW during the second UNDW challenge was not significantly different from that obtained during the initial test on that day (p greater than 0.05), indicating that refractoriness did not occur. We suggest that inhibitory prostaglandins are involved in the development of refractoriness after UNDW inhalation.     

Effect of terfenadine on the bronchoconstriction induced by ultrasonically nebulized distilled water

Ultrasonically nebulized distilled water (UNDW) has been shown to induce bronchoconstriction in asthmatics. The proposed mechanism is through changes in osmolarity of the airway fluids and subsequent release of mediators from airway mast cells. We investigated whether terfenadine has a protective effect on UNDW challenges. Twelve mild-to-moderate asthmatics responded to screening a methacholine and UNDW challenge. For four hours after the ingestion of 0, 120, and 240 mg of terfenadine pulmonary responses were performed, followed by a UNDW challenge. Nine of 12 subjects dropped 20% after 120 mg and after 240 mg. There was a suggestion of a protective effect at 120 mg (P = .054), which was significant at 240 mg (P = .012) when the areas under the dose-response curves were compared. Bronchoconstriction induced by UNDW may in part be caused by histamine release and was attenuated by an oral antihistamine.     

Pulmonary function response to EDTA, an additive in nebulized bronchodilators

BACKGROUND: Some nebulized bronchodilator solutions contain additives, such as EDTA, benzalkonium chloride (BAC), or both. OBJECTIVE: Although BAC-induced bronchoconstriction has been well documented in patients with asthma, there is no information on the effects of EDTA on FEV(1) when inhaled in the amounts that would be administered during emergency department treatment of asthma. METHODS: Eighteen subjects with stable asthma and airway responsiveness to methacholine were randomly assigned to inhale up to four 600-microg nebulized doses of EDTA, BAC (positive control), and normal saline (placebo) in a double-blind crossover manner on separate days. FEV(1) was measured 15 minutes after each dose. Treatments were repeated every 20 minutes until FEV(1) decreased by 20% or greater or a maximum of 4 doses were administered. RESULTS: Mean +/- SD maximum percent decrease in FEV(1) was 1.8% +/- 5.8% after EDTA, 16.6% +/- 13.9% after BAC, and 3.6% +/- 8.2% after placebo (P <.001); there was no significant difference between EDTA and placebo. CONCLUSION: The amount of EDTA contained in maximum recommended doses of nebulized bronchodilators does not induce bronchospasm. In contrast, BAC induces clinically important bronchospasm, which could decrease the efficacy of a bronchodilator during an emergency.     

Long-lasting protective effect of slow-release theophylline on asthma induced by ultrasonically nebulized distilled water

We investigated the intensity and duration of the effect of a single dose of slow-release theophylline on bronchial hyperresponsiveness to ultrasonically nebulized distilled water in asthma. In six subjects with a history of mild asthma, we measured airway responsiveness to ultrasonically nebulized distilled water and serum theophylline at 4, 8, and 12 hours after treatment with placebo or slow-release theophylline (10 +/- 1 mg/kg, orally). To assess bronchial responsiveness, dose-response curves were established by plotting the baseline value of FEV1 and the largest FEV1 after each doubling dose of nebulized distilled water against the dose of nebulized water. The degree of bronchoconstriction induced by ultrasonically nebulized distilled water was significantly inhibited at 4, 8, and 12 hours after treatment with theophylline, at serum levels of 14.8 +/- 4.6, 14.4 +/- 2.8, and 12.0 +/- 2.5 micrograms/mL theophylline (mean +/- SD). Tremor occurred in three patients and was associated with nausea, epigastric pain, and tachycardia in one of them. We conclude that a single dose of slow-release theophylline has a prolonged protective effect on bronchoconstriction induced by ultrasonically nebulized distilled water, but in some subjects is associated with side effects that limit its clinical usefulness.     

The role of suggestion in asthma. I. Effects of inactive solution on bronchial reactivity under bronchoconstrictor or bronchodilator suggestion

Twenty-eight subjects affected by perennial asthma were selected in order to investigate the possibility of inducing or relieving an asthmatic attack by means of suggestion. Twenty-five were positive to methacholine challenge test and, among them, eleven reacted to an ultrasonic nebulized distilled water test. The effect of suggestion on airway response was assessed by eight inhalations of normal saline at 32 degrees C alternately presented as a bronchoconstrictor or as a bronchodilator drug. Eight inhalations of the same diluent without any psychic stimulus were used as control test. Seven patients reacted with bronchoconstriction to both positive and negative suggestion and to control test. Further, this group of patients showed a lower methacholine PD20 when compared with the other subjects. In this study, the effects of suggestion on bronchial reactivity were not observed and bronchoconstriction belonged to an individual hyperreactivity of the airways.     

Inhalation of hypertonic saline as a bronchial challenge in children with mild asthma and normal children

The response to bronchial challenge with ultrasonically nebulized 4.5% saline was compared to the response to histamine and isocapneic hyperventilation in a group of children with mild asthma and control subjects. Challenge with 4.5% saline was found to have an accuracy of approximately 80%, compared to 90% for histamine and 80% for hyperventilation. The challenge test was well tolerated by all children. Increasing the dose of 4.5% saline delivered to the children by use of a nebulizer with a higher output improved the accuracy of challenge with 4.5% saline to approximately 90%. This finding suggests that the nebulizer output is an important determinant of the accuracy of bronchial challenge with 4.5% saline. Bronchial challenge with 4.5% saline appears to be a promising addition to the tests of bronchial responsiveness in children, but further studies, particularly documenting the reproducibility and the relationship to clinical asthma, are needed before it can replace the current standard tests.     

Protective activity of inhaled nonsteroidal antiinflammatory drugs on bronchial responsiveness to ultrasonically nebulized water.

Relatively high doses of oral aspirin are needed to afford a significant protective effect against the bronchial obstructive reaction to ultrasonically nebulized distilled water (UNDW) in asthmatic patients. Sodium salicylate at similar doses and indomethacin at normal dose afford no protection. The present study was undertaken to assess the protective activity of these drugs taken by inhalation. Thirteen asthmatic patients performed two UNDW challenges 20 minutes and 24 hours after inhalation of 900 mg lysine acetylsalicylate (L-ASA) or placebo. The volume of UNDW causing a 20% fall in FEV1 (UNDW PD20) was calculated by linear interpolation on the dose-response curve. UNDW response after placebo was not significantly different from the preliminary test (PD20 4.3 +/- 0.7 and 4.1 +/- 04 ml, respectively, mean +/- SE), whereas after L-ASA, UNDW PD20 increased to 17 +/- 2.7 ml (p < 0.01 vs placebo) and remained significantly increased after 24 hours. In another group of 12 patients under the same experimental conditions, an equivalent dose of inhaled sodium salicylate caused no effect. Finally, in a third group of asthmatic patients pretreatment with inhaled indomethacin at two dose levels (6 patients, 25 mg; 10 patients, 50 mg) resulted in a significant dose-related protective effect. These findings indicate that inhaled indomethacin and especially L-ASA exert against UNDW-induced bronchoconstriction a potent protective effect, which appears to be mediated by inhibition of local prostaglandin synthesis in the airways. This fact could have therapeutic implications.     

Late bronchial response and increase in methacholine hyperresponsiveness after exercise and distilled water challenge in atopic subjects with asthma with dual asthmatic response to allergen inhalation

We investigated the occurrence of late asthmatic response and increased methacholine responsiveness after exercise and ultrasonically nebulized distilled water (UNDW) inhalation in 12 subjects with asthma with dual asthmatic response and increased responsiveness after allergen challenge. On 3 separate days, allergen, exercise, and UNDW challenges were performed 2 hours after methacholine. FEV1 was measured for 8 hours to detect any delayed change in airway caliber. If there were a further significant reduction in FEV1 after the recovery from the immediate bronchoconstriction, methacholine challenge was performed again when FEV1 had returned to baseline. Reproducibility of any observed late response to exercise and UNDW was also investigated by repeating these challenges on 2 subsequent days. After allergen inhalation only nine subjects had an early asthmatic response, whereas all the tested subjects demonstrated a late reaction and increased methacholine responsiveness. Ten subjects had an immediate response to exercise, and this was followed by a late response in only four patients. Nine subjects demonstrated early response to UNDW inhalation, and five subjects also had a late reaction. These late responses were associated with an increase in methacholine responsiveness in a subset of the tested subjects. Late-phase reactions to exercise and UNDW were not reproducible.     

Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma

Although H1 antihistamine compounds (H1) are highly effective in the treatment of allergic rhinitis (AR), their role in the treatment of asthma is still controversial. Because a strong association between AR and bronchial hyperresponsiveness (BHR) has been reported, this study was designed to assess the effect of a new H1 anti histamine, cetirizine (C), on nonspecific BHR in patients with AR. Twelve patients were included in a double-blind, crossover, placebo-controlled trial. All patients had positive skin tests for common allergens and showed BHR to inhaled methacholine after specific nasal allergenic challenge. After a washout period of 1 week to ensure the stability of the BHR, the patients received, by crossover randomization, C 10 mg daily or placebo (P) for 2 weeks. After each treatment period, BHR and nasal blocking index (NBI) were measured 1 and 6 h after nasal challenge. Bronchial responsiveness was expressed as methacholine PD20, the provocation dose of methacholine causing a 20% decrease in FEV1. Measurements were then performed after 2 weeks of C and after 2 weeks of P. Baseline values of PD20 (median) measured before challenge showed no difference after cetirizine or after placebo (1.36 mg). Results 1 h after allergen did not show significant differences between C (methacholine PD20=0.522 mg) and placebo (methacholine PD20=0.455 mg). By contrast, 6 h after challenge, methacholine PD20 was 0.918 mg for C and 0.483 mg for P (P=0.042). Similarly, NBI showed no change between C and P 1 h after challenge, whereas the difference was significant 6 h after challenge (P=0.011 ). These data demonstrate a protective nasal effect of C against BHR measured 6 h after nasal allergen challenge in patients with AR. They suggest that C may be useful in patients with asthma associated with AR.     

Effect of inhaled furosemide on the bronchial response to methacholine and cold-air hyperventilation challenges

Inhaled furosemide has been recently demonstrated to inhibit the bronchoconstrictive effects of exercise, ultrasonically nebulized distilled water, and antigen challenge. The presumed mechanism of action of these challenges is through mast cell degranulation. We report on the effect of inhaled furosemide on cold-air hyperventilation challenge (CAHC) and methacholine challenge. We studied 10 subjects with mild to moderate asthma in a double-blind, placebo-controlled, crossover study. Inhaled furosemide did not affect FEV1 in the hour after inhalation, and there was no significant difference between placebo or furosemide on the dose of methacholine causing a 20% fall in FEV1. Our results demonstrated inhaled furosemide significantly attenuated the bronchoconstrictive effect at 6 and 9 minutes after CAHC (p less than 0.05 and 0.029, respectively) when furosemide was compared to placebo and approached significance at 12 and 15 minutes after CAHC (p = 0.052 and 0.56, respectively). Inhaled furosemide attenuates CAHC but does not effect methacholine-induced bronchoconstriction.     

The effect of inhaled allergen on circulating basophils in atopic asthma.

There is increasing evidence for the role of basophils in the allergen-induced late asthmatic response (LAR). To study the effect of inhaled allergen on basophil function in subjects with asthma, ex vivo basophil spontaneous histamine release (SHR) in peripheral blood and plasma histamine was measured before and 2, 5, 10, and 15 minutes, and 2, 4, 6, and 8 hours after allergen bronchial challenge (allergen study day) in six subjects with atopic asthma. Allergen inhalation induced an early response and LAR consisting of a mean (+/- SD) 32.5% (+/- 7.9%) and 28.8% (+/- 7.7%) fall in FEV1, respectively. As a control for the effects of bronchoconstriction, on another occasion, methacholine challenge was performed to produce a mean 33.4% (+/- 3.4%) fall in FEV1 during the early response and no LAR, and blood was obtained to measure basophil histamine release (HR) and plasma histamine. There was a small, but significant (p less than 0.05), rise in median SHR from 4.6% to 6.1% of total basophil histamine after allergen but not after methacholine inhalation. HR remained high after allergen inhalation during the 8 hours of study, whereas it demonstrated a steady, significant, decrease between 4 to 8 hours after methacholine inhalation. No significant changes in plasma histamine were recorded on either allergen or methacholine study days. On a third occasion, SHR was measured after challenge with physiologic saline to control for any effects of methacholine on SHR, and a decrease in HR was recorded during the day similar to HR observed after methacholine challenge. These studies suggest an enhancing effect of inhaled allergen on SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated inhalation of low doses of cat allergen that do not induce clinical symptoms increases bronchial hyperresponsiveness and eosinophil cationic protein levels.

The aim of this study was to investigate whether repeated exposure to subclinical doses of cat allergens, not inducing asthma symptoms, could affect eosinophil cationic protein (ECP) levels in bronchoalveolar lavage (BAL) or in peripheral blood, without the appearance of clinical symptoms. Twelve patients with mild asthma, all sensitized to cats and not exposed to cat allergen at home, underwent a series of inhalations of cat allergen or placebo for 8 days over 2 weeks. A methacholine challenge was performed before and after the allergen and saline exposures, and BAL and blood were sampled for ECP measurements and eosinophil counts. No patients experienced asthma symptoms. However, PD20 methacholine (geometric mean) decreased significantly from 263 microg before to 126 microg after inhalation of allergen. Inhalation of saline did not induce any significant change in PD20. The change in log PD20 before and after cat allergen exposure was statistically different from the change in log PD20 before and after saline. Median ECP levels in BAL and serum increased significantly after allergen exposure, from 0.8 to 3.1 microg/l (p<0.02) and from 15.9 to 31.4 microg/l (p<0.05), respectively. No change was observed after saline inhalations. The change in BAL and serum ECP levels was statistically significant compared to that in the control group. The number of eosinophils did not change, however, nor did IL-5 and RANTES levels in BAL and serum. In conclusion, our results show that (1) exposure of asthma patients to repeated low doses of allergen, which did not provoke any clinical symptoms, is capable of inducing a local eosinophil activation associated with an increase in nonspecific bronchial hyperresponsiveness and (2) the increase in serum ECP levels due to eosinophil activation precedes the occurrence of asthma symptoms and may thus be a marker of allergen exposure in allergic asthma.     

Comparison of ultrasonically nebulized distilled water and hyperventilation with cold air in asthma

To assess the potential value of brief non-pharmacologic challenge tests in the measurement of bronchial responsiveness and to investigate whether the responses are induced by similar mechanisms, we carried out comparative five-minute inhalation challenges with ultrasonically nebulized distilled water and cold air hyperventilation in nine asthmatic subjects. Decrements in FEV1 following both challenges were closely correlated (r = 0.885) and ranged from 8% to 59% of baseline following challenge with the former and from 6% to 59% following the latter. Each method was therefore equally effective in demonstrating bronchial hyperresponsiveness. Moreover, the strong correlation between the responses to both challenges coupled with previous observations suggests that the two stimuli may act by similar mechanisms.     

Absence of hyper-responsiveness to methacholine after specific bronchial provocation tests in a worker with hydroxyapatite-induced occupational asthma

Hydroxyapatite is commonly used as a filler to replace amputated bone or as a coating to promote bone ingrowth into prosthetic implants. Many modern implants, such as hip replacements and dental implants, are coated with hydroxyapatite. We report a patient with occupational asthma due to hydroxyapatite, proven by a specific inhalation challenge, who experienced an early asthmatic reaction after exposure to hydroxyapatite, without increased airway responsiveness to methacholine despite an increased eosinophil count in the peripheral blood. A 38-year-old male dental implant worker visited our allergy department for the evaluation of occupational asthma. He had treated dental implant titanium surfaces with hydroxyapatite for 1.5 years. One year after starting his employment, he noticed symptoms of rhinorrhea, paroxysmal cough, and chest tightness. His symptoms were aggravated during and shortly after work and subsided several hours after work. When he stopped working for 2 months because of his chest symptoms, he became asymptomatic. After restarting his work, his symptoms reappeared and were aggravated. A methacholine bronchial challenge test had a negative response. The following day, a specific bronchial provocation test with wheat powder was negative. On the third day, a specific bronchial provocation test with hydroxyapatite powder produced an early asthmatic response. On the fourth day, a methacholine bronchial challenge test was negative. Further studies are needed to evaluate the exact pathogenetic mechanism of hydroxyapatite-induced occupational asthma.     

Exercise in elite summer athletes: Challenges for diagnosis

BACKGROUND: There is a high prevalence of asthma and exercise-induced bronchoconstriction (EIB) in elite athletes when the diagnosis is based on symptoms and medication use. Objective measurements are now required by some sporting bodies to support a diagnosis of asthma or EIB to justify use of beta-agonists. Such measurements could include bronchial provocation with methacholine, with eucapnic voluntary hyperpnea (EVH) of dry air (a surrogate for exercise), or both. OBJECTIVE: The aim of the study was to investigate the relationship between asthma symptoms and responses to methacholine and the EVH challenge in a group of unselected elite summer-sport athletes. The outcome would be to inform practitioners of a suitable objective approach to identifying those with asthma and EIB. METHODS: Fifty elite summer-sport athletes with or without asthma were recruited from sporting teams and sports medicine centers throughout Melbourne, Australia. All subjects completed a respiratory questionnaire and, on separate days, underwent a bronchoprovocation challenge test with methacholine and EVH. RESULTS: Forty-two subjects reported one or more respiratory symptoms in the past year, 9 had positive methacholine challenge results (mean PD(20) of 1.69 +/- 2.05 micromol), and 25 had positive EVH challenge results (mean fall in FEV(1) of 25.4% +/- 15%). Although all subjects with positive methacholine challenge results had positive EVH challenge results, methacholine had a negative predictive value of only 61% and a sensitivity of 36% for identifying those responsive to EVH. CONCLUSION: These findings suggest that the pathogenesis of EIB in elite athletes might be different from that of asthma, and as such, neither symptoms nor the methacholine challenge test should be used exclusively for identifying EIB.     

Time course of drug concentrations in nebulizers and nebulized solutions]

The drug concentrations in nebulizers and nebulized solutions generated by the ultrasonic nebulizer OMRON NE-U10B and the jet nebulizer INSPIRON NEBULIZER 002305 were examined. With the ultrasonic nebulizer, increases in the concentrations of saline, DSCG and isoproterenol in the nebulizer were observed; the concentrations of those in the nebulized solutions also increased. The increase was most dramatic just before the solution was emptied. No degradations of DSCG or isoproterenol were detected in the nebulized solutions, indicating that these drugs are stable against ultrasonic nebulization. An increase in the drug concentrations in the jet nebulizer was also observed. The concentrations of the nebulized solutions also increased, but the concentrations in the nebulized solution were lower than those in the nebulizer at any time. On inhalation therapy, it is important to give consideration to these concentration changes. The nebulizer should not, for example, be refilled with a new drug solution.     

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Significant changes of bronchial responsiveness to methacholine after early asthmatic reaction to toluene diisocyanate (TDI) in a TDI-sensitive asthmatic worker

Current asthma is often diagnostically excluded by the presence of normal bronchial responsiveness. We report on a TDI-induced occupational asthma patient with normal bronchial responsiveness. He had suffered from shortness of breath during and after TDI exposure for several months. His initial methacholine bronchial challenge test showed a negative response. The bronchoprovacation test with TDI showed an isolated immediate bronchoconstriction. The following methacholine bronchial challenge tests revealed that the bronchial hyperresponsiveness developed seven hours after the TDI challenge (methacholine PC20:5.1 mg/ml), progressed up until 24 hours, and returned to normal on the seventh day. This case provides evidence that the response of the airway to TDI may not always be accompanied by bronchial hyperresponsiveness to methacholine. Screening programs utilizing methacholine challenges may not always identify TDI-sensitized asthmatic workers.