Methacholine Inhalation Research Articles

Total serum IgD is increased in atopic subjects

We have developed a sandwich‐type ELISA system for measuring total IgD levels in the serum of atopics and non‐atopic controls. In this ELISA system, affinity purified goat anti‐human IgD was used for capture. Results were superior to those obtained with monoclonal anti‐human IgD antibody. No cross‐reactivity could be demonstrated to IgG, IgM, IgA or IgE. The assay showed minimal non‐specific binding even with initial serum dilutions of 1:2. The results obtained were reproducible among replicates (Mean CV SEM = 0.03 0.002; n= 251), between dilutions (CV = 0.08 0.006; n= 108), and between assays (CV = 0.05 0.12; n = 5). We used routine radioimmunoassay for measuring total serum IgE. Using these assays total serum IgD and IgE levels were measured in 75 atopic patients and 33 normal subjects. None of the atopics had recent immunotherapy. As expected, the geometric mean serum IgE in atopics (373 ng/ml) was significantly higher than that in normal subjects (49 ngiml) (P < 0.01). However, geometric mean serum IgD was also significantly higher in atopics (20.3 μg/ml) than that in normal subjects (8.4 μg/ml) (P < 0.02). In both atopic and normal groups, mean serum IgD level did not differ significantly on the bases of age, sex or asthmatic status. Furthermore, total serum IgD was not significantly correlated with total serum IgE (r = 0.14; P= 0.14; n = 108), indicating that immunoregulatory control of the basal levels of the two isotypes is not linked. In a subset of more thoroughly studied atopic patients, total serum IgD but not serum IgE was correlated with D2O‐induced basophil histamine release (r = 0.34: P < 0.05; n = 37). There was no correlationship of serum IgD or serum IgE to methacholine inhalation challenge, to spontaneous basophil histamine release or that induced by anti‐IgE, calcium ionophore, or a platelet‐derived histamine releasing factor (PD‐HRF). However, among poor responders to PD‐HRF, serum IgD was also correlated with PD‐HRF induced histamine release (r = 0.59; P < 0.025; n= 21). Our preliminary results indicate that the role of IgD in atopic disorders deserves further investigation.

THE EFFECTS OF AGE ON BRONCHIAL HYPER-RESPONSIVENESS IN CHILDREN USING METHACHOLINE INHALATION CHALLENGE

We studied bronchial responsiveness in 325 asthmatic patients (200 boys and 125 girls, 0 to 18 years old, mean age, 8.7 years) and 133 disease control subjects (67 boys and 66 girls, 0 to 19 years old, mean age, 7.8 years). The bronchial responsiveness was measured by the methacholine inhalation challenge test. Those over six years old took the methacholine challenge using the Astograph method while those aged five or less used, the tcPO2-method. The tcPO2-method, which uses a transcutaneous oxygen pressure monitoring system, is useful for measuring bronchial responsiveness, especially in younger children.Dmin (bronchial sensitivity) was statistically lower in the asthmatic groups than in age-matched disease control groups. St (bronchial reactivity) was not statistically different between the asthmatic and disease control groups. Dmin was statistically lower in children aged 6 to 7 (8.07±1.61unit) than that in children aged 14 to 15 (28.58±5.96unit). The results showed a significant correlation between age and bronchial responsiveness in asthmatic and disease control groups. But there was no significant correlation between age and bronchial reactivity in either group.We found that age has a significant effect on bronchial hyper-responsiveness, especially in young children. When we evaluate the bronchial hyper-responsiveness in young children, we must consider the influence of age.

Bronchial hyperresponsiveness to methacholine in patients with primary Sjogren's syndrome.

The prevalence of bronchial hyperresponsiveness (BHR) to methacholine inhalation in a consecutive series of 21 patients with primary Sjögren's syndrome was studied prospectively. Slight to severe BHR was seen in 12/20 (60%) of the patients. Ten of 12 patients with BHR (83%) had a non-productive cough, wheezing, or intermittent breathlessness. Bronchial hyperresponsiveness was more common in patients with extraglandular symptoms (10/14, 71%) than in those with only glandular symptoms (29%). Spirometrically 29% (6/21) of the patients had 'small airways' disease', and all those had BHR. Of 6/21 (29%) who had diffuse interstitial lung disease, two had BHR. Three of the four patients with obstructive lung function were challenged with methacholine and two of them had BHR. Only two patients with BHR had normal spirometry findings. The data showed that respiratory disease--mostly mild or moderate but even severe bronchial hyperresponsiveness--is commonly seen in patients with primary Sjögren's syndrome.

Effect of a thromboxane A 2 receptor antagonist (AA-2414) on bronchial hyperresponsiveness to methacholine in subjects with asthma

Bronchial hyperresponsiveness (BHR) to various stimuli is one of the major clinical features of bronchial asthma. In this study, the effect of a thromboxane A 2 (TXA 2) receptor antagonist, AA-2414, on BHR to methacholine was evaluated in 15 patients with asthma. The methacholine inhalation test was performed before and after oral administration of AA-2414 for 4 days (20 or 40 mg/day). The provocative concentration of methacholine producing a 20% fall in FEV 1 (PC 20) was measured as an index of BHR. There was a significant increase in PC 20 ( p < 0.01) from 0.43 (geometric SEM, 1.42) mg/ml to 0.93 (geometric SEM, 1.43) mg/ml after 40 mg/day of AA-2414, whereas baseline values of FVC and FEV 1 were not changed by the treatment. Twenty milligrams per day of AA-2414 did not alter the PC 20 value nor the parameter of baseline pulmonary functions. These findings might support our hypothesis that the subthreshold concentration of TXA 2 in the bronchial tissues, which has no effect on bronchomotor tone per se, may be involved in BHR in asthma. Further studies with more potent and specific TXA 2 receptor antagonists are needed to confirm the conclusion.

Airway hyperresponsiveness in patients with microvascular angina. Evidence for a diffuse disorder of smooth muscle responsiveness.

Anginal chest pain in patients with angiographically normal coronary arteries may be caused by a limited coronary flow response to stress because of abnormal function of the coronary microcirculation (microvascular angina). Studies of forearm arterial function suggested that patients with microvascular angina may have a diffuse disorder of smooth muscle tone. Because dyspnea is common in these patients and seems disproportionate to the severity of myocardial ischemia, we studied air flow (forced expiratory volume in 1 second, or FEV1) in the basal state and after methacholine inhalation to determine whether bronchial smooth muscle is affected in this syndrome. Five of 36 patients with microvascular angina had a basal FEV1 of less than 70% of that predicted and did not receive methacholine. Of the remaining 31 patients, 14 (45%) had a more-than-20% reduction in FEV1 after methacholine inhalation (as much as 25 mg/ml), a response significantly greater than that of nine patients with heart disease (0%, p less than 0.025) and 24 normal volunteers of similar age and gender distribution (13%, p less than 0.025). Furthermore, the product of the methacholine dose inhaled and the magnitude of decline in FEV1 from baseline (methacholine response score) was significantly lower in patients with microvascular angina than in normal volunteers (16 +/- 8.6 versus 22.2 +/- 3.7, p = 0.026). We conclude that airway hyperresponsiveness is frequently demonstrable in patients with microvascular angina; these findings are consistent with our hypothesis that this syndrome may represent a more generalized abnormality of vascular and nonvascular smooth muscle function.

Bronchial Hyperreactivity in Patients with Mitral Valve Disease

To elicit the mechanism of bronchial hyperreactivity (BHR) in chronic heart failure (CHF), a methacholine inhalation test, pulmonary function test, and cardiac catheterization were performed in 19 patients with mitral valve disease (MVD), and the change of severity of BHR before and after mitral valve replacement (MVR) was also examined in seven of 19 patients with MVD. Sixteen of 19 patients with MVD showed significant increase in respiratory resistance in methacholine inhalation test, while all normal subjects did not. The maximal expiratory flow at 25 percent of vital capacity (Vmax25), a parameter of small airway disease, correlated significantly with log cumulative dose producing a 35 percent decrease in respiratory conductance (PD35Grs) (r = 0.536) and the duration of symptoms (r = -0.682). There was a significant correlation between log PD35Grs and mean pulmonary artery wedge pressure (r = -0.466). After MVR, log PD35Grs was significantly improved in all seven operated-on patients, although six patients retained BHR. We conclude that patients with long-term MVD have marked BHR and that BHR in long-term MVD is related to peripheral airway narrowing with organic remodeling, which was not ameliorated with MVR procedure, in addition to pulmonary congestion.

Endogenous Opioids Modulate the Increase in Ventilatory Output and Dyspnea during Severe Acute Bronchoconstriction

The aim of this study was to evaluate whether endogenous opioids are involved in the regulation of breathing pattern and respiratory drive during bronchoconstriction induced by methacholine (MCh). We studied six male asymptomatic asthmatics 18 to 35 yr of age. In a preliminary study we determined the concentration of MCh causing a 60% fall in FEV1 (PC60 FEV1). On two subsequent days, we measured breathing pattern, dyspnea sensation (Borg scale), mouth occlusion pressure (P0.1), and FEV1 before and 10 min after an intravenous injection of either naloxone (0.1 mg/kg) or saline according to a randomized double-blind crossover design. A MCh concentration equal to the PC60 FEV1 was then inhaled, and measurements were repeated 5 min later. Neither placebo nor naloxone affected baseline breathing pattern, P0.1, and FEV1. Naloxone pretreatment did not influence airway response to MCh; the mean percent fall in FEV1 was 65.9 +/- 1.3 and 64.7 +/- 1.2% (mean +/- 1 SE) on the placebo day and the naloxone day, respectively. After MCh inhalation no significant changes in VE, VT, and breathing frequency occurred when patients received placebo. However, P0.1 increased from 1.48 +/- 0.17 to 3.43 +/- 0.70 cm H2O (p less than 0.05), and VT/TI fell from 0.66 +/- 0.08 to 0.52 +/- 0.04 L/s (p less than 0.05). Naloxone pretreatment resulted in an increase in breathing frequency (from 18.2 +/- 1.7 to 22.8 +/- 2.6 breaths/min; p less than 0.05) and VT/TI (from 0.58 +/- 0.06 to 0.74 +/- 0.05 L/s; p less than 0.05) after MCh.(ABSTRACT TRUNCATED AT 250 WORDS)

Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects

Methacholine inhalation tests measure airway responsiveness in asthmatic and normal subjects. Tachyphylaxis occurs with repeated methacholine inhalations in normal subjects. The purpose of this study was to examine the time course and mechanisms of methacholine tachyphylaxis in normal subjects and to determine whether this occurs in mildly asthmatic subjects. Fifteen normal and nine asthmatic subjects were studied on 2 study days, at least 48 h apart. Each day, two inhalation tests were carried out. On one day, subjects performed two methacholine inhalation tests 3 h later by a methacholine test. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1), (PC20). All normal subjects developed methacholine tachyphylaxis. The mean PC20 increased from 47.3 mg/ml (%SE 1.34) to 115.6 (%SE 1.51) (P less than 0.0001) in a 3-h interval. This increase lasted for greater than or equal to 6 h (P = 0.012). Asthmatic subjects did not develop methacholine tachyphylaxis. Their mean methacholine PC20s were 1.6 mg/ml (%SE 1.4) and 1.5 (%SE 1.4) (P = 0.75) 3 h later. In two other series of experiments, normal subjects were pretreated with the cyclooxygenase inhibitors indomethacin (100 mg/day) or flurbiprofen (150 mg/day) or a placebo for 3 days before two methacholine tests 3 h apart. Both indomethacin and flurbiprofen significantly inhibited the development of methacholine tachyphylaxis. These results confirm that methacholine tachyphylaxis occurs in normal subjects, lasts greater than or equal to 6 h, and may occur through the release of inhibitory prostaglandins. By contrast, methacholine tachyphylaxis does not occur in asthmatic subjects.

The daily variability of bronchial responsiveness to methacholine

Ten mild atopic asthmatics on inhaled beta 2-agonists alone were studied in order to determine the repeatability of methacholine inhalation provocation tests at 24 h intervals over a period of 5 days. Such patients are most frequently studied in therapeutic trials of anti-asthmatic medications. There were no significant differences in results obtained on any of the days and no evidence for the development of tolerance to methacholine in this group of patients at one day intervals. The 95% confidence interval for repeatability of the results was +/- 1.05 doubling doses of methacholine, and 95% range +/- 2.36 doubling doses, comparable to the results obtained by other investigators on similar patients. Some investigators have produced more highly repeatable results but these have generally been obtained using highly selected groups of patients.

Comparison of the in‐vivo and in‐vitro response to ragweed immunotherapy in children and adults with ragweed‐induced rhinitis

In order to compare results of allergen immunotherapy in paediatric and adult populations, 22 children with a history of ragweed hay fever were matched with an equal number of adults for skin sensitivity to ragweed and all were given a 1-year course of immunotherapy with a partially purified ragweed extract. Biological responses were measured by nasal challenges with ragweed before therapy was started, after 12 weekly injections and when the maintenance dose had been reached and also by methacholine bronchoprovocation tests before and after 12 months of therapy. Skin-test sensitivity to ragweed and control allergens, and ragweed-specific IgE and IgG antibody responses were measured at the same intervals as the challenges and at the end of the study. The effect of the therapy on clinical symptoms was not evaluated. Before therapy the groups of adults and children were comparable by all indices, except for TAME esterase activity in nasal washes during ragweed nasal challenge which was significantly lower in children. During treatment, mediators released during sequential nasal challenges declined to undetectable levels in most patients and changes in nasal ragweed sensitivity were comparable in both groups. Ragweed IgE increases after 12 weeks of therapy and IgG levels at maintenance therapy tended to be higher in the children, but neither difference was statistically significant. At the end of the study IgE and IgG antibody levels were comparable in both groups. Results of methacholine inhalation tests did not change significantly in either group. The decrease in skin sensitivity to ragweed was similar in both groups. We conclude that ragweed immunotherapy leads to immunological and biological consequences that are comparable in children and adults.

Terfenadine, a potent histamine H1‐receptor antagonist in the treatment of grass pollen sensitive asthma.

1. We have assessed the effect of a specific histamine H1-receptor antagonist, terfenadine, in the treatment of atopic asthmatics during the grass pollen season. 2. Eighteen mild, grass pollen sensitive asthmatics (10F, 8M, mean +/- s.e. mean age 34.7 +/- 5.6 years), all of whom were controlled on inhaled beta 2-adrenoceptor agonists alone, took part in a 9 week, double-blind, crossover study using terfenadine 180 mg three times daily and placebo. Throughout the study patients recorded peak expiratory flow rate (PEFR) twice daily, symptoms of cough, wheeze, breathlessness and chest tightness (scored 0-3), and their use of bronchodilators. Methacholine inhalation challenge tests were performed each week. Data were analysed by a method suitable for a two group, two period crossover trial with baseline measurements. 3. Terfenadine significantly reduced symptoms of cough by 76.9% (P less than 0.05) and wheeze by 46.9% (P less than 0.02). Symptoms of breathlessness and chest tightness were reduced by 16.8 and 30.3% respectively but these were not statistically significant. Morning and evening PEFR rose by 5.5 (P less than 0.001) and 6.2% (P less than 0.003) respectively on treatment with terfenadine and bronchodilator use fell by 40.3%. A progressive increase in methacholine sensitivity was seen in both treatment groups throughout the study but did not reach statistical significance. 4. We conclude that treatment with terfenadine during the grass pollen season in sensitive asthmatics reduced their symptoms and bronchodilator requirements and produced a modest improvement in their lung function without affecting the development of increased methacholine sensitivity that occurred during the grass pollen season.

Mechanisms of hyperinflation in asthma

We studied 11 mild asthmatics to verify whether the mechanisms of hyperinflation in asthma could be inhibited or overcome by passively changing lung volumes. On day 1, we induced a fall in forced expiratory volume in one second (FEV1) of 30-60% by methacholine inhalation and measured the resulting increase in FRC (delta FRC). The delta FRC was 729 +/- 378 ml (mean +/- SD). On day 2, with the subject supine in an iron lung, we measured oesophageal (Poes), gastric (Pgas) and transdiaphragmatic (Pdi) pressures, and changes in functional residual capacity (FRC) (delta V) induced by extrathoracic pressures from -20 to +20 cmH2O before and after bronchoprovocation. With positive pressures, the FRC decreased and reached a plateau at 10 cmH2O pressure or higher. This plateau was at a mean FRC of 839 ml higher after the bronchoprovocation than before. Pdi at FRC varied in the same direction as the extrathoracic pressure and was not modified by the bronchospasm. Peak inspiratory Pdi, without pressure applied in the iron lung, increased from 13.6 +/- 5.4 to 28.1 +/- 13.5 cmH2O after methacholine; extrathoracic pressure of -20 cmH2O decreased this latter value to 15.4 +/- 7.3 cmH2O (p less than 0.01). The increased lung volume and the displaced chest wall recoil curve after provocation were not inhibited by positive or negative extrathoracic pressures. Our data show that the mechanisms of hyperinflation are not eliminated or overcome by passively changing lung volumes and support the hypothesis that persisting activity of inspiratory muscles other than the diaphragm during expiration and perhaps a prolonged expiratory time constant are responsible for hyperinflation in asthma.

Comparative effects of dilevalol and atenolol on lung function and airway response to methacholine in hypertensive subjects.

1. In this double-blind randomized study, after a 4-weeks placebo period, 18 patients with mild to moderate primary hypertension were assigned to treatment with either dilevalol (n = 9) daily or atenolol (n = 9) over a period of 3 months. 2. Expiratory flows, lung volumes and airway responsiveness (AR) to methacholine were assessed at the end of the placebo period and after an active treatment of 12 weeks. Blood pressure (BP), heart rate (HR) and ECG were monitored during the methacholine challenges. Twice daily peak expiratory flow rates and respiratory symptoms were recorded on a diary card. 3. No significant effects on ECG, HR and BP were observed after methacholine inhalation. In all but one subjects there was no significant change in expiratory flows, lung volumes or AR throughout the study. Mean FEV1, FVC, PEFR, FRC and PC20 methacholine were unchanged after 3 months of treatment, and not statistically different between patients on dilevalol or atenolol. 4. One subject, without previous history of asthma, developed transient airflow obstruction 8 weeks after beginning dilevalol. 5. Dilevalol and atenolol have no significant effects on pulmonary function and AR in most subjects with no baseline airflow limitation. 6. Airflow obstruction may develop in normal subjects on dilevalol. Methacholine challenges are safe in subjects with uncomplicated hypertension.

Respiratory Rate during Acute Asthma

Asthmatic patients hyperventilate during acute attacks, but controversy persists as to whether they breathe rapidly, deeply or both. We monitored respiratory rate under the three following conditions: (1) asthma treated in the emergency room; (2) airways obstruction provoked by methacholine inhalation; and (3) airways obstruction provoked by exercise. In 47 acutely ill asthmatic patients, respiratory rate was higher than in 42 nonasthmatic control patients in the emergency room. Pretreatment respiratory rate correlated with peak expiratory flow rate and forced expired volume in one second. In 17 asthmatic patients and 16 healthy volunteers, breathing pattern was monitored by respiratory inductance plethysmography. Methacholine inhalation and exercise provoked significant airways obstruction in asthmatic patients but not in control subjects. In asthmatic patients, minute ventilation and tidal volume increased above that of control subjects following methacholine and exercise, but the rate was no higher than in control subjects. We conclude that the respiratory rate is increased in naturally occurring asthma, but not when acute airways obstruction is induced transiently in the laboratory. In the former setting, the respiratory rate is correlated with spirometric measures of airflow obstruction, but the weakness of the correlation does not allow the respiratory rate to be used as a substitute for spirometry.

Adenosine-induced bronchoconstriction in human asthmatics: Effects of pretreatment with indomethacin or atropine sulfate

The present investigation was designed to evaluate the effects of pre-treatment with the cholinergic muscarinic receptor antagonist, atropine sulfate, or with the cyclooxygenase inhibitor, indomethacin, on adenosine-induced bronchoconstriction in human asthmatics. Eight male subjects with a FEV 1 of > 70% of the predicted normal value underwent bronchial provocation challenges with adenosine and with the cholinergic agonist, methacholine, in a double-blind, randomized, cross-over fashion. The log 10 of the agonist dose provoking a 20% decrease in FEV 1 (log PD 20FEV 1) was used to assess airways responsiveness. Challenges were performed in the untreated state and 30 min after inhalation of atropine sulfate (0.05 mg/kg). Pre-challenge FEV 1 values after atropine inhalation were higher than in the untreated state (p < 0.01). Without atropine, the log PD 20FEV 1 values for adenosine were higher than those for methacholine (p < 0.01). Atropine prevented a decrease in the FEV 1 of 20% or more in seven of the eight subjects following inhalation of methacholine up to a concentration of 25 mg/ml, but did not significantly change the log PD 20FEV 1 for adenosine. The effects of a 75 mg oral dose of indomethacin or placebo, administered in a double-blind, randomized, cross-over fashion two hours before adenosine or methacholine challenge, were assessed in 12 asthmatics. In four subjects (two after placebo and two after indomethacin pretreatment), aerosols of the highest adenosine concentration (10 mg/ml) failed to decrease the FEV 1 by 20% or more. In the remaining eight subjects, log PD 20FEV 1 values for adenosine or methacholine after indomethacin were not significantly different from those after placebo. These data corroborate observations with the quaternary atropine cogener, ipratropium bromide, that adenosine-induced bronchoconstriction is not mediated via efferent vagal pathways. The data further suggest that adenosine's effects on bronchial smooth muscle tone in human asthmatics are not mediated or modulated by cyclooxygenase products of arachidonic acid metabolism.

Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia

We obtained maximal partial expiratory flow-volume (PEFV) curves using the rapid compression technique in three infants with intrathoracic tracheomalacia. Maximum flows were quantitated at functional residual capacity (VmaxFRC). Studies were performed at baseline, after inhalation of methacholine (MCh) and after inhalation of albuterol. At baseline, all three patients had significantly lower than normal VmaxFRC values, and two patients displayed expiratory flow limitation during tidal breathing. VmaxFRC improved significantly after MCh administration, but fell back toward or below baseline after albuterol. Additionally, the ratio of forced to tidal flows at mid-tidal volume (Vmid(forced/tidal), a reflection of expiratory flow reserve, increased after MCh administration and decreased after albuterol. Two patients also received oral bethanechol: 2.9 mg/M2, q 8 hr for 10 days, after which PEFV curves were repeated. Both Vmax FRC and Vmid(forced/tidal) were increased over baseline after bethanechol administration, but decreased after albuterol. These results suggest that in patients with abnormally collapsible tracheae, stimulation of tracheal smooth muscle can improve airway stability, thereby increasing forced expiratory flows. Additionally, relaxation of airway smooth muscle by bronchodilators can have the opposite effect and exacerbate obstruction.

The Response of Plasma Histamine to Bronchoprovocation with Methacholine, Adenosine 5′-monophosphate, and Allergen in Atopic Nonasthmatic Subjects

To investigate the possible role of mast cell histamine release in mediating adenosine 5'-monophosphate (AMP)-induced bronchoconstriction, we have measured the histamine concentration in peripheral venous plasma following inhalation of methacholine, AMP, and allergen in concentrations sufficient to provoke mean maximum decreases in FEV1 of 42.8 +/- 2.2%, 46.5 +/- 3.9%, and 40.9 +/- 4.6%, respectively, in 10 atopic, nonasthmatic subjects. Mean baseline plasma concentrations of histamine were 0.25 +/- 0.02, 0.22 +/- 0.03, and 0.29 +/- 0.03 ng/ml on the methacholine, AMP, and allergen study days, respectively. Plasma histamine did not change following methacholine-induced bronchoconstriction, but increased in 9 out of 10 subjects to a mean maximum value of 0.78 +/- 0.15 ng/ml following inhalation of allergen (p less than 0.005). Following bronchial challenge with AMP, there was a significant elevation in plasma histamine in 9 out of 10 subjects to a mean maximum value of 0.39 +/- 0.03 ng/ml (p less than 0.005). We conclude that AMP-induced bronchoconstriction is associated with the enhanced release of histamine in the airways, probably from airway mast cells. However, the rise in plasma histamine, in being smaller than that occurring with a dose of allergen that provoked a similar degree of bronchoconstriction, suggests that additional mechanisms are operative in mediating the airways response to this nucleotide.

Pattern of Airway Response to Allergen Extract of &lt;i&gt;Phleum pratensis&lt;/i&gt; in Asthmatic Patients during and outside the Pollen Season

In order to evaluate the pattern of airway response to a specific bronchial provocative test (sBPT) with an extract of Phleum pratensis standardized in biological units (BU), we studied 27 patients with seasonal asthma due to grass pollen by means of allergologic evaluations, methacholine inhalation test and sBPT, outside the pollen season in all patients and, in 10 of them, also during the pollen season. We used a DeVilbiss 646 nebulizer with a dosimeter, giving increasing doses (0.01-2.5 BU) of the allergen solution and we monitored FEV1 to assess early (EAR) and late (LAR) airway responses. Outside the pollen season sBPT elicited an isolated EAR in 16 and a dual asthmatic response (DAR) in 11 patients. We observed no significant difference between EAR and DAR patients as regards the provocative dose causing a 15% fall in FEV1 (PD15FEV1) methacholine, EAR (expressed by PD15FEV1 allergen) or allergologic data. There was a significant relationship between PD15FEV1 allergen and PD15FEV1 methacholine (r = 0.43, p less than 0.05). The reproducibility of sBPT was assessed in 11 patients outside the pollen season. The correlation coefficients between the two tests were: r = 0.91, p less than 0.001 for the total delivered dose of allergen during sBPT; r = 0.79, p less than 0.01 for PD15FEV1 allergen; r = 0.95, p less than 0.001 for the maximum percent fall in FEV1 during LAR. Ten patients repeated all tests during the grass pollen season. PD15FEV1 methacholine and baseline FEV1 decreased significantly during the pollen season, but PD15FEV1 allergen did not change significantly during the season.(ABSTRACT TRUNCATED AT 250 WORDS)

Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma?

We investigated the hypothesis that prior airway muscarinic receptor stimulation (with aerosolized methacholine) would modify the bronchoconstrictor response to histamine, which is, in part, vagally mediated. On four different experiment days, the following combinations of methacholine and histamine inhalation challenges were performed in 15 subjects (nine normal and six asthmatic) in a random fashion: methacholine-histamine, histamine-methacholine; methacholine-methacholine and histamine-histamine. Cumulative provocative dose of each agonist which caused a 50 percent decrease in SGaw was estimated (PD50). The second challenge was performed approximately 1 hour after the first challenge, when SGaw had returned to baseline. In normal subjects, prior muscarinic stimulation with methacholine suppressed the subsequent bronchoconstrictor response to histamine (mean +/- SE PD50 histamine increased from 13.7 +/- 3.1 to 28.4 +/- 7.2 breath units), without modifying the bronchoconstrictor response to methacholine. In asthmatic subjects, prior methacholine exposure failed to modify the bronchoconstrictor responses to histamine and methacholine. In contrast, prior challenge with histamine did not modify the subsequent bronchoconstrictor responses to histamine and methacholine in both normal and asthmatic subjects. Pretreatment with ipratropium bromide attenuated the histamine-induced bronchoconstriction, suggesting that airway effects of histamine, in part, are vagally mediated. These data suggest that prior muscarinic stimulation has a protective effect on histamine-induced bronchoconstriction in normal subjects and the absence of this inhibitory effect in asthmatic patients may represent loss of a protective muscarinic receptor mechanism.

Recognizing and Managing Clinical Problems in Atopic Dermatitis

Atopic dermatitis is a pruritic, inflammatory cutaneous disorder found most frequently among patients with a personal or family history of atopic disease. A primary defect is found in bone marrow cells. The most consistent abnormality relates to the overproduction of IgE. Pharmacophysiologic abnormalities include abnormal vascular responses, abnormal sweating responses, and a reduced threshold for itch. In addition, seven of 12 patients with pure atopic dermatitis with no respiratory disease have an abnormal methacholine inhalation test. There is an abnormal response of leukocyte cyclic AMP to a variety of adenylate cyclase stimulants. Characteristic histological findings are interepidermal edema, called spongiosis, which is consistent with a composite of late-phase and delayed hypersensitivity. The brittle stratum corneum can be treated with hydration, a commonly neglected aspect of management. An overlooked complication is herpes simplex infection of the eye. Overall management includes stress control, treating allergenic trigger factors, topical steroids, systemic antibiotics, antihistamines, ultraviolet light, and hospitalization in severe cases.