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PubMed1986

Increase in gastroesophageal reflux during methacholine-induced bronchospasm.

There is an increased incidence in gastroesophageal reflux (GER) in subjects with asthma. The cause-effect relationship remains controversial. We compared 15 subjects with mild asthma to 15 control subjects (nonasthmatic) to ascertain if GER might be induced by bronchospasm. Continuous monitoring of lower esophageal sphincter pressure and pH at 5 cm above the lower esophageal sphincter was performed in seated subjects for 3 hours in total: 1 hour of baseline measurements, 1 hour of methacholine inhalation with a dosimeter, and 1 hour after the inhalation of 200 micrograms of salbutamol (albuterol). During bronchospasm, subjects with asthma had more episodes of GER (3.9 +/- 1.5) and dropped their pH to lower levels (pH 2.23 +/- 0.3) than did the control subjects (0.8 +/- 0.3 episodes, pH 3.22 +/- 0.3) p less than 0.05. We conclude that in these subjects with mild asthma, methacholine-induced bronchospasm produced GER episodes of greater frequency and severity.

Adult↗
PubMed1986

The origin of airway hyperresponsiveness.

Consideration of the origin of airway hyperresponsiveness appears central to understanding the origin of asthma. Subjects with and without asthma differ both in the ease with which airway narrowing is produced by inhalation of histamine or methacholine and in the ability to demonstrate a maximal response to these agents. The latter appears, on present evidence, to be due to an added mechanism in asthma rather than the absence of a potent inhibitory process. Airway hyperresponsiveness is probably acquired during life as a result of airway reactions to various stimuli, although genetic factors such as atopy are likely to predispose the person to develop hyperresponsiveness. Environmental stimuli include inhaled allergens, chemical sensitizers, airway infections, immunization, and ozone. Allergen-induced airway hyperresponsiveness occurs in association with late-phase asthmatic responses. This and ozone-induced hyperresponsiveness have been demonstrated to be associated with release of chemical mediators and the cellular phase of inflammation. Their effect does not appear to be accounted for by increase in airway epithelial permeability, decrease in airway caliber, reflex bronchoconstriction, or beta-adrenoceptor blockade. The mechanism(s) responsible for the induced hyperresponsiveness are unknown but may involve airway epithelial damage, edema in and around the airway walls, stimulation of the noncholinergic excitatory or inhibition of the nonadrenergic inhibitory systems, or a change in function of airway smooth muscle. Airway hyperresponsiveness can be transient or persistent. Transient increases in responsiveness are almost certainly associated with mediator release and inflammation. It is not known whether persistent hyperresponsiveness is due to the same process, fired, for example, by leaky mediator-releasing cells and/or to some persisting change in neurogenic or smooth muscle function.

Allergens↗
PubMed1986

Predictive accuracy of late asthmatic reaction to Dermatophagoides pteronyssinus.

Sixteen patients with asthma were challenged with solutions of Dermatophagoides pteronyssinus extracts. Fifteen patients demonstrated an early asthmatic reaction, and 10 patients also demonstrated a late asthmatic reaction, as demonstrated by a 15% decrease of FEV1 within 1 hour or between 3 and 8 hours after challenge, respectively. Airway responsiveness to inhaled methacholine, expressed as the dose causing a fall of FEV1 of 15% (Pd15), and the serum IgE level (RAST), expressed as percent of the total radioactivity added, were also measured. Multiple regression analysis of data demonstrated that both early asthmatic reaction, expressed as the allergen Pd15, and late asthmatic reaction, expressed as the FEV1 maximum fall from control values, can be predicted with similar accuracy (explained variance of 63% and 68%, respectively) by a model that incorporates simultaneously methacholine Pd15, percent of total radioactivity added by RAST, and baseline values of FEV1. We conclude that the late asthmatic reaction is more likely to occur and is more severe in patients with more severe underlying disease.

Adolescent↗
PubMed1986

Plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness in western red-cedar workers.

In a cross-sectional survey of 652 workers in a western red-cedar sawmill, we obtained data on symptoms, pulmonary function, immediate skin reactivity to common allergens, nonspecific bronchial responsiveness, total IgE level, and sensitization to plicatic acid conjugated with human serum albumin as measured by RAST. Dust exposure was estimated by personal and area sampling for total dust during a work shift and cumulative exposure by duration of employment. Seven percent of the workers had an elevated RAST, and 20% had nonspecific bronchial hyperresponsiveness. Elevation in RAST was associated with bronchial hyperresponsiveness. Almost half (46%) of the workers with RAST elevation had bronchial hyperresponsiveness compared to 18% in workers with no RAST elevation. The association was unaffected by total IgE level or by limiting the analysis to workers without respiratory symptoms and was most apparent in younger workers. Bronchial hyperresponsiveness was associated with increased prevalence of respiratory symptoms as well as with lower levels of pulmonary function. The likelihood of bronchial hyperresponsiveness increased with increasing age but was unrelated to the dust-exposure concentration. RAST elevation was unrelated to employment duration or dust exposure and was not associated with an increased prevalence of symptoms or lower levels of pulmonary function independent of bronchial hyperresponsiveness. We conclude that plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness are associated in western red-cedar workers and that this association may reflect a causal connection.

Adult↗
PubMed1986

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.

Administration, Inhalation↗
PubMed1986

Segregation analysis of bronchial response to methacholine inhalation challenge in families with and without asthma.

A segregation analysis was performed on the bronchial response to a standardized methacholine inhalation challenge obtained from members of 83 families that were part of a Natural History of Asthma study population. Each bronchial response was expressed as the area under the best fitting parabolic dose-response curve. Standard methods of statistical analysis demonstrated that age, sex, and recent respiratory infection had a significant effect on the bronchial response to methacholine inhalation. Segregation analysis indicated that, although a familial component exists in the transmission of bronchial response to methacholine, the bimodal distribution of the bronchial response is not due to segregation at a single autosomal locus.

Asthma↗
PubMed1986

Beta-adrenergic responses in drug-free subjects with asthma.

Young atopic subjects with asthma who had taken no medication for 30 days and had normal pulmonary function were compared to atopic and nonatopic control subjects in several measures of beta-adrenergic response. Subjects with asthma required a larger dose of infused isoproterenol (14.3 +/- 3.9 ng/kg/min) to increase pulse pressure by a target greater than 22 mm Hg than nonatopic control subjects (8.7 +/- 3.3 ng/kg/min). Asymptomatic atopic control subjects had intermediate sensitivity (12.0 +/- 6.0 ng/kg/min) (F = 3.67; p less than 0.05). At the dose of infused isoproterenol producing the target pulse pressure response, the increase in low-frequency (1 to 8 cycles per minute) heart rate variability was less in subjects with asthma (107 +/- 34% increase in normal subjects versus 9 +/- 21% increase in subjects with asthma; p less than 0.05). In addition, subjects with the least beta-adrenergic responsiveness had the most reactive airways. Airway reactivity (assessed by the provocative concentration of methacholine causing a 20% fall in FEV1) correlated with both the dose of isoproterenol required for the target pulse pressure response (Rs = -0.46; p less than 0.05) and the isoproterenol-induced increase in low-frequency heart-rate variability (Rs = 0.47; p less than 0.05). In contrast, in lymphocytes and granulocytes from these same subjects, the cAMP response to isoproterenol and beta-adrenergic receptor number were identical in normal subjects and subjects with asthma and unrelated to airway reactivity or to cardiovascular beta-adrenergic responses. Thus, different results for beta-adrenergic responsiveness in subjects with asthma are obtained in different tests in the same subjects.

Adult↗
PubMed1986

Pupillary responses and airway reactivity in asthma.

Pupillary responses to phenylephrine and carbachol and airway reactivity were determined in 19 drug-free persons with mild allergic asthma, 21 nonatopic control subjects, and six asymptomatic atopic control subjects. The concentration of phenylephrine required to dilate the pupil 1 mm, obtained by interpolation on the dose-response curve, was taken as a measure of alpha-adrenergic sensitivity. This concentration was significantly lower for subjects with asthma than for atopic or nonatopic control subjects (1.11 +/- 0.68% [mean +/- SD], 1.86 +/- 0.81%, and 1.52 +/- 0.67%, respectively; p less than 0.05 by analysis of variance). The concentration of carbachol required for pupillary constriction of 1 mm, obtained by interpolation on the dose-response curve, was taken as a measure of cholinergic sensitivity. This value was significantly lower for subjects with asthma than for atopic or nonatopic control subjects (0.23 +/- 0.12%, 0.41 +/- 0.14%, and 0.35 +/- 0.19%, respectively; p less than 0.05 by analysis of variance). Pupillary alpha-adrenergic and cholinergic sensitivity were significantly correlated (Spearman's rank correlation coefficient, Rs = 0.42, p less than 0.05). Both alpha-adrenergic and cholinergic sensitivity of the pupils correlated with airway reactivity expressed as concentration of methacholine causing a 20% fall in FEV1 (Rs = 0.35, p less than 0.05, and Rs = 0.45, p less than 0.05, respectively). The autonomic aberrations cannot be attributed to drug use or significantly abnormal pulmonary mechanics. Autonomic abnormalities are associated with allergic asthma and may contribute to the airway reactivity characteristic of the disease.

Adolescent↗
PubMed1986

Seasonal variation of airway function in allergic rhinitis.

We set out to examine seasonal variation in airway bronchoconstriction in patients with seasonal allergic rhinitis. Airway conductance and response to methacholine challenge were measured during pollen season, as well as in winter when pollen exposure was not present. Airway conductance and spirometry were performed on 17 subjects during allergy season and in winter. In eight of these subjects the measurements were repeated in the successive allergy season. Methacholine bronchoprovocation was performed on 17 of the subjects in winter and in eight subjects in allergy season. We found airway constriction in both allergy seasons as evidenced by specific airway conductance (SGaw) of 0.188 +/- 0.06 and 0.203 +/- 0.03. In contrast, SGaw during winter was 0.27 +/- 0.11. When winter and summer seasons were compared, both summer SGaw values were significantly lower than winter SGaw, p less than 0.01 and p less than 0.05, respectively. Mean airway sensitivity to methacholine during allergy season was 16.1 breath units and not different than out of season 11.7 breath units; p = NS. The reactivity to methacholine (slope of the dose-response curve) and spirometry (FVC, FEV1, FEV1/FVC) in and out of allergy season were likewise not different. The data indicate that patients with allergic rhinitis have unique physiologic behavior separating them from patients with asthma or normal subjects. They develop seasonal bronchoconstriction unassociated with clinical bronchospasm, but this seasonal bronchoconstriction does not potentiate their sensitivity to methacholine. However, they have increased airway sensitivity to methacholine, and this feature distinguishes them from normal subjects.

Adolescent↗
PubMed1987

A new method of inhalation challenge with propranolol: comparison with methacholine-induced bronchoconstriction and role of vagal nerve activity.

To establish a safe procedure for examining propranolol-induced bronchoconstriction, we have developed a new method for performing inhalation challenge with propranolol. Monitoring respiratory resistance during tidal breathing with continuous inhalation of propranolol in 1.5-fold increasing concentrations from 0.78 to 30 mg/ml for 1 minute at each concentration, we tested 43 subjects with stable asthma and 10 normal subjects. We also compared bronchial responsiveness with responsiveness to inhaled methacholine on separate days. In addition, to determine the role of vagal nerve activity in propranolol-induced bronchoconstriction, we studied the effect of atropine. Inhaled propranolol caused dose-related bronchoconstriction in all subjects with asthma but not in normal subjects. None of the subjects suffered severe asthmatic attack during the test, which was performed in 15 minutes or less. The minimum cumulative dose of methacholine and of propranolol, at the point where respiratory conductance began to decrease, was not significantly correlated. Increased respiratory resistance was reversed by atropine in 70% of the subjects with asthma with marked individual differences. These data suggest that, although in most subjects with asthma, vagal nerve activity contributes in varying degree to bronchoconstriction, other constricting factors may contribute in the remaining subjects. It is also suggested that the mechanism of bronchial response to propranolol differs from that of the nonspecific airway reactivity estimated by methacholine challenge.

Adolescent↗
PubMed1987

The role of the methacholine challenge in children with chronic cough.

Thirty-nine male and 35 female subjects, aged 6 to 20 years, with chronic cough were studied with spirometry and standard methacholine (MCH) challenge. The duration of their cough before the MCH challenge ranged from 2 months to 13 years. Their FEV1 ranged 62% to 132% predicted. Thirty-six (49%) patients had a positive MCH challenge. The MCH concentration inhaled to decrease the FEV1 by 20% ranged from 0.55 to 25 mg/ml. Follow-up data (mean 14 months) were available on all 74 patients. Fifty-four patients received asthma medications, and 93% improved in mean 3.6 weeks. At the end of the follow-up, 22 (30%) were asymptomatic, 39 (53%) were improved, and 13 patients (17%) were symptomatic. We were unable to predict bronchial hyperreactivity in this population on the basis of duration of the cough, personal or family history of allergies, or baseline spirometry. Thus, MCH challenge is helpful in evaluating children with chronic cough and in guiding therapy. Follow-up of children with chronic cough is important. Eleven percent of this study population progressed to develop bronchial asthma. Forty percent of these patients, initially doing well, were asymptomatic at the end of the follow-up period.

Adolescent↗
PubMed1987

Prevalence and characteristics of late asthmatic responses to exercise.

The prevalence and characteristics of late asthmatic responses to exercise were studied in an adult asthmatic population. Twenty-four subjects (eight male and 16 female), aged 17 to 39 years (mean, 23.7 years), performed a 6-minute exercise on a bicycle ergometer at 75% of their maximum oxygen intake. FEV1 was measured at regular time intervals up to 8 hours after exercise. Seven subjects demonstrated a late asthmatic reaction defined as a fall in FEV1 greater than 10% between 2 to 8 hours. Bronchial reactivity to histamine was unchanged 24 hours after the exercise, compared to baseline. On a control day, a fall in FEV1 similar to the one observed after exercise was induced by methacholine inhalation. Measurements of FEV1 were done at the same time intervals as on exercise day. Neutrophil chemotactic activity was measured in the serum of 15 subjects, on exercise day for early responders, and on the 3 test days for subjects with a dual response. There was no difference between subjects with an isolated early or late response for age, sex, or atopic status. Baseline expiratory flows and nonspecific bronchial reactivity to histamine were similar in both groups. These results demonstrate the occurrence of a late asthmatic response in 30.4% of the population studied. There was no significant change of nonspecific bronchial responsiveness after the late asthmatic response to exercise. No significant increase in neutrophil chemotactic activity could be observed.

Adolescent↗
PubMed1987

The relationship between mast cell-mediator release and bronchial reactivity in allergic asthma.

The relationship between mast cell-mediator release and nonspecific bronchial reactivity was investigated in allergen-induced asthma. Two groups of subjects with asthma, one group with markedly reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 0.07 mg/ml) and the other group with less reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 3.83 mg/ml), had allergen bronchoprovocation. After challenge, bronchoconstriction was measured as change in specific airway conductance (SGaw), and mast cell-mediator release was measured as change in both plasma histamine and serum neutrophil chemotactic activity (NCA). In the group with more reactive airways, allergen challenge, while it produced a mean fall in SGaw of 58.1%, was not associated with any significant increase in plasma histamine from a mean resting level of 3.69 nmol/L-1. In contrast, a comparable mean fall in SGaw of 52.4% in the group with less reactive airways was associated with a significant (p less than 0.005) increase in plasma histamine from 1.17 to 3.60 nmol/L-1, maximal 5 minutes after allergen challenge. There were, however, significant increments in serum NCA in both groups with asthma after allergen challenge. The changes in NCA in the group with less reactive airways (136.7 +/- 38.1% above baseline; p less than 0.01; 1% sera dilution) were significantly greater (p less than 0.05) than changes identified in the group with more reactive airways (68.3% above baseline; p less than 0.01; 20% sera dilution). These findings directly support the concept that both mast cell-mediator release and nonspecific bronchial reactivity are separate factors that influence the airway response to inhaled allergen in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Passive transfer of methacholine sensitivity from man to monkey.

A model of human allergic disease, in which nonhuman primates were infused with serum from allergic humans and challenged with appropriate antigen, was used to determine whether the animals also develop hyperreactive airways characteristic of asthma. Anesthetized monkeys were insufflated with increasing concentrations of methacholine aerosol, and changes in pulmonary function were measured. Airway reactivity as assessed by the dose of methacholine aerosol culminating in apnea was determined after infusion of serum from allergic or nonallergic humans or with heated allergic serum. A comparison of the results indicated that only infusion of unheated serum from allergic humans resulted in an increase in airway reactivity to aerosolized methacholine. These results suggest that a factor in the serum of allergic humans may play a role in the hyperreactivity of airways characteristic of asthma.

Animals↗
PubMed1987

Distribution of methacholine inhalation challenge responses in a selected adult population.

To determine bronchial reactivity patterns in adults, 211 subjects, 22 to 86 years of age, underwent a methacholine challenge in a Natural History of Asthma study. The diagnosis of asthma or nonasthmatic allergic diseases was based on a standardized respiratory questionnaire. Subjects were nonsmokers and had not had an infection for 1 month. Intradermal skin tests were done to a battery of common antigens. The methacholine challenge response was expressed as the area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units. Thirty-three subjects with asthma, 47 normal subjects from normal families (NF), 59 normal subjects from families with asthma (AF), 31 allergic subjects without asthma, 23 subjects with questionable asthma, and 18 subjects with prior asthma were studied. Overall, 50% of the subjects without asthma had a negative response to methacholine. There was a difference (p less than 0.02) in the distribution of log10 methacholine area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units responses in normal subjects from NFs compared to normal subjects from AFs. The allergic subjects from AF had a greater degree of bronchial reactivity compared to normal individuals from NF. The age of the normal subjects had an influence on the degree of bronchial reactivity. Methacholine challenge studies in adult patients need to be interpreted with age and family history in mind.

Administration, Inhalation↗
PubMed1988

Cat- or dog-induced immediate and late asthmatic responses before and after immunotherapy.

To assess the effect of specific immunotherapy (IT) on the immediate and late asthmatic responses induced by cat or dog extract bronchial provocation testing, we studied seven cat-sensitive and six dog-sensitive subjects with asthma. Among the cat-sensitive subjects, two of three subjects displaying only an immediate asthmatic response before IT lost the response after 3 months of IT with cat extract, whereas only one of four subjects with the dual (immediate and late) asthmatic responses had ablation of such responses (no significance for the one-tailed test). Three subjects had worsening of the immediate response after IT. Among dog-sensitive subjects with asthma, three of five subjects with only an immediate response demonstrated an ablation of the immediate response, whereas the one subject who was the only subject with a dual response before IT lost the dual response after dog-extract IT (p value of 0.005 on one-tailed test). Immediate systemic side effects, including one episode of anaphylaxis, occurred on seven occasions of 326 injections with cat extract compared to only one episode of rhinitis of 289 injections with dog extract.

Adult↗
PubMed1988

Leukocyte count and bronchial hyperresponsiveness.

The relationship of total and differential blood leukocyte counts with bronchial methacholine response was studied in a population-based sample of 324 men. Geometric mean total leukocyte counts were significantly higher in reactors (6567 cells/mm3) than in nonreactors (5732 cells/mm3; p = 0.003). After adjusting for smoking habits, a factor contributing to both an elevation in peripheral leukocyte count and an increased level of airway responsiveness, reactor status remained significantly associated with leukocyte count. This association also persisted after controlling, with a logistic model, for atopy and common cold (marker of infection) and after excluding men with a history of asthma, chronic bronchitis, or low FEV1. Study of the differential leukocyte counts has shown that an increase was present for almost every type of leukocyte, and particularly evident for neutrophils. Whether these findings reflect an association between bronchial hyperresponsiveness and cellular inflammation needs more investigation.

Adult↗