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PubMed1983

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma.

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV1) obtained by linear interpolation from log stimulus vs. response curves (PD20). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV1 in each subject. The PD20 for M correlated significantly with the PD20 for HV (p less than 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD20 and HV PD20 expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.

Adolescent↗
PubMed1983

Effects of aspirin on nasal responses in atopic subjects.

Preliminary experiments indicated that solutions of aspirin (ASA) in buffered saline, pH 7.35, did not significantly change nasal airways resistance (NAR) when 0.1 ml of solution containing 22.5 mg (or less) per deciliter was sprayed into each nostril. Subsequently it was shown that this quantity of ASA administered intranasally did not significantly change NAR responses 15 min later to intranasal administration of increasing concentrations of histamine, methacholine, or an irritant (NH3 gas). However, the same atopic subjects demonstrated significantly decreased responses to intranasal challenge with short ragweed extract (SRW) after intranasal ASA. In addition, prior oral administration of ASA, Na salicylate, and indomethacin significantly inhibited nasal challenge responses to SRW in sensitive subjects under controlled conditions.

Administration, Intranasal↗
PubMed1984

Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses.

The efficacy of immunotherapy in cat-induced asthma was studied by use of a purified fraction of cat-pelt extract and a double-blind protocol. Nine active-treatment subjects who received a mean cumulative dose of cat allergen, 1 of 10.9 units, and eight placebo-treatment subjects completed the study. Active treatment resulted in significant reductions in bronchial sensitivity (p less than 0.05) and prick test titer (p less than 0.01). In addition, active treatment resulted in a significant delay in the onset of ocular (p less than 0.05) and pulmonary (p less than 0.02) symptoms on exposure to living cats. Significant increases in IgG antibody to cat allergen 1 (p less than 0.001) and cat albumin (p less than 0.01) also occurred with active treatment. There was no significant change in bronchial reactivity to methacholine or in the sensitivity of circulating basophils. These results confirm the validity of immunotherapy in allergic asthma where there is careful patient selection and well defined treatment preparations.

Allergens↗
PubMed1984

Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children.

The provocative dose of inhaled methacholine required to cause a 20% drop in the forced expiratory volume in 1 sec was evaluated in two selected pediatric populations. On the basis of a standardized respiratory questionnaire, 165 individuals 5 to 21 yr of age were identified. Included were 110 normal nonatopic individuals and 55 current asthmatic subjects. Methacholine inhalation challenges were performed by use of a standard inhalation procedure. Fifty-four (98.1%) of the asthmatic subjects responded to methacholine with a 20% drop in the forced expiratory volume in 1 sec. Seventy (63.1%) of the normal individuals did not respond to methacholine. The specificity and sensitivity of the methacholine challenge was best obtained at a provocative dose of 100 breath units of methacholine.

Adolescent↗
PubMed1984

A comparison of late reactions to antigen and exercise.

Immediate and late asthmatic reactions may occur after inhalation of specific antigens such as house dust mites or pollens. Recently, similar dual reactions have been found to occur after asthma induced by exercise. The immediate reaction to an antigen is believed to be due to the release of preformed and newly formed mediators derived primarily from mast cells via IgE antibodies. The late reaction also appears to be the result of an IgE reaction but involves inflammation in which cells play a role. The late reaction to antigen is often more severe than the immediate reaction and may be followed by a prolonged period of "nonspecific" bronchial hyperreactivity. By contrast, the late reaction to exercise is usually less severe than the immediate reaction. Both immediate and late exercise reactions are also associated with peaks of neutrophil chemotactic factor activity. Cromolyn sodium administered before challenge modifies both the immediate and the late response to antigen and exercise. Glucocorticoids block the late but not the early reaction to antigens. Their effect on the late exercise reaction is not yet known. Albuterol prevents the initial reaction to both exercise and antigen and may modify the late reaction to exercise as well.

Albuterol↗
PubMed1984

Methacholine challenge--relevance for the allergic athlete.

Methacholine challenge for diagnosing hyperreactive airways has been valuable in both research and clinical care settings. There are two methods of challenge that are commonly used. With the dosimeter method, five breaths of sequential concentrations of methacholine are inhaled with use of a solenoid valve timing device to standardize the quantity of inhaled methacholine solution. Pulmonary function is assessed after each concentration is inhaled. With the continuous breathing method, each concentration of methacholine is inhaled by tidal volume breathing for 2 min. Pulmonary function is assessed after each concentration. With both methods, a fall in FEV1 of 20% after inhalation of methacholine is diagnostic of hyperreactive airways. Several evaluations demonstrate that pharmacologic bronchial provocation with methacholine is more sensitive than exercise challenge for making the diagnosis of hyperreactive airways. If the allergic athlete complains of exercise-related symptoms, such as cough, dyspnea, or chest pain, and an exercise tolerance test fails to reproduce these symptoms, a methacholine challenge should be performed before the possibility of exercise-induced asthma is dismissed. If the allergic athlete has symptoms of cough or dyspnea that are unrelated to exercise, methacholine challenge is the most sensitive method to evaluate airways hyperreactivity indicative of asthma.

Bronchial Provocation Tests↗
PubMed1984

Simplified eucapnic voluntary hyperventilation challenge.

A simplified scheme for eucapnic voluntary hyperventilation ( EVH ) is described that requires only that a source of dry gas containing 5% CO2, 21% O2, and 74% N2 be hyperventilated at 40 L/min or greater. Refrigeration or measurement of end tidal CO2 is not required. When the ventilation pattern of a standardized treadmill exercise challenge in a group of exercise-sensitive asthmatics breathing dry air was matched according to this EVH procedure, the magnitude of the resultant bronchospasm and the exclusive nature of the postchallenge refractory period were similar, since patients in both cases were still fully responsive to methacholine. It is concluded that such an EVH challenge may be used to reproduce the bronchial heat and water fluxes that occur with exercise challenge as well as the consequential challenge-specific refractoriness that follows.

Air↗
PubMed1984

Rhinitis in the athlete.

Trauma is the most common problem involving the nose in sports and athletic events. Injury may lead to "vasomotor syndrome" and chronic rhinitis. Nasal and sinus obstruction may cause additional discomfort. Exposure to irritants, particularly solvents, cleaning solutions, paints, and varnishes as well as air pollutants exacerbates vasomotor rhinitis. Allergic rhinitis is another major problem of atopic athletes. It may be caused by exposure to pollens, molds, dust, or animal danders. Treatment is aimed at reducing the exposure to etiologic factors as well as pharmacologic management. Antihistamines, topical cromolyn, and topical steroids may be used to control rhinitis without violating " antidoping " regulations.

Allergens↗
PubMed1985

Asymptomatic bronchial hyperresponsiveness in rhinitis.

Methacholine inhalation tests are used to help in the diagnosis of asthma when spirometry is normal. However, the significance of increased methacholine responsiveness in patients with rhinitis and no symptoms of asthma is not known. One possibility is that it is a false positive result; another possibility is that it indicates subclinical asthma. We investigated these possibilities in 25 patients with rhinitis, whose attending physician had not made a diagnosis of asthma, by comparing responsiveness to methacholine expressed as the provocation concentration to cause a fall in FEV1 of 20% (PC20) with responsiveness to the natural stimulus of isocapnic hyperventilation of cold air and the diurnal variation of peak flow rate. Asthma was recognized objectively by variable airflow obstruction documented by one of the latter two tests. The PC20 ranged between 4 and greater than 64 mg/ml. In 10 patients the PC20 was less than 16 mg/ml. Five of these patients had bronchoconstriction in response to hyperventilation, and a further two patients demonstrated increased variability of peak flow rates. Thus, in seven of 10 patients, increased bronchial responsiveness was confirmed by the use of two different methods, although they were asymptomatic, and the increased response to methacholine was not a false positive result. In the remaining three patients the PC20 was borderline increased (8 to 16 mg/ml). The results indicate that methacholine responsiveness in the asthmatic range in patients with rhinitis is associated with variable airflow obstruction and subclinical asthma.

Adolescent↗
PubMed1985

Mediators, airway responsiveness, and asthma.

There appears to be a close interrelationship among airway responsiveness to mediators and to natural stimuli, the presence and severity of asthma, and endogenous mediator release in the airways. Histamine and methacholine have been most commonly used to measure airway responsiveness. Airway responsiveness to the two drugs is increased in patients with current symptoms of asthma, and the degree of increase relates closely to the degree of variable airflow obstruction and the therapy to control symptoms. The degree of airway responsiveness to histamine also correlates closely with the degree of responsiveness to methacholine and less closely with responsiveness to PGF2 alpha and to natural stimuli such as exercise and allergens. The less close correlations with responsiveness to exercise and allergens is probably because of variations in the ease and type of endogenous mediator release in the airways by these stimuli. Endogenous mediator release from a number of stimuli including allergens and ozone causes inflammation in the airways, asthma, and airway hyperresponsiveness. These various interrelationships indicate that the treatment of asthma should be directed to reduce airway responsiveness, prevent mediator release, and prevent or reverse inflammation.

Airway Resistance↗
PubMed1985

The effect of inspiratory flow rate regulation on nebulizer output and on human airway response to methacholine aerosol.

Increased inspiratory flow rate has been demonstrated to decrease pulmonary deposition of inhaled aerosols. To study the effect of inspiratory flow rate regulation on the physiologic response to an active substance administered by aerosol, we compared the effect of high unregulated flow rate (66 to 212 L/min) with regulated low flow rate (20 to 35 L/min) on nebulizer output and on the pulmonary response to methacholine in patients with asthma. Four No. 646 DeVilbiss nebulizers were used in sequence with a nebulization dosimeter to deliver tenfold incremental concentrations of methacholine aerosol (mass median aerodynamic diameter = 1.52 micron; geometric standard deviation = 1.96) ranging from 0.025 to 25 mg/ml. When flow was unregulated, nebulizer output was not greater than when flow was regulated, but coefficients of variation of output were significantly greater (p less than 0.01). The PD20 on the two unregulated days was significantly different (p = 0.01), whereas the PD20 on the two flow regulated days was not significantly different (p greater than 0.05). We conclude that regulation of inspiratory flow rate at rates within the range of tidal breathing significantly decreases variability in nebulizer output and variation of pulmonary responses to methacholine challenge.

Aerosols↗
PubMed1985

Elevated leukocyte phosphodiesterase as a basis for depressed cyclic adenosine monophosphate responses in the Basenji greyhound dog model of asthma.

The BG dog manifests various characteristics of human asthma, including airway hyperreactivity to low concentrations of methacholine. Studies have suggested that airway hyperreactivity in asthma is related to inadequate intracellular cAMP responses. We studied cAMP characteristics in MNL from 19 BG and 14 mongrel dogs. beta-Adrenergic receptors were assessed by 125I CYP in the presence and absence of propranolol. The responses of cAMP to ISO were measured by radioimmunoassay. Adenylate cyclase activity was determined in homogenized MNL preparations by cAMP generation. PDE activity was quantitated by radioenzyme assay. Mongrel dog leukocyte ISO-stimulated cAMP levels doubled, whereas there were negligible increases in MNL from BG dogs. Basal PDE levels were higher in BG dogs than in mongrel dogs. The PDE inhibitor Ro 20-1724 restored ISO-stimulated cAMP responses in MNL of BG dogs. Adenylate cyclase activity was not lower in MNL homogenates from BG dogs than in mongrel dogs. Cells from both BG and mongrel dogs demonstrated similar receptor numbers and affinities of saturable, specific beta-adrenergic binding over a 10 pM to 400 pM range. Our results suggest that depressed cAMP responses in BG dogs are due to high PDE activity rather than to a defect in the beta-adrenergic receptor adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1985

Cholinergic nasal hyperreactivity in atopic subjects.

Increased nasal secretions are a fundamental component of allergic rhinitis. In order to analyze various parameters of nasal secretions, a relatively nontraumatic method for collecting nasal secretions was required. A small, flexible rubber catheter connected to a vacuum and inserted 4 cm into the nose proved to be an efficient method for recovering secretions produced from a series of nasal washes. An average of 67% of the washings were recovered and analyzed for protein content. Topical methacholine (5 to 100 mg) stimulated a dose-related increase in the amount of protein secreted with atopic patients demonstrating significantly more responsiveness than nonatopic patients (29.9 times the prechallenge production of protein for atopic patients and 4.8 times for nonatopic patients). Pretreatment with atropine (10 micrograms) reduced the effects of methacholine in atopic subjects, indicating that the secretory activity was in response to muscarinic receptor stimulation. Therefore, in addition to the array of autonomic abnormalities already recognized in atopic patients, these subjects are also hyperresponsive to nasal cholinergic stimulation.

Adolescent↗
PubMed1985

Population differences in cutaneous methacholine reactivity and circulating IgE concentrations.

We evaluated the incidence of allergic and vasomotor symptoms, serum IgE concentrations, and the cutaneous responses to allergens and/or methacholine in 229 Waorani Indians residing at 300 m altitude near the headwaters of the Amazon River, 39 Tibetans residing at 4000 m in the Himalayas, and 84 healthy subjects residing at 150 m in the piedmont region of North Carolina. The Waorani Indians had a high level of intestinal parasitism, an intermediate level of parasitism occurs in Tibetans, and parasitism is rare in the control population. One Waorani Indian (less than 1%), six Tibetans (15%), and 59 North Carolina subjects (88%) had a past history of allergic or vasomotor symptoms. The prevalence of positive epicutaneous allergen skin tests among the Waorani was 40 in 2910 tests and was significantly less (chi-squared = 184.5; p less than or equal to 0.0001) than the 151 in 1344 incidence in the North Carolina subjects. Large highly significant differences (p less than or equal to 0.0001) were detected between the geometric mean IgE concentrations (international unit per milliliter) and methacholine-induced cutaneous flare responsiveness (millimeter) elicited, respectively, in comparisons between the Waorani Indians (9806 IU/ml; less than 1.0 mm), Tibetans (2930 IU/ml; 2.06 mm), and North Carolina subjects (108 IU/ml; 4.49 mm). Differences in methacholine sensitivity were small and not significant. A highly significant inverse relationship (r = -0.50, p less than or equal to 0.0001) was detected between the circulating IgE concentrations and the methacholine-induced cutaneous flare responsiveness in this cross-cultural, cross-environmental comparison of three populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Altitude↗
PubMed1985

Quantitative assays of pharmacologic aerosols used in studying asthma.

To more nearly accurately quantitate the dose of pharmacologic agents delivered to human and animal airways via aerosols, we have developed a monodisperse aerosol containing either methacholine or histamine that permits a light scattering device (tyndallometry) to measure accurately the quantity of inspired and expired particles. These aerosols (described in previous studies) are simultaneously tagged with a radioactive label (technetium 99m) to permit the use of external gamma camera imaging. Present work focuses on the development of assay techniques to measure the quantity of methacholine delivered in these aerosols. The lack of specific radioimmune or radioenzyme assays coupled with the cross-reaction of organic contaminants with conventional chemical reagents for measuring methacholine required the development of separative techniques to isolate the methacholine from the organic aerosol contaminants. With aqueous extraction and column separation we have been able to completely isolate the methacholine from these contaminants. This allows the application of standard spectrophotometric assays for methacholine to quantitate the methacholine in the resulting solution. These separative techniques will permit the use of these aerosols in quantitative studies of airway reactivity.

Aerosols↗
PubMed1985

The effect of age on methacholine response.

Bronchial reactivity to inhaled methacholine exists in subjects with asthma but may occur in subjects with allergic rhinitis, chronic lung diseases, and during respiratory infections. In the absence of these factors, we found that age also has a significant effect on the methacholine response. One hundred forty-eight subjects, 5 to 76 years of age, were studied as normal control subjects in a natural history of asthma study. The methacholine response was measured by standard techniques. The analysis demonstrated that age had a significant effect on the methacholine response. In addition to known factors influencing the results of methacholine inhalation, young and older subjects may exhibit bronchial responses that may falsely suggest hyperreactive airway disease.

Adolescent↗
PubMed1985

The effect of ketotifen on bronchial hyperreactivity in childhood asthma.

Eighteen children with perennial bronchial asthma with an average age of 9.6 yr were studied with respect to the protective effect of ketotifen on bronchial hyperreactivity. All children included demonstrated bronchial reversibility after inhalation of salbutamol, and the methacholine challenge produced a decrease of the forced expiratory volume during the first second of at least 20% in the concentration interval of 0.25 mg/ml to 4.0 mg/ml. The study was double-blind with patients divided into two parallel groups treated for 12 wk with ketotifen or placebo. Methacholine provocation tests were performed every fourth week during this period. No differences between the challenges before and during the treatment period were found in either group, nor were any differences found between the ketotifen and placebo groups. Long-term treatment with ketotifen does not appear to alter the bronchial hyperreactivity in children with bronchial asthma.

Adolescent↗