Effect of PAF-acether inhalation on nonspecific bronchial reactivity and adrenergic response in normal and asthmatic subjects

Bronchial hyperreactivity, although recognized as a hallmark of asthma, is not totally understood. Mast cell-derived mediators, including histamine, have been shown to cause immediate bronchoconstriction, but until recently, no single mediator has been shown to induce prolonged changes in airway reactivity. Recent reports indicate PAF-acether (PAF) can induce increased nonspecific bronchial reactivity in normal subjects but not in asthmatics. We sought to elucidate the role of PAF in airway hyperreactivity by comparing the effect of inhaled PAF on methacholine and isoproterenol airway responsiveness in six nonasthmatic and six asthmatic subjects. Neither nonspecific airway reactivity nor isoproterenol responsiveness was changed following PAF inhalation in the nonasthmatic subjects in the six days following PAF. Asthmatics had increased airway responsiveness to methacholine at two hours post-PAF, which did not persist. Responsiveness to isoproterenol did not change in the asthmatic subjects. Additional evaluation of the role of PAF in causing changes in airway reactivity is warranted.     

Airway response to carbachol in normal and asthmatic subjects: distinction between bronchial sensitivity and reactivity.

By constructing cumulative dose-response curves to inhaled carbachol in 12 normal and 17 asthmatic subjects with comparable baseline specific airway conductance, we have shown that there were wide variations among subjects in the dose of carbachol needed to cause a 25 per cent decrease in specific airway conductance (bronchial sensitivity) and in the slopes of the curves (bronchial reactivity). Furthermore, there was no significant correlation between these 2 characteristics of the bronchial response to carbachol. The mean dose-response curves of the asthmatic and the normal subjects were widely divergent, indicating that the asthmatic subjects differed from normal subjects more in terms of bronchial reactivity than in bronchial sensitivity. This suggests that different mechanisms determine the sensitivity and reactivity of the bronchial tree, and that hyper-reactivity is the main feature of the asthmatic response. Both should be assessed when the bronchial response to bronchoconstrictor agents is measured.     

Comparative study of histamine and exercise challenges in asthmatic children

Fifty asthmatic children were tested with both a standardized treadmill exercise and a histamine inhalation on 2 separate days. Ninety per cent had a positive response to histamine, whereas 74 per cent had demonstrable exercise-induced bronchoconstriction. There was a close relationship between responsiveness to histamine and exercise, because all patients who responded to histamine had exercise-induced bronchoconstriction. Eight children (16 per cent) responded to histamine only. Although prechallenge pulmonary function has an effect on the incidence of exercise-induced bronchoconstriction, it does not appear to influence the responsiveness to histamine. Therefore, when provocation testing is being done for the purpose of diagnosing asthma, histamine is preferable to exercise.     

Aspects of bronchial reactivity to prostaglandins and aspirin in asthmatic patients.

The behaviour of bronchial reactivity to PGF2alpha was studied in asthmatic patients under various experimental conditions. Premedication with aminophylline, i.v., and, to a lesser extent, with DSCG afforded a partial protection, while beclomethasone dipropionate was inactive under this point of view. Diftalone, a new non-steroid anti-inflammatory agent, was well tolerated in 9 aspirin-intolerant asthmatic patients, and did not modify the bronchial response to PGF2alpha which was found to be generally lower then that of other aspirin-tolerant asthmatic patients. PGE 1-2 and DSCG prevented the bronchospasm induced by inhalation or ingestion of acetylsalicylic acid in a small group of patients. Good protection was also reached with PGE1-2 in the exercise-induced bronchospasm.     

Longitudinal changes in bronchial hyperresponsiveness in asthmatic and previously asthmatic children.

To determine if nonspecific bronchial hyperresponsiveness is present to the same degree in previously asthmatic children compared with currently asthmatic children, a longitudinal study was conducted. On the basis of a standardized respiratory questionnaire, 139 children from asthmatic families, between the ages of 6 and 21 years, were identified. Subjects had skin tests, a serum IgE level, and a methacholine challenge test. IgE and skin tests demonstrated atopy in both the previously and currently asthmatic children, which persisted over time. Bronchial hyperresponsiveness within the asthmatic children was not significantly different between visits. Previously asthmatic children did have significantly decreased airway hyperresponsiveness over time. Age did not affect the results of the bronchial hyperresponsiveness in the currently asthmatic children. Currently asthmatic children, however, were significantly more atopic when compared with previously asthmatic children at their initial evaluation. Currently asthmatic children were also more bronchial responsive and remained so over time. Bronchial hyperresponsiveness is persistent in children with current asthma symptoms.     

Nonspecific bronchial reactivity in asthmatic children depends on severity but not on age

Bronchial reactivity to inhaled methacholine was measured by the steady-state tidal breathing method in asthmatic children aged 1 to 17 yr. The children were divided into three clinical groups according to their minimal therapeutic requirements: mild asthma, children requiring infrequent treatment with inhaled beta-agonists (81 patients); moderate asthma, children requiring daily preventive treatment with either cromolyn sodium or slow-release theophylline (67 patients); and severe asthma, children requiring daily preventive treatment with oral or inhaled steroids (34 patients). They were also divided into three age groups: from 1 to 6 yr, tested by using bronchial provocation with tracheal auscultation (BPTA) to determine the methacholine concentration causing wheezing (PCW); and from 7 to 11 yr and 12 to 17 yr, using lung function testing to determine the concentration causing a 20% fall in FEV1 (PC20). For the whole group the mean level of bronchial reactivity to methacholine correlated inversely with the severity of bronchial asthma according to the minimal drug requirements (p less than 0.0001) and was similar over the whole age range (p less than 0.9965) for each severity grouping. In the older children the difference between moderate and severe asthma was not significant, but this may have been a result of the effect of corticosteroids in the severe group. We concluded that age has no significant effect on the methacholine response in asthmatic children over a wide age range.     

Response to isometric exercise in children and young adults with aortic regurgitation

We studied the hemodynamic response to isometric exercise in 28 children and young adults with aortic regurgitation (AR). Results were compared with those of 18 control subjects without heart disease. Sustained isometric exercise at 33% maximal handgrip capability produced similar increase in heart rate in the two groups. Systolic blood pressure rose to a greater extent in patients with AR than in controls (mean rise 33 mm Hg vs 13 mm Hg). Thirteen of 28 patients with AR had elevated left ventricular end-diastolic diameters at rest. During isometric exercise, left ventricular end-diastolic diameter remained constant in both groups. However, end-systolic diameter increased in patients with AR, resulting in a fall in shortening fraction. The mean left ventricular shortening traction of the patients with AR fell from 36.0 ± 1.0% to 32.8 ± 1.2% (p < 0.001), but did not change in controls. The fall in shortening fraction was most marked in patients with severe AR. We conclude that patients with AR have an abnormal cardiovascular response to isometric exerclse consisting of greater increase in blood pressure and a decrease in left ventricular fractional shortening.     

Comparison of airway reactivity induced by cold air and methacholine challenges in asthmatic children

Bronchial responsiveness to isocapnic hyperventilation with cold air (CAH) and to inhaled methacholine (MCH) was compared in 17 children with bronchial asthma. The response to cold air was expressed as the percent drop in FEV₁ from baseline at 4 min. after the challenge (Δ% FEV₁ CAH), and the response to methacholine as the provocative concentration required to reduce the FEV₁ by 20% from baseline (PC₂₀MCH). Both tests were sensitive (94%) for detecting airway hyperreactivity. There was no statistically significant relationship between A% FEV, CAH and the log PC₂₀MCH (r = 0.39; P = 0.12). In clinical practice, methacholine test is easier to perform, but in the research field cold air challenge may be preferable because it avoids potential drug effects. © 1995 Wiley-Liss, Inc.     

Hering-Breuer reflex in young asthmatic children.

The aim of this study was to assess if the Hering-Breuer reflex could be provoked in young children. Thirty asthmatic children with a mean age of 5.3 years and 18 healthy children with a mean age of 7.0 years were studied. The presence of the reflex was indicated by prolongation of the spontaneous expiratory time following application of continuous positive airways pressure (CPAP). The occurrence of the reflex was then related to age, compliance of the respiratory system (Crs) measured by weighted spirometry, functional residual capacity (FRC) determined by helium gas dilution, and the change in lung volume resulting from the application of CPAP. The asthmatic children in whom the Hering-Breuer reflex was observed tended to be younger (P less than 0.01) and the reflex was present in those children of both groups who had more compliant lungs (P less than 0.05). The FRC was not different in asthmatic children with and without the Hering-Breuer reflex, but healthy children in whom the reflex was present tended to have smaller lung volumes. The change in lung volume resulting from application of CPAP was significantly greater in those children of both groups in whom the reflex was present (P less than 0.01 asthmatics, P less than 0.02 healthy children). We conclude that the Hering-Breuer reflex may be provoked in young children.     

Effect of inhaled furosemide on the bronchial response to lysine-aspirin inhalation in asthmatic subjects.

It has been demonstrated recently that inhaled furosemide inhibits bronchoconstriction induced by cold air, physical exercise, various antigens, and metabisulfite. The goal of the present study was to determine if the inhalation of furosemide would inhibit the bronchoconstriction resulting from the inhalation of lysine-aspirin in aspirin-sensitive asthmatics. Six female subjects with known hypersensitivity to aspirin participated in this crossover study comparing 20 mg of inhaled furosemide and placebo. The volunteers inhaled increasing concentrations of lysine-aspirin after the inhalation of furosemide or placebo. The geometric mean provocative dose causing a 20 percent decrease in the FEV1 (PD20) after the inhalation of placebo was 30.4 mg/ml and the PD20 was equal or below 90 mg/ml in all patients. In contrast, the FEV1 did not decrease by 20 percent in any of the patients pretreated with furosemide when the inhaled concentration was increased to 360 mg/ml. From this study, we conclude that the administration of furosemide blocks the bronchospasm induced by the inhalation of lysine-aspirin in aspirin-sensitive asthmatics.     

Bronchoconstriction due to exercise combined with cold air inhalation does not generally influence bronchial responsiveness to inhaled histamine in asthmatic subjects

We investigated immediate and late changes in airway responsiveness to histamine, after bronchoconstriction due to exercise combined with inhalation of cold air, in ten asthmatic subjects who came on six days. On the first visit, the provocation concentration producing 20% fall in FEV1 (PC20) histamine was obtained. After functional recovery, each subject walked on a treadmill whilst breathing dry, cold air. This resulted in an immediate fall greater than 15% (mean +/- SD = 31.9 +/- 11.0%) in forced expiratory volume in one second (FEV1). Following recovery, PC20 was measured again. FEV1 was then monitored for up to 6-8 h. PC20 was measured then and on the two following days at the same time of the day. Subjects were studied on three control days using the same design except that a resting period replaced the exercise with cold air. The mean changes in PC20 at each interval after exercise combined with cold air were not statistically significant. Physiologically significant changes were obtained in only two subjects, reaching a maximum 8 h after the manoeuvre. In these subjects, changes in PC20 were reproducible during a second series of visits. It is concluded that bronchial responsiveness to histamine is not generally influenced by the bronchoconstriction due to exercise combined with cold air.     

Atopic disposition and bronchial reactivity to inhaled acetylcholine in young adults with a history of asthma in childhood

The atopic disposition, indicated by positive skin reactions and IgE antibody titers etc., and the bronchial reactivity to inhaled acetylcholine were examined on the following three groups: (1) 20 young adults with a history of childhood asthma who have been symptom-free for more than 4 yr; (2) 20 current asthmatics, and (3) 20 healthy young adults. Young adults with a history of childhood asthma remained atopic in their disposition even after complete clinical remissions of their childhood asthma. However, they had a lower bronchial reactivity as compared with current asthmatics, although the bronchial reactivities of both groups were apparently higher than the control group.     

Cough receptor sensitivity and bronchial responsiveness in normal and asthmatic subjects.

We examined whether airway cough receptor sensitivity correlates to nonspecific bronchial responsiveness. We measured cough threshold, the lowest concentration of inhaled tartaric acid eliciting five or more coughs, and the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20FEV1) in 38 normal and 11 asthmatic subjects. All subjects were nonsmokers. The geometric mean value of PC20FEV1 was 25.7 mg.ml-1 (GSEM1.29) and 0.63 mg.ml-1 (GSEM1.29) and the geometric mean value of the cough threshold was 115 mg.ml-1 (GSEM1.20) and 95.5 mg.ml-1 (GSEM1.35) in normal and asthmatic subjects, respectively. The PC20FEV1 was significantly (p less than 0.01) lower in asthmatics than in normals but the cough threshold did not differ between them. No significant correlation was observed between the cough threshold and the PC20FEV1 in normal subjects or in asthmatics. These results indicate that cough sensitivity does not directly correlate to bronchial responsiveness in normal and asthmatic subjects.     

Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects

BACKGROUND: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyperreactivity. OBJECTIVE: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. PATIENTS AND METHODS: A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 microg (2.5, 10.5, 42, 45 microg). After each provocation and up to 24 h later, FEV(1) was determined; the procedure was stopped when FEV(1) declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. RESULTS: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV(1) decrease and basal eNO levels. CONCLUSIONS: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.     

The effect of nifedipine on bronchial reactivity to inhaled histamine and methacholine: a comparative study in normal and asthmatic subjects

The effect of pretreatment with nifedipine 20 mg sublingually on the bronchoconstrictor response to inhaled histamine and methacholine in asthmatic and normal subjects has been studied. For each agonist the provocation concentration required to produce a 15% fall in FEV1 (PC15) and a 35% fall in specific conductance (PC35) was determined. In the group of asthmatic subjects the responses to histamine were significantly attenuated by histamine, PC15 increasing from 0.29 mg/ml to 0.68 mg/ml (P less than 0.001) and PC35 increasing from 0.25 mg/ml to 0.58 mg/ml (P less than 0.001). Responses to methacholine showed less modification by nifedipine. PC15 increased from 0.23 mg/ml to 0.32 mg/ml (P less than 0.05). Changes in PC35 were not significant. In the group of normal subjects no attenuation of the response to methacholine was produced by nifedipine but significant increases of PC15 (P less than 0.002) and PC35 (P less than 0.005) were produced by the agent. The results are consistent with nifedipine exerting an effect principally on mediators dependent on external calcium sources for stimulus-contraction coupling in the airways. The magnitude of change in the histamine response of the two groups was similar, suggesting calcium dependent mechanisms are not involved in asthmatic hyper-responsiveness.     

Spacer inhalation technique and deposition of extrafine aerosol in asthmatic children.

The aim of the present study was to measure airway, oropharyngeal and gastrointestinal deposition of (99m)Tc-labelled hydrofluoroalkane-beclomethasone dipropionate after inhalation via a pressurised metered-dose inhaler and spacer (Aerochamber Plus) in asthmatic children. A group of 24 children (aged 5-17 yrs) with mild asthma inhaled the labelled drug. A total of 12 children took five tidal breaths after each actuation (tidal group). The other 12 children used a slow maximal inhalation followed by a 5 - 10-s breath-hold (breath-hold group). Simultaneous anterior and posterior planar gamma-scintigraphic scans (120-s acquisition) were recorded. For the tidal group, mean+/-sd lung deposition (% ex-actuator, attenuation corrected) was 35.4+/-18.3, 47.5+/-13.0 and 54.9+/-11.2 in patients aged 5-7 (n = 4), 8-10 (n = 4) and 11-17 yrs (n = 4), respectively. Oropharyngeal and gastrointestinal deposition was 24.0+/-10.5, 10.3+/-4.4 and 10.1+/-6.2. With the breath-hold technique, lung deposition was 58.1+/-6.7, 56.6+/-5.2 and 58.4+/-9.2. Oropharyngeal and gastrointestinal deposition was 12.9+/-3.2, 20.1+/-9.5 and 20.8+/-8.8. Inhalation of the extrafine formulation with the breath-hold technique showed significantly improved lung deposition compared with tidal breathing across all ages. Oropharyngeal and gastrointestinal deposition was markedly decreased, regardless of which inhalation technique was applied, compared with a previous paediatric study using the same formulation delivered via a breath-actuated metered-dose inhaler.