Effect of negative ionisation of inspired air on the response of asthmatic children to exercise and inhaled histamine

To evaluate the effect of negative ionisation of inspired air on bronchial reactivity, 11 asthmatic children were challenged twice by exercise and 10 were challenged twice by histamine inhalation. The children breathed negatively ionised air (4 X 10(5) - 10 X 10(5) ions/cm3) or control room air in random order in a double-blind fashion. All challenges were matched in terms of basal lung function and the exercise tests were matched in terms of ventilation and respiratory heat loss. Exercise-induced asthma was significantly attenuated by exposure to negatively ionised air, the mean postexercise fall in one-second forced expiratory volume (FEV1) being 29% (SE 5%) of the initial value after the control and 21% (3%) after the ionised air test (p less than 0.02). Ten of the 11 subjects developed less exercise-induced asthma while breathing ionised air. Although the median dose of histamine (cumulative breath units) which caused a constant fall in FEV1 for each individual was higher with the ionised air challenge than with the control challenge the difference was not significant. Five of the 10 subjects were less sensitive to histamine and the other five more sensitive when breathing ionised air. It is concluded that negative ionisation of inspired air can modulate the bronchial response to exercise but the effect on the response to histamine is much more variable.     

Mechanical loading and control of breathing in patients with severe chronic obstructive pulmonary disease.

BACKGROUND--High neural drive to the respiratory muscles and rapid and shallow breathing are frequently observed in patients with chronic obstructive pulmonary disease (COPD), and both mechanical and chemical factors are thought to play a part. However, the interrelation between these factors and the modifications in the control of breathing are not clearly defined. The effects of an acute decrease in mechanical load by the administration of a high dose of a beta 2 agonist were studied. METHODS--Nine spontaneously breathing patients with severe COPD took part in the study. Criteria for entry were FEV1 of < 40% of predicted and an improvement in FEV1 of < 200 ml after inhalation of 400 micrograms fenoterol. The following parameters were measured: lung volumes, tidal volume (VT), respiratory frequency (Rf), maximal pleural pressure during a sniff manoeuvre (PPLmax), pleural pressure swings (PPLsw), lung resistance (RL), RL/PPLmax ratio, and surface electromyographic activity (EMG) of diaphragm (EDI) and parasternal (EPS) muscles. Arterial oxygen saturation (SaO2), end tidal carbon dioxide pressure (PETCO2), and the electrocardiogram were also monitored. Each variable was measured under control conditions and 20 and 40 minutes after the inhalation of 800 micrograms fenoterol. In five patients the effects of placebo were also studied. RESULTS--Fenoterol resulted in an increase in FEV1 and decrease in FRC. SaO2 did not change, while PETCO2 fell and heart rate increased. The VT increased, and Rf decreased, PPLsw fell and PPLmax increased, thus the PPLsw/PPLmax ratio fell. Both RL and RL/PPLmax also fell, and a substantial decrease in EDI and EPS was observed. Changes in PPLsw were related to changes in FEV1 and RL. Changes in VT and Rf, and EDI/TI and EPS/TI were also related to changes in PPLsw and RL/PPLmax ratio, but not to changes in FEV1. No variation was observed with placebo. CONCLUSIONS--In patients with severe COPD a decrease in inspiratory muscle loading relative to the maximal available strength, as expressed by the RL/PPLmax and PPLsw/PPLmax ratios, appears to be the major determinant of changes in breathing pattern and inspiratory muscle activity (decrease in EMG).     

Histamine dose-response curves in asthma: reproducibility and sensitivity of different indices to assess response

In 18 clinically stable asthmatic patients histamine inhalation challenges were performed with a Wright's nebuliser and tidal volume breathing for two minutes on two to four occasions for each subject at a maximum interval of two weeks. The response was measured in terms of specific lung conductance (sGL) by the subtraction technique, maximum partial and maximum complete expiratory flow at 40% and 50% of vital capacity respectively (Vmax40p and Vmax50c), and FEV1 from the maximum flow-volume curve. Dose-response curves were analysed for (1) provocative concentration (PC) of histamine causing a 20% fall in FEV1 and a 40% change in the other measurements; (2) threshold concentration (TC)--the concentration at which changes in the measurement exceed 2 SD from control values; (3) reactivity (R)--the slope of the dose-response curve beyond TC. We found that PC20-FEV1 was the most reproducible index, the 95% confidence intervals based on a single determination being +/- 1.6 single two-fold concentration difference. PC20-FEV1 was more reproducible than PC values for other measurements and more reproducible than any of the TC values. The 95% confidence intervals based on a single determination of R varied from +/- 52% to +/- 74% change/log histamine concentration. Both sGL and Vmax40p detected the bronchoconstrictor response assessed by PC and TC at a significantly lower histamine concentration than FEV1 (p less than 0.01 and p less than 0.05 respectively). PC and TC results showed a significant correlation, but neither were correlated with R.     

Analysis of tidal expiratory flow pattern in the assessment of histamine-induced bronchoconstriction.

BACKGROUND--There are times in clinical practice when it would be useful to be able to assess the severity of airways obstruction from tidal breathing. Three indices of airways obstruction derived from analysis of resting tidal expiratory flow have previously been described: (1) Tme/TE = time to reach maximum expiratory flow/expiratory time; (2) Krs = decay constant of exponential fitted to tidal expiratory flow versus time curve; and (3) EV = extrapolated volume--that is, area under the curve when the fitted exponential is extrapolated to zero flow. In this paper a further index--dtr/TE, time from the beginning of expiration till the rapid decay of flow begins/expiratory time--is evaluated. The aim of this study was to assess the ability of these indices to detect mild airways obstruction. METHODS--A histamine bronchial provocation test was performed in 20 adult patients with a diagnosis of asthma or symptoms of cough and/or shortness of breath. Baseline forced expiratory volume in one second (FEV1), functional residual capacity (FRC), and specific inspiratory conductance (sGaw) were measured and the measurements repeated after the final inhalation of histamine. Expiratory flow patterns during quiet breathing over five consecutive representative breaths were analysed before and after histamine. The test was concluded in 12 subjects when FEV1 had decreased by 20% of the post saline value, and in the remaining eight after inhalation of 16 or 32 mg/ml histamine. RESULTS--FEV1, sGaw, FRC, Krs, EV, and dtr/TE were all different after histamine (paired t test). For Tme/TE no difference was shown. Change in EV detected change in end tidal volume but underestimated it compared with the change measured by body plethysmography. Percentage fall in Krs after histamine correlated with percentage fall in FEV1 (r = 0.527, Pearson correlation coefficient). This was of a similar order to the correlation between the percentage fall in sGaw and in FEV1 (r = 0.543). CONCLUSIONS--Analysis of expiratory tidal flow-time patterns predicted a decrease in FEV1 following histamine challenge as did measurement of sGaw. This analysis of tidal breathing would be useful in circumstances where forced expiratory manoeuvres are unreliable or inapplicable.     

Citric acid cough threshold and airway responsiveness in asthmatic patients and smokers with chronic airflow obstruction.

The relation between citric acid cough threshold and airway hyperresponsiveness was investigated in 11 non-smoking patients with allergic asthma (mean FEV1 94% predicted) and 25 non-atopic smokers with chronic airflow obstruction (mean FEV1 65% predicted). Cough threshold was determined on two occasions by administering doubling concentrations of citric acid. Seven of the 11 asthmatic subjects and 14 of 25 smokers with chronic airflow obstruction had a positive cough threshold on both test days. Cough threshold measurements were reproducible in both groups (standard deviation of duplicate measurements 1.2 doubling concentrations in asthma, 1.1 doubling concentrations in chronic airflow obstruction). Citric acid provocation did not cause bronchial obstruction in most patients, though four patients had a fall in FEV1 of more than 20% for a short time on one occasion only. No significant difference in cough threshold was found between the two patient groups despite differences in baseline FEV1 values. There was no significant correlation between cough threshold and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) histamine in either group. Thus sensory nerves can be activated with a tussive agent in patients with asthma and chronic airflow obstruction without causing bronchial smooth muscle contraction.     

Relationship between the acid-induced cough response and airway responsiveness and obstruction in children with asthma.

BACKGROUND: In children with asthma little is known about the direct effect of the bronchoconstrictor and bronchodilator response on the cough threshold, or the relationship between bronchial responsiveness and the cough threshold. A study was undertaken to determine the effect of histamine-induced bronchoconstriction and salbutamol-induced bronchodilatation on the cough threshold in response to inhaled acetic acid, and to examine the relationship between the acetic acid cough threshold and bronchial hyperresponsiveness to histamine in children with asthma. METHODS: Nineteen children with asthma (16 boys) of mean (SE) age 10.6 (0.6) years were enrolled in the study. On day 1 each underwent a histamine inhalation challenge to determine the provocative concentration causing a fall in forced expiratory volume in one second (FEV1) of more than 20% (PC20) as an index of individual bronchial hyperresponsiveness. On day 2 the acetic acid cough threshold was determined before and just after the inhalation of the PC20 concentration of histamine, and then salbutamol (1 mg/m2) was inhaled to relieve the bronchoconstriction. Ten of the 19 patients (eight boys) of mean age 12.2 (0.7) years also tried acetic acid inhalation challenge just after salbutamol inhalation. RESULTS: There was no relationship between the bronchial responsiveness to histamine and acetic acid cough threshold in these patients. The acetic acid cough threshold after histamine inhalation was similar to that before histamine, although FEV1 decreased after histamine. In the 10 patients who also tried acetic acid inhalation challenge after salbutamol the cough threshold did not change. CONCLUSIONS: These findings suggest that acid-induced cough sensitivity and bronchomotor tone are independently regulated in children with asthma.     

Pattern of carbon dioxide stimulated breathing in patients with chronic airway obstruction

The pattern of stimulated breathing during carbon dioxide inhalation was studied in a group of 21 patients with severe irreversible airways obstruction (mean FEV1 = 0.9 litre, mean FEV1/FVC% = 50%). Carbon dioxide rebreathing experiments were performed, the ventilatory response being defined in terms of total ventilation (V) and CO2 sensitivity (S). Breathing pattern was defined by the changes in tidal volume (delta VT) and respiratory frequency (delta f) and the maximum VT achieved (VTmax). Contrary to some previous studied no significant relationship could be demonstrated between the severity of airway obstruction (FEV1/FVC%, Raw) and the ventilatory response to rebreathing (V, S, delta VT, delta f, VTmax). However, measurements of dynamic lung volume (FEV1, FVC, IC) were found to be significantly correlated with the breathing pattern variables (delta VT, delta f, VTmax). Resting PaO2 and PaCO2 were significantly correlated with delta VT but not delta f. Results indicate that the degree of airway obstruction does not dictate the ventilatory or breathing pattern response to carbon dioxide induced hyperpnoea. In contrast it is the restriction of dynamic lung volume, by limiting the VT response, that appears to determine the ventilatory and breathing pattern response in patients with severe airway obstruction.     

Bronchial hyperreactivity to histamine in aspirin sensitive asthmatics: relationship to aspirin threshold and effect of aspirin desensitisation.

Twenty seven aspirin sensitive asthmatic patients were studied to determine the relationship between non-specific bronchial responsiveness to inhaled histamine and the degree of sensitivity to aspirin (aspirin threshold dose). No correlation was found between provocative concentration of histamine (PC20H) and aspirin threshold dose. In 11 patients the influence of aspirin desensitisation on bronchial reactivity to inhaled histamine was examined. Mean PC20H measured the day after the patients were desensitised to 600 mg of aspirin did not change significantly from the values before desensitisation. These observations suggest that sensitivity to aspirin and non-specific bronchial hyperreactivity in asthmatic patients are independent phenomena.     

Relation of the perception of airway obstruction to the severity of asthma

BACKGROUND: Patients with a poor perception of their symptoms of asthma seem to have an increased risk of an asthma attack. The influence of factors such as airway calibre, bronchial hyperresponsiveness, age and sex on the "perceptiveness" of a patient are poorly understood. It is of clinical importance to identify patients who are likely to have a poor perception of their symptoms. We have studied the perception of bronchoconstriction by asthmatic patients during a histamine provocation test and analysed the influence of bronchial obstruction, hyperresponsiveness, sex, and age. We were particularly interested to establish whether there was any difference in perception between subjects with a greater or lesser severity of asthma (expressed as bronchial obstruction, hyperresponsiveness). METHODS: One hundred and thirty four patients with allergic asthma underwent a histamine provocation test. The FEV1 was measured after each inhalation of histamine. Subjects were asked to rate subjective quantification of the sensation of breathlessness on a visual analogue scale (VAS). The relationship between changes in VAS values and the reduction in FEV1 as a percentage of the baseline value was analysed by determining the linear regression slope (alpha) between the two parameters and indicates the perception of airway obstruction. Multiple regression analysis was performed to investigate the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the "perceptiveness" for bronchoconstriction. RESULTS: The median value of the slope alpha (indicating the perception of airway obstruction) was 0.91 (25-75th percentile: 0.48-1.45). Age and sex had no influence on the perception of bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial hyperresponsiveness (PC20) showed a significant correlation with the perception of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the multiple regression model were 0.20 and 0.10. Patients who had a low baseline FEV1 and/or a high bronchial responsiveness to histamine were more likely to show a low perceptiveness for bronchoconstriction during the challenge test. CONCLUSIONS: Low baseline FEV1 and high bronchial responsiveness are associated with a low degree of "perceptiveness" for bronchoconstriction. This suggests that patients with a more severe degree of asthma either show adaptation of "perceptiveness" for airway obstruction or that low perceptiveness leads to more severe asthma.     

Measurement of responsiveness to inhaled histamine using FEV1: comparison of PC20 and threshold

Two methods of interpreting histamine inhalation dose-response curves were compared in 27 normal and 41 asthmatic subjects. The histamine provocation concentration producing a 20% fall (PC20) in forced expiratory volume in one second (FEV1) was calculated on the basis of the lowest FEV1 after inhalation of saline and the lowest value after inhalation of histamine. The histamine threshold was determined as the first histamine concentration causing the FEV1 to fall more than 2 SD below the mean of five pre-histamine (three pre-saline, two post-saline) FEV1 determinations. The PC20 was on average one doubling concentration larger than the threshold. The PC20 provided better discrimination between asthmatic and normal subjects than did the histamine threshold and was significantly more reproducible. These findings suggest that the histamine threshold may prove useful for studies on populations, particularly those with a low degree of responsiveness to histamine, because of the possibility of measuring a response at a lower histamine concentration. On the other hand, the PC20 is preferable for clinical use in individuals because of its better discriminating power and better reproducibility.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.     

Circadian change in bronchial responsiveness and airflow obstruction in asthmatic children.

To throw light on the question of whether the increase in bronchial responsiveness seen during the night is due to increased airflow obstruction, nine asthmatic children with increased airflow obstruction at night (group 1) were compared with nine without (group 2). The mean fall in forced expiratory volume in one second (FEV1) between 16.00 and 04.00 hours was 21.9% in group 1 and 2.3% in group 2. Selection of patients was based on the amplitude of change in peak expiratory flow (PEF) measured every four hours for three consecutive days at home. The study was performed in hospital on four consecutive days. Medication was withheld for three days before and during the measurements at home and in hospital. On the first day in hospital (day 4) FEV1 was measured every four hours for 24 hours. On day 6 inhaled histamine provocation tests were performed at the same times as the FEV1 measurements on day 4. Both groups showed a nocturnal fall in the provocative dose of histamine causing a 20% fall in FEV1 (PC20). The mean change in histamine PC20 from 16.00 to 04.00 hours was 1.1 doubling doses of histamine in group 1 and 1.5 doubling doses in group 2. The results indicate that the increase in nocturnal bronchial responsiveness that occurs at night is not due to an increase in airflow obstruction.     

Role of sputum differential cell count in detecting airway inflammation in patients with chronic bronchial asthma or COPD.

BACKGROUND: Sputum may provide an alternative source of bronchial cells to investigate characteristics of airway inflammation and its functional correlates in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Two groups of clinically stable patients were studied: a group of 43 patients with mild or moderate asthma and a group of 18 patients with COPD. Twenty normal subjects formed a control group. Sputum production was either spontaneous or induced with inhaled hypertonic saline for five minute periods for up to 20 minutes. The concentration of saline was increased at intervals of 10 minutes from 3% to 4%. Plugs from the lower respiratory tract were selected for differential counting in cytocentrifugation preparations. Bronchial provocation tests were performed by inhaling progressive concentrations of histamine from a DeVilbiss 646 nebuliser and the concentration of histamine which caused a 20% fall in the forced expiratory volume in one second (FEV1) was calculated (PC20FEV1). RESULTS: Neutrophils predominated in the sputum of subjects with COPD while eosinophils predominated in the sputum of those with chronic asthma. However, in 28% of asthmatic subjects an increased percentage of neutrophils was found. In asthmatic patients the differential count of eosinophils was inversely related to the FEV1, FEV1/VC, and bronchial hyperresponsiveness, and directly related to clinical scores. CONCLUSIONS: The cellular profile of sputum in normal subjects and in patients with asthma and COPD is different. The concentration of eosinophils in the sputum correlates with the severity of asthma.     

Assessment of food chemical intolerance in adult asthmatic subjects.

BACKGROUND: Identification of food chemical intolerance in asthmatic subjects can be reliably assessed by changes in the forced expiratory volume in one second (FEV1) in response to double blind, placebo controlled challenges on a strict elimination diet. However, this method is cumbersome and time consuming. A study was undertaken to determine whether changes in bronchial responsiveness to histamine following food chemical challenge without an elimination diet might be a faster, more convenient method. METHODS: Eleven adult asthmatic subjects were challenged twice with metabisulphite, aspirin, monosodium glutamate, artificial food colours, sodium nitrite/ nitrate, 0.5% citric acid solution (placebo), and sucrose (placebo) on separate days. During the first set of challenges subjects consumed a normal diet. Bronchial responsiveness to histamine was assessed 90 minutes after each challenge. A greater than twofold increase in bronchial responsiveness was considered positive. For one month prior to and during the second set of challenges subjects followed a strict elimination diet and FEV1 was monitored during and for two hours after each challenge. A fall in FEV1 of 20% or more was considered positive. RESULTS: Of the 77 food chemical challenges performed on an unmodified diet, 20 were positive (six placebo responses). In two subjects it was not possible to perform a histamine test after one of the chemical challenges because of poor spirometric function. Of the 77 food chemical challenges performed on an elimination diet, 11 were positive (no placebo responses). Excluding the two challenges in which there were no corresponding histamine tests, only on two occasions did the positive responses in both methods coincide, giving the unmodified diet method a sensitivity of 22%. CONCLUSIONS: Strict dietary elimination and measurement of FEV1 after double blind food chemical challenge remains the most reliable method for the detection of food chemical intolerance in asthmatic subjects.     

Airway calibre as a confounder in interpreting bronchial responsiveness in asthma.

BACKGROUND: The relation between airway responsiveness to constrictor agents and forced expiratory volume in one second (FEV1) is important when interpreting change in airway responsiveness after an intervention. The aim of the study was to analyse the relation between FEV1 as a percentage of predicted values (% predicted) and airway responsiveness between and within asthmatic subjects. METHODS: Results of non-specific bronchial challenge tests were pooled from two randomised crossover studies comparing the effect of a non-sedative antihistamine with placebo in 35 patients with moderate asthma. The design of the two studies was similar: the provocative concentration of either histamine (first study) or methacholine (second study) resulting in a 20% decrease in ventilatory capacity (PC20) was repeated at two week intervals while patients were treated with the antihistamine or placebo. The dose of inhaled corticosteroid was gradually reduced during the study. Data were analysed with PC20 as the dependent variable in a general linear model so that the influence on PC20 of inhaled corticosteroid dose, antihistamine, and choice of bronchoconstricting agent could be separated from the influence of FEV1% predicted. RESULTS: The correlation coefficient between mean PC20 and mean prechallenge FEV1 for each patient was 0.45. In the general linear model two thirds (65%) of the variation in PC20 was due to variation between subjects. One third of the within subject variation in PC20 could be explained by variation in prechallenge FEV1% predicted (a change in FEV1 of 27% predicted was associated with one doubling or halving of PC20). Treatment with the antihistamine had no influence on PC20, except when histamine was used as the bronchoconstricting agent. The dose of inhaled corticosteroid had a small but significant effect. CONCLUSIONS: The variation in a patient's PC20 over time (several months) is related to changes in FEV1% predicted. Variation in FEV1% predicted explains less of the variation in bronchial responsiveness between subjects where a patient specific factor, which is probably related to the pathogenesis of bronchial asthma, seems to dominate.     

Relation between the bronchial obstructive response to inhaled lipopolysaccharide and bronchial responsiveness to histamine.

BACKGROUND: Bronchoconstriction has developed after inhalation of lipopolysaccharide in a dose of 20 micrograms in asthmatic patients and of 200 micrograms in normal subjects. This study set out to determine whether the bronchial response to lipopolysaccharide was related to non-specific bronchial responsiveness and atopy. METHODS: Sixteen subjects with a fall in specific airway conductance of 40% (PD40sGaw) after inhaling up to 900 micrograms histamine inhaled 20 micrograms lipopolysaccharide (from Escherichia coli type 026:B6) a week after bronchial challenge with a control solution of saline. The bronchial response over five hours was measured as change in FEV1 and area under the FEV1-time curve. RESULTS: FEV1 fell significantly more after lipopolysaccharide than after diluent inhalation, the difference in mean (SE) FEV1 being 4.6% (5.4%); response was maximal 60 minutes after lipopolysaccharide inhalation and lasted more than five hours. Histamine PD20FEV1 and PD40sGaw correlated with the fall in FEV1 after lipopolysaccharide inhalation. There was no difference in the proportions of responders and non-responders to lipopolysaccharide who were atopic. CONCLUSION: Lipopolysaccharide induced bronchial obstruction is associated with non-specific responsiveness but not with atopy.     

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.     

Lung function and bronchial reactivity in farmers.

The purpose of this study was to evaluate the prevalence and type of lung function disorders in Danish farmers. Three samples of farmers were drawn from a group of unselected farmers who had participated in an epidemiological study. Group I (47 persons) was a sample of the 8% of all farmers who had reported that they had asthma; group II (63 persons) was a sample of the 28% of farmers who had had wheezing, shortness of breath, or cough without phlegm; and group III (34 persons) a sample of the farmers (64% of the total) who had no asthma and no respiratory symptoms. The farmers with symptoms (groups I and II) had low mean levels of FEV1 and high values for residual volume, whereas the symptomless farmers had normal lung function and no airways obstruction. The proportion of farmers with an FEV1 below the 95% confidence limit for predicted values was 43% in group I and 23% in group II; there were none in group III. Bronchial hyperreactivity to histamine occurred in 96% of asthmatic farmers, 67% of farmers with wheezing or shortness of breath, and 59% of symptomless farmers. A low level of FEV1 was associated with the number of years in pig farming and bronchial hyperreactivity in group II but not group I or III. Most of the bronchial hyperreactivity was explained in the multiple regression analysis by a low FEV1, though this was significant only for farmers in group II. Thus farmers who reported asthma, wheezing, shortness of breath, or a dry cough in general had airways obstruction with an increased residual volume, whereas symptomless farmers had normal lung function. Severe bronchial hyperreactivity was mostly explained by a diagnosis of asthma and poor lung function, though some farmers with normal lung function and no respiratory symptoms had increased bronchial reactivity.     

Distribution of immunocompetent cells in the bronchial wall of clinically healthy subjects showing bronchial hyperresponsiveness.

BACKGROUND--Nearly all asthmatic subjects show bronchial hyperresponsiveness, in that the provocative concentration of histamine reducing forced expiratory volume in one second (FEV1) by 20% (PC20FEV1) is < or = 8 mg/ml histamine, and have underlying chronic inflammation of the bronchial wall mediated by T cells. The possible cause and effect relationship between these phenomena remains an enigma. As a proportion of clinically healthy subjects show bronchial hyperresponsiveness, this study was undertaken to determine whether they also show evidence of bronchial inflammation. METHODS--Bronchial biopsy specimens were obtained from 27 clinically healthy subjects with no history of lung disease. Samples were taken perioperatively before elective knee arthroscopy for sports injuries. Specimens were frozen and cryostat sections analysed immunocytochemically with monoclonal antibodies to identify the presence of T lymphocytes, antigen presenting cells, and the expression of HLA-DR. Double immunofluorescence studies were performed with monoclonal antibodies RFD1 and RFD7 to show the relative proportions of RFD1+ RFD7- antigen presenting cells, RFD1- RFD7+ mature phagocytes, and RFD1+ RFD7+ suppressor macrophages. Histological stains were performed to show the presence of eosinophils and mast cells. Three to four weeks after bronchoscopy spirometry was performed on these subjects to record FEV1, forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75). Bronchial hyperreactivity was recorded by determining PC20FEV1 to histamine. RESULTS--Nine of the 27 subjects showed bronchial hyperresponsiveness as defined by a PC20FEV1 of < or = 8 mg/ml histamine. Segregated subjects with and without bronchial hyperresponsiveness showed no difference in spirometric results. Immunohistological analysis showed no evidence of inflammation in either group. Numbers of T cells, eosinophils, and mast cells were the same in both groups as was the expression of HLA-DR antigen. No neutrophils were observed in any tissues. Interestingly, reduced numbers of macrophages with the phenotype of antigen presenting cells (monoclonal antibodies RFD1+ RFD7-) were recorded in the subjects with bronchial hyperresponsiveness, who also had a significant increase in the proportion of RFD1+ RFD7+ suppressor macrophages. CONCLUSIONS--Up to 30% of selected clinically healthy subjects may have a PC20FEV1 of < or = 8 mg/ml histamine. This physiological trait can exist in the absence of bronchial inflammation. This suggests that bronchial hyperresponsiveness as currently defined is not dependent on immunopathological changes in the bronchial wall and does not necessarily promote even subclinical inflammation.