Prevalence of asthma, atopy, and bronchial hyperreactivity in bronchiectasis: a controlled study.

The prevalence of atopic diseases and bronchial reactivity to histamine and methacholine was determined in 36 patients with bronchiectasis and in 36 control patients matched for age, sex, and smoking history. There was no difference in the prevalence of asthma, other atopic diseases, family history of atopic diseases, or positive responses to skinprick tests (nine versus five) in the two groups. The prevalence of bronchial hyperreactivity, however, was significantly higher in the group with bronchiectasis than in the control group for both histamine (7 v 0 patients) and methacholine (6 v 0 patients). The group with bronchiectasis had more airflow obstruction (mean FEV1 67% predicted), but there was no correlation between spirometric indices and log PD20 (the log dose of histamine or methacholine causing a 20% fall in FEV1). This suggests that, although reduced airway calibre may be a factor underlying bronchial hyperreactivity in bronchiectasis, it is not the only mechanism. Further studies are needed to determine whether bronchial hyperreactivity has a causative role in the pathogenesis of bronchiectasis or whether it occurs as a result of the disease.     

Comparison of the effects of salbutamol and adrenaline on airway smooth muscle contractility in vitro and on bronchial reactivity in vivo.

BACKGROUND--The effect of adrenergic agonists in asthma depends on their net effect on microvascular leakage, mucosal oedema, vascular clearance of spasmogens, inhibition of cholinergic neurotransmission, and airway smooth muscle contractility. It has been postulated that adrenaline, by virtue of its alpha effects on the vasculature and cholinergic neurotransmission, may have additional useful properties in asthma compared with selective beta agonists such as salbutamol. METHODS--The airway effects of adrenaline (a non-selective adrenoreceptor agonist) were compared with the selective beta 2 agonist salbutamol. Their airway smooth muscle relaxant potencies and effect on histamine contraction in human bronchi in vitro were compared with their effects on airway calibre and histamine reactivity in asthmatic subjects in vivo. For the in vitro studies changes in tension were measured in response to these agents in thoracotomy specimens of human airways. In vivo the effects of adrenaline and salbutamol on airway calibre and histamine reactivity were measured in eight subjects with mild to moderate asthma in a randomised crossover study. RESULTS--Salbutamol and adrenaline had approximately equivalent airway smooth muscle relaxant potencies in vitro and bronchodilator potency in vivo. However, their effects on histamine induced contraction in vitro were significantly different from their effects on histamine reactivity in vivo. Salbutamol was less potent in vitro producing a mean (SE) 2.4 (0.15) doubling dose increase in the histamine EC20 and adrenaline a 5.2 (0.18) doubling dose increase (mean difference between salbutamol and adrenaline 2.8 doubling doses; 95% CI 1.1 to 4.5). Salbutamol had no effect on the maximal response to histamine whereas adrenaline reduced it by 54%. In contrast, salbutamol was more potent in vivo producing a mean (SE) increase in PD20 histamine of 1.84 (0.5) doubling doses whereas adrenaline was without effect increasing PD20 by only 0.06 (0.47) doubling doses (mean difference between adrenaline and salbutamol 1.78, 95% CI 0.26 to 3.29 doubling doses). CONCLUSIONS--These findings suggest that the alpha adrenergic airway effects of non-selective adrenoreceptor agonists such as adrenaline offer no additional protection against histamine-induced broncho-constriction in vivo than beta 2 selective drugs such as salbutamol, despite adrenaline providing greater protection against histamine-induced contraction in vitro. The differences between the effects of these agents in vitro and in vivo may be related to their opposing vascular effects in vivo.     

Seasonal variation in non-specific bronchial reactivity: a study of wheat workers with a history of wheat associated asthma.

To investigate seasonal variation in non-specific bronchial reactivity in wheat workers, we carried out histamine inhalation tests in 29 workers (28 of them men) from a small farming community with symptoms of wheat associated asthma before, during and after the 1983-4 Australian wheat harvest season. Four were cigarette smokers, and the age range was 12-54 (mean (SD) 30 (10)) years. Twenty eight subjects were atopic (one positive skinprick test result in tests with 10 common antigens), 60% reacting to house dust mite and all to at least one of eight wheat antigens. Baseline spirometry gave normal results (mean FVC1 90% (SD 8%) predicted; FVC 91% (7%) predicted). Bronchial reactivity was tested by the method of Yan et al. The cumulative doses of histamine acid phosphate (up to 3.91 mumol) that caused a fall of 20% from baseline in FEV1 was determined (PD20) and expressed as the geometric mean. In the low exposure season, May 1983, nine subjects had a PD20 (mean 1.2, range 0.3-3.9 mumol). The number rose to 19 in the summer harvest season, December 1983 (mean 0.8, range 0.07-3.9 mumol) and returned to nine in the subsequent winter, July 1984 (mean 1.8, range 0.4-3.9 mumol). The change in the number of subjects with a PD20 was significant (p less than 0.01). Four additional subjects probably had increased bronchial reactivity in the harvest season: in two the post-saline FEV1 was too unstable to give them histamine challenge and in two the challenge was inadvertently discontinued prematurely. Baseline FEV1 and FVC fell by 8% between the first and second studies (p less than 0.001); values were intermediate in the third study (FEV1 3.74, 3.44, and 3.57; FVC 4.66, 4.28, and 4.41 litres respectively). Linear modelling analysis of log PD20, season, FEV1, FVC, age, seasonality of asthma symptoms and skin test data indicated that the harvest season was the only significant determinant of variation in log PD20. It is concluded that in these wheat workers there is a seasonal variation in bronchial reactivity that may reflect a response to allergens associated with grain.     

Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.     

Analysis of bronchial reactivity in epidemiological studies.

The measurement of bronchial reactivity in epidemiological studies has the advantage of quantifying an objective physiological feature of asthma. Bronchial reactivity was developed in a clinical setting and has been conventionally expressed as the dose of agonist producing a 20% fall in FEV1 (PD20). As PD20 can be estimated for less than 20% of subjects in general community surveys with the doses of agonist that are usually given, data from most subjects must be censored. Thus PD20 alone is a poor index of bronchial reactivity for epidemiological studies. Data from 809 aluminium smelter workers were used to evaluate alternative methods of analysing bronchial reactivity. Dose-response relationships were analysed by four methods: (1) PD20 by the conventional method of interpolating the dose on a logarithmic scale between the last two measurements of FEV1; (2) PD20 (with allowance for extrapolation), estimated by fitting an exponential curve to the dose-response data; (3) the linear regression slope between dose and FEV1 when significant; (4) the dose-response slope obtained in all subjects as the % change in FEV1 from baseline in response to total dose. When each of these measures was related to symptoms, diagnosis, and treatment of asthma, all differentiated between "asthmatic" and "non-asthmatic" subjects. The dose-response slope (method 4) had the advantages of simplicity and no censored data, and was shown to be clinically relevant. It is suggested that the dose-response slope should be used for the analysis of bronchial reactivity in epidemiological studies.     

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

Relation of the hypertonic saline responsiveness of the airways to exercise induced asthma symptom severity and to histamine or methacholine reactivity.

BACKGROUND: Conflicting views exist over whether responsiveness of the airways to hypertonic saline relates to non-specific bronchial hyperresponsiveness measured by histamine or methacholine challenge. The bronchoconstrictor responses to exercise and hypertonic saline are reported to be closely related, but the relationship between the symptoms of exercise induced asthma and airway responsiveness to hypertonic saline is not known. METHODS: In 29 asthmatic patients with a history of exercise induced asthma, the response to an ultrasonically nebulised hypertonic saline (3.6% sodium chloride) aerosol, measured as the volume of hypertonic saline laden air required to produce a fall in forced expiratory volume in one second (FEV1) of > or = 20% (PD20), was compared with the concentration of histamine (PC20; group 1) and methacholine (PC20; group 2) producing a 20% fall in baseline FEV1 and exercise induced asthma symptom severity score (groups 1 and 2). The hypertonic responsiveness was determined in a dose-response manner to a maximum dose of 310 1 and the exercise induced asthma symptom severity was scored on a scale of 0-5. RESULTS: Of the 29 patients, 23 (79%) were responsive to the hypertonic saline, with PD20 values ranging from 9 to 310 1. A significant correlation was found between the PD20 hypertonic saline and the exercise induced asthma symptom score. There was no significant correlation between the PD20 response to hypertonic saline and the histamine PC20 or methacholine PC20. The exclusion of those subjects who failed to respond to hypertonic saline improved the relationship between hypertonic saline and methacholine PC20. No significant correlation was found between the exercise induced asthma symptom score and histamine PC20 or methacholine PC20. CONCLUSION: These findings suggest that hypertonic saline responsiveness bears a closer relationship to the severity of exercise induced asthma symptoms than to the non-specific bronchial hyperresponsiveness measured by histamine or methacholine reactivity.     

Effect of nifedipine on arterial hypoxaemia occurring after methacholine challenge in asthma.

To investigate whether the effects of nifedipine on methacholine induced broncho-constriction could impair pulmonary gas exchange in bronchial asthma a randomised, double blind, crossover study in 13 symptom free asthmatic subjects was designed. Each patient underwent a methacholine bronchial challenge test on two separate days one week apart, after having either oral nifedipine (20 mg thrice daily) or placebo for three days. Arterial blood gases were measured before and after methacholine challenge in nine subjects. Prechallenge values of forced expiratory volume in one second (FEV1) and arterial oxygen tension (Pao2) were similar after nifedipine and after placebo. After challenge, the cumulative doses of methacholine required to produce a 20% fall in FEV1 (PD20 FEV1) were significantly larger after nifedipine (280 (SD 347)) cumulative breath units (CBU) than after placebo (120 (183) CBU; p less than 0.01). After challenge the fall in Pao2 values (17.1 (1.6) mm Hg; (2.28 (0.21) kPa)) was significantly greater than after placebo (11.7 (2.4) mm Hg; (1.56 (0.32) kPa) p less than 0.03). Our data show that although oral nifedipine significantly reduces airway reactivity in patients with mild bronchial asthma, it also adversely affects pulmonary gas exchange, resulting in a lowered postchallenge Pao2, probably because of worsening ventilation-perfusion relationships.     

Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma.

BACKGROUND: It has been suggested that inhaled corticosteroids may provide greater protection against constrictor stimuli that act indirectly such as exercise than those that act directly such as histamine. METHODS: The effects of six weeks treatment with inhaled budesonide (800 micrograms twice daily) on bronchial reactivity to histamine, exercise, and eucapnic voluntary hyperventilation of dry air were compared in a double blind, placebo controlled, non-crossover study in 40 subjects with asthma. Change in bronchial reactivity to histamine and eucapnic hyperventilation over the six weeks was measured as change in the provocative dose of histamine or dry air causing a 20% fall in FEV1 (PD20 histamine and PV20 eucapnic hyperventilation (EVH) of dry air); this was not possible for exercise because of the development of refractoriness. To enable the change in response to all three stimuli to be compared, the response (percent fall in FEV1) to a fixed dose was measured for all three challenge tests. RESULTS: After budesonide there was an increase in PD20 histamine from 0.48 to 2.81 mumol and in PV20 EVH from 364 to 639 litres, and a significant correlation between the changes in PD20 histamine and PV20 EVH (r = 0.63). The median percentage fall in FEV1 in response to eucapnic hyperventilation, exercise, and histamine was similar before budesonide (25.5%, 26.6%, and 24.5%); the reduction in the percentage fall in FEV1 with budesonide was also similar for the three challenges (18.9%, 17.5%, and 16.6%), and all differed significantly from the changes following placebo. There was a significant correlation between change in percentage fall in FEV1 after budesonide with the three stimuli (histamine v exercise: r = 0.48; histamine v eucapnic hyperventilation: r = 0.46; exercise v eucapnic hyperventilation: r = 0.63). CONCLUSION: The similar magnitude of change in bronchial reactivity to all three stimuli after budesonide and the within subject correlation obtained between these changes suggest that corticosteroids act by a common mechanism to protect against eucapnic hyperventilation, exercise, and histamine.     

Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children.

The prevalence of bronchial hyperreactivity to inhaled methacholine and of a clinical history of symptoms of asthma was determined in a birth cohort of 9 year old New Zealand children. A history of current or previous recurrent wheezing was obtained in 220 of 815 children. Of 800 who had spirometric tests, 27 (3.4%) had resting airflow obstruction (FEV1/FVC less than 75%). Methacholine challenge was undertaken without problem in 766 children, the abbreviated protocol being based on five breaths and four concentrations. A fall in FEV1 of more than 20% was observed in 176 children (23% of challenges, 22% of the full cohort) after inhalation of methacholine in concentrations of up to 25 mg/ml. The prevalence of bronchial reactivity in children with symptoms was related to the frequency of wheezing episodes in the last year, and the degree of reactivity to the interval since the last episode. Sixty four children (8.0%) with no history of wheeze or recurrent dry cough were, however, also responsive to methacholine 25 mg/ml or less, while 35% of children with current or previous wheezing did not respond to any dose of methacholine. Bronchial challenge by methacholine inhalation was not sufficiently sensitive or specific to be useful as a major criterion for the diagnosis of asthma in epidemiological studies. The occurrence of airway reactivity in children without symptoms of asthma, however, raises the possibility that adult onset asthma and the development of airways obstruction in some subjects with chronic bronchitis could have origins in childhood.     

Repeatability of lung function tests during methacholine challenge in wheezy infants

BACKGROUND: The repeatability of lung function tests and methacholine inhalation tests was evaluated in recurrently wheezy infants over a one month period using the rapid thoracic compression technique. METHODS: Eighty-one wheezy, symptom free infants had pairs of methacholine challenge tests performed one month apart. Maximal flow at functional residual capacity (VmaxFRC) and transcutaneous oxygen tension (Ptco2) were measured at baseline and after methacholine inhalation. Provocative doses of methacholine causing a 15% fall in Ptco2 (PD15 Ptco2) or a 30% fall in VmaxFRC (PD30 VmaxFRC) were determined. RESULTS: Large changes in VmaxFRC were measured from T1 to T2 with a mean difference between measurements (T2-T1) of 7 (113) ml/s and a 95% range for a single determination for VmaxFRC of 160 ml/s. The mean (SD) difference between pairs of PD30 VmaxFRC measurements was 0.33 (1.89) doubling doses with a 95% range for a single determination of 2.7 doubling doses. Repeatability of PD15Ptco2 was similar. A change of 3.7 doubling doses of methacholine measured on successive occasions represents a significant change. CONCLUSIONS: Baseline VmaxFRC values are highly variable in wheezy, symptom free infants. Using either VmaxFRC or Ptco2 as the outcome measure for methacholine challenges provided similar repeatability. A change of more than 3.7 doubling doses of methacholine is required for clinical significance.     

Effect of prior bronchoconstriction on the airway response to histamine in normal subjects.

We have examined the effect of prior bronchoconstriction on the bronchial responsiveness to inhaled histamine in nine normal subjects. The airway response to increasing concentrations of histamine aerosol was assessed by measurement of specific airways conductance (sGaw) in a body plethysmograph. The threshold provocative dose of histamine needed to cause a 35% fall in starting sGaw (PD35) and the steepest slope of the response were measured from cumulative log dose response curves. Histamine challenges were performed in duplicate after premedication with 0.9% sodium chloride (control) or methacholine aerosol on separate days. The mean starting sGaw did not change significantly after inhalation of 0.9% sodium chloride but methacholine caused a mean reduction in sGaw of 42%. Mean control PD35 values did not differ significantly from mean PD35 values after methacholine. The mean steepest slope of the response after methacoline was 47% lower than the mean control value. There was a significant linear relationship between starting sGaw and the steepest slope for the control and for the methacholine premedicated challenges. The reduction in slope after methacholine was accounted for by the fall in starting sGaw. Because histamine PD35 was not altered by prior bronchoconstriction, it is concluded that the bronchial hyperresponsiveness of asthmatic subjects to non-specific bronchoconstrictor stimuli is unlikely to be a direct consequence of their low starting airway calibre.     

Methacholine bronchial challenge using a dosimeter with controlled tidal breathing.

A new inhalation synchronised dosimeter triggered by low inspiratory flow rates has been assessed. The methacholine challenge test using dosimeter nebulisation with controlled tidal breathing was compared with continuous nebulisation using De Vilbiss No 40 nebulisers with deep inhalations in 11 asthmatic subjects. Within subject PD20 FEV1 values were lower with the dosimeter method than with the continuous nebulisation method (geometric means 158 and 588 micrograms). The repeatability of the dosimeter method with controlled tidal breathing was studied in 11 asthmatic subjects, and the 95% range for a single measurement was +/- 0.72 doubling doses of methacholine. The dosimeter method has greater efficacy because aerosol is delivered during the first part of an inhalation, minimising loss of aerosol outside the respiratory tract. The dosimeter technique combined with controlled tidal breathing appears to be a useful method for carrying out standardised non-specific bronchoprovocation tests.     

Effect of inhaled prostaglandin E2 on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma.

Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine.     

Repeatability of bronchial hyperresponsiveness to adenosine-5'-monophosphate (AMP) by a short dosimeter protocol

BACKGROUND: To study bronchial responsiveness to adenosine 5'-monophosphate (AMP) in population surveys, repeatability of a rapid dosimetric method with quadrupling doses was evaluated. METHODS: Volunteers with symptoms of airway respiratory allergy or asthma were invited for AMP challenges on two occasions. After each dose the fall in forced expiratory volume in one second (FEV(1)) compared with the post-saline value was determined. The cumulative doses of AMP needed to cause a fall in FEV(1) of 20% (PD(20)), 15% (PD(15)), and 10% (PD(10)) were calculated. Agreement was evaluated by means of kappa values. After excluding systematic differences in PD values on two occasions (t test), repeatability of a single estimation of the chosen PD values was calculated and expressed in doubling doses (DD). RESULTS: In 28 of 76 subjects a PD(20) was estimated on the two visits, in 29 subjects a PD(15) was estimated, and in 32 a PD(10) was obtained. Kappa values for a positive threshold were 0.89 for a cut off level for a 20% fall in FEV(1), 0.78 for a 15% fall in FEV(1), and 0.76 for a fall in FEV(1) of 10%. The PD values did not differ between the two visits and 95% repeatability of a single estimation was +/-1.7 DD for PD(20), +/-2.2 DD for PD(15), and +/-2.4 DD for PD(10). The quadrupling dose method reduced time by 40% in non-hyperresponsive subjects and no adverse effects were observed. CONCLUSION: The short dosimeter protocol with quadrupling doses for AMP challenges is a rapid, reproducible tool for estimating bronchial responsiveness in population surveys.     

Use of tracheal auscultation for the assessment of bronchial responsiveness in asthmatic children.

BACKGROUND: It can be difficult to assess bronchial responsiveness in children because of their inability to perform spirometric tests reliably. In bronchial challenges lung sounds could be used to detect the required 20% fall in the forced expiratory volume in one second (FEV1). A study was undertaken to determine whether a change in lung sounds corresponded with a 20% fall in FEV1 after methacholine challenge, and whether the occurrence of wheeze was the most important change. METHODS: Fifteen children with asthma (eight boys) of mean age 10.8 years (range 8-15) were studied. All had normal chest auscultation before the methacholine challenge test. Lung sounds were recorded over the trachea for one minute and stored on tape. They were analysed directly and also scored blindly from the tape recording by a second investigator. Wheeze, cough, increase in respiratory rate, and prolonged expiration were assessed. RESULTS: The total cumulative methacholine dose causing a fall in FEV1 of 20% or more (PD20) was detected in 12 children by a change in lung sounds - in four by wheeze and in eight by cough, increased respiratory rate, and/or prolonged expiration. In two subjects altered lung sounds were detectable one dose step before PD20 was reached. In three cases in whom no fall in FEV1 occurred, no change in lung sounds could be detected at the highest methacholine dose. CONCLUSION: Changes in lung sounds correspond well with a 20% fall in FEV1 after methacholine challenge. Wheeze is an insensitive indicator for assessing bronchial responsiveness. Cough, increase in respiratory rate, and prolonged expiration occurs more frequently.     

Repeatability of methacholine challenge in asthmatic children measured by change in transcutaneous oxygen tension.

BACKGROUND: The airway response to bronchial provocation may be evaluated by monitoring the fall in transcutaneous oxygen tension (PtcO2) but the repeatability of this method has not been rigorously assessed. METHODS: To determine the repeatability of this indirect method of assessment, bronchial challenge was performed with methacholine in nine children with stable asthma (age range 6-12 years) and was repeated 24 hours later. The response was determined by the fall both in forced expiratory volume in one second (FEV1) and in PtcO2. A modified tidal inhalation protocol was used in which quadrupling concentrations of methacholine were given, thereby reducing the time taken for the full challenge by almost half. The concentrations of methacholine that provoked a 20% decrease in FEV1 (PC20FEV1) and 15% and 10% falls in PtcO2 (PC15PtcO2, PC10PtcO2) were calculated. RESULTS: Repeatability measures, assessed as the 95% range for a single determination, were +/- 0.96 and +/- 1.12 doubling concentration differences respectively for PC15PtcO2 and PC10PtcO2 and +/- 0.80 for PC20FEV1. CONCLUSION: This challenge method using quadrupling concentrations and an indirect assessment of the response by PtcO2 was sufficiently repeatable for clinical use and compared favourably with repeated challenge assessed by FEV1. The PtcO2 method is simple and effort independent, and should prove particularly useful for measuring bronchial reactivity in young children.     

Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects

BACKGROUND: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed. METHODS: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing. RESULTS: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD(20), geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p=0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p=0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens. CONCLUSION: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.     

Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma.

BACKGROUND--Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. METHODS--Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. RESULTS--Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. CONCLUSIONS--These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.