A multinational study of treatment failures in asthma management.

SETTING: Emergency rooms. OBJECTIVE: To assess quality of care and its determinants for asthma patients before emergency room treatment. DESIGN: Consecutive patients with acute severe asthma attending emergency rooms were questioned about the severity of their disease and treatment in the previous 4 weeks. Prescriptions of inhaled corticosteroids were recorded. Other outcomes included self-reported adherence to treatment and loss of work. RESULTS: Thirteen centres in 11 countries recruited 1156 patients. Only 36% of patients with persistent asthma had been prescribed an adequate dose of inhaled corticosteroids. This percentage improved in those receiving regular care from the same doctor (OR 2.86, 95%CI 1.38-5.96), and was at least as good for the 10% of patients receiving 'private' health care (OR 3.08, 95%CI 1.69-5.62). Forty-four per cent of patients had health insurance covering some asthma medications. These patients were more likely to be receiving adequate inhaled corticosteroids (OR 1.74, 95%CI 1.17-2.58), and reported better adherence than those without insurance (OR 3.00, 95%CI 1.64-5.50). Of those on adequate inhaled corticosteroids, 18% had lost work in each of the 4 previous weeks compared with 59% among those more than one treatment step below the recommended dose. CONCLUSIONS: Access to adequate treatment is critical for better management of asthma.

Reliability, repeatability and sensitivity to change of externally and self-paced walking tests in COPD patients.

In COPD, several walking tests have been proposed to measure exercise tolerance but their relative merits are uncertain. We studied 57 moderate-to-severe, stable COPD patients (mean FEV1 35 +/- 12% predicted). Within a 2-month period, we compared reliability (inter-subject variability) and repeatability (intra-subject variability) of the most widely used 6-min walks (6MWD), with self-paced 2-min walks (2MWD) and externally paced, incremental shuttles (Shuttle). On 9 separate days either of the three 6MWD, 2MWD or Shuttles were performed (nine walks of each type). Then, each walk was performed before and after bronchodilators (BD) to assess sensitivity to change (mean change/standard deviation of change (sensitivity index--SI)). For all exercise tests, reliability was >90% (2MWD 95%, 6MWD 92% and Shuttle 91%). Repeatability was excellent (overall <10% intra-subject variation; for 2MWD 5%, 6MWD 8% and Shuttle 9%). On average, the first walking distance was significantly shorter, but there were no significant differences between second and third walks. Dyspnoea scores were much less reproducible. BD produced highly significant improvements in Shuttle (pre-BD 27 SD=11 --> post-BD 30 SD=11), 6MWD (424 m SD=115 --> 462 m SD=106) and 2MWD (153 m SD=35 --> 162 m SD=34), (P < 0.0001). SI was similar for all walks (6MWD 0.84, 2MWD 0.75 and Shuttle 0.76). In moderate-to-severe COPD, 2MWDs are as informative as 6MWDs without their disadvantages. Self-paced walks are as useful as externally paced Shuttles.

Does the mode of inhalation affect the bronchodilator response in patients with severe COPD?

Spacing devices improve lung deposition of aerosols from metered dose inhalers (MDI) but it is sometimes difficult for dyspnoeic patients to perform maximal breaths with breath-holds needed to inhale the aerosols from them. Our aim was to determine whether the response to bronchodilators (BD) depended on the method of inhalation. We studied 20 patients with moderately severe chronic obstructive pulmonary disease (COPD) with a mean age of 68 years and a mean of forced expiratory volume in 1 sec (FEV1) of 41% predicted. In a randomized, cross-over fashion they inhaled terbutaline 1.5 mg (six puffs) followed by ipratropium 120 microg (six puffs) via MDI and nebuhaler with either two inspirations to total lung capacity and a 10-sec breath-hold per puff or with six tidal breaths per puff. Before and after BDs we measured FEV1, forced vital capacity (FVC), airways resistance using interrupter method (Rint) and 6-min walking distance (6MWD). Subsequently, we re-tested nine of these patients with the two methods of inhalation, before and after conventional doses (terbutaline 500 microg+ipratropium 40 microg), then after terbutaline 1 mg and ipratropium 80 microg and finally after nebulized terbutaline 5 mg and ipratropium 500 microg to sec whether there was a dose-dependent difference in effect between the two methods. Spirometry, slow vital capacity (SVC). inspiratory capacity and shuttle walking tests were monitored. In the original 20 patients there were highly significant improvements in all parameters after inhalers, with no significant difference between methods of inhalation. Median improvements after BDs were: FEV1 0.221 and 0.191, FVC 0.501 and 0.381 and 6MWD 40 m and 44 m, for maximal breaths and tidal breathing, respectively. For nine patients, tidal and maximal breaths produced similar effects on lung function and exercise tolerance at both doses of BDs. Nebulized BDs only improved shuttle distances slightly when compared with either method of inhalation from MDI and spacer but had no additional effect on lung function. In conclusion, in patients with moderately severe COPD, BDs given by metered dose inhaler via nebuhaler have similar effects whether given by six easy tidal breaths or the more difficult two maximal breaths with breath-hold. This holds true at small or larger doses of BD. Either method of inhaling six puffs of the BDs can be used as an effective alternative to nebulized aerosol.

The role of domiciliary nebulizers in managing patients with severe COPD.

The difficulty of assessing nebulizer responses in chronic obstructive pulmonary disease (COPD) has been demonstrated before. This study aims to re-examine both the role of domiciliary nebulizers in COPD and also bronchodilator (BD) assessment in individuals. In a double-blind, randomized, cross-over trial, 19 stable patients with severe COPD were given the following medication 6-hourly for 2-week periods: (1) nebulized salbutamol 2.5 mg with ipratropium 0.5 mg and placebo inhalers (MDI) with spacer; (2) placebo nebules and inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer; (3) inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer (but no placebo nebulized drugs). Both nebulized and MDI drugs produced highly significant improvements in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), specific airways conductance, 6-min walking distance (6MWD) and residual volume. There were no significant differences between BD responses obtained after active nebulized and active MDI BDs. From the diary cards, 2 weeks of active nebulized BDs produced a slightly higher median peak expiratory flow (PEF) than active MDI BDs (236 and 219 l m(-1), respectively, P=0.01) and slightly less extra inhaler use (0.8 and 1.1 puffs, respectively, P<0.05) but no significant difference in dyspnoea or quality of life (QOL) scores. There were significant correlations between domiciliary PEF and acute BD-induced changes in FVC and 6MWD, and also between domiciliary dyspnoea scores and acute changes in both total lung capacity and 6MWD. In conclusion, nebulized medication conferred little clinical advantage over the regular use of inhalers with spacers in this group of patients with severe COPD. However, acute changes in total lung capacity, FVC and 6MWD may be useful predictors of the longer-term effects of nebulized BDs in individual patients.

Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.

BACKGROUND: Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds. METHODS: We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%). FINDINGS: Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees. INTERPRETATION: Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.

Effects of psychotherapy in moderately severe COPD: a pilot study.

Anxiety is common in the "pink puffer" syndrome associated with chronic obstructive pulmonary disease (COPD). The degree of anxiety correlates well with perceived dyspnoea. This pilot study examines the effect of group psychotherapy on anxiety, exercise tolerance, dyspnoea and quality of life. Ten patients with moderately severe, stable COPD (mean forced expiratory volume in one second (FEV1)-1.15 L) had six 90 min sessions of cognitive and behavioural psychotherapy at weekly intervals. Patients completed the Hospital Anxiety and Depression Scale (HADS), Medical Research Council Questionnaire (MRCQ) and St George's Respiratory Questionnaires (SGRQ), 1 week before and after therapy. FEV1, forced vital capacity (FVC), slow vital capacity (SVC), blood gas tensions and 6 min walking distance (6MWD) were measured. Eight control patients attended weekly for lung function and 6MWD for 6 weeks, but had no psychotherapy. Mean baseline HADS score was significantly higher in the psychotherapy group (12) than in controls (7), but otherwise there were no differences in lung function, blood gas tensions, 6MWD, or the other questionnaire scores between groups. After treatment, the physiological and psychological parameters where unchanged in both groups with the exception of the mean 6MWD, which had improved in the psychotherapy group only, from 351 to 423 m (p<0.001), an increase of 24%. Three months after treatment, the 6MWD was still 16% above the baseline value (p=0.02). In conclusion, six sessions of cognitive and behavioural psychotherapy produced a sustained improvement in exercise tolerance in a group of 10 anxious patients with severe chronic obstructive pulmonary disease, without any change in anxiety scores on the Hospital Anxiety and Depression Scale. Further studies of more prolonged, intensive psychotherapy would establish whether better symptom and quality of life scores accompany more dramatic increases in exercise tolerance in "pink puffers".

Histamine receptors in the human nose.

The aim of this study was to determine the role of histamine receptors in the nose. The effects of intranasal histamine challenge were compared with those of a specific H1-receptor agonist, betahistine and a specific H2-receptor agonist, impromidine, in 11 normal individuals and four with rhinitis. Sneezing, nasal irritation and hypersecretion were induced by histamine and the H1-receptor agonist, betahistine only. Nasal airway resistance (Rna) was measured by passive anterior rhinomanometry. Histamine, betahistine and impromidine all induced rises in Rna in both normal individuals and those with rhinitis but histamine had the most potent effect; the H2-receptor effect on Rna was predominant over that of the H1-receptor. The sensitivity to all three agonists was greater in the individuals with rhinitis.

Evaluation of active anterior and posterior rhinomanometry in normal subjects.

In this study active anterior (AAR) and active posterior (APR) rhinomanometry were performed by 100 normal subjects with a Mercury rhinomanometer according to the recommendations of the International Standardization Committee. There was no significant difference between total nasal airway resistance (Rna) values obtained with APR by direct measurement and those calculated from AAR. Mean total Rna was 0.31 Pa/cm3/s (range 0.13-0.84) at a reference pressure of 75 Pa. Measurements by AAR were more reproducible than those by APR, mean intrasubject coefficients of variation were 12 and 16% respectively. This reproducibility was similar to that of lower airways' resistance measurements. Rna values from this population did not conform to a normal Gaussian distribution. Rna was higher during expiration than inspiration and values were higher in women than in men.

Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer" syndrome.

The aim of this study was to assess the effects of diamorphine on breathlessness and exercise tolerance in patients with severe chronic airflow obstruction and normal arterial carbon dioxide tension (PCO2) levels ("pink puffer" syndrome). In this double-blind, cross-over, randomized study we examined both acute and chronic effects of single and multiple doses of oral diamorphine in 14 "pink puffer" patients. Their mean resting forced expiratory volume in one second (FEV1) was 36% predicted normal, mean arterial oxygen tension (PaO2) was 9.2 kPa and mean PaCO2 was 5.2 kPa. Ten patients took either diamorphine 2.5 or 5 mg or placebo elixir 6 hourly for 2 weeks, recording on a diary card dyspnoea, sleepiness and well-being on a visual analogue scale (VAS). The final treatment was given 30 min before measuring spirometry, arterial blood gases, plasma morphine levels, 6 min walking distances, time walked on treadmill and self-assessment of dyspnoea on a VAS scale after exercise. On two further days, eight patients took two doses, 4 h apart, of either diamorphine 7.5 mg or placebo elixir. Spirometry, 6 min walking distance with a VAS score for dyspnoea were measured before and at 1 h after each dose. Morphine levels and blood gases were also measured. Whether given in single or repeated doses, oral diamorphine had no significant effect on exercise tolerance and breathlessness when compared with placebo. Diamorphine 2.5-7.5 mg produced neither sleepiness nor a deterioration in blood gases. However, plasma levels associated with analgesic efficacy were not achieved with these doses. Thus, as given in this study, oral diamorphine is unlikely to have therapeutic potential in the treatment of dyspnoea in the "pink puffer" syndrome.

The effect of a beta 2-adrenergic agonist and a histamine H1-receptor antagonist on the late asthmatic response to inhaled antigen.

In this double-blind, randomized, cross-over trial, the role of histamine and the possible protective effect of a beta 2-adrenergic agonist in the later asthmatic response to inhaled antigen was investigated in nine atopic asthmatic patients. On four study days, 2-4 weeks apart, patients were given either: placebo; salbutamol aerosol 400 micrograms before and 200 micrograms 2-hourly after challenge; oral terfenadine 120 mg 2 h before and 10 h after challenge; and, on the final day, lung function was monitored without medication or antigen challenge. A nebuliser-dosimeter system was used to deliver a predetermined, single dose of antigen aerosol. Response was assessed by specific airways conductance (SGAW) measured in a body plethysmograph; FEV1 and PEFR were measured with a Pocket Spirometer. All measurements were made for 10 h in the clinic and then the patients continued to record PEFR and FEV1 at home for at least 2 more hours. Similar findings were obtained with all three lung function parameters. After challenge, the early response (ER) was small when compared with the late response (LR). All patients had a definite LR on the placebo day when FEV1 was compared with 'no challenge day'. Neither drugs had much effect on the small ER. The LR was not altered by terfenadine but was very significantly attenuated by salbutamol; the mean maximum fall in FEV1 during LR being 31, 29 and 12% after placebo, terfenadine and salbutamol, respectively. It is unlikely that histamine plays an important role in the LR to inhaled antigen but beta 2-adrenergic stimulants can attenuate LR, probably by directly preventing bronchial smooth muscle constriction and also by stabilising bronchial mast cells.

Comparison of oscillation with three other methods for measuring nasal airways resistance.

In this study we have compared the sensitivity and reproducibility of nasal airways resistance measurements made using an oscillometer, with those made by passive anterior, active anterior and active posterior rhinomanometry. Nasal airways resistance values were compared in 12 patients with rhinitis and 15 normal subjects, of whom ten had additional measurements after a vasoconstrictor spray, oxymetazoline. The coefficients of variation of 6-8 technically satisfactory measurements were 9-19%. The decongestant effect of oxymetazoline was detected by all methods, with no decrease in reproducibility. Post vasoconstrictor nasal airways resistance fell by 28% (passive anterior), 35% (active anterior), 36% (active posterior) and 58% (oscillometry). In conclusion, the oscillation method for deriving nasal airways resistance is a useful, new, simple and noninvasive way of assessing nasal airways patency. Results compare favourably with other, more established techniques.

Effect of dietary supplementation with fish oil lipids on mild asthma.

Recruitment of inflammatory leucocytes to the airways may play a part in the pathogenesis of asthma. As dietary enrichment with fish oil lipids can suppress leucocyte function, the effect of these lipids on asthma control and neutrophil function was studied in 20 subjects with mild asthma. Twelve subjects received capsules containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily and eight subjects received placebo capsules containing olive oil for 10 weeks in a double blind fashion. Baseline specific airways conductance, airways responsiveness to histamine and exercise, diurnal peak expiratory flow, symptom scores, and bronchodilator use were measured. Neutrophil fatty acid composition was evaluated by gas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 and LTB5 generation were measured by reverse phase high performance liquid chromatography and radioimmunoassay, and neutrophil chemotactic responses to formyl-methionyl-leucyl-phenylalanine (FMLP) and LTB4 were assessed by a microchemotaxis technique. Although the fish oil supplemented diet produced a greater than 10 fold increase in the eicosapentaenoic acid content of neutrophil phospholipids, there was no significant change in airways responsiveness to histamine or any change in any of the clinical measurements. After dietary supplementation with fish oil there was a 50% inhibition of total LTB (LTB4 + LTB5) generation by ionophore stimulated neutrophils and neutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged in the placebo group. It is concluded that in subjects with mild asthma a fish oil enriched diet attenuates neutrophil function without changing the severity of asthma.

Pulmonary epithelial permeability in bronchiectasis.

We measured pulmonary epithelial permeability in 17 non-smoking patients with generalized bronchiectasis, of whom six had cystic fibrosis, by determining the half-time clearance from lung to blood (T1/2LB) of inhaled 99mTc-labelled diethylene triamine pentaacetate. Their age range was 15-79 years and the range of their FEV1 measurements was 20-87% of the predicted normal. Sputum obtained by prestudy chest physiotherapy revealed significant colonies of Pseudomonas aeruginosa in six, Haemophilus influenzae in three, Staphylococcus aureus in three and Pasteurella mitocida in one patient, while in the remainder there was normal flora only. Lung clearance was significantly faster in the 13 culture-positive patients (mean T1/2LB = 28 minutes) compared with the four culture-negative patients (mean T1/2LB = 54 minutes). There was no correlation between T1/2LB and prestudy FEV1. The study was repeated in six patients following a course of antibiotics. In two patients only was the sputum cleared of organisms and in those the lung permeability decreased significantly. There was no change in lung permeability in the four patients in whom it was impossible to eradicate the sputum organisms. Thus, in our patients with generalized bronchiectasis, lung permeability was increased only in those with both purulent sputum and significant colonization of the respiratory tract by bacterial pathogens. However, this increase in lung permeability was not associated with worse lung function.

Histamine receptors and pulmonary epithelial permeability.

In seven normal subjects and five asthmatics we have compared the effects of inhaled histamine with that of betahistine (a relatively selective H1-receptor agonist) and that of impromidine (a relatively H2-receptor agonist) on pulmonary epithelial permeability, as measured by the half-time clearance from lung to blood of inhaled 99mTc-DTPA (t1/2LB). Both histamine and betahistine produced statistically significant falls in baseline t1/2LB and peak expiratory flow rate, while impromidine produced no significant effects on either parameter. Similar results were obtained in normal subjects and asthmatics alike. In four of the normal subjects, histamine-induced falls in t1/2LB and peak expiratory flow rate were prevented by oral pretreatment with terfenadine 120 mg but not by cimetidine 400 mg. Histamine-induced increases in lung permeability and bronchoconstriction are both mediated via H1-receptors in normal and asthmatic subjects.

Comparison of the effects of histamine H1- and H2-receptor agonists on large and small airways in normal and asthmatic subjects.

It is accepted that histamine H1-receptors are present on human bronchial smooth muscle and that they mediate bronchoconstriction. However, the role of the histamine H2-receptor in the airways of man is less certain. In ten non-asthmatic and five asthmatic subjects we have compared the effects of inhalation of a specific H1-receptor agonist, betahistine, a specific H2-receptor agonist, impromidine and the combined H1- and H2-receptor agonist, histamine, on specific airways conductance and measurements from partial expiratory flow-volume curves. Both histamine and betahistine induced reproducible dose-dependent bronchoconstriction in all subjects, as assessed by all measurements made. Impromidine had no effect on measurements of airways function in either group of subjects. These results confirm the presence of bronchoconstricting H1-receptors, and the absence of significant numbers of H2-receptors on human bronchial smooth muscle. There is no difference in the distribution of these receptors in normal and asthmatic subjects.

Effect of an oral H1-receptor antagonist, terfenadine, on antigen-induced asthma.

We have investigated the effect of a specific H1-receptor antagonist, terfenadine, on antigen-induced asthma. In a double-blind, randomized fashion, nine stable asthmatics were given placebo, or terfenadine 60, 120 or 180 mg orally, 12 and 4 hours before challenge. Cumulative bronchial challenge with specific antigen aerosols were delivered from a nebulizer attached to a breath-actuated dosimeter. Response was monitored by specific airway conductance and measurements from partial expiratory flow-volume curves, performed in a body plethysmograph, on line to a computer. Initially the histamine dose-response curves of four subjects were found to be shifted 10-fold to the right by terfenadine 60 mg, given orally. Compared with placebo, terfenadine 60 mg, given orally. Compared with placebo, terfenadine significantly shifted the mean antigen dose-response curves of all measurements to the right. However, this shift was small and not correlated to the dose of terfenadine. There was marked intersubject variation in the effect. Terfenadine produced no side effects. The immediate bronchial response to antigen can be attenuated by an oral H1-receptor antagonist, but the effect is small and, in general, unlikely to be clinically useful.

Assessment of nasal airway patency: a comparison of four methods.

Two established methods (active posterior and passive anterior rhinomanometry) and 2 new methods (peak nasal inspiratory flow rate and apparent nasal volume) were used in 12 volunteers to assess the patency of the nasal airways under each of 4 conditions (baseline, post-exercise, nasal histamine and nasal cocaine). All methods showed the congestant effect of histamine but the peak nasal inspiratory flow and apparent nasal volume techniques were more sensitive to the 'decongesting' manoeuvres, (exercise and cocaine). Useful objective quantitative data on the patency of the nasal airways and its changes in response to stimuli can be obtained by simple, cheap and readily available techniques. Subjective sensation is a poor guide to the state of patency of the nasal airways.