Using BAL, we studied the effects of 8 wk of treatment with salmeterol on airway inflammation in nine asthmatic subjects in a double-blind crossover placebo-controlled protocol. The study patients were all receiving regular inhaled corticosteroid therapy (400 to 1,000 micrograms beclomethasone dipropionate per day) and inhaled albuterol for symptomatic relief, i.e., subjects who might be considered suitable for treatment with salmeterol. The asthmatic group had significant differences in numbers of epithelial cells and eosinophils in BAL compared with a group of 15 normal control subjects (p < 0.01). During salmeterol treatment mean morning and evening peak flow rates were increased (p < 0.05). There was no significant change in BAL cell profile and no change in percentages of CD4 and CD8 lymphocytes or proportion of lymphocytes expressing HLA-DR after salmeterol. In conclusion, we were unable to demonstrate any significant anti-inflammatory effect of regular salmeterol therapy on airway inflammation using BAL in these asthmatic patients. At the same time, there was equally no evidence of a deterioration in the underlying inflammatory disease process.

Background The value of measuring airway responsiveness in asthma research is currently limited by the number of different methods used by different investigators, by the lack of a standardised method of expressing precision, and by an inability to equate the results of one method with those of another. Methods Two pairs of measurements of airway responsiveness to methacholine were performed in 20 asthmatic subjects, one pair using a dosimeter method (AR-D) and one pair using the conventional Wright nebuliser tidal breathing method (AR-W). The two methods normally use different techniques for quantifying changing levels in forced expiratory volume in one second (FEV,) after each dose of methacholine (the mean of the highest three of six measurements for AR-D, the lower of two measurements for AR-W), and different techniques for expressing measurements of airway responsiveness (the provoking dose (PD20) and the provoking concentration (PCQ0) respectively responsible for a 20% decrement in FEV,). Results The coefficient of repeatability (and hence precision) for the measurement of airway responsiveness was significantly better for AR-D (3.0) than for AR-W (10.9), but the technique for quantifying FEV, contributed more to this than the technique for delivering methacholine. A PCQ0 of 1 mg/ml with AR-W was equivalent to a PD,0 of 103 pg withConclusions It is practical as well as desirable to compare the precision of different techniques for the measurement of airway responsiveness and to derive conversion factors so that results may be equated. (Thorax 1993;48:239-243) Airway responsiveness provides a useful concept in understanding asthma and its measurement is valuable in asthma research. Of the various bronchoconstrictor stimuli used, nebulised methacholine is probably the most popular. At present several different methods of methacholine delivery are employed together with various different methods of expressing or measuring airway responsiveness. This limits the value of such measurements because the results from one laboratory cannot readily be compared with those from another. There is consequently a need to establish some means of defining precision in measurement-for example, coefficient of repeatability-and of equating results between methods.Of the two measurement methods which are currently most popular, that using the Wright nebuliser has become the conventional one throughout much of Canada, Australasia and Europe.' Aerosol is generated continuously over successive periods of two minutes from doubling concentrations of methacholine and is inhaled by the test subject during tidal breathing. The dose delivered consequently depends on tidal volume and ventilatory frequency as well as on aerosol output and so is not readily quantified, although it may be closely repeatable for the individual subject. As a result airway responsiveness is expressed by the provoking concentration of methacholine (rather than the delivered dose) which is estimated to provoke a 20% decrement in the forced expirator...

The authors investigated changes in asthma prevalence and perception of bronchoconstriction over 6 yrs in adults of Newcastle-upon-Tyne.Postal questionnaires were sent to 6,000 subjects aged 20-44 yrs in 1992-1993 and 1998-1999. Random samples of 600 responders had assessments of atopy, airway responsiveness, and their ability to perceive methacholine-induced bronchoconstriction. The prevalences of asthmatic symptoms, physician-diagnosis, and medication use increased by an average of 4.4%, particularly in subjects aged v30 yrs (8.7 versus 2.7). Atopy prevalence increased from 25% to 31% but atopics and nonatopics had similar mean changes in questionnaire data (5.2 versus 3.4). The probability of a positive methacholine test decreased as did the mean methacholine dose/response slope (0.00527 to 0.00379), indicating lower levels of airway responsiveness. This can be largely explained by an increase in use of inhaled corticosteroids (5.0-9.3%). The proportion of subjects perceiving bronchoconstriction during methacholine tests increased from 63 to 77%.The authors conclude that current changes in asthma epidemiology in adults may result from increased awareness of symptoms (and/or an increased willingness to report them), and from an increased willingness of physicians to make the diagnosis and prescribe treatment, not from increased disease prevalence. Eur Respir J 2002; 20: 826-833.

A digital subtraction imaging technique was used to visualise directly the anatomical distribution of 3 x 60 ml aliquots of saline containing a low concentration of radio-opaque dye, introduced sequentially into a segment of the middle lobe. It was possible to estimate the relative movement of fluid within the segment during the sequential aspiration of each of these aliquots. The first 60 ml aliquot introduced stayed close to the bronchoscope and probably sampled only the proximal airways. With the introduction of cumulative volumes of 120 ml or more, the fluid filled the segment more evenly. Aspiration then moved fluid back from the periphery, implying that the aspirate had also lavaged both distal airways and alveoli.Bronchoalveolar lavage has become increasingly popular as a diagnostic and research tool over the last 15 years. Its applications have been as diverse as the measurement of mediators after antigen challenge in asthmatic patients' and the diagnosis of Pneumocystis carinii infection in immunosuppressed patients,2 although it is most widely used in the assessment and diagnosis of interstitial lung disease.3 The anatomical distribution of fluid introduced during bronchoalveolar lavage, however, has never been thoroughly investigated and there is wide variation in the way the procedure is performed. The volume instilled by different operators has ranged from 204 to 3005 ml and the site of lavage has varied from first order bronchi6 to subsegmental bronchi.7 In this study we have attempted to define the fluid distribution occurring during a standard bronchoalveolar lavage protocol, as routinely used in our practice, and to assess the movement of fluid that occurs at aspiration. muscularly 30 minutes before bronchoscopy, and 10 mg of diazepam was injected intravenously immediately before the start of the procedure. Over 15 minutes 4ml of 2% lignocaine were administered by nebuliser (Porta-Neb, Medic-aid) and I ml was injected into the trachea via the cricoid membrane, which allowed the procedures to be completed with no more than 2 ml of additional local anaesthetic. Peroral bronchoscopy was then performed with the subject supine and the instrument was wedged into a segment of the middle lobe. The medial segment was chosen for lavage in the first subject (study 1) and the lateral segment in the second (study 2). Both studies were recorded with a computer linked digital radiography system (Picker DAS 21 1), which exposed each subject to a total of 15 chest radiographs. A baseline image of the right hemithorax was taken in the anteroposterior plane at functional residual capacity (FRC) at the beginning of each study for subtraction from subsequent images. This allowed better low contrast sensitivity. Three successive aliquots of sterile phosphate buffered saline containing a 5% solution of the radioopaque iodinated dye lopamidol (Merck) were introduced at 25°C. This dye concentration was selected as a result of a preliminary series of experiments in which test tubes containing 1%, 5%, and 10% iop...

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A randomized double-blind placebo-controlled parallel group study with inhaled fluticasone propionate over 6 weeks, designed to quantify the beneficial effect on airway responsiveness, and so assess whether short pulses of intermittent prophylactic treatment might serve as an alternative means of managing mild asthma, is reported.The 20±50-yr-old participants, who were recruited from an epidemiological study of the general population, had never knowingly received any regular treatment for asthma. Fluticasone propionate at the maximum recommended dose level (2,000 mg daily) and placebo were administered via metered-dose inhalers, and airway responsiveness was quantified conventionally by the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20) at 2-week intervals during the treatment phase and at various intervals subsequently.Compared with placebo fluticasone propionate was associated with a highly significant decrease in airway responsiveness (1.9 doublings of the geometric mean PD20), which was maximal at the end of the 6-week treatment period. No persisting benefit was detectable at the next measurement 2 weeks later, or thereafter. Multiple linear regression analysis showed that the magnitude of the fluticasone propionate effect was significantly greater in males than in females (3.2 versus 1.2 doublings respectively of the geometric mean PD20), but was uninfluenced by current smoking, age or FEV1.In conclusion, in the absence of any possibility of tachyphylaxis, inhaled fluticasone propionate at this dose causes a steadily increasing improvement in airway responsiveness over a 6-week period, which is modified by sex but lost almost immediately on treatment cessation. Short pulses of intermittent prophylactic treatment would not, therefore, be useful as a means of managing mild asthma. Eur Respir J 2000; 15: 19±24. In an epidemiological study of a normal population of males and females many subjects were identified in whom airway responsiveness could be quantified but who had never knowingly received corticosteroid treatment, whether for asthma or other diseases, nor knowingly received any regular medication for asthma for >3 months [1]. The majority were not recognized to have (or to have had) asthma. Volunteers from among them were sought to evaluate the effect on airway responsiveness of inhaled fluticasone propionate, a potent topical steroid thought to have an enhanced benefit-risk ratio because of a high level of "first pass" hepatic metabolism and low oral bioavailability [2].The aim of this study was to quantify the effect of 6 weeks treatment at the maximum recommended dose by its peak and duration over the following 20 weeks. It was wondered whether short "pulses" of intermittent prophylactic treatment might offer an alternative means of management of mild asthma (or a means of preventing 'subclinical asthma' from becoming symptomatic) if the initial effect was sufficiently strong and sufficiently prolonged. The secondary aims were to...

Background -To assess the possible magnitude of differences between normal populations an epidemiological investigation ofasthma was conducted in two strongly contrasting districts of northern England -rural West Cumbria on the west coast and urban Newcastle upon Tyne on the east coast. Methods -A cross sectional survey of randomly identified men aged 20-44 years was conducted in two phases: phase 1, a postal survey of respiratory symptoms and asthma medication in 3000 men from each district; and phase 2, a clinical assessment of 300 men from each district comprising investigator administered questionnaires, skin prick tests, spirometry, and methacholine challenge tests. Results -The phase 1 (but not phase 2) study showed a small excess of "ever wheezed" in Newcastle (44% versus 40%), but neither phase showed differences between the two districts for recent wheeze or for other symptoms characteristic of asthma. There were also no differences with regard to diagnosed asthma, current asthma medication, spirometric parameters, or airways responsiveness. The prevalence of quantifiable airways responsiveness (PD20 < 6400 dg) was 27 7% in West Cumbria and 28-2% in Newcastle. Regression analyses showed that PD20 was negatively associated with atopy and positively with forced expiratory volume in one second (FEV,); that an association between PD20 and current smoking could be explained by diminished FEV,; and that PD20 was not related to geographical site of residence. Conclusions -Neither airways responsiveness nor the other parameters of diagnostic relevance to asthma varied much between the two study populations, despite the apparent environmental differences. The most obvious of these were the levels of outdoor air pollution attributable to vehicle exhaust emissions, the ambient levels of which were 2-10 fold greater in Newcastle. Our findings consequently shed some doubt over the role of such pollution in perceived recent increases in asthma prevalence. It is possible, however, that an air pollution effect in Newcastle has been balanced by asthmagenic effects of other agents in West Cumbria. (Thorax 1996;51:169-174) Keywords: asthma, epidemiology, airways responsiveness, air pollution.There is concern at present over reported increases in asthma symptoms, diagnosis, medication, sickness absence, hospital admission, and death.'-7 These apparent increases in morbidity and mortality have occurred despite advances in the understanding and management of the disease,89 and despite diminishing morbidity and mortality from other diseases amenable to effective preventive and therapeutic intervention.'0 A plausible and popular explanation is that the incidence of asthma is increasing, though trends may have been exaggerated by changes in diagnostic fashion."Migration and twin studies have shown that asthma is largely an acquired disease determined by environmental factors. 1-14 A logical step towards their elucidation is standardised investigation of populations living under different environmental conditions. Al...

Hypersensitivity to formalin used to sterilise artificial kidney machines was shown by inhalation provocation tests to be responsible for attacks of wheezing accompanied by productive cough in two members of the nursing staff of a haemodialysis unit. Three further members of the staff of 28 who were continually exposed to this substance occupationally had developed similar recurrent but less frequent episodes since joining the unit. Two underwent inhalation provocation tests with formalin which did not reproduce these symptoms. Single episodes of these symptoms had been noted by three additional staff members so that altogether eight (29 %) had experienced attacks described as bronchitic since becoming exposed to formalin. We suggest that, while exposure to formalin did not seem Although contact dermatitis caused by formalin sensitivity is well recognised, the intrathoracic airways appear to be surprisingly immune to this toxic substance despite its immediate intense irritative effect on the eyes and upper respiratory tract. Both pneumonitis (Porter, 1975) and asthma (Sakula, 1975) have recently been reported after occupational exposure to formalin, and there are three previous reports of occupational asthma shown to be attributable to formalin sensitivity by inhalation provocation tests. Vaughan (1939) described a match factory worker with this disorder and Popa et al. (1969) reported a number of similarly affected workers engaged in the tanning and rubber industries. More recently we described a nursing sister from a renal haemodialysis unit who had developed asthma as a result of continual exposure to the formalin used to sterilise the artificial kidney machines (Hendrick and Lane, 1975). Since then another nurse from the same haemodialysis unit has been shown to be affected and this prompted a survey of all the members of the staff in an attempt