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To determine predictors for failed reduction of inhaled corticosteroids (ICS), in 50 subjects with well-controlled asthma (age 43.7 [18–69]; 22 males) taking a median dose of 1,000 μ g ICS/d (100–3,600 μ g/d), ICS were halved every 8 wk. Airway hyperresponsiveness (AHR) to a bronchial provocation test (BPT) with histamine was measured at baseline. AHR to BPT with mannitol, spirometry, exhaled nitric oxide (eNO), and, in 31 subjects, sputum inflammatory cells were measured at baseline and at monthly intervals. Thirty-nine subjects suffered an asthma exacerbation. Seven subjects were successfully weaned off ICS. Using a Kaplan– Meier survival analysis, the significant predictors of a failure of ICS reduction were being hyperresponsive to both histamine and mannitol at baseline (p = 0.039), and being hyperresponsive to mannitol during the dose-reduction phase of the study (p = 0.02). Subjects older than 40 yr of age tended to be at greater risk of ICS reduction failure (p = 0.059). Response to mannitol and p...

To evaluate the association between growth in height and growth in lung function, and to identify the potential temporal relationships between airway hyperresponsiveness (AHR), respiratory symptoms, and lung function growth during adolescence and young adulthood, we analyzed data collected from the Belmont cohort. Among the 718 schoolchildren initially studied at 1982 (aged 8-10 yr), 557 were studied between two times and six times at 2-yr intervals until 1992. Baseline lung function, AHR by histamine inhalation test, and recent wheeze by questionnaires, were measured at each visit. We found that between 17 and 19 yr of age, when growth in height had stopped, growth in FEV(1) was approximately 200 ml/yr in boys and 100 ml/yr in girls. Peak growth velocity of height occurred at age 13 both in boys and in girls, whereas peak growth velocity of FEV(1) occurred at the same age only in girls and 1 yr later in boys. Having AHR and recent wheeze at the previous study time were both associated with lower subsequent growth in FEV(1), but not with subsequent growth in FVC. We conclude that lung function continues to grow after the cessation of height growth and that growth in FEV(1) is reduced in subjects with AHR and/or recent wheeze.

In epidemiologic studies of asthma there is a group with recent wheeze, but with no airway hyperresponsiveness (AHR), in whom it is unclear whether any significant airway abnormality exists. Exhaled nitric oxide (NO) has been proposed as a measure of airway inflammation. We measured exhaled NO in a population sample of 306 young adults who also underwent bronchial challenge with histamine or a bronchodilator test. Subjects blew into a 3-L Tedlar bag against a 2-mm-diameter resistance to close the soft palate and exclude nasal air. The NO content of expired gas from a single breath was analyzed by chemiluminescent analyzer. Exhaled NO was log-normally distributed in the population sample and duplicate measurements were highly reproducible (intraclass correlation coefficient = 0.98). Exhaled NO correlated significantly with airway responsiveness, measured as the dose-response ratio to histamine (r = 0.39, p < 0.001) and with peripheral blood eosinophils (r = 0.35, p < 0.001). Exhaled NO was significantly greater in asthmatic subjects (geometric mean, 22.2; 95% confidence intervals, 16.1 to 30.7 ppb) than in normal subjects (7.8, 7.1 to 8.4, p < 0.001) or in subjects with wheeze but no AHR (8.8, 7.5 to 10.3, p < 0.001). We conclude that exhaled NO is log-normally distributed, is highly reproducible and discriminates well among subjects, suggesting that it is both a feasible and useful measurement for epidemiologic studies of asthma. The findings suggest that wheeze in the absence of AHR is unlikely to be associated with airway inflammation.

The absence of a maximal dose-response plateau as well as gas trapping and increases in closing capacity (CC) suggest that increased airway closure is an important mechanical abnormality of asthmatic airways. We compared the extent and distribution of airway closure in 13 normal and in 23 asthmatic subjects. Airway closure (LVclosed) was measured with single-photon emission computed tomography (SPECT) and an inhaled Technegas bolus as the percentage of lung volume without Technegas (LVtrans), and with CC, using nitrogen washout. LVclosed was compared in the apical, middle and lower zones, each being of equal vertical height. Values of mean LVclosed +/- 95% confidence interval (CI) were similar in normal (30 +/- 6.0% LVtrans) and asthmatic subjects (30 +/- 7.8% LVtrans). In normal subjects, LVclosed correlated with both age (r = 0.89, p < 0. 01) and CC (r = 0.86, p < 0.01), was more extensive in the lower zone (58 +/- 18.8% LVtrans, p < 0.01) than in the middle and upper zones (17 +/- 8.7% and 26 +/- 8.2 LVtrans, respectively), and increased with age in both the middle and lower zones (r = 0.94 and r = 0.90, respectively, p < 0.01). In asthmatic subjects, LVclosed did not correlate with age; was greatest in the lower zone, intermediate in the middle zone, and lowest in the apical zone (59 +/- 13.2%, 22 +/- 5.8%, and 12 +/- 4.4% LVtrans, respectively, p < 0. 01); and correlated weakly with age in the middle zone only (r = 0. 46, p < 0.05). We conclude that there is a predictable pattern of airway closure in normal subjects and that it is primarily influenced by pulmonary elastic recoil. This pattern is lost in asthmatic subjects. This may be explained by an increased range of closing pressures and a patchy distribution of airway closure, probably secondary to allergic inflammation.

Little is known about the effects of drugs on small airways. However, the small airways respond to constricting and dilating substances in vitro. Pathologic assessment demonstrates that small airways are inflamed, and the physiology suggests that they narrow and dilate. If after a period of treatment for asthma, all tests including the SBNT are normal, it would be safe to say that the small airways had been treated. However, we need to have some way of imaging the airways to decide whether or not there is abnormality in the small airways and to target the drugs that we are using to treat them. New ways of imaging, measuring, and performing a biopsy of the small airways are needed if we are going to make progress in this area.

Absence of a maximal dose-response plateau and mathematical modeling suggest that asthmatic airways close during bronchoconstriction. Finding segmental areas affected by closure would be important in understanding asthmatic airway function. The aim of this study was to evaluate single-photon emission computed tomography (SPECT) as a method of investigating airway closure. Simultaneous SPECT transmission and emission studies were performed on a thoracic phantom to develop analysis methodology, and on 13 normal subjects after they inhaled a Technegas bolus from residual volume (RV), to measure airway closure. Single-breath nitrogen test values and lung volumes were measured. Airway closure was defined as the percent of Technegas-free lung volume (LVclosed). The mean error +/- 95% CI of the error, as determined by transmission scan, was 1.1 ml +/- 165 ml (0.8% +/- 15% lung volume) in the phantom studies, and 112 ml +/- 419 ml (4% +/- 31% of supine functional residual capacity [FRC]) in the human studies. LVclosed correlated with closing capacity (r = 0.86, p < 0.01 ) and closing volume (r = 0.86, p < 0.01), but not with RV/total lung capacity (TLC). This study indicates that simultaneous SPECT emission and transmission scans, using a Technegas bolus, are a valid method of measuring airway closure in vivo, with the added advantage of providing three-dimensional data that allow the detection of small, discrete areas of airway closure and determination of their volumes and shapes.

If house dust mite allergen (Der p I) is an important cause of asthma, there should be a direct relationship between level of exposure to this allergen and asthma severity. To examine this, we studied six large random samples of children in different regions of New South Wales, Australia. We measured recent wheeze by questionnaire, airway hyperresponsiveness (AHR) by histamine inhalation test and sensitization to house dust mites by skin prick tests. Current asthma was defined as the presence of recent wheeze and AHR. We measured Der p I levels in the beds of approximately 80 children in each region. In regions where Der p I levels were high, more children were sensitized to house dust mites, and these children had significantly more AHR and recent wheeze. After adjusting for sensitization to other allergens, we found that the risk of house dust mite-sensitized children having current asthma doubled with every doubling of Der p I level. There was a modest correlation between AHR and Der p I exposure in individuals (r = 0.23, p0.03). These data suggest that house dust mite allergens are an important cause of childhood asthma and that reducing exposure to these allergens could have a large public health benefit in terms of asthma prevention.

Calculation of diurnal peak expiratory flow (PEF) variability using values before and after bronchodilator is no longer possible for many asthmatic patients because they now use beta-agonists "as needed" for symptoms rather than regularly. This study assesses the usefulness of a number of alternative PEF indices as markers of airway liability in subjects with stable, although not necessarily well-controlled, asthma. Forty-six adult subjects completed a questionnaire about symptoms and treatment in the previous 3 mo. Spirometric function and airway hyperresponsiveness (AHR) were assessed; AHR was expressed as dose response ratio (DRR) (maximal percent fall in FEV1 divided by final dose of histamine). Subjects recorded PEF morning and evening, before and after bronchodilator (if used) for 2 wk. Nine different PEF indices were calculated. Diurnal variability (amplitude percent maximum) without bronchodilator was significantly less than diurnal variability with bronchodilator. Normal indices of PEF lability were found in 42% of subjects with reduced maximal midexpiratory flow (MMEF). Most of the PEF indices correlated strongly with DRR, and less strongly with symptom score and airway obstruction. Minimum morning prebronchodilator PEF over a week (expressed as percent recent best or percent predicted) is recommended as the best PEF index of airway lability in patients with stable asthma because it correlates strongly with AHR, patients are more likely to comply with a once-daily reading, the calculation is simple, and regular use of a beta-agonist is not required.

The nature of the relationship between airway hyperresponsiveness (AHR) and atopy (specific IgE to aeroallergens) is unknown and one of the most important questions about asthma. Is AHR a consequence of airway inflammation caused by allergic or other responses or is it a separately inherited state? It is clear from epidemiological studies that these two abnormalities are linked. However, not all allergic (atopic) people have AHR and not all airway-hyperresponsive people are allergic. Furthermore, there is some suggestion that the risk factors for the two abnormalities are different. In Australian children, there has been little increase in the prevalence of atopy but AHR and symptoms have increased so that more of the atopic group now have asthma (1). The data suggest that over the years between 1982 and 1992 in atopic children, the risk factors for AHR have increased or that protective factors have been lost. There have been almost no other studies of atopic status and AHR in randomly selected populations over a period of time to determine if this is happening elsewhere. This article outlines what is known, what is partially known, and the important questions that need to be answered.

Although progress seems slow, it is urgent to find ways to prevent asthma in children and CAL in smokers. Understanding the mechanisms of disease is usually important to preventing them. In airway disease there remain many opportunities to make progress in understanding causes by studying the nature of the pathological changes present. In particular, the use of immunocytochemistry and DNA probing to define the specific abnormalities present in the inflammatory cells and the relation of those changes to the clinical manifestations and pathogenetic mechanisms should be productive.

The perception of bronchoconstriction may be modulated by airway inflammation. However, the effect of inhaled corticosteroid (ICS) treatment on perception in subjects with asthma has received limited study. The aim of this study was to determine the effect of inhaled budesonide on the perception of breathlessness induced by histamine challenge. Thirty-five subjects with poorly controlled asthma were randomized to receive budesonide (1,600 or 3,200 microg/d) for 8 wk, followed by 8 wk at 1,600 microg/d and subsequent downtitration according to a clinical algorithm. Borg scores were recorded during histamine challenges performed at baseline and at 8, 16, 24, 48, and 72 wk. Perception was estimated as the slope of Borg/% fall FEV(1). The Borg/FEV(1) slope increased significantly after 8 wk of budesonide (0.09 [0.08-0.12] to 0.15 [0.11-0.19], p = 0.002), and remained increased compared with baseline values at all subsequent visits. There were no significant differences in Borg/ FEV(1) slope between subjects who were and were not taking ICS at study entry. The magnitude of change in the Borg/FEV(1) slope did not differ significantly between treatment groups and was not related to changes in baseline FEV(1), airway hyperresponsiveness, blood eosinophils, or serum eosinophil cationic protein (ECP). We conclude that treatment with budesonide enhances the perception of airway narrowing, but the effect is unrelated to budesonide dose, or to changes in circulating eosinophil markers.