Is the increase in bronchial responsiveness or FEV1 shortly after cessation of beta2-agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting beta2-agonists.

Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased forced expiratory volume in 1 sec (FEV1). It has been suggested that these possible detrimental effects are not a real deterioration of the disease, but that it might be only a transient (rebound) effect shortly after discontinuing this regular use. Moreover, these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use. The aim of this study was to invest gate whether a rebound effect (a pharmacological deterioration effect diminishing after several hours) in FEV1 and PC20 (concentration of histamine causing a 20% fall in FEV1 with regard to baseline) occurred after cessation of regular use of beta2-agonists, and whether this occurred both after short-acting and long-acting beta2-agonists. Allergic asthmatic patients (n = 134) were randomly allocated to the use of a short-acting (salbutamol), a long-acting beta2-agonist (formoterol) or placebo for 12 weeks (double-blind, double-dummy). No other asthma medication was allowed, including inhaled corticosteroids. At the start and every 4 weeks later FEV and PC20 were measured, each time at least 12 h after the last doses of study medication, which is in the possible rebound period. To investigate whether a (transient) rebound effect occurred, parameters were additionally measured at least 72 h later after discontinuation of the study medication. After 12 weeks of short-acting beta2-agonist use, a drop was seen in FEV1 from 85.6 (+/- 2.21)% predicted to 78.8 (+/- 2.9)% predicted, measured 15 h (median) after the last doses of medication. This was significantly different compared to placebo. When measured 168 h (median) later FEV1 recovered to 85.5 (+/- 2.4)% predicted, comparable to baseline. PC20 decreased with -1.17 (+/- 0.44) doubling dose after 12 weeks of short-acting beta2-agonist use, measured 15 h after the last doses of medication, which was significantly different compared to placebo. However, 168 h later PC20 recovered slightly with +0.55 (+/- 0.34) doubling dose, but this value was still lower compared to placebo. In contrast, during long-acting beta2-agonist and placebo use no significant changes were seen. In conclusion, the use of short-acting beta2-agonists resulted in a transient (rebound) effect in FEV while the effects on PC20 may point to a real deterioration of the disease. Long-acting beta2-agonist and placebo use showed no changes. We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma.

Potential masking effect on dyspnoea perception by short- and long-acting beta2-agonists in asthma.

Asthma patients evaluate the effect of medication treatment through the degree of their asthma symptoms, which might be affected by their ability to perceive these symptoms. It has been suggested that beta2-agonists may mask the effects of an increase in airway inflammation. This study compared the perception of histamine-induced bronchoconstriction during monotherapy with short- or long-acting beta2-agonists. Asthmatic patients (68 male and 60 female, mean age 35+/-11 yrs, forced expiratory volume in one second (FEV1) 86+/-15% of the reference value, provocative concentration causing a 20% fall in FEV1 (PC20) geometric mean 0.97 mg x mL(-1) (95% confidence interval (CI): 0.73-1.30)) were selected and randomly allocated to use either a short-acting (salbutamol, n=41) or long-acting beta2-agonist (formoterol, n=46) or placebo (n=41) for 12 weeks. Perception of dyspnoea provoked by histamine-induced bronchoconstriction was measured at the start and every 4 weeks thereafter. Subjects quantified their sensation of breathlessness during the challenge tests on a modified Borg scale at the start of the study and every 4 weeks thereafter. The sensitivity to changes in FEV1 was analysed by the linear regression slope (alpha) Borg versus % fall in FEV1. The absolute perceptual magnitude (PS20) was determined by the perception score at the 20% fall in FEV1. Although the geometric mean PC20 decreased significantly within the group using short-acting beta2-agonists (in the group with initial PC20 > or = 2 mg x mL(-1) there was a drop from 5.26-1.94 mg x mL(-1); p=0.013), repeated measurement analysis showed no difference in the course of time of perception (both slope alpha and PS20) between the three medication groups. This study showed that chronic use of short- or long-acting beta2-agonists in asthmatics for a period of 12 weeks, did not significantly change the perception of histamine-induced bronchoconstriction compared with placebo. Further investigation is required to establish whether this suggests that these drugs do not mask a deterioration of asthma.

Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma.

The relationship between asthma medication and the perception of asthma symptoms is of interest for daily practice. Poor perception of asthma symptoms might influence patients' health care behavior and subsequently might lead to undertreatment and deterioration of their disease. This study investigated the influence of the chronic use of short-acting and long-acting beta(2)-agonists, compared with the additional use of inhaled corticosteroids on the perception of histamine-induced bronchoconstriction. Patients with asthma (33 male and 31 female, mean age 35 +/- 11 yr, FEV(1) 87 +/- 14% of the reference value, PC(20) geometric mean 1.08 mg/ml (95% CI: 0.76-1.52) were selected and randomly allocated to the use of either a short-acting beta(2)-agonists (salbutamol, n = 22) or a long-acting beta(2)-agonists (formoterol, n = 22) or placebo (n = 20), which has been used for 12 wk. This medication treatment was repeated exactly 1 yr later, with patients receiving the same medication plus an inhaled corticosteroid. Perception of histamine-induced bronchoconstriction was measured at the start of each treatment period and every 4 wk thereafter. Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale. The perceptive "sensitivity" for changes in FEV(1) was analyzed by the linear regression slope (alpha) "Borg versus percentage fall in FEV(1)." The "absolute perceptual magnitude" was determined by the perception score at the 20% fall in FEV(1) (PS(20)). The additional use of inhaled corticosteroids during the second year resulted in an improved perception of histamine-induced bronchoconstriction (slope alpha) compared with the first year for only the long-acting beta(2)-agonists group (p value 0.036). This improvement was not observed for the "absolute perceptual magnitude" (PS(20)). The additional use of inhaled corticosteroids during chronic use of long-acting beta(2)-agonists improves the perceptive "sensitivity" for changes in FEV(1) during histamine-induced bronchoconstriction, which was not observed for short-acting bronchodilators. This result might indicate that the positive effects on perception of airway obstruction might be another reason (besides the beneficial effects on the clinical condition) for prescribing a combination of long-acting beta(2)-agonists and inhaled steroids.

A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients.

BACKGROUND: Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma. It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens. Moreover, it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists. METHODS: Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting beta(2)-agonist (SA; n = 48), a long-acting beta(2)-agonist (LA; n = 50), or placebo (n = 47), double blind, double dummy. The study covered three periods: (1) a 4-week run-in period, in which no changes took place; followed by (2) cessation of treatment with asthma medication including inhaled corticosteroids, introduction of allergen avoidance measures (active/placebo treatment) to lower HDM exposure in the active group, and an 8-week washout period to adjust patients to these changes; followed by (3) a 12-week study medication period. At the start of the 12-week medication period, and every 4 weeks thereafter, spirometric measurements (FEV(1) and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)]) were performed. Peak flow and asthma symptoms were recorded daily. Additionally, at the start and every 6 weeks thereafter, dust samples were collected from mattresses and living room and bedroom floors to assess HDM (der p 1) concentrations. Effects on FEV(1), PC(20), peak flow, and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens. RESULTS: There were no significant differences among the three medication groups after 12 weeks for FEV(1). However, a significant decrease in mean FEV(1) percent predicted (95% confidence interval [CI]) was observed within the SA group: - 6.6 (- 10.4 to - 2.8) (p = 0.0002). A decrease in geometric mean PC(20) (95% CI) of - 1.2 (- 1.96 to - 0.44) doubling concentration was observed within the SA group (p = 0.05). No significant changes in FEV(1) and PC(20) were observed > 12 weeks within the LA group or the placebo group. There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups. Moreover, none of the parameters showed interactive effects with allergen exposure. CONCLUSION: There were no significant differences among the three medication groups for FEV(1) and PC(20). The within-treatment group comparison showed a significant small decline in FEV(1) for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV(1). This was not seen during regular use of LAS: No clear pathophysiologic mechanism can explain these findings at the moment. Relatively high or low exposure to allergens did not alter these findings.

Perception of respiratory sensation assessed by means of histamine challenge and threshold loading tests.

BACKGROUND: Some asthmatic patients perceive the severity of their disease rather poorly. These patients may not receive optimal therapy because of underpresentation of their respiratory symptoms. It is therefore important to identify these patients. The present study evaluates a new threshold loading device for measuring the perception of respiratory sensation. This method for measuring the perception of respiratory sensation may be a viable alternative to the bronchial provocation test. The aim of the present study was to investigate whether the assessment of the perception of respiratory sensation based on a threshold loading test (inspiratory and expiratory) identifies the same subjects as poor perceivers as compared to assessment by histamine bronchial provocation test. METHOD: In 36 subjects, the perception of respiratory sensation through a threshold loading device was compared to the perception of respiratory sensation during a histamine provocation test. Each test was performed with scoring of the magnitude of the respiratory sensation on a visual analog scale (VAS). The magnitude of the stimulus intensity was indicated by the percentage of decrease in FEV(1) during the histamine challenge test and by the percentage of the subject's maximum mouth pressure (percent maximal inspiratory pressure and percent maximal expiratory pressure) during the threshold loading test. The relationship between VAS values and the stimulus intensity was analyzed by determining the linear regression coefficient between the two parameters. RESULTS: No relationship was found between the perception of the sensation induced by the histamine challenge and that during breathing through a threshold loading device for both inspiration (Rs = 0.15; p = 0.40) and expiration (Rs = 0.13; p = 0.47). We did find a significant relation between the perception of respiratory sensation during the inspiratory and expiratory threshold loading test (Rs = 0.67; p = 0. 0001). Furthermore, we defined a subgroup of patients of special interest: those with low symptoms of breathlessness and high bronchial responsiveness. Compared to the inspiratory and expiratory threshold loading test, the histamine challenge test identified more patients in the special interest group as poorest perceivers. CONCLUSION: The measurement of perception by means of a threshold loading device and a histamine provocation test did not identify the same subjects as poor perceivers, probably because we did not measure the patient's perceptiveness for exactly the same stimuli. In the population with relatively more severe asthma and very low symptoms of breathlessness, the histamine-induced bronchoconstriction test identified more patients as poorest perceivers compared to the threshold loading test.

Perception of bronchoconstriction in asthma patients measured during histamine challenge test.

This study investigated two aspects of the perception of bronchoconstriction ("sensitivity" and "absolute perceptual magnitude") in asthmatic patients and identified which clinical characteristics are related to these two aspects of perception of bronchoconstriction. The perception of histamine induced bronchoconstriction was measured in 128 asthmatic patients. Subjects quantified their breathlessness on a Visual Analogue Scale (VAS) before forced expiratory volume in one second (FEV1 was measured after each inhalation of histamine. The perceptive "sensitivity" for changes in FEV1 was analysed by the "VAS percentage fall in FEV1" slope. The "absolute perceptual magnitude" was determined by the VAS value at a 20% fall in FEV1. Spearman correlations were used for analysis between the two aspects of perception and asthma symptoms, peak flow variability, bronchial responsiveness and FEV1 % predicted. Patients with a low "sensitivity" for changes in FEV1 were more likely to show a frequent peak flow variability (Rs=-0.21; p<0.05), a high bronchial responsiveness (Rs= 0.37; p<0.001) and a low baseline FEV1 % pred (Rs=0.22; p<0.05). Patient's "absolute perceptual magnitude" correlated positively with symptoms during daily life (significant correlations varied 0.21-0.32) but not with the lung function parameters. The severity of asthma reflected by a low lung function and a high bronchial responsiveness, is associated with a low "sensitivity" for changes in forced expiratory volume in one second. A patient's "absolute perceptual magnitude" is positively related with asthma symptoms during daily life.

Effects of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids.

BACKGROUND: Exposure to house dust mite (HDM) allergens often results in worsening of asthma. Therefore, avoidance of exposure to HDM allergens is often proposed. Unfortunately, the most effective and feasible avoidance strategy is still not completely assessed. Consequently, we investigated the effects of a combined HDM avoidance strategy on HDM allergen concentrations and clinical condition of allergic, mild asthmatic, patients using no inhaled steroids. METHODS: Asthmatic patients, allergic to HDM, using no inhaled corticosteroids, were randomly allocated to an active (n = 76) or a placebo allergen-avoidance group (n = 81). Avoidance measures consisted of applying Acarosan(R) (placebo: water) to the living room and bedroom floors, and the use of HDM-impermeable covers for mattresses and bedding (placebo: cotton covers for mattresses only). Effects on allergen concentrations (Der p 1), FEV1, bronchial hyperresponsiveness, peak flow parameters and asthma symptom scores were studied during 20 weeks and controlled for the allergic status of the patients. RESULTS: The active covers reduced Der p 1 concentrations to 9.4% (P = 0.0001), and were always significant lower than in the placebo group (P = 0.0002). Acarosan(R) resulted in slight but significant decreases (twofold, P = 0.0001), both on living room and bedroom floors, but concentrations were never significantly lower than the placebo group. Although the combined avoidance strategy resulted in a considerable reduction in allergen load in the active group, no differences were seen between the two groups in any of the clinical parameters during the follow-up period in this group of allergic asthmatics, using no inhaled corticosteroids. Corrections for the allergic status did not alter these results. CONCLUSIONS: The combined avoidance strategy was effective in reducing HDM allergen concentration. This was especially achieved by the allergen-impermeable covers, while the effects of Acarosan(R) were only marginal. However, this allergen reduction was not reflected in a convincing improvement in clinical condition in this group of mild allergic asthmatics, using no inhaled steroids. Perhaps, a longer follow-up period would have resulted in more pronounced effects.

Measuring breathlessness during histamine challenge: a simple standardized procedure in asthmatic patients.

One of the problems in research on symptom perception during histamine challenge has been the difficulty in finding both a valid and practical parameter of the "perceptiveness" for bronchoconstriction in a subject. The purpose of this study was to validate whether the slope in the linear regression model between stimulus and sensation during histamine challenge is an appropriate index for the "perceptiveness" for bronchoconstriction by comparing it with the classical Stevens' law. One hundred and thirty-four asthmatic patients were included in the study and underwent a bronchial challenge with histamine. The relationship between the change in visual analogue scale (VAS) values and the change in forced expiratory volume in one second (FEV1) as percentage of baseline value was analysed by determining both the exponent n in deltaVAS=k x (%deltaFEV1)n and the slope alpha in deltaVAS=k + alpha(%deltaFEV1). The best-fitting line of both the exponential and the linear regression model were determined by the least-squares method in which the percentage explained variation (R2) was compared. The median value of R2 of the exponential regression line and the linear regression line was 0.76 and 0.83, respectively, and significantly different. The Spearman rank correlation coefficient between exponent n in the exponential model deltaVAS=k x (%deltaFEV1)n and the slope alpha in the linear regression model deltaVAS=k + alpha(%deltaFEV1) was 0.87 (95% confidence interval 0.83-0.91). On the basis of the results, it was concluded that the linear regression coefficient can be used as a valid expression to describe the "perceptiveness" of an asthmatic subject instead of Stevens' power function during histamine challenge.

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

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

Exertional dyspnoea in patients with airway obstruction, with and without CO2 retention.

BACKGROUND: Dyspnoea is a common and disabling symptom in patients with cardiopulmonary disease. Unfortunately the mechanisms that produce dyspnoea are still poorly understood. The relationship between dyspnoea and the load on the ventilatory muscles, chemical drive, and ventilatory indices was therefore assessed in patients with obstructive pulmonary disease during an incremental exercise test. METHODS: Fifty patients with a wide range of obstructive pulmonary disease (mean forced expiratory volume in one second (FEV1) 66.1 (28.8)% predicted) performed an incremental cycle ergometer test. A subdivision was made between subjects with CO2 retention (delta PaCO2 > or = 0, n = 22) and subjects without CO2 retention (delta PaCO2 < 0, n = 28) during exercise. During the test dyspnoea (Borg score), oesophageal pressures (mechanical load on the ventilatory muscles (time tension index (TTI), blood gas tensions, and minute ventilation were measured. Correlations for changes in mechanical and chemical factors with changes in dyspnoea score were calculated to assess relevant factors. An analysis of covariance was used to examine whether there was a relationship between dyspnoea score and each of these factors and whether this relationship was different between the subgroups with and without CO2 retention. Multiple regression analysis was used to assess the independent effect of each parameter on dyspnoea sensation. Furthermore, the amplitude of pleural pressure swing ((Pi + Pe)act) generated at maximal work load (Ptot, an indication of the load on all respiratory muscles) was calculated. Analysis of covariance was used to assess whether there was a relationship between tidal volume (VT) and Ptot and whether this relationship was different between the groups (slopes are an expression of the length-tension inappropriateness, LTI). RESULTS: In the total group and the group without CO2 retention a significant correlation between dyspnoea and the increase in the inspiratory time tension index (TTIi) was present. In the group with CO2 retention a significant correlation was seen between dyspnoea and delta PaCO2. The factors delta PaO2, delta VE%MVV and delta (VT/Ti) showed a correlation with a p value of < or = 0.10 both in the total group and in those without CO2 retention. In an analysis of covariance the relationship between dyspnoea score and delta PaCO2 appeared to be significantly different between the two subgroups, being more pronounced in the group with CO2 retention. No other relationships with change in dyspnoea score were found. There was no significant relationship between VT and Ptot in the total group nor in the two subgroups, indicating some length-tension inappropriateness in both groups. CONCLUSIONS: In patients with distinctive pulmonary disease who are normocapnic or hypocapnic the mechanical load (delta TTIi) and length-tension inappropriateness (LTI) on ventilatory muscles seem to be the main determinant of exertional dyspnoea. As soon as hypercapnia occurs, this seems to override all other inputs for dyspnoea.

House dust mite avoidance measures improve peak flow and symptoms in patients with allergy but without asthma: a possible delay in the manifestation of clinical asthma?

BACKGROUND: Asthma caused by allergy to house dust mite is a growing problem. Patients with allergy who do not have asthma (yet) might develop asthma depending on exposure to precipitating factors. OBJECTIVE: We sought to determine whether house dust mite avoidance measures have an effect on the development of asthma. METHODS: Patients with allergy (n = 29) who had no diagnosis of asthma (FEV1 of 99.1% +/- 10.6% of predicted, peak flow variability of 5.21% +/- 3.41%, reversibility of FEV1 after 400 microg salbutamol of 3.92% +/- 3.75% according to the reference values) were randomly allocated (subjects blinded) to a treatment (n = 16) and a placebo group (n = 13). House dust mite avoidance treatment consisted of applying Acarosan (Allergopharma, J. Ganzer KG, Hamburg, Germany) (the placebo group used water) to the floors (living room, bedroom), and the use of covers for mattresses and bedding that were impermeable to house dust mite (the placebo group used cotton covers for mattresses only). We tested whether the intervention had an effect on peak flow parameters and asthma symptom scores during 6 weeks of treatment. RESULTS: Significant improvements were seen in the treatment group in symptom scores (Borg score) for disturbed sleep, breathlessness, wheeze, and overall symptom score. Slight but statistically significant improvements in peak flow (morning, evening, and variability) were seen in the treatment group also. No significant changes were seen in the placebo group. CONCLUSIONS: Although this study is not long enough to study the development of asthma, the results indicates that house dust mite avoidance measures had an effect on peak flow parameters and asthma symptoms in patients with allergy but without asthma. These findings might implicate that a shift in developing clinically manifest asthma could be achieved with house dust mite avoidance measures. To give a better answer to whether preventing the development of asthma is possible, larger studies with a longer follow-up period are necessary.