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Clinical Investigations: ASTHMA |

A Placebo-Controlled Clinical Trial of Regular Monotherapy With Short-Acting and Long-Acting β2-Agonists in Allergic Asthmatic Patients* FREE TO VIEW

Sonja G. M. Cloosterman, MSc, PhD; Ingrid D. Bijl-Hofland, MSc, PhD; Cees L. A. van Herwaarden, MD, PhD; Reinier P. Akkermans, Sc; Frank J. J. van den Elshout, MD, PhD; Hans T. M. Folgering, MD, PhD; Constant P. van Schayck, MSc, PhD
Author and Funding Information

*From the Department of General Practice and Social Medicine (Drs. Cloosterman, Bijl-Hofland, and Akkermans), University of Nijmegen, and Department of Pulmonology (Drs. van Herwaarden and Folgering), Medical Centre Dekkerswald, University of Nijmegen, Nijmegen; the Department of Pulmonology (Dr. Elshout), Rijnstate Hospital, Arnhem; and University of Maastricht (Dr. van Schayck), Maastricht, The Netherlands.

Correspondence to: Sonja G. M. Cloosterman, MSc, PhD, Department of General Practice and Social Medicine, 229, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands; e-mail: S.Cloosterman@hsv.kun.nl



Chest. 2001;119(5):1306-1315. doi:10.1378/chest.119.5.1306
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Background: Some recent studies suggest that regular β2-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 β2-agonists.

Methods: Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting β2-agonist (SA; n = 48), a long-actingβ 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 (FEV1 and provocative concentration of histamine causing a 20% fall in FEV1[ PC20]) 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 FEV1, PC20, 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 FEV1. However, a significant decrease in mean FEV1 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 PC20 (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 FEV1 and PC20 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 FEV1 and PC20. The within-treatment group comparison showed a significant small decline in FEV1 for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV1. 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.

Figures in this Article

In the last 5 to 10 years, interest in the possible detrimental effects of regularβ 2-agonist use for treating asthma has increased. This started with the observation that there was a connection between the increased use of β2-agonists and death from asthma.13 The concern grew when clinical trials reported increased bronchial hyperresponsiveness (BHR),46 increased decline in lung function,7and less overall control of asthma during continuous use ofβ 2-agonists.8

Several studies observed that regular use ofβ 2-agonists led to tolerance to its protective effects against bronchoconstrictive stimuli, whereas its bronchodilatory properties remained unchanged.6,910 Bronchoconstrictive stimuli can act either directly on smooth muscles or indirectly by stimulating the release of mediators. It has been found that tolerance to direct bronchoconstrictive stimuli is of a smaller magnitude compared to indirect stimuli.11 Tolerance is thought to be due to a downregulation ofβ 2-receptors on airway smooth muscle,5 or on mast cells.1112 O’Connor and colleagues11found that after regular use of terbutaline, the protective effect against adenosine monophosphate was more diminished than the protective effect against methacholine (a direct bronchoconstrictor). Cockcroft and colleagues12 found similar results: after regular use of salbutamol for 2 weeks, airway responsiveness to allergens (mast cell mediator release-induced bronchoconstriction) had increased, whereas responsiveness to methacholine had not changed. Furthermore, they found that regular use of salbutamol caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both methacholine and allergens. These findings support the possibility of β2-receptor downregulation on airway smooth muscle and probably to an even greater extent on mast cells or other inflammatory cells. The latter may result in an enhanced effect of the late asthmatic response, which is the more important consequence of allergen inhalation. Consequently, it is hypothesized that regular use of β2-agonists in conjunction with allergen exposure might result in increased BHR.,1214

Several other studies did not find any deleterious effect of the regular use of short-acting β2-agonists (SA)1516 or long-actingβ 2-agonists (LA).20 One of the possible explanations for the controversy might be that some asthmatic patients are more sensitive to the deleterious effects of bronchodilators than others. Reanalyzing our original data of patients who used bronchodilators continuously during 2 years7 showed that especially asthmatic patients who were allergic and also had a high reversibility of obstruction had an increased decline in lung function.14 This result, together with the findings of O’Connor et al11and Cockcroft et al1213 indicate that, especially in allergic asthmatic patients, there might be an interactive effect on inflammation between regular use ofβ 2-agonists and the exposure to allergens, resulting in an increased airway responsiveness. We have proposed a hypothesis that might explain the observed deleterious effects in some studies, assuming a high exposure to specific and nonspecific irritants during regular use of bronchodilators (Fig 1 ).14 Thus far, this hypothesis has not been investigated in everyday life. It is questionable whether the above-mentioned laboratory findings (tolerance) result in negative effects on clinical parameters in the long term. Furthermore, it is questionable whether this hypothesis applies to LA as well as to SA.21 To test this hypothesis and investigate these aspects, we performed a study in allergic asthma patients to answer the following questions: (1) Does regular use of β2-agonists result in detrimental effects, and do these effects become worse when allergic asthmatic patients are at the same time exposed to a high allergen concentration? (2) Is there a difference between SA and LA?

Patients

We selected asthmatic patients allergic to house dust mite (HDM) who should not use inhaled corticosteroids or should be able to cease treatment with this medication, so that we would be able to study the isolated effects of regular bronchodilator use. Patients were first selected from an allergy laboratory (HDM positive). Secondly, patients were examined by their general practitioner (GP) for having bronchial symptoms or diagnosed asthma.22 Eligible patients (n = 456) visited the lung function laboratory for an inclusion assessment, where they had to meet the following criteria: (1) FEV1 > 50% of predicted and > 65% of predicted after inhalation of 800 μg of salbutamol; (2a) provocative concentration of histamine causing a 20% fall in FEV1 (PC20) ≤ 8 mg/mL and/or (2b) reversibility of obstruction ≥ 15% after inhalation of 800 μg of salbutamol; (3) positive intradermal allergen test finding for HDM (histamine equivalent wheal size > 0.7 on 10,000 biological units); and (4) treatment with bronchodilator monotherapy possible, according to GP and lung physician (if applicable). Additional selection criteria to avoid possible confounding of other allergens include the following: (1) patients with a positive reaction to dogs, rabbits, guinea pigs, or birds that was greater than the reaction to HDM were excluded when these pets were still present in the domestic situation; (2) patients allergic to cats, irrespective of the magnitude of the reaction, were excluded when the cat was present in the domestic situation at the time, or had been so in the 12 months before the start of the study. Eventually, 258 patients met these inclusion/exclusion criteria, of whom 204 agreed to participate in the study (Table 1 ). The study protocol was approved by the Medical Ethical Committee of the Department of Pulmonology Dekkerswald, University of Nijmegen, and all patients gave written informed consent.

Study Design

Selected patients were randomly allocated to an active or placebo allergen avoidance group and simultaneously to the use of SA (salbutamol via metered-dose inhaler; two inhalations of 100 μg qid), LA (formoterol via metered-dose inhaler; one inhalation of 12 μg bid), or placebo treatment (Fig 2 ).

The study involved three periods: (1) a 4-week run-in period with no interventions, (2) an 8-week washout period during which time allergen avoidance measures (active and placebo treatments) were implemented and treatment with all pulmonary medication apart fromβ 2-agonists was discontinued, and (3) a 12-week double-blind, double-dummy treatment period with study medications.

Allergen avoidance measures were performed in order to achieve a wide range in allergen exposure (blinded for patient and lung function technician). Patients who used pulmonary medication (inhaled corticosteroids, cromoglycates, bronchodilators, etc) discontinued this use and were instructed to use only the rescue medication on demand (fenoterol/ipratropium combination via dry powder inhaler). The fenoterol/ipratropium combination was chosen because it primarily contains an anticholinergic bronchodilator (ipratropium bromide, 40μ g) and a low dose of a β2-agonist (fenoterol hydrobromide, 100 μg). Rescue medication use was carefully recorded during the whole study period, and the record was subsequently used as an effect parameter indicating asthma control. During the 8-week washout period, the patients could adjust to the changes in allergen load and the cessation of treatment with their medications. After those 8 weeks, the patients received the study medication but rescue medication use was still allowed. The patients were carefully instructed how to use the study medication (inhaler technique and time schedule), and this use was checked every time the patient visited the lung function laboratory. Used canisters were collected and were weighed before and after use in order to check compliance.

If any of the patients had an exacerbation, as judged by their GP, they were treated with an oral prednisone course and, if necessary, with antibiotics in a standardized way. Prescribed prednisone courses were also seen as an effect parameter indicating asthma control. If this treatment was not sufficient and patients had to resume their medication of inhaled steroids because of a further deterioration of their asthma, this was considered an end point; these patients no longer met the inclusion criteria and were therefore withdrawn.

Spirometry, BHR, and Diary Card

Spirometry and BHR were measured during inclusion, at the start of the study medication period, and after every 4 weeks of follow-up, each time at least 12 h after stopping treatment with the study medication. Spirometric parameters (FEV1, postbronchodilator FEV1) were measured by means of a microspirometer (HI-298; Chest Corporation; Tokyo, Japan).23BHR was determined by stepwise inhalation of increasing concentrations of histamine solution in accordance with the European Respiratory Society standards.24 Doubling concentrations of histamine acid phosphate, from 0.03 to 16.0 mg/mL, were administered. PC20 from baseline was obtained from the log-concentration response curve by linear interpolation. After spontaneous recovery to ≥ 90% of the prehistamine value, bronchodilator response was measured before and 15 min after 400 μg of salbutamol via metered-dose inhaler. This reversibility of FEV1 was calculated as a percentage of the prebronchodilator value.

During the entire study period, the patients recorded rescue medication use, asthma symptoms, and peak flow values (Pocket Peak Flow Meter; Micro Medical; Rochester, Kent, UK) on a diary card. Before the start the study, they had been trained in performing peak flow maneuvers. Three readings were performed each morning before breakfast and each evening before dinner. The highest of three measurements (both in the morning and in the evening) was recorded. Asthma symptoms included cough, breathlessness, wheezing, expectoration, tiredness, and sleep disturbance (due to nocturnal asthma symptoms) and were scored on a modified Borg scale (0 = no symptoms to 10 = severe symptoms).25

Allergen Avoidance Measures and Dust Sampling

Active HDM avoidance measures were performed in order to create a lower exposure to HDM allergens. These measures consisted of treatment of carpets and rugs in bedrooms and living rooms with an acaricidal moist powder (Acarosan; Allergopharma; J. Ganzer KG; Hamburg, Germany) in accordance with the instructions of the manufacturer. Smooth floors (eg, parquet, flagstones) were not treated. Mattresses, duvets, and pillows were enclosed in covers impermeable to HDM and its allergens (Intervent Bedding Systems; W.L. Gore & Associates; Livingstone, UK). The patients’ environment without HDM allergen avoidance served as an environment with a relatively high allergen exposure. However, to blind the patients, placebo measures were performed, which consisted of spraying a small volume of water on the carpets and rugs from a bottle with an acaricide label, and encasement of mattresses with mite- and allergen-permeable cotton covers (specially designed for easy penetration by house dust by Intervent Bedding Systems).

Separate dust samples were collected from the living room floor, bedroom floor, and mattresses with a vacuum cleaner (Philips Turbo Exclusive TC836, 1400 W; Philips; Eindhoven, the Netherlands). This was done prior to the introduction of the avoidance measures and 8 weeks, 14 weeks, and 20 weeks later as follow-up. Floors were vacuumed totally (intensity, 1 min per square meter) in a standardized way. For the baseline assessment, the upper surface of the bare mattress of both the patient and the partner (if present) was sampled, again in a standardized way (intensity, 5 min per square meter). After encasing the mattresses, follow-up samples were taken from the upper surface of the encasing.

Detection of Der p 1 was performed by radioallergosorbent testing as described by Van der Heide et al26 and expressed in nanograms per gram.

Statistical Methods

PC20 values were log2-transformed to achieve a normal distribution. Changes in PC20 could then be interpreted as doubling concentrations. FEV1 was presented as a percentage of the reference value (European Respiratory Society/European Community for Coal and Steel standard).27 Compliance rates for medication were assessed by comparing the used medication with the prescribed medication (percentage). Der p 1 concentrations were ln-transformed to achieve a normal distribution and presented as a geometric mean (95% confidence interval [CI]). Der p 1 concentrations of the three follow-up measurements were averaged for mattresses, living room floor, and bedroom floor independently. These factors then described the whole range of allergen loads, from low to high levels. This continuous factor “der p 1-concentration” was included in the analysis, not the dichotomous factor “high exposure vs low exposure.”

Repeated-measurement analysis of variance was performed to assess effects during use of β2-agonists. PC20 was used as dependent variable, and type of medication (SA, LA, placebo) as the independent variable. Subsequently, allergen concentration (mattresses, living room floor, and bedroom floor, independently) was added as a second independent variable, together with a term defining the interaction between the medication parameters and the allergen parameter. In this way, we could assess whether there was interaction between medication use and allergen concentration on BHR. Finally, a variable defining measurements over time was incorporated to see whether this possible interaction was changing over time. Consequently, the following three models were tested:

BHR was the primary effect parameter, but effects on FEV1, peak flow parameters, and symptoms were also studied. Moreover, repeated-measurement analyses were also performed within each medication group.

Patients were included in the analysis as far as they had completed the study, according to the intention-to-treat principle, but with a minimum condition of two measurements (baseline plus one follow-up measurement). The data are presented as mean (95% CI).

A power calculation was performed on the basis that a difference of one doubling dose (with a between-patient SD of two doubling dose) could be detected between the two groups. A power of 0.90 was used and was set at 0.05. The sample size of the groups should then be at least 53.

Patients

After applying the inclusion/exclusion criteria, 204 patients started the 8-week washout period (Table 1). During this period, 42 subjects dropped out; consequently, 162 patients started the medication period. During this medication period, five subjects dropped out because they had to restart their use of inhaled corticosteroids before the first follow-up measurement (SA group, n = 2; LA group, n = 0; placebo group, n = 3). Five subjects stopped taking the study medication within 4 weeks after the start (SA group, n = 2; LA group, n = 1; placebo group, n = 2). Six patients stopped due to motivational factors within 4 weeks after the start (SA group, n = 4; LA group, n = 1; placebo group, n = 1). One subject (LA group) had only one suitable measurement. Consequently, these 17 subjects (SA group, n = 8; LA group, n = 3; placebo group, n = 6) performed only the baseline measurement and could not be included in the analysis. Eventually, 145 subjects completed the study. Patient characteristics are shown in Table 2 .

HDM Allergen

To assess whether the avoidance measures successfully resulted in a discrimination between low and high allergen exposures, the der p 1 values after the intervention were compared. Geometric mean der p 1 concentration on the encased mattresses in the low-exposure group was 158 (94 to 266) ng/g and 686 (444 to 1061) ng/g in the high-exposure group, which was significantly different (p = 0.00). Geometric mean (95% CI) der p 1 concentration on the bedroom floor was 568 ng/g (387 to 834 ng/g) in the low-exposure group and 585 ng/g (394 to 870 ng/g) in the high-exposure group (p = 0.92). For the living room floor, these concentrations were 520 ng/g (322 to 841 ng/g) for the low-exposure group and 413 ng/g (271 to 630 ng/g) for the high-exposure group (p = 0.47). Only the HDM-impermeable covers reduced allergen exposure.

BHR

Repeated measurements analysis showed that there was a tendency toward a difference in the course of BHR over time among the three medication groups (p = 0.07; Fig 3 , top). Because the course over time tended to be different among the three groups (interaction between time and medication group), repeated-measurements analyses were also performed within each of the three medication groups independently. These analyses showed that there was no significant trend in BHR over time within the placebo group or within the LA group. However, BHR showed a significant increasing trend over time within the SA group, geometric mean (95% CI) PC20 values decreased by − 1.2 mg/mL (− 1.96 to − 0.44 mg/mL), doubling concentration during the 12 weeks (p = 0.05). When these analyses were corrected for allergen concentrations of mattresses, bedroom floors, and living room floors, no interactive effects were observed between medication use and allergen concentration (all three p values > 0.05).

FEV1

After 12 weeks of follow-up, there were no differences among the three medication groups in the course of FEV1 over time (p = 0.17; Fig 3, bottom). Looking at the result in the figure, we were interested in repeated-measurement analyses within each of the three medication groups independently. These analyses showed that there was a significant decreasing trend in FEV1 within the SA group: FEV1 percent predicted decreased by − 6.6 (− 10.4 to − 2.8) during the 12 weeks (p = 0.00). No significant trends in FEV1 were observed within the placebo or within the LA group. When corrections for allergen concentrations were made, no interaction between medication use and allergen concentration was observed (for all three samples sites p values> 0.05).

Peak Flow Parameters

As baseline peak flow variability was slightly, but significantly, different among the three groups (higher in the placebo group), corrections for baseline values were made for this variable during the analysis by adding the baseline value as a covariant. First, only medication effects were tested. There was no significant difference in course time among the three medication groups for morning peak flow (p = 0.34), evening peak flow (p = 0.52), and peak flow variability (p = 0.87). Moreover, there were no significant trends within each of the three medication groups for all three parameters (all p values> 0.10). No interactive effects between medication use and allergen concentrations of the three sample sites were observed.

Asthma Symptom Scores

Because all symptom scores showed the same tendencies, only the overall symptom score was presented. The simple model showed that there was no difference among the three medication groups (p = 0.15) in overall symptom score. When the overall symptom score was tested within each medication group, no significant trends were observed. When analyses were done with corrections for allergen concentrations, no interactions were observed for each sample site.

Asthma Control

The number of oral prednisone courses used and the amount of rescue medication used in the three medication groups were taken as indicators for asthma control. There were nine prednisone courses prescribed during the study medication period (Table 3 ). There was no difference in the number of prescribed prednisone courses among the three study groups.

During the visits to the lung function laboratory, the patients handed over the remaining capsules of the fenoterol/ipratropium combination, which were counted, so that an indication about the rescue medication could be obtained (median plus interquartile range). During the washout period, the SA group used 0.12 (0.0 to 1.0) capsules a day and the LA group and placebo group used 0.09 (0.0 to 0.41) and 0.25 (0.0 to 1.22) capsules per day, respectively, which did not lead to any difference among the three groups (p = 0.56). During the medication period, the SA group used a median of 0.07 (0.0 to 0.75) capsules per day. During LA use, this use was 0.04 (0.0 to 0.41) capsules per day, and during placebo use, it was 0.15 (0.0 to 0.95) capsules per day, again not significant among the three groups (p = 0.22). These data showed that there was no excessive use of rescue medication in any of the three medication groups before and during the study medication period.

This study indicates that regular use of the SA, salbutamol, may result in a deterioration of BHR and lung function, which was not the case during regular use of the LA, formoterol. Although no significant difference was observed between groups, significant effects were observed within the SA group, but not within the LA group.

Whereas some studies found deleterious effects of regularβ 2-agonist use,48 others did not.9,16,20 This contradiction might be a result of selecting different study populations. We hypothesized that asthmatic patients with a high reversibility of obstruction who are exposed to a high allergen level are the most vulnerable for these detrimental effects.14 This was also hypothesized by Cockcroft et al1213: the regular use ofβ 2-agonist is especially deleterious when allergen exposure occurs at the same time. However, no interactive effects between allergen exposure and the regular use ofβ 2-agonists on lung function and BHR during both SA and LA use were observed in this study.

Both FEV1 (− 6.6%) and BHR (− 1.2 doubling concentration) deteriorated during regular SA use. Cockcroft et al12 found no increase in BHR after regular use of salbutamol for 2 weeks, when tested with methacholine. However, they did find an increased BHR (− 0.91 doubling concentration) when tested with allergen. They also showed that there was reduced protection, both for methacholine and allergen, but this was not measured during the present study. Wahedna et al28 observed a decrease in FEV1 (absolute) of 10% and a decrease in PC20 of 1.47 doubling concentration, after 3 weeks use of albuterol. Although these studies investigated a shorter period of regular use of β2-agonists, these findings are comparable with our findings.

We found no statistically significant difference among the three medication groups. It might be possible that with slightly larger sample sizes and a longer follow-up period, differences would have become significant. This is suggested by the fact that the within-treatment group effect of SA was highly significant for FEV1 (p = 0.0002) and nearly significant for PC20 (p = 0.05) and clinically relevant for both, and the fact that differences among groups were more pronounced at the end of the 12 weeks.

Several authors1012 suggest that these negative effects are caused by tolerance to the protective effect ofβ 2-agonists. This reduced protection is thought to be due to β2-receptor downregulation on smooth muscle cells and inflammatory cells, such as mast cells. This would indicate that subjects are becoming less and less protected against bronchoconstrictive stimuli (direct and indirect), resulting in a deterioration of pulmonary parameters in the long term, which will probably become even greater when subjects are exposed to allergens. Several laboratory studies,1112 did indeed find reduced protection after regular β2-agonist use but also found that there remained still a considerable amount of protection. Most of these studies,5,1012,17,29 investigated a period of 1 to 8 weeks of regular use. Therefore, the clinical relevance of these findings for the long term remains uncertain.30 We did not measure the protective effects ofβ 2-agonists in this study; instead, we assessed the clinical consequence of this possible tolerance during a period of 12 weeks. It was assumed that if a clinical relevant and persistentβ 2-receptor downregulation (tolerance) occurs after regular β2-agonist use, resulting in reduced protection, clinical consequences (a deterioration of FEV1 and PC20) should become manifest in the long term. This study shows this is the case to a certain extent for the regular use of SA.

Theoretically, the use of LA produces prolonged occupancy onβ 2-receptors,21 which could result in greater downregulation, compared with regular use of SA.21 This is even more plausible for formoterol, because this is nearly a full agonist, whereas salbutamol and salmeterol are not.31 However, several studies5,1112 showed that both SA and LA (including formoterol) led to persistentβ 2-receptor downregulation (tolerance). In our study, downregulation was noted in the SA group (with negative clinical effects), but not in the LA group. Detrimental effects were found for both SA and LA in laboratory settings,,1012,3233 but, in clinical studies, no adverse effects have been attributed to LA.19,34The effect of inhaled corticosteroids might confound these findings, as they might overcome a possible deterioration.35

An explanation for the differences between SA and LA found in the present study is hard to give, as there is no clear pathophysiologic mechanism. One explanation might be that the persistentβ 2-receptor downregulation caused by regular use of SA, resulting in reduced protection in the long term, does result in detrimental clinical effects. During use of LA, this persistent β2-receptor downregulation still seems to give enough protection, and consequently does not result in detrimental effects. Furthermore, it has been found that formoterol has a greater mast cell-stabilizing effect than albuterol36 and salmeterol,37which might explain the effects of formoterol in the present study. Finally, the time of measurement after the last doses of study medication might have influenced our data. Patients had to stop taking their medication for at least 12 h. It is suggested in the literature that LAs have effects far beyond 12 h.3839 So it might be that medication was still partly active in this group at the time of measurement, which might result in slightly elevated values. The median time of stopping treatment with the study medication in the total LA group was 15 h at all occasions. Additionally, we analyzed a subgroup of subjects who stopped treatment with their medication for at least 20 h and 24 h. Analyses of these subgroups did not result in different findings, implicating that the β2-agonist activity was probably marginal at the time of measurement for the whole LA group. We therefore believe that the time of measurement did not seriously confound the results of this study. Nevertheless, the LA group was measured each time in this (probably partly) protected stage.

Several studies5,28,40 observed a rebound decrease in FEV1 and PC20 during the period just after stopping treatment withβ 2-agonists, which is thought to subsequently recover within a few hours. These observations indicate that detrimental effects might not be a structural effect of regular use ofβ 2-agonists, but rather a temporal pharmacologic consequence of this regular use. If our observations are due to a rebound effect, it seems that this only occurs after discontinuing regular use of SA, and not after discontinuing use of LA. This discrepancy is also observed in the literature.,5,10,32 It is possible that the results of this study are (partly) due to this rebound effect, especially in the SA group, because pulmonary parameters were measured between 12 h and 15 h after the last concentration of study medication. This was done to avoid still existing bronchodilating effects of theseβ 2-agonists (functional antagonism), though this might not be the case in the LA group. To assess whether the deterioration is structural after discontinuing regular use of SA or recovers after a certain time, parameters should be additionally measured at least 72 h after stopping treatment with the medication and not only in this possible rebound period. Whether or not a rebound effect occurs after discontinuing LA therapy cannot completely be ruled out by this study, as there might be a possibility that subjects were still in a partly protected stage. To give a better answer to this, longer periods of discontinuation (eg, 24 h) are necessary. However, this period should also not be too long; otherwise, this possible rebound effect might be missed.

We deliberately studied patients who did not use inhaled corticosteroids or were able to stop using this medication, as we wanted to investigate the isolated effects of regular use ofβ 2-agonists. One could argue that this study is mostly theoretical, as regular monotherapy withβ 2-agonists is not generally advocated in guidelines nowadays. Because we wanted to select only patients who could do without inhaled steroids, a considerable number of patients dropped out, as several of them could not do without their inhaled steroids. So, it is likely that the patients who remained in the study were those with less severe asthma, because they were steroid independent. Consequently, these patients may be considered as not fully representative of the total allergic asthmatic population. Nevertheless, the present study population is probably more representative of the subjects who do sometimes rely onβ 2-agonist monotherapy. Although inhaled steroids are also advised in guidelines for this group of patients, it might be that, because these patients have relatively mild conditions and consequently have lesser symptoms, their compliance toward inhaled corticosteroids is diminished and, consequently, they only useβ 2-agonists in their daily lives.9,41

As mentioned before, and in contrast to our original hypothesis, we found no additional deteriorating effect of relatively high allergen exposure. It might be that the exposure to HDM allergens in this study was not high enough to evoke a possible interacting effect. The mean (geometric) HDM allergen loads found in this study were just below 1,000 ng/g. Compared with other countries, for instance Australia or South Africa, this is relatively low.4243 Although measured der p 1 concentrations are generally low in the Netherlands, the prevalence of HDM allergy is 21.8% for subjects< 45 years old.44 So, despite the relatively low allergen levels, patients in this country are also sensitized to HDM, and exposure to these allergens might result in possible interactive effects during use of β2-agonists.

In conclusion, we can say that, in this study, we observed a worsening of lung function and BHR within a group of asthmatic allergic patients who received monotherapy with salbutamol. This was not observed during the regular use of LAs. Effects were seen only within the medication groups, while the effects between the medication groups were not statistically significant. No interactive effects were observed between allergen exposure and the regular use ofβ 2-agonists on the deterioration of lung function during both LA and SA use.

Abbreviations: BHR = bronchial hyperresponsiveness; CI = confidence interval; GP = general practitioner; HDM = house dust mite; LA = long-acting β2-agonist; PC20 = provocative concentration of histamine causing a 20% fall in FEV1; SA = short-actingβ 2-agonist

This study was supported by the Dutch Asthma Foundation, Novartis Pharma, 3M Pharma Industries, and Boehringer Ingelheim.

Figure Jump LinkFigure 1. Theoretical model explaining the decrease in lung function observed in some cohorts receiving regular treatment withβ 2-agonists. Regular use of β2-agonists might result in negative effects on clinical parameters. Exposure to allergens might also result in negative effect. When both exposures occur, it might result in an even greater effect than just the sum of the two effects (interactive effect).Grahic Jump Location
Table Graphic Jump Location
Table 1. Patient Participation*
* 

IC = inhaled corticosteroids.

 

Exclusion criterion.

 

Due to not stopping treatment with study medication or rescue medication on time, or because FEV1 ≤ 50% of predicted.

Figure Jump LinkFigure 2. Study scheme. LF = lung function measurements; HDM0, HDM1, HDM2, HDM3 = dust samples.Grahic Jump Location
Table Graphic Jump Location
Table 2. Baseline Characteristics of the Three Medication Groups*
* 

Data are presented as mean (SD) (tested with analysis of variance) unless otherwise indicated.

 

Geometric mean (95% CI).

 

Peak flow variability: (evening–morning)/mean.

§ 

Median (25th–75th percentiles).

Figure Jump LinkFigure 3. Changes compared to baseline in (top, A) BHR (PC20) and (bottom, B) FEV1 percent predicted within each of the three medication groups (mean change ± SEM). p = 0.07 among the three groups for PC20; p = 0.17 among the three groups for FEV1.Grahic Jump Location
Table Graphic Jump Location
Table 3. Medication Courses*
* 

N = total number of subjects in each group; n = the number of patients who used an oral prednisone course; % = these totals in percentages.

We thank the research assistants for obtaining the dust samples, Mr. H. Hovenga (University Hospital Groningen) for analyzing all the dust samples, Professor R. Aalberse (University of Amsterdam) for kindly supplying the cell line producing monoclonal antibody against Der p 1, and the four lung function technicians (Mrs. M. Habes, Mrs. I. Van Den Heuvel, Mrs. E. Snakenborg, Mrs. M. Thies) for performing spirometric measurements.

Miller, BD, Strunk, RC (1989) Circumstances surrounding the deaths of children due to asthma.Am J Dis Child143,1294-1299. [PubMed]
 
Grainger, J, Woodman, K, Pearce, N, et al Prescribed fenoterol and death from asthma in New Zealand, 1981–7: a further case-control study.Thorax1991;46,105-111. [CrossRef] [PubMed]
 
Spitzer, WO, Suissa, S, Ernst, P, et al The use of β-agonists and the risk of death and near death from asthma.N Engl J Med1992;326,501-506. [CrossRef] [PubMed]
 
Kraan, J, Koëter, GH, vd Mark, TW, et al Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutalineJ Allergy Clin Immunol1985;76,628-636. [CrossRef] [PubMed]
 
Vathenen, AS, Knox, AJ, Higgins, BG, et al Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline.Lancet1988;12,554-558
 
Schayck, CP, Graafsma, SJ, Visch, MB, et al Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol.J Allergy Clin Immunol1990;86,793-800. [CrossRef] [PubMed]
 
Schayck, CP, Dompeling, E, Herwaarden, CLA, et al Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? a randomised controlled study.BMJ1991;303,1426-1431. [CrossRef] [PubMed]
 
Sears, MR, Taylor, DR, Print, CG, et al Regular inhaled β-agonist treatment in bronchial asthma.Lancet1990;336,1391-1396. [CrossRef] [PubMed]
 
Arvidsson, P, Larsson, S, Lofdahl, CG, et al Inhaled formoterol during 1-year in asthma: a comparison with salbutamol.Eur Respir J1991;4,1168-1173. [PubMed]
 
Cheung, D, Timmers, MC, Zwinderman, AH, et al Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med1992;327,1198-1203. [CrossRef] [PubMed]
 
O’Connor, BJ, Aikman, SL, Barnes, PJ Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma.N Engl J Med1992;327,1204-1208. [CrossRef] [PubMed]
 
Cockcroft, DW, McParland, CP, Britto, SA, et al Regular inhaled salbutamol and airway responsiveness to allergen.Lancet1993;342,833-837. [CrossRef] [PubMed]
 
Cockcroft, DW, O’Byrne, PM, Swystun, VA, et al Regular use of inhaled albuterol and the allergen-induced late asthmatic response.J Allergy Clin Immunol1995;96,44-49. [CrossRef] [PubMed]
 
Schayck, CP, Cloosterman, SGM, Hofland, ID, et al How detrimental is chronic use of bronchodilators in asthma and chronic obstructive pulmonary disease?Am J Respir Crit Care Med1995;151,1317-1319. [PubMed]
 
Kerstjens, HAM, Brand, PLP, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airway disease.N Engl J Med1992;327,1413-1419. [CrossRef] [PubMed]
 
Town, GI, O’Donnell, TV, Purdie, G Bronchial responsiveness during regular fenoterol therapy: four months prospective study.N Z Med J1991;104,3-5. [PubMed]
 
Booth, H, Fishwick, K, Harkawat, R, et al Changes in methacholine induced bronchoconstriction with the long-acting β2-agonist salmeterol in mild to moderate asthmatic patients.Thorax1993;48,1121-1124. [CrossRef] [PubMed]
 
Woolcock, A, Lundback, B, Ringdal, N, et al Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids.Am J Respir Crit Care Med1996;153,1481-1488. [PubMed]
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticosteroids in asthma patients with symptoms on existing inhaled corticosteroids.Lancet1994;344,219-224. [CrossRef] [PubMed]
 
Molen, T, Postma, DS, Turner, MO, et al Effects of the long-acting β agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids.Thorax1996;52,535-539
 
Lipworth, BJ Airway subsensitivity with long-acting β2-agonists: is there cause for concern?Drug Safety1997;16,295-308. [CrossRef] [PubMed]
 
Cloosterman, SGM, Schermer, TRJ, Bijl-Hofland, ID, et al Effects of house-dust mite avoidance measures onDer p1 concentrations and clinical condition of mild adult house-dust mite allergic asthmatic patients, using no inhaled steroids.Clin Exp Allergy1999;29,1336-1346. [CrossRef] [PubMed]
 
Dompeling, E, Schayck, CP, Folgering, H, et al Accuracy, precision and linearity of the portable flow-volume meter Microspiro HI-298.Eur Respir J1991;4,612-615. [PubMed]
 
Sterk, PJ, Fabbri, LM, Quanjer, PH, et al Airway responsiveness: standardized challenge testing with pharmacologic, physical and sensitizing stimuli in adults.Eur Respir J1993;6,53-83. [PubMed]
 
Borg, GAV Psychophysical bases of perceived exertion.Med Sci Sports Exerc1982;14,377-381. [PubMed]
 
van der Heide, S, de Monchy, JGR, de Vries, K, et al Seasonal variation in airway hyperresponsiveness and natural exposure to house dust mite allergens in patients with asthma.J Allergy Clin Immunol1993;93,470-475
 
Quanjer, PH, Tammeling, GJ, Cotes, JE, et al Lung volumes and forced ventilatory flows.Eur Respir J1993;6,5-40. [PubMed]
 
Wahedna, I, Wong, CS, Wisniewski, AFZ, et al Asthma control during and after cessation of regular β2-agonist treatment.Am Rev Respir Dis1993;148,707-712. [CrossRef] [PubMed]
 
Grove, A, Lipworth, BJ Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients.Lancet1995;346,201-206. [CrossRef] [PubMed]
 
Cockcroft, DW, Swynstun, VA Functional antagonism: tolerance produced by inhaled β2-agonists.Thorax1996;51,1051-1056. [CrossRef] [PubMed]
 
Tattersfield, AE Clinical pharmacology of long-acting β-receptor agonists.Life Sci1993;52,2161-2169. [CrossRef] [PubMed]
 
Yates, DH, Sussman, HS, Shaw, MJ, et al Regular formoterol treatment in mild asthma: effect on bronchial responsiveness during and after treatment.Am J Respir Crit Care Med1995;152,1170-1174. [PubMed]
 
Booth, H, Bish, R, Walters, J, et al Salmeterol tachyphylaxis in steroid treated asthmatic subjects.Thorax1996;51,1100-1104. [CrossRef] [PubMed]
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma.N Engl J Med1997;337,1405-1411. [CrossRef] [PubMed]
 
Mak, JCW, Nishikawa, M, Shirasaki, H, et al Protective effects of a glucocorticoid on down regulation of pulmonary β2-adrenergic receptorsin vivo.J Clin Invest1995;96,99-106. [CrossRef] [PubMed]
 
Nightingale, JA, Rogers, DF, Barnes, PJ Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma.Am J Respir Crit Care Med1999;159,1786-1790. [PubMed]
 
Taylor, DA, Jensen, MW, Aikman, SL, et al Comparison of salmeterol and albuterol-induced bronchoprotection against adenosine monophosphate and histamine in mild asthma.Am J Respir Crit Care Med1997;156,1731-1737. [PubMed]
 
Maesen, FPV, Smeets, JJ, Gubbelmans, HLL, et al Bronchodilator effect of inhaled formoterol vs salbutamol > 12 hours.Chest1990;97,590-594. [CrossRef] [PubMed]
 
Rabe, KF, Jörres, R, Nowak, D, et al Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness > 24 hours in bronchial asthma.Am Rev Respir Dis1993;147,1436-1441. [PubMed]
 
Jong, JW, Mark, TW, Koëter, GH, et al Rebound airway obstruction and responsiveness after cessation of terbutaline: effects of budesonide.Am J Respir Crit Care Med1996;153,70-75. [PubMed]
 
McIvor, RA, Pizzichini, E, Turner, MO, et al Potential masking effects of salmeterol on airway inflammation in asthma.Am J Respir Crit Care Med1998;158,924-930. [PubMed]
 
Marks, GB, Tovey, ER, Green, W, et al House dust mite allergen avoidance: a randomized controlled trial of surface chemical treatment and encasement of bedding.Clin Exp Allergy1994;24,1078-1083. [CrossRef] [PubMed]
 
Manjra, A, Berman, D, Toerien, A, et al The effects of a single treatment of an acaricide, Acarosan, and a detergent, Metsan, on Der p I allergen levels in the carpets and mattresses of asthmatic children.S Afr Med J1994;84,278-280. [PubMed]
 
Rijcken, B, Kerkhof, M, Graaf, AD, et al European respiratory health survey: Dutch ECRHS Group.1996,\ University of Groningen. Groningen, The Netherlands:
 

Figures

Figure Jump LinkFigure 1. Theoretical model explaining the decrease in lung function observed in some cohorts receiving regular treatment withβ 2-agonists. Regular use of β2-agonists might result in negative effects on clinical parameters. Exposure to allergens might also result in negative effect. When both exposures occur, it might result in an even greater effect than just the sum of the two effects (interactive effect).Grahic Jump Location
Figure Jump LinkFigure 2. Study scheme. LF = lung function measurements; HDM0, HDM1, HDM2, HDM3 = dust samples.Grahic Jump Location
Figure Jump LinkFigure 3. Changes compared to baseline in (top, A) BHR (PC20) and (bottom, B) FEV1 percent predicted within each of the three medication groups (mean change ± SEM). p = 0.07 among the three groups for PC20; p = 0.17 among the three groups for FEV1.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Patient Participation*
* 

IC = inhaled corticosteroids.

 

Exclusion criterion.

 

Due to not stopping treatment with study medication or rescue medication on time, or because FEV1 ≤ 50% of predicted.

Table Graphic Jump Location
Table 2. Baseline Characteristics of the Three Medication Groups*
* 

Data are presented as mean (SD) (tested with analysis of variance) unless otherwise indicated.

 

Geometric mean (95% CI).

 

Peak flow variability: (evening–morning)/mean.

§ 

Median (25th–75th percentiles).

Table Graphic Jump Location
Table 3. Medication Courses*
* 

N = total number of subjects in each group; n = the number of patients who used an oral prednisone course; % = these totals in percentages.

References

Miller, BD, Strunk, RC (1989) Circumstances surrounding the deaths of children due to asthma.Am J Dis Child143,1294-1299. [PubMed]
 
Grainger, J, Woodman, K, Pearce, N, et al Prescribed fenoterol and death from asthma in New Zealand, 1981–7: a further case-control study.Thorax1991;46,105-111. [CrossRef] [PubMed]
 
Spitzer, WO, Suissa, S, Ernst, P, et al The use of β-agonists and the risk of death and near death from asthma.N Engl J Med1992;326,501-506. [CrossRef] [PubMed]
 
Kraan, J, Koëter, GH, vd Mark, TW, et al Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutalineJ Allergy Clin Immunol1985;76,628-636. [CrossRef] [PubMed]
 
Vathenen, AS, Knox, AJ, Higgins, BG, et al Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline.Lancet1988;12,554-558
 
Schayck, CP, Graafsma, SJ, Visch, MB, et al Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol.J Allergy Clin Immunol1990;86,793-800. [CrossRef] [PubMed]
 
Schayck, CP, Dompeling, E, Herwaarden, CLA, et al Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? a randomised controlled study.BMJ1991;303,1426-1431. [CrossRef] [PubMed]
 
Sears, MR, Taylor, DR, Print, CG, et al Regular inhaled β-agonist treatment in bronchial asthma.Lancet1990;336,1391-1396. [CrossRef] [PubMed]
 
Arvidsson, P, Larsson, S, Lofdahl, CG, et al Inhaled formoterol during 1-year in asthma: a comparison with salbutamol.Eur Respir J1991;4,1168-1173. [PubMed]
 
Cheung, D, Timmers, MC, Zwinderman, AH, et al Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med1992;327,1198-1203. [CrossRef] [PubMed]
 
O’Connor, BJ, Aikman, SL, Barnes, PJ Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma.N Engl J Med1992;327,1204-1208. [CrossRef] [PubMed]
 
Cockcroft, DW, McParland, CP, Britto, SA, et al Regular inhaled salbutamol and airway responsiveness to allergen.Lancet1993;342,833-837. [CrossRef] [PubMed]
 
Cockcroft, DW, O’Byrne, PM, Swystun, VA, et al Regular use of inhaled albuterol and the allergen-induced late asthmatic response.J Allergy Clin Immunol1995;96,44-49. [CrossRef] [PubMed]
 
Schayck, CP, Cloosterman, SGM, Hofland, ID, et al How detrimental is chronic use of bronchodilators in asthma and chronic obstructive pulmonary disease?Am J Respir Crit Care Med1995;151,1317-1319. [PubMed]
 
Kerstjens, HAM, Brand, PLP, Hughes, MD, et al A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airway disease.N Engl J Med1992;327,1413-1419. [CrossRef] [PubMed]
 
Town, GI, O’Donnell, TV, Purdie, G Bronchial responsiveness during regular fenoterol therapy: four months prospective study.N Z Med J1991;104,3-5. [PubMed]
 
Booth, H, Fishwick, K, Harkawat, R, et al Changes in methacholine induced bronchoconstriction with the long-acting β2-agonist salmeterol in mild to moderate asthmatic patients.Thorax1993;48,1121-1124. [CrossRef] [PubMed]
 
Woolcock, A, Lundback, B, Ringdal, N, et al Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids.Am J Respir Crit Care Med1996;153,1481-1488. [PubMed]
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticosteroids in asthma patients with symptoms on existing inhaled corticosteroids.Lancet1994;344,219-224. [CrossRef] [PubMed]
 
Molen, T, Postma, DS, Turner, MO, et al Effects of the long-acting β agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids.Thorax1996;52,535-539
 
Lipworth, BJ Airway subsensitivity with long-acting β2-agonists: is there cause for concern?Drug Safety1997;16,295-308. [CrossRef] [PubMed]
 
Cloosterman, SGM, Schermer, TRJ, Bijl-Hofland, ID, et al Effects of house-dust mite avoidance measures onDer p1 concentrations and clinical condition of mild adult house-dust mite allergic asthmatic patients, using no inhaled steroids.Clin Exp Allergy1999;29,1336-1346. [CrossRef] [PubMed]
 
Dompeling, E, Schayck, CP, Folgering, H, et al Accuracy, precision and linearity of the portable flow-volume meter Microspiro HI-298.Eur Respir J1991;4,612-615. [PubMed]
 
Sterk, PJ, Fabbri, LM, Quanjer, PH, et al Airway responsiveness: standardized challenge testing with pharmacologic, physical and sensitizing stimuli in adults.Eur Respir J1993;6,53-83. [PubMed]
 
Borg, GAV Psychophysical bases of perceived exertion.Med Sci Sports Exerc1982;14,377-381. [PubMed]
 
van der Heide, S, de Monchy, JGR, de Vries, K, et al Seasonal variation in airway hyperresponsiveness and natural exposure to house dust mite allergens in patients with asthma.J Allergy Clin Immunol1993;93,470-475
 
Quanjer, PH, Tammeling, GJ, Cotes, JE, et al Lung volumes and forced ventilatory flows.Eur Respir J1993;6,5-40. [PubMed]
 
Wahedna, I, Wong, CS, Wisniewski, AFZ, et al Asthma control during and after cessation of regular β2-agonist treatment.Am Rev Respir Dis1993;148,707-712. [CrossRef] [PubMed]
 
Grove, A, Lipworth, BJ Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients.Lancet1995;346,201-206. [CrossRef] [PubMed]
 
Cockcroft, DW, Swynstun, VA Functional antagonism: tolerance produced by inhaled β2-agonists.Thorax1996;51,1051-1056. [CrossRef] [PubMed]
 
Tattersfield, AE Clinical pharmacology of long-acting β-receptor agonists.Life Sci1993;52,2161-2169. [CrossRef] [PubMed]
 
Yates, DH, Sussman, HS, Shaw, MJ, et al Regular formoterol treatment in mild asthma: effect on bronchial responsiveness during and after treatment.Am J Respir Crit Care Med1995;152,1170-1174. [PubMed]
 
Booth, H, Bish, R, Walters, J, et al Salmeterol tachyphylaxis in steroid treated asthmatic subjects.Thorax1996;51,1100-1104. [CrossRef] [PubMed]
 
Pauwels, RA, Lofdahl, CG, Postma, DS, et al Effect of inhaled formoterol and budesonide on exacerbations of asthma.N Engl J Med1997;337,1405-1411. [CrossRef] [PubMed]
 
Mak, JCW, Nishikawa, M, Shirasaki, H, et al Protective effects of a glucocorticoid on down regulation of pulmonary β2-adrenergic receptorsin vivo.J Clin Invest1995;96,99-106. [CrossRef] [PubMed]
 
Nightingale, JA, Rogers, DF, Barnes, PJ Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma.Am J Respir Crit Care Med1999;159,1786-1790. [PubMed]
 
Taylor, DA, Jensen, MW, Aikman, SL, et al Comparison of salmeterol and albuterol-induced bronchoprotection against adenosine monophosphate and histamine in mild asthma.Am J Respir Crit Care Med1997;156,1731-1737. [PubMed]
 
Maesen, FPV, Smeets, JJ, Gubbelmans, HLL, et al Bronchodilator effect of inhaled formoterol vs salbutamol > 12 hours.Chest1990;97,590-594. [CrossRef] [PubMed]
 
Rabe, KF, Jörres, R, Nowak, D, et al Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness > 24 hours in bronchial asthma.Am Rev Respir Dis1993;147,1436-1441. [PubMed]
 
Jong, JW, Mark, TW, Koëter, GH, et al Rebound airway obstruction and responsiveness after cessation of terbutaline: effects of budesonide.Am J Respir Crit Care Med1996;153,70-75. [PubMed]
 
McIvor, RA, Pizzichini, E, Turner, MO, et al Potential masking effects of salmeterol on airway inflammation in asthma.Am J Respir Crit Care Med1998;158,924-930. [PubMed]
 
Marks, GB, Tovey, ER, Green, W, et al House dust mite allergen avoidance: a randomized controlled trial of surface chemical treatment and encasement of bedding.Clin Exp Allergy1994;24,1078-1083. [CrossRef] [PubMed]
 
Manjra, A, Berman, D, Toerien, A, et al The effects of a single treatment of an acaricide, Acarosan, and a detergent, Metsan, on Der p I allergen levels in the carpets and mattresses of asthmatic children.S Afr Med J1994;84,278-280. [PubMed]
 
Rijcken, B, Kerkhof, M, Graaf, AD, et al European respiratory health survey: Dutch ECRHS Group.1996,\ University of Groningen. Groningen, The Netherlands:
 
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