Background In a previous study, we found that two years of treatmentwith an inhaled corticosteroid, budesonide, was more effectivethan treatment with an inhaled 2-agonist, terbutaline, in patientswith newly diagnosed, generally mild asthma. We continued thisstudy for a third year to investigate whether the steroid dosecould be reduced or discontinued and what effect crossover ofpatients from 2-agonist therapy to corticosteroid therapy wouldhave.
Methods A total of 37 patients treated for two years with inhaledbudesonide at a dose of 1200 µg per day were randomlyassigned to treatment with 400 µg of budesonide per day(19 patients) or placebo (18 patients) in a double-blind manner.Another 37 patients, who had received terbutaline during thefirst two years, were crossed over in an open-label manner totreatment with 1200 µg of budesonide per day during thethird year.
Results Treatment with the reduced dose of budesonide was sufficientlyeffective in 74 percent of the patients to maintain bronchialresponsiveness at a level similar to that achieved with thehigher dose. In contrast, improvement was maintained in only33 percent of the patients receiving placebo, and the differencesin pulmonary function between the steroid and placebo groupswere significant (for forced expiratory volume in one second,P = 0.007; for bronchial responsiveness to histamine, P = 0.025;and for peak expiratory flow in the morning, P = 0.040). Thecondition of patients who were crossed over from terbutalinetherapy to treatment with 1200 µg of budesonide per dayimproved. However, the degree of improvement in these patientsappeared to be less than in those who were treated with budesonideat the beginning of the three-year study.
Conclusions Early treatment with inhaled budesonide resultsin long-lasting control of mild asthma. Maintenance therapycan usually be given at a reduced dose, but discontinuationof treatment is often accompanied by exacerbation of the disease.
In a previous two-year study of patients with generally mildasthma, we found that treatment with an inhaled corticosteroid,budesonide (1200 µg per day), resulted in rapid improvementin symptoms and lung function, whereas similar changes werenot observed with the inhaled bronchodilator terbutaline1. Weconcluded that even in patients with mild asthma, treatmentshould be initiated with an inhaled corticosteroid such as budesonide.
There is some evidence that the early initiation of treatmentwith inhaled corticosteroids may provide long-lasting improvementeven after asthma therapy has been stopped2,3. We continuedour study for a third year to answer the following questions:Would the beneficial effects of treatment with budesonide bemaintained with a lower dose (400 µg per day)? How longwould the treatment effects last after budesonide was discontinued?What level of treatment efficacy could be obtained when budesonidetherapy was started after a delay -- that is, after two yearsof treatment with terbutaline?
Methods
In our initial, 2-year study we treated patients with newlydiagnosed asthma (with symptoms present for less than 12 months)and compared the effects of budesonide (600 µg twice daily)and terbutaline (375 µg twice daily), delivered from apressurized metered-dose inhaler through a large volume spacer(Nebuhaler, Astra, Sodertalje, Sweden)1. After two years thestudy was divided into a double-blind arm and an open arm andcontinued for a third year.
Study Design
Double-Blind Study Arm
In the double-blind study arm, patients from the previous budesonidegroup were treated either with budesonide at a reduced dose(200 µg twice daily) or with placebo. An inspiratory-flow-driven,multidose powder inhaler (Turbuhaler, Astra) was chosen fordrug delivery to permit the use of a placebo (lactose, 200 µgper dose) without the possible effects of chlorofluorocarbonsand lubricants4.
The study was performed as a multicenter, double-blind, randomized,placebo-controlled, parallel-group trial. Five centers participated,and the patients entered the trial at staggered intervals overa 12-month period immediately after completing the previous2-year treatment period with budesonide. During a four-weekrun-in period, the patients were switched over to open treatmentwith budesonide given by a flow-driven inhaler in a dose of600 µg twice a day. Lung function was evaluated by measuringforced expiratory volume in one second (FEV1) and forced vitalcapacity (FVC). Bronchial responsiveness was tested by challengewith six doubling concentrations, or dose steps, of histamine(1, 2, 4, 8, 16, and 32 mg per millimeter) administered by nebulizer.The FEV1 was measured after each 10-breath challenge. The histamineconcentration that induced a 15 percent decrease in the FEV1was called the "provocative concentration" (PC15). Peak expiratoryflow (PEF) was measured each morning and evening. Asthma symptomsand supplemental use of a 2-agonist were also assessed. Randomizationinto two treatment groups was made separately for each centerin blocks of four at the end of the run-in period.
During the treatment period, the patients received either budesonidegiven by a flow-driven inhaler in a dose of 200 µg twicea day or placebo, also given by a flow-driven inhaler. The patientsalso received terbutaline (500 µg per dose) to be givenby a flow-driven inhaler as needed. If, after randomization,asthma control was insufficient with the study medication andsupplemental terbutaline, the responsible physician could prescribeoral slow-release theophylline (Theo-Dur, 300 mg twice a day).Patients with severe exacerbations of asthma were allowed toreceive oral prednisolone for six days in decreasing doses (30,25, 20, 15, 10, and 5 mg per day).
Open Study Arm
The patients entered the open study arm of the trial at staggeredintervals over a 12-month period after completing the previous2-year treatment with terbutaline. The treatment was identicalto that used in the budesonide group during the initial two-yearstudy -- that is, budesonide delivered from a metered-dose inhalerat a dose of 600 µg twice a day. No run-in period wasincluded. If supplemental medication was needed, the patientswere allowed to take terbutaline from a metered-dose inhaler(250 µg per dose). The use of concomitant antiasthmatictherapy followed the guidelines established for the double-blindstudy.
Compliance
The use of study medication was checked by the investigatorat each visit. No objective method for confirming compliancewas available.
Patients
Informed consent was obtained from all patients. The study wasapproved by the Finnish Medical Board and the local ethics committees.
Double-Blind Study Arm
At the beginning of the initial two-year study, 50 patientswere randomly assigned to treatment with budesonide. Three patientsdid not fulfill all the inclusion criteria1. During the two-yearstudy, one patient was withdrawn because of insufficient treatmenteffect and seven were withdrawn for previously reported reasons1.Two patients did not wish to continue, since they deemed themselves"cured." The remaining 37 patients participated in the thirdyear of the study.
Open Study Arm
Initially, 53 patients were randomly assigned to treatment withterbutaline. Three patients did not fulfill all the inclusioncriteria. Ten patients were withdrawn during the two-year studybecause of insufficient treatment effect, and 3 were withdrawnfor other reasons. The remaining 37 patients continued in theopen study with budesonide for the third year.
Similarity of the Groups
When the three newly formed treatment groups were compared withthe use of patient data obtained at the start of the two-yearstudy, the groups were found to be similar in most respects(Table 1). However, the placebo group in the double-blind studyhad lower PC15 values than the two other groups. In the openstudy, a larger proportion of nonatopic patients had been withdrawnduring the two-year study, so that the group subsequently hadrelatively more patients with atopy (86 percent) than the twogroups in the double-blind study (68 percent in the group receivingbudesonide and 67 percent in the group receiving placebo) (Table 1).
Table 1. Characteristics of the Treatment Groups Assessed at the Start of the Initial Two-Year Study.
Recording Outcomes
The methods used to record outcomes were similar to those usedin the preceding study1 and will be described here briefly.During the run-in period (double-blind study only), the first12 weeks, and the last 4 weeks of the third year, the patientsrecorded their PEF values each morning and evening. They alsorecorded their asthma symptoms every day, assigning a singlescore of 0 (no symptoms) to 10 (severe symptoms) for each 24-hourperiod. The use of supplemental 2-agonist medication and adversereactions were also recorded.
The assessments performed at the clinic at the start and endof the 4-week run-in period (double-blind study only) and thenafter 6, 12, 28, 44, and 48 weeks of treatment included spirometry,a test for bronchial responsiveness, and checks of the patients'diaries.
Statistical Analysis
For the measurement of the three variables reflecting lung function-- FVC, FEV1 and PC15 -- the time of randomization was usedas the point of reference in the double-blind study, whereasthe start of treatment was used as the point of reference inthe open study. In the analyses, logarithmic values for PC15were used and the result was expressed as dose steps (i.e.,step 0 equaled 1 mg of histamine diphosphate per milliliter;step 1, 2 mg per milliliter; step 2, 4 mg per milliliter; andso on). The values for the four variables recorded in the diaries-- the morning PEF, the evening PEF, the asthma score, and thenumber of puffs of supplemental 2-agonist -- were first reducedto averages over the four-week run-in period (double-blind studyonly) and over the first week, the sixth week, and the lastmonth. The average for the run-in period was used as the referencevalue in the double-blind study, and the average for the lastfour weeks preceding the start of the new treatment was usedin the open study.
All seven variables were analyzed with respect to change fromthe reference value. Analyses between and within groups wereperformed by t-tests with averages for the last month (diarydata) or the last measurement (FVC, FEV1, and PC15) of the treatmentperiod. P values below 0.05 were considered to indicate statisticalsignificance. All tests were two-tailed.
Results
Lung Function and Symptoms
Double-Blind Study Arm
FVC values did not change significantly during the third yearor differ significantly between the groups (Table 2). The FEV1and PC15 values did not change significantly in the budesonidegroup, but in the placebo group the FEV1 fell by an averageof 0.25 liter (P = 0.010) and PC15 by 1.5 dose steps (P = 0.037).The differences in the changes in FEV1 and PC15 values betweenthe groups were significant (P = 0.007 and P = 0.025, respectively)(Table 2 and Figure 1). Bronchial responsiveness worsened duringthe third year in 5 of the 19 patients in the budesonide group(26 percent) and 12 of the 18 patients in the placebo group(67 percent).
Figure 1. Mean (±SE) PC as a Measure of Bronchial Responsiveness.
The PC15 dose steps 0, 1, 2, 3, 4, and 5 represent histamine concentrations of 1, 2, 4, 8, 16, and 32 mg per milliliter, respectively. The three groups of patients were treated as follows: double-blind budesonide for three years (solid line), double-blind budesonide for two years followed by double-blind placebo for one year (dotted line), and double-blind terbutaline for two years followed by open-label budesonide for one year (dotted-and-dashed line). The first two groups were treated as one until the beginning of the third year.
Morning and evening PEF values did not change significantlyin the budesonide group, but fell significantly in the placebogroup (P<0.001 and P = 0.017, respectively) (Table 2 andFigure 2A). In the placebo group the average decrease in PEF(from base line) was 22 liters per minute in the morning and13 liters per minute in the evening. There was a significantdifference between the two groups with respect to the changesin morning PEF values (P = 0.040). The asthma-symptom scoreincreased significantly in the placebo group (P = 0.037) (Table 2and Figure 2B). The use of supplemental terbutaline did notchange significantly in the two groups.
Figure 2. Day-to-Day Mean PEF (Panel A) and Asthma-Symptom Score (Panel B).
The PEF was measured in the morning. The range of possible asthma scores was 0 to 10. The groups of patients were treated as follows: double-blind budesonide for three years (thick solid line), double-blind budesonide for two years followed by double-blind placebo for one year (dotted line), and double-blind terbutaline for two years followed by open-label budesonide for one year (thin solid line).
Open Study Arm
The FVC and FEV1 values did not change significantly duringthe third year, but the improvement in PC15 approached significance(P = 0.05) (Table 2).
Morning PEF values increased by an average of 15 liters perminute (P = 0.005). An average increase in the evening PEF of6 liters per minute was not significant (P = 0.11) (Table 2and Figure 2A). The asthma-symptom score fell significantly(P = 0.009) (Table 2 and Figure 2B), as did the use of supplementalterbutaline (P = 0.009).
Comparison of Early and Late Therapy with Budesonide
We compared the changes observed in the group treated with budesonidefrom the beginning and the changes in the group treated withbudesonide after two years of terbutaline therapy. The changesin the measures of treatment efficacy were calculated for the1st week, the 6th week, and the 12th month after the start oftreatment with budesonide. There was a greater degree of improvementin all lung-function measures in the patients treated initiallywith budesonide (Table 3). A similar trend was seen for theasthma-symptom score and for the use of supplemental terbutaline.
Table 3. Comparison of Improvements in Patients Treated with Budesonide as First-Line Therapy within One Year of the Diagnosis of Asthma and Patients Treated More Than Two Years after Diagnosis.
Withdrawal, Extra Medication, and Side Effects
A 60-minute cosyntropin test7 to examine the adrenocorticalresponse was carried out in 42 of the 50 patients who had beenreceiving budesonide for two years and were eligible for thedouble-blind study. All patients fulfilled the criteria fora normal response and had a mean increase in plasma cortisolconcentrations of 369 nmol per liter (from 399 to 768 nmol perliter; reference value, >150 nmol per liter) at 30 minutesand of 542 nmol per liter (from 399 to 941 nmol per liter) at60 minutes.
Double-Blind Study Arm
During the third year three patients were withdrawn from thebudesonide group, two because of insufficient treatment effect(after 98 and 161 treatment days) and one because of pregnancy(after 219 days). Three patients were also withdrawn from theplacebo group, all because of insufficient treatment effect(after 50 days, 121 days, and nearly a year). Five of 19 patientstreated with budesonide reported throat irritation, as comparedwith 1 of 18 in the placebo group. No cases of oropharyngealcandidiasis or hoarseness occurred. Nine courses of oral prednisolonewere given to four patients in the budesonide group, and twoof them used two and three courses soon after the dose of budesonidewas reduced. Six patients in the placebo group used eight coursesof prednisolone. Theophylline was added to the treatment regimenof three patients in the placebo group (a total of 218 treatmentdays), but to none in the budesonide group.
Open Study Arm
One patient was withdrawn from the open study because of noncompliance.None of the patients dropped out because of adverse effects.Twelve courses of oral prednisolone were given to eight patients.Theophylline was added to the treatment regimen of five patients.
Discussion
During the third year of our study, one group of patients whohad previously received 1200 µg of budesonide per dayreceived a reduced dose, 400 microg. Measures of lung functionand clinical variables recorded in the patients' diaries remainedessentially unchanged after the dose of budesonide was reduced.A slight decrease in PEF values was observed at the beginningof the third year, but this was not accompanied by significantchanges in other measures of lung function or by an increasein symptoms. The PEF values improved again toward the end ofthe study year. In a few patients early deterioration of theclinical condition was observed, and 2 of the 19 patients hadto be withdrawn during the year because of insufficient treatmenteffect. Nevertheless, it is obvious that in the majority ofpatients the dose of budesonide can be reduced without importantdeterioration of lung function.
In the parallel double-blind placebo group, all variables deterioratedduring the third year. There seemed to be a gradual declineof lung function, which became more pronounced toward the endof the year. Bronchial responsiveness worsened -- the PC15 valuedecreased by an average of 1.5 dose steps -- but still remained1.2 steps above the base-line value observed at the start ofthe three-year study. At the beginning of the three-year study,the placebo group had worse bronchial reactivity than the othertwo groups, which indicates more severe asthma. However, theimprovements in lung function were maintained in 6 of the 18patients in the placebo group, which suggests that treatmentwith an inhaled steroid may be discontinued in some patients.Unfortunately, we have no means of identifying those whose conditionwill or will not deteriorate when treatment is discontinued.
In a previous study, when budesonide was stopped after onlysix weeks of treatment, the severity of symptoms and lung functionreverted rapidly to base-line values8. The beneficial effectremained for three months when treatment had continued for oneyear3. In both studies, patients had chronic asthma of at leastmoderate severity. When patients with newly diagnosed asthmawere treated with 400 µg per day of budesonide for oneyear, and treatment was then discontinued, mean bronchial responsivenessdeteriorated during the following six months; however, the meanremained better than that recorded before therapy9.
The patients in our open study arm, who had inhaled 750 µgof terbutaline per day for two years and then 1200 µgof budesonide per day during the third year, had a significantdecrease in asthma symptoms and in the use of supplemental terbutaline,and an improvement in morning PEF values during treatment withbudesonide. When the responses were compared with those in thegroup treated with budesonide from the outset, it was observedthat delayed treatment with budesonide resulted in consistentlypoorer responses. This trend was statistically significant atall time points for increases in morning PEF values from baseline.
Before the start of the third year, 16 of 53 patients in theoriginal terbutaline group had been withdrawn for various reasons.When these 16 patients were compared with the 37 patients whocontinued the study, their age, duration of asthma, blood eosinophilcount, spirometric values, and PC values were similar. The frequencyof atopy was different: it was 50 percent in the group thatwithdrew and 86 percent in those who continued. This does notexplain the differences in the response to budesonide treatment,since patients with atopy would be expected to respond as favorablyas those without atopy to treatment with an inhaled steroid10.Some of the patients who withdrew had obviously more severeasthma than those who were able to continue receiving terbutaline.This could have resulted in a selection bias affecting the responseto steroid therapy. On the other hand, the remaining patientsin the open study group and the group treated with budesonidefrom the beginning had similar base-line values for lung function(Table 1) and, on these grounds, as much room for improvement.
It has been suggested that bronchodilators may mask the underlyingdisease and the ongoing inflammatory process by temporarilyrelieving symptoms while allowing slow deterioration in lungfunction to proceed11,12. The poorer response to delayed steroidtreatment that we observed is in line with this idea, but furtherconfirmation is needed. Further studies are also needed to uncoverthe underlying mechanisms.
From our three-year study, we reach the following general conclusions.It seems possible to obtain long-term control of asthma withearly treatment with an inhaled corticosteroid (in this case,budesonide). Control of the disease in most patients can bemaintained with a lower dose of the corticosteroid than wasinitially needed to normalize lung function. Decreasing thedose should reduce the risk of side effects. If treatment isdiscontinued, patients should be monitored carefully, sincelung function will often deteriorate. In addition, we foundsome indication that delays in initiating inhaled corticosteroidtherapy may lead to an impaired response. This observation shouldbe confirmed before clinical conclusions are drawn.
Source Information
From Helsinki University Central Hospital, Helsinki, Finland (T.H., K.K., A.S., B.S.-A., L.A.L.); Kanta-Hame Central Hospital, Hameenlinna, Finland (M.J.); Pohjois-Karjala Central Hospital, Joensuu, Finland (T.K.); Kiljava Hospital, Kiljava, Finland (S.K., R.T.); Etela-Saimaa Central Hospital, Lappeenranta, Finland (K.L.); and Astra Draco AB, Lund, Sweden (K.N., T.P., O.S., T.S.).
Address reprint requests to Dr. Haahtela at the Department of Allergic Diseases, Helsinki University Central Hospital, Meilahdentie 2, SF-00250 Helsinki, Finland.
References
Haahtela T, Jarvinen M, Kava T, et al. Comparison of a 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-392. [Abstract]
Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832-836. [Medline]
Juniper EF, Kline PA, Vanzieleghem MA, Hargreave FE. Reduction of budesonide after a year of increased use: a randomized controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained. J Allergy Clin Immunol 1991;87:483-489. [CrossRef][Medline]
Engel T, Heinig JH, Malling H-J, Scharling B, Nikander K, Madsen F. Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or Turbuhaler. Allergy 1989;44:220-225. [CrossRef][Medline]
Gregg I, Nunn AJ. Peak expiratory flow in normal subjects. BMJ 1973;3:282-284.
Maynard DE, Folk RL, Riley TR, Wieland RG, Gwinup G, Hamwi GJ. A rapid test for adrenocortical insufficiency. Ann Intern Med 1966;64:552-556.
Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis 1991;143:1317-1321. [Medline]
Osterman K, Carlholm M, Erlandsson G, et al. Long-term treatment with inhaled budesonide (dry powder) 400 µg daily in newly detected asthmatics. Eur Respir J 1993;6:Suppl 17:119s-119s.abstract
Brogden RN. Factors which may affect the response to inhaled steroids; side effects. In: Clark TJH, ed. Steroids in asthma: a reappraisal in the light of inhalation therapy. Auckland, New Zealand: ADIS Press, 1983:154-65.
Page C, Costello J. Controversies in respiratory medicine: regular inhaled beta-agonists -- clear clinical benefit or a hazard to health? Why beta-agonists should not be used regularly. Respir Med 1992;86:477-479. [Medline]
Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 1993;48:134-138. [Free Full Text]
Bourdin, A, Gras, D, Vachier, I, Chanez, P
(2009). Upper airway {middle dot} 1: Allergic rhinitis and asthma: united disease through epithelial cells. Thorax
64: 999-1004
[Abstract][Full Text]
Montuschi, P., Pagliari, G., Fuso, L.
(2009). Pharmacotherapy of asthma: regular treatment or on demand?. Ther Adv Respir Dis
3: 175-191
[Abstract]
Lemanske, R. F. Jr.
(2009). Asthma Therapies Revisited: What Have We Learned?. Proc Am Thorac Soc
6: 312-315
[Abstract][Full Text]
O'Byrne, P. M., Pedersen, S., Lamm, C. J., Tan, W. C., Busse, W. W., on behalf of the START Investigators Group,
(2009). Severe Exacerbations and Decline in Lung Function in Asthma. Am. J. Respir. Crit. Care Med.
179: 19-24
[Abstract][Full Text]
Turpeinen, M, Nikander, K, Pelkonen, A S, Syvanen, P, Sorva, R, Raitio, H, Malmberg, P, Juntunen-Backman, K, Haahtela, T
(2008). Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study). Arch. Dis. Child.
93: 654-659
[Abstract][Full Text]
Walters, E. H., Reid, D. W., Johns, D. P., Ward, C.
(2007). Nonpharmacological and pharmacological interventions to prevent or reduce airway remodelling. Eur Respir J
30: 574-588
[Abstract][Full Text]
Black, P. N., Chen, R., Zitt, M. J., Rachelefsky, G. S., Peters, S. P., Castro, M., Holbrook, J. T.
(2007). Reducing Asthma Treatment. NEJM
357: 504-506
[Full Text]
Papi, A., Canonica, G. W., Maestrelli, P., Paggiaro, P., Olivieri, D., Pozzi, E., Crimi, N., Vignola, A. M., Morelli, P., Nicolini, G., Fabbri, L. M., the BEST Study Group,
(2007). Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma. NEJM
356: 2040-2052
[Abstract][Full Text]
Yawn, B. P., Wollan, P. C., Bertram, S. L., Lowe, D., Butterfield, J. H., Bonde, D., Li, J. T. C.
(2007). Asthma Treatment in a Population-Based Cohort: Putting Step-Up and Step-Down Treatment Changes in Context. Mayo Clin Proc.
82: 414-421
[Abstract][Full Text]
Haahtela, T, Tuomisto, L E, Pietinalho, A, Klaukka, T, Erhola, M, Kaila, M, Nieminen, M M, Kontula, E, Laitinen, L A
(2006). A 10 year asthma programme in Finland: major change for the better.. Thorax
61: 663-670
[Abstract][Full Text]
Humbert, M.
(2006). The Right Tools at the Right Time. Chest
130: 29S-40S
[Abstract][Full Text]
Haahtela, T.
(2006). Lung Function Decline in Asthma and Early Intervention With Inhaled Corticosteroids. Chest
129: 1405-1406
[Full Text]
O'Byrne, P. M., Pedersen, S., Busse, W. W., Tan, W. C., Chen, Y.-Z., Ohlsson, S. V., Ullman, A., Lamm, C. J., Pauwels, R. A.
(2006). Effects of Early Intervention With Inhaled Budesonide on Lung Function in Newly Diagnosed Asthma. Chest
129: 1478-1485
[Abstract][Full Text]
Lange, P, Scharling, H, Ulrik, C S, Vestbo, J
(2006). Inhaled corticosteroids and decline of lung function in community residents with asthma. Thorax
61: 100-104
[Abstract][Full Text]
Ernst, P
(2006). Inhaled corticosteroids moderate lung function decline in adults with asthma. Thorax
61: 93-94
[Full Text]
Dijkstra, A, Vonk, J M, Jongepier, H, Koppelman, G H, Schouten, J P, ten Hacken, N H T, Timens, W, Postma, D S
(2006). Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax
61: 105-110
[Abstract][Full Text]
Boushey, H. A.
(2005). Daily Inhaled Corticosteroid Treatment Should Not Be Prescribed for Mild Persistent Asthma. Am. J. Respir. Crit. Care Med.
172: 412-414
[Full Text]
Ratnawati, R, Thomas, P S
(2005). Exhaled nitric oxide in paediatric asthma. Chronic Respiratory Disease
2: 163-174
[Abstract]
Watson, L., Kerstjens, H. A., Rabe, K. F, Kiri, V., Visick, G. T, Postma, D. S
(2005). Obtaining optimal control in mild asthma: theory and practice. Fam Pract
22: 305-310
[Abstract][Full Text]
Chu, E. K., Drazen, J. M.
(2005). Asthma: One Hundred Years of Treatment and Onward. Am. J. Respir. Crit. Care Med.
171: 1202-1208
[Abstract][Full Text]
Boushey, H. A., Sorkness, C. A., King, T. S., Sullivan, S. D., Fahy, J. V., Lazarus, S. C., Chinchilli, V. M., Craig, T. J., Dimango, E. A., Deykin, A., Fagan, J. K., Fish, J. E., Ford, J. G., Kraft, M., Lemanske, R. F. Jr., Leone, F. T., Martin, R. J., Mauger, E. A., Pesola, G. R., Peters, S. P., Rollings, N. J., Szefler, S. J., Wechsler, M. E., Israel, E., the National Heart, Lung, and Blood Institute's As,
(2005). Daily versus As-Needed Corticosteroids for Mild Persistent Asthma. NEJM
352: 1519-1528
[Abstract][Full Text]
Homer, R. J., Elias, J. A.
(2005). Airway Remodeling in Asthma: Therapeutic Implications of Mechanisms. Physiology
20: 28-35
[Abstract][Full Text]
Nathell, L.
(2005). Effects on sick leave of an inpatient rehabilitation programme for asthmatics in a randomized trial. Scand J Public Health
33: 57-64
[Abstract]
Postma, D. S., Boezen, H. M.
(2004). Rationale for the Dutch Hypothesis: Allergy and Airway Hyperresponsiveness as Genetic Factors and Their Interaction With Environment in the Development of Asthma and COPD. Chest
126: 96S-104S
[Abstract][Full Text]
Larj, M. J., Bleecker, E. R.
(2004). Therapeutic Responses in Asthma and COPD: Corticosteroids. Chest
126: 138S-149S
[Abstract][Full Text]
Sin, D. D., Man, J., Sharpe, H., Gan, W. Q., Man, S. F. P.
(2004). Pharmacological Management to Reduce Exacerbations in Adults With Asthma: A Systematic Review and Meta-analysis. JAMA
292: 367-376
[Abstract][Full Text]
McKenzie, J. E, Cruz-Rivera, M.
(2004). Compatibility of Budesonide Inhalation Suspension with Four Nebulizing Solutions. The Annals of Pharmacotherapy
38: 967-972
[Abstract][Full Text]
Wiley, R. E., Cwiartka, M., Alvarez, D., Mackenzie, D. C., Johnson, J. R., Goncharova, S., Lundblad, L., Jordana, M.
(2004). Transient Corticosteroid Treatment Permanently Amplifies the Th2 Response in a Murine Model of Asthma. J. Immunol.
172: 4995-5005
[Abstract][Full Text]
Castro, M., Bloch, S. R., Jenkerson, M. V., DeMartino, S., Hamilos, D. L., Cochran, R. B., Zhang, X. E. L., Wang, H., Bradley, J. P., Schechtman, K. B., Holtzman, M. J.
(2004). Asthma Exacerbations after Glucocorticoid Withdrawal Reflects T Cell Recruitment to the Airway. Am. J. Respir. Crit. Care Med.
169: 842-849
[Abstract][Full Text]
Kraft, W. K., Steiger, B., Beussink, D., Quiring, J. N., Fitzgerald, N., Greenberg, H. E., Waldman, S. A.
(2004). The Pharmacokinetics of Nebulized Nanocrystal Budesonide Suspension in Healthy Volunteers. J Clin Pharmacol
44: 67-72
[Abstract][Full Text]
Prieto, L., Bruno, L., Gutierrez, V., Uixera, S., Perez-Frances, C., Lanuza, A., Ferrer, A.
(2003). Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects. Chest
124: 1325-1333
[Abstract][Full Text]
Murphy, K. R., Fitzpatrick, S., Cruz-Rivera, M., Miller, C. J., Parasuraman, B.
(2003). Effects of Budesonide Inhalation Suspension Compared With Cromolyn Sodium Nebulizer Solution on Health Status and Caregiver Quality of Life in Childhood Asthma. Pediatrics
112: e212-219
[Abstract][Full Text]
Hawkins, G., McMahon, A. D, Twaddle, S., Wood, S. F, Ford, I., Thomson, N. C
(2003). Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ
326: 1115-
[Abstract][Full Text]
Strube, G., Ward, C, Reid, D, Walters, E H
(2003). Revision of BTS guidelines for treatment of asthma. Thorax
58: 280-280
[Full Text]
Beckett, P A, Howarth, P H
(2003). Pharmacotherapy and airway remodelling in asthma?. Thorax
58: 163-174
[Abstract][Full Text]
Lozano, P., Finkelstein, J. A., Hecht, J., Shulruff, R., Weiss, K. B.
(2003). Asthma Medication Use and Disease Burden in Children in a Primary Care Population. Arch Pediatr Adolesc Med
157: 81-88
[Abstract][Full Text]
Decramer, M., Roussos, C.
(2003). Early detection: introduction. Eur Respir J
21: 1S-2s
[Full Text]
van Schayck, C.P., Chavannes, N.H.
(2003). Detection of asthma and chronic obstructive pulmonary disease in primary care. Eur Respir J
21: 16S-22s
[Abstract][Full Text]
Alvarez Puebla, M. J., Castillo, R., Rey, A., Ortega, N., Blanco, C., Carrillo, T.
(2002). Sputum Eosinophilia and Maximal Airway Narrowing in Dermatophagoides pteronyssinus Allergic Rhinitis Patients: Only Rhinitis or Rhinitis Plus Mild Asthma?. Chest
122: 1560-1565
[Abstract][Full Text]
Pao, C. S., McKenzie, S. A.
(2002). Randomized Controlled Trial of Fluticasone in Preschool Children with Intermittent Wheeze. Am. J. Respir. Crit. Care Med.
166: 945-949
[Abstract][Full Text]
Wood, R. A.
(2002). Pediatric Asthma. JAMA
288: 745-747
[Full Text]
Remes, S T, Pekkanen, J, Remes, K, Salonen, R O, Korppi, M
(2002). In search of childhood asthma: questionnaire, tests of bronchial hyperresponsiveness, and clinical evaluation. Thorax
57: 120-126
[Abstract][Full Text]
Douma, W. R., Kerstjens, H. A. M., de Gooijer, A., Overbeek, S. E., Koeter, G. H., Postma, D. S.
(2002). Initial Improvements in Lung Function and Bronchial Hyperresponsiveness Are Maintained During 5 Years of Treatment With Inhaled Beclomethasone Dipropionate and Terbutaline. Chest
121: 151-157
[Abstract][Full Text]
Botkin, J. R., Clayton, E., Nelson, R., Wilfond, B., Munger, M. A., Miller, F. G., Shorr, A. F., Friedman Ross, L., Fowler, S. J., Lipworth, B. J., Lazarus, S. C., Lemanske, Jr, R. F.
(2001). Salmeterol and Inhaled Corticosteroids in Patients With Persistent Asthma. JAMA
286: 3075-3078
[Full Text]
VAN DEN BOOM, G., RUTTEN-VAN MOLKEN, M. P. M. H., MOLEMA, J., TIRIMANNA, P. R. S., VAN WEEL, C., VAN SCHAYCK, C. P.
(2001). The Cost Effectiveness of Early Treatment with Fluticasone Propionate 250 {micro}g Twice a Day in Subjects with Obstructive Airway Disease . Results of the DIMCA Program. Am. J. Respir. Crit. Care Med.
164: 2057-2066
[Abstract][Full Text]
Matsumoto, H., Ishihara, K., Hasegawa, T., Umeda, B.-i., Niimi, A., Hino, M.
(2001). Effects of Inhaled Corticosteroid and Short Courses of Oral Corticosteroids on Bone Mineral Density in Asthmatic Patients : A 4-Year Longitudinal Study. Chest
120: 1468-1473
[Abstract][Full Text]
Cazes, E., Giron-Michel, J., Baouz, S., Doucet, C., Cagnoni, F., Oddera, S., Korner, M., Dasic, G., Testi, R., Azzarone, B., Canonica, G. W.
(2001). Novel Anti-inflammatory Effects of the Inhaled Corticosteroid Fluticasone Propionate During Lung Myofibroblastic Differentiation. J. Immunol.
167: 5329-5337
[Abstract][Full Text]
Naureckas, E. T., Solway, J.
(2001). Mild Asthma. NEJM
345: 1257-1262
[Full Text]
PARTRIDGE, M R
(2001). The profile of respiratory conditions: why government action is necessary. Thorax
56: 744-745
[Full Text]
Haahtela, T, Klaukka, T, Koskela, K, Erhola, M, Laitinen, L A
(2001). Asthma programme in Finland: a community problem needs community solutions. Thorax
56: 806-814
[Full Text]
O'BRIEN, A., RUSSO-MAGNO, P., KARKI, A., HIRANNIRAMOL, S., HARDIN, M., KASZUBA, M., SHERMAN, C., ROUNDS, S.
(2001). Effects of Withdrawal of Inhaled Steroids in Men with Severe Irreversible Airflow Obstruction. Am. J. Respir. Crit. Care Med.
164: 365-371
[Abstract][Full Text]
Milgrom, H., Berger, W., Nayak, A., Gupta, N., Pollard, S., McAlary, M., Taylor, A. F., Rohane, P.
(2001). Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody (Omalizumab). Pediatrics
108
: e36-e36
[Abstract][Full Text]
Lazarus, S. C., Boushey, H. A., Fahy, J. V., Chinchilli, V. M., Lemanske, R. F. Jr, Sorkness, C. A., Kraft, M., Fish, J. E., Peters, S. P., Craig, T., Drazen, J. M., Ford, J. G., Israel, E., Martin, R. J., Mauger, E. A., Nachman, S. A., Spahn, J. D., Szefler, S. J., for the Asthma Clinical Research Network of the Na,
(2001). Long-Acting {beta}2-Agonist Monotherapy vs Continued Therapy With Inhaled Corticosteroids in Patients With Persistent Asthma: A Randomized Controlled Trial. JAMA
285: 2583-2593
[Abstract][Full Text]
Chanez, P., Karlstrom, R., Godard, P.
(2001). High or standard initial dose of budesonide to control mild-to-moderate asthma?. Eur Respir J
17: 856-862
[Abstract][Full Text]
Beasley, R., Sterk, P.J., Kerstjens, H.A.M., Decramer, M.
(2001). Comparative studies of inhaled corticosteroids in asthma. Eur Respir J
17: 579-580
[Full Text]
Bourdet, S. V., Williams, D.
(2001). Management Considerations for Chronic Asthma. Journal of Pharmacy Practice
14: 108-125
[Abstract]
Sin, D.D., Tu, J.V.
(2001). Inhaled corticosteroid therapy reduces the risk of rehospitalization and all-cause mortality in elderly asthmatics. Eur Respir J
17: 380-385
[Abstract][Full Text]
Sin, D. D., Tu, J. V.
(2001). Underuse of Inhaled Steroid Therapy in Elderly Patients With Asthma. Chest
119: 720-725
[Abstract][Full Text]
VANACKER, N. J., PALMANS, E., KIPS, J. C., PAUWELS, R. A.
(2001). Fluticasone Inhibits But Does Not Reverse Allergen-Induced Structural Airway Changes. Am. J. Respir. Crit. Care Med.
163: 674-679
[Abstract][Full Text]
LEUPPI, J. D., SALOME, C. M., JENKINS, C. R., ANDERSON, S. D., XUAN, W., MARKS, G. B., KOSKELA, H., BRANNAN, J. D., FREED, R., ANDERSSON, M., CHAN, H.-K., WOOLCOCK, A. J.
(2001). Predictive Markers of Asthma Exacerbation during Stepwise Dose Reduction of Inhaled Corticosteroids. Am. J. Respir. Crit. Care Med.
163: 406-412
[Abstract][Full Text]
Wenzel, S.
(2000). Proceedings of the ATS Workshop on Refractory Asthma . Current Understanding, Recommendations, and Unanswered Questions. Am. J. Respir. Crit. Care Med.
162: 2341-2351
[Full Text]
The Childhood Asthma Management Program Research G,
(2000). Long-Term Effects of Budesonide or Nedocromil in Children with Asthma. NEJM
343: 1054-1063
[Abstract][Full Text]
BOULET, L.-P., TURCOTTE, H., LAVIOLETTE, M., NAUD, F., BERNIER, M.-C., MARTEL, S., CHAKIR, J.
(2000). Airway Hyperresponsiveness, Inflammation, and Subepithelial Collagen Deposition in Recently Diagnosed versus Long-standing Mild Asthma . Influence of Inhaled Corticosteroids. Am. J. Respir. Crit. Care Med.
162: 1308-1313
[Abstract][Full Text]
Reicin, A., White, R., Weinstein, S. F., Finn, A. F. Jr, Nguyen, H., Peszek, I., Geissler, L., Seidenberg, B. C., for the Montelukast/Loratadine Study Group,
(2000). Montelukast, a Leukotriene Receptor Antagonist, in Combination With Loratadine, a Histamine Receptor Antagonist, in the Treatment of Chronic Asthma. Arch Intern Med
160: 2481-2488
[Abstract][Full Text]
MELLON, M., LEFLEIN, J., WALTON-BOWEN, K., CRUZ-RIVERA, M., FITZPATRICK, S., SMITH, J. A.
(2000). Comparable Efficacy of Administration with Face Mask or Mouthpiece of Nebulized Budesonide Inhalation Suspension for Infants and Young Children with Persistent Asthma. Am. J. Respir. Crit. Care Med.
162: 593-598
[Abstract][Full Text]
BUSH, A., TIDDENS, H., SILVERMAN, M.
(2000). Clinical Implications of Inflammation in Young Children. Am. J. Respir. Crit. Care Med.
162: S11-14
[Full Text]
van Schayck, C P, van der Heijden, F M M A, van den Boom, G, Tirimanna, P R S, van Herwaarden, C L A
(2000). Underdiagnosis of asthma: is the doctor or the patient to blame? The DIMCA project. Thorax
55: 562-565
[Abstract][Full Text]
BOUSQUET, J., JEFFERY, P. K., BUSSE, W. W., JOHNSON, M., VIGNOLA, A. M.
(2000). Asthma . From Bronchoconstriction to Airways Inflammation and Remodeling. Am. J. Respir. Crit. Care Med.
161: 1720-1745
[Full Text]
PEDERSEN, S.
(2000). Why Does Airway Inflammation Persist? Is It Failure to Treat Early?. Am. J. Respir. Crit. Care Med.
161: S182-185
[Full Text]
ANDERSON, G. P.
(2000). Interactions between Corticosteroids and beta -Adrenergic Agonists in Asthma Disease Induction, Progression, and Exacerbation. Am. J. Respir. Crit. Care Med.
161: S188-196
[Full Text]
Werk, L. N., Steinbach, S., Adams, W. G., Bauchner, H.
(2000). Beliefs About Diagnosing Asthma in Young Children. Pediatrics
105: 585-590
[Abstract][Full Text]
(2000). The use of inhaled corticosteroids in adults with asthma. DTB
38: 5-8
[Abstract][Full Text]
Quinn, T. J., Taylor, S., Wohlford-Lenane, C. L., Schwartz, D. A.
(2000). IL-10 reduces grain dust-induced airway inflammation and airway hyperreactivity. J. Appl. Physiol.
88: 173-179
[Abstract][Full Text]
JATAKANON, A., LIM, S., BARNES, P. J.
(2000). Changes in Sputum Eosinophils Predict Loss of Asthma Control. Am. J. Respir. Crit. Care Med.
161: 64-72
[Abstract][Full Text]
Strube, G., Rudolf, M.
(2000). For and against: Should steroids be the first line treatment for asthma? • For • Against. BMJ
320: 47-49
[Full Text]
GROL, M. H., GERRITSEN, J., VONK, J. M., SCHOUTEN, J. P., KOËTER, G. H., RIJCKEN, B., POSTMA, D. S.
(1999). Risk Factors for Growth and Decline of Lung Function in Asthmatic Individuals up to Age 42 years . A 30-year Follow-up Study. Am. J. Respir. Crit. Care Med.
160: 1830-1837
[Abstract][Full Text]
(1999). Inhaled glucocorticosteroids in adults and children. CMAJ
161: s24-28
[Full Text]
Hackner, D., Tu, G., Weingarten, S., Mohsenifar, Z.
(1999). Guidelines in Pulmonary Medicine: A 25-Year Profile. Chest
116: 1046-1062
[Abstract][Full Text]
Fernandes, D., Guida, E., Koutsoubos, V., Harris, T., Vadiveloo, P., Wilson, J. W., Stewart, A. G.
(1999). Glucocorticoids Inhibit Proliferation, Cyclin D1 Expression, and Retinoblastoma Protein Phosphorylation, but Not Activity of the Extracellular-Regulated Kinases in Human Cultured Airway Smooth Muscle. Am. J. Respir. Cell Mol. Bio.
21: 77-88
[Abstract][Full Text]
VEEN, J. C. C. M.i.`t, SMITS, H. H., HIEMSTRA, P. S., ZWINDERMAN, A. E., STERK, P. J., BEL, E. H.
(1999). Lung Function and Sputum Characteristics of Patients with Severe Asthma During an Induced Exacerbation by Double-Blind Steroid Withdrawal. Am. J. Respir. Crit. Care Med.
160: 93-99
[Abstract][Full Text]
CROCKETT, A.
(1999). Screening older patients for obstructive airways disease. Thorax
54: 472-473
[Full Text]
van Rensen, E. L J, Straathof, K. C M, Veselic-Charvat, M. A, Zwinderman, A. H, Bel, E. H, Sterk, P. J
(1999). Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax
54: 403-408
[Abstract][Full Text]
SONT, J. K., WILLEMS, L. N. A., BEL, E. H., van KRIEKEN, J.H. J. M., VANDENBROUCKE, J. P., STERK, P. J., the AMPUL Study Group,
(1999). Clinical Control and Histopathologic Outcome of Asthma when Using Airway Hyperresponsiveness as an Additional Guide to Long-Term Treatment. Am. J. Respir. Crit. Care Med.
159: 1043-1051
[Abstract][Full Text]
LAATIKAINEN, A. K., KROGER, H. P. J., TUKIAINEN, H. O., HONKANEN, R. J., SAARIKOSKI, S. V.
(1999). Bone Mineral Density in Perimenopausal Women with Asthma . A Population-based Cross-sectional Study. Am. J. Respir. Crit. Care Med.
159: 1179-1185
[Abstract][Full Text]
Malmstrom, K., Rodriguez-Gomez, G., Guerra, J., Villaran, C., Pineiro, A., Wei, L. X., Seidenberg, B. C., Reiss, T. F., for the Montelukast/Beclomethasone Study Group*,
(1999). Oral Montelukast, Inhaled Beclomethasone, and Placebo for Chronic Asthma: A Randomized, Controlled Trial. ANN INTERN MED
130: 487-495
[Abstract][Full Text]
Frantz, E. A., Shenenberger, D. W., Kao, N. L., Whitmore, S. E., Wasserman, S. I., Kemp, J. P., Rachelefsky, G. S., Fireman, P., Shapiro, G. G., Busse, W. W., Hassaballa, H., Garbe, E., Suissa, S., LeLorier, J.
(1999). Inhaled Corticosteroids and Likelihood of Cataract Extraction. JAMA
281: 791-793
[Full Text]
Jatakanon, A., Kharitonov, S., Lim, S., Barnes, P. J
(1999). Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax
54: 108-114
[Abstract][Full Text]
WENZEL, S. E.
(1998). Should Antileukotriene Therapies Be Used Instead of Inhaled Corticosteroids in Asthma? . No. Am. J. Respir. Crit. Care Med.
158: 1699-1701
[Full Text]
van den BOOM, G., van SCHAYCK, C. P., RUTTEN-van MOLKEN, M. P. M. H., TIRIMANNA, P. R. S., den OTTER, J. J., van GRUNSVEN, P. M., BUITENDIJK, M. J., van HERWAARDEN, C. L. A., van WEEL, C.
(1998). Active Detection of Chronic Obstructive Pulmonary Disease and Asthma in the General Population . Results and Economic Consequences of the DIMCA Program. Am. J. Respir. Crit. Care Med.
158: 1730-1738
[Abstract][Full Text]
HAAHTELA, T., KLAUKKA, T.
(1998). Societal and health care benefits of early use of inhaled steroids. Thorax
53: 1005-1006
[Full Text]
Blais, L., Suissa, S., Boivin, J.-F., Ernst, P.
(1998). First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma. Thorax
53: 1025-1029
[Abstract][Full Text]
HIRST, S. J., LEE, T. H.
(1998). Airway Smooth Muscle as a Target of Glucocorticoid Action in the Treatment of Asthma. Am. J. Respir. Crit. Care Med.
158: S201-S206
[Abstract][Full Text]
Lange, P., Parner, J., Vestbo, J., Schnohr, P., Jensen, G.
(1998). A 15-Year Follow-Up Study of Ventilatory Function in Adults with Asthma. NEJM
339: 1194-1200
[Abstract][Full Text]
Britton, J., Lewis, S.
(1998). Objective measures and the diagnosis of asthma. BMJ
317: 227-228
[Full Text]
van der MOLEN, T., MEYBOOM-DE JONG, B., MULDER, H. H., POSTMA, D. S.
(1998). Starting with a Higher Dose of Inhaled Corticosteroids in Primary Care Asthma Treatment. Am. J. Respir. Crit. Care Med.
158: 121-125
[Abstract][Full Text]
NADEL, J. A., BUSSE, W. W.
(1998). Asthma. Am. J. Respir. Crit. Care Med.
157: S130-S138
[Full Text]
Awadh, N., Müller, N. L, Park, C. S, Abboud, R. T, FitzGerald, J M.
(1998). Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning. Thorax
53: 248-253
[Abstract][Full Text]
Mclean, A. N, Sproule, M. W, Cowan, M. D, Thomson, N. C
(1998). High resolution computed tomography in asthma. Thorax
53: 308-314
[Full Text]
STRUBE;, G., RUDOLF, M.
(1998). Should steroids be first choice for asthma?. Thorax
53: 328-328
[Full Text]
2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from 
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