In-Patient Pulmonary Rehabilitation to Improve Asthma Control
A randomized controlled study (EPRA, Effectiveness of Pulmonary Rehabilitation for Patients with Asthma)
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Background: Despite the availability of effective pharmaceutical treatment options, many patients with asthma do not manage to control their illness. This randomized trial with a waiting-list control group examined whether a 3-week course of inpatient pulmonary rehabilitation (PR) improves asthma control (primary endpoint) and other secondary endpoints (e.g., quality of life, cardinal symptoms, mental stress). The subsequent observational segment of the study investigated the long-term outcome after PR.
Methods: After approval of the rehabilitation´ by the insurance providers (T0), 412 adults with uncontrolled asthma (Asthma Control Test [ACT] score < 20 points) undergoing rehabilitation were assigned to either the intervention group (IG) or the waiting-list control group (CG). PR commenced 1 month (T1) after randomization in the IG and 5 months after randomization (T3) in the CG. Asthma control and the secondary endpoints were assessed 3 months after PR in the IG (T3) as an intention-to-treat analysis by means of analyses of covariance. Moreover, both groups were observed for a period of 12 months after the end of PR.
Results: At T3 the mean ACT score was 15.76 points in the CG, 20.38 points in the IG. The adjusted mean difference of 4.71 points was clinically relevant (95% confidence interval [3.99; 5.43]; effect size, Cohen‘s d = 1.27). The secondary endpoints also showed clinically relevant effects in favor of the IG. A year after the end of rehabilitation the mean ACT score was 19.00 points, still clinically relevant at 3.54 points higher than when rehabilitation began. Secondary endpoints such as quality of life and cardinal symptoms (dyspnea, cough, expectoration, pain) and self-management showed moderate to large effects.
Conclusion: The trial showed that a 3-week course of PR leads to clinically relevant improvement in asthma control and secondary endpoints. Patients who do not achieve control of their asthma despite outpatient treatment therefore benefit from rehabilitation.
The Global Initiative for Asthma (GINA) defines asthma as a heterogeneous disease characterized by chronic airway inflammation and varying symptoms, such as wheeze, shortness of breath, and cough (1). The diagnosis is based on clinical symptoms and evidence of reversible obstruction and / or bronchial hyperreactivity (2, 3).
With an estimated 300 million people affected, asthma is one of the most common chronic diseases worldwide (1). In Germany, the 12-month prevalence is 6.3% (4). Cross-sectional studies found a high number of patients with uncontrolled asthma in many countries (5, 6). Therefore, complementary approaches to improving asthma control are needed.
The current German asthma guidelines (2, 3) recommend pulmonary rehabilitation (PR) if, despite adequate outpatient medical care, the physical, psychological, or social consequences of the illness persist, or if asthma control cannot be achieved. Observational studies (7, 8, 9) have shown positive changes in quality of life, key symptoms, physical performance, and asthma control. Randomized controlled trials (RCTs) have proven the effectiveness of individual components of PR, such as patient education (10), physiotherapy breathing retraining (11), and aerobic training therapy (12). To date, however, no German or international RCTs have tested the effectiveness of complex rehabilitation, which comprises different components.
The EPRA (Effectiveness of Pulmonary Rehabilitation for Patients with Asthma) study  combines an RCT that has a waiting list control design with a subsequent observational study. The RCT examines the effectiveness of a three-week, in-patient PR for patients with poorly controlled asthma, based on differences in the Asthma Control Test (ACT) between the intervention group (IG) and the waiting list control group (CG), at three months after rehabilitation of the IG.
Secondary outcomes are quality of life, physical performance, dyspnea, anxiety, depression, self-management skills, therapy adherence, smoking status, illness perception, subjective work ability, and subjective prognosis of gainful employment.
The subsequent observational study examined the outcomes up to twelve months after end of rehabilitation. In addition, the short-term effects on lung function parameters, 6-minute walk distance (6MWD) test, and fractional exhaled nitric oxide (FeNO) are reported before and after rehabilitation for both groups.
The study design of the single-center EPRA study has been described previously (13). The study protocol was approved by the Ethics Committee of the Bavarian Chamber of Physicians (Bayerische Landesärztekammer) (Nr. 15017; 21 April, 2015). This study has been registered with the German Clinical Trials Register (DRKS00007740; 15 May, 2015), and was funded by the German Statutory Pension Insurance of South Bavaria (Deutsche Rentenversicherung Bayern Süd).
Study design and data collection
Between June 2015 and August 2017, all patients with asthma who were referred to the Bad Reichenhall Clinic and who met the inclusion criteria were informed by letter about the study and, if they were interested in participating, asked for their consent. At the same time, asthma control was recorded by the patients using the self-administered asthma control test (ACT).
Inclusion criteria were poorly controlled asthma (ACT <20 points) and an asthma diagnosis confirmed by a pulmonologist at the start of rehabilitation, which was based on typical asthma symptoms as well as a documented (partially) reversible airway obstruction and bronchial hyperreactivity. Exclusion criteria were not being able to participate due to insufficient German language ability or cognitive inability, or having a serious concomitant disease.
Randomization was carried out in a 1:1 ratio for both groups in the order in which the written informed consent forms were received. A randomization list (eMethods) was stratified according to age (< 55 years, < 65 years, ≥ 65 years) and was used externally by one of the authors (M.S.).
The IG started rehabilitation at one month after randomization, and the CG, at five months after randomization. Data for the RCT were collected at time of randomization (T0), and at one month (T1), two months (T2), and five months (T3) after randomization (see study design, eFigure). For the observational study, data were recorded for both groups at the start and end of rehabilitation, as well as at three, six, nine, and twelve months after the end of rehabilitation (for information about the number of cases planned and achieved, see eMethods; for further details on the study design, see eFigure).
Patients in the IG went through an intensive, three-week PR in accordance with the quality guidelines of the German statutory health insurers. The PR not only included medical diagnostics and modified drug therapy (as appropriate) but also the following mandatory (M) and optional (O) therapy components:
- Endurance and strength training (M)
- Whole-body vibration training (O)
- Inspiratory muscle training (O)
- Patient education about asthma (M)
- Inhalation technique training (M)
- Allergen avoidance education (O)
- Group respiratory physiotherapy (M) or individual respiratory physiotherapy (O)
- Buteyko breathing technique training (O)
- Respiratory physiotherapeutic mucolysis procedures (O)
- Psychological individual and group interventions (O)
- Social counseling (O)
- Nutritional counseling/therapy (O)
- Smoking cessation (O)
A more detailed description can be found in the eMethods section. Note that the CG received the same interventions from T3 to T4.
Outcomes and assessment tools
Asthma control was assessed using the ACT. This questionnaire is recommended by guidelines (1, 2, 3) and comprises a scale from 5 to 25 points, with 20 to 25 points indicating controlled asthma (1). The ACT focuses on asthma symptom control, and a score below 20 is also associated with an increased exacerbation frequency and an unfavorable asthma prognosis (“future risk”) (14, 15). Changes by three or more points are considered clinically relevant (14).
Secondary outcomes were documented with different questionnaires: health-related quality of life with the Asthma Quality of Life Questionnaire (AQLQ [S]) (16) and the St. George´s Respiratory Questionnaire (SGRQ) (17); depression with the Patient Health Questionnaire-9 (PHQ-9) (18); anxiety with the Generalized Anxiety Disorder Questionnaire (GAD-7) (19); adherence to drug therapy with the Medication Adherence Report Scale (MARS-D) (20); perceptions about the illness with the Brief Illness Perception Questionnaire (Brief IPQ) (21); self-management with the Skill and Technique Acquisition scale of the Health Education Impact Questionnaire (heiQ) (22); subjective work ability with the Work Ability Scale (WAS) (23); subjective prognosis of employment status with the SPE scale (24); and dyspnoea, cough, sputum, and pain with an 11-point numerical rating scale (NRS; 0–10).
At the beginning and end of rehabilitation, the following objective measured values were also collected:
- Spirometry / body plethysmography with bronchodilator testing (FEV1, VC, FEV1/VC, FIV1, RV, TLC, RV/TLC, sRtot)
- 6MWD test
In addition, at the start of rehabilitation, an in vitro allergy screening was carried out, and blood eosinophil count was measured.
Descriptive statistics were given for all times points. All outcomes of the RCT were evaluated using analyses of covariances. The results of each respective outcome at the corresponding time point (T2, T3) served as the outcome, while group membership (IG/CG), age group allocation, and the T0 value of the outcome were considered independent variables. All randomized patients for whom at least one measured value was available at time T0 (intention-to-treat [ITT] analysis) were included in the analysis. Missing values were handled by multiple imputation (creating ten complete datasets).
Adjusted mean differences (AMD) to T2/T3 including 95% confidence intervals (95% CI) as well as standardized effect sizes (Cohen’s d ) are reported. Standardized effects of > 0.2/0.5/0.8 are considered small, medium, and large, respectively. Ordinal regressions were calculated for the SPE scale, and logistic regressions, for the current smoking status. For the observational study, data were evaluated using structural equation models based on the Chi² difference test (for details, see eMethods section).
All calculations were carried out with the software programs SPSS (version 25) and R (3.61). The alpha level for the analysis of the primary outcome was set to 0.05 (eMethods).
Patient recruitment is shown in Figure 1. The study included N = 412 patients, with 202 in the IG (40.1% female; Mage = 50.7 years) and 210 in the CG (43.3% female; Mage = 51.6 years). In both groups, more than 85% of patients had moderate to severe asthma (Global Initiative for Asthma [GINA] 3–5). In total, 49.4% participated in the German asthma disease management program, and 52.8% had already received patient education about asthma (Table 1). In the year prior to study inclusion, 87.9% of participants had at least one exacerbation. In the three months prior to study inclusion, 35.7% had performed at least one short course of oral corticosteroids (corticosteroid tablets), and 75.0% had consulted a pulmonologist at least once. Both groups were already on intensive medication at time T0. For example, 93.6% of patients in the IG, and 92.9% of those in the CG, used an inhaled corticosteroid (ICS), mostly in combination with a long-acting beta-agonist (LABA) (ICS-LABA combination preparation used by 79.2% or 74.8% of the IG or CG patients, respectively). In the previous week, 19.3% (IG) and 12.4% (CG) of the patients had taken corticosteroid tablets (for further details on drug therapy, see eMethods, eTable 4).
Randomized controlled trial
The adjusted mean difference in ACT (primary outcome) showed a 4.71 [3.99; 5.43] point increase for the IG (see Figure 2). This corresponds to a large effect (Cohen’s d = 1.21). At time T3, 68.9% of the IG patients, but only 20.1% of the CG patients, had controlled asthma (p < 0.001).
With respect to secondary outcomes, the IG performed better, showing medium to strong effects at times T2 and T3. Strong effects at time T3 were shown in quality of life (AQLQ/SGRQ), main symptoms (NRS), self-management (heiQ), and better understanding the asthma illness (IPQ-7).
No significant differences were observed in the observational study between IG and CG for any outcome measure at the start of rehabilitation, the end of rehabilitation, or any equivalent follow-up times (all results of the Chi²-difference-test were p > 0.05; see eTable 5, eTable 6). At twelve months after the end of rehabilitation, the mean ACT score was 19.00 points [18.51; 19.48], which is 3.54 points [3.08; 3.99] above the score at the start of rehabilitation, and asthma was under control for 55.9% of patients. The results of other outcomes were similar.
Lung function parameters and 6-minute walking distance (6MWD) during rehabilitation
Both groups had comparable baseline values at the start of rehabilitation, and comparable improvements in lung function parameters and the 6MWD test at the end of rehabilitation. For example, during the rehabilitation process, the FEV1 value prior to the bronchospasmolysis test improved by 0.31 (IG) or 0.27 (CG) liters, and the distance in the 6MWD test improved by 87 meters (IG) or 90 (CG) meters (eTable 3).
This RCT showed, for the first time worldwide, that a multimodal PR can significantly improve the degree of asthma control in a clinically relevant manner up to three months after the end of rehabilitation, as determined by the ACT (primary endpoint). While improvement in ACT lowered slightly in the twelve months after rehabilitation, it still remained clinically relevant (with a mean difference in ACT > 3 points). In addition, clinically relevant improvements were found in secondary endpoints, such as key symptoms (shortness of breath, cough, sputum), quality of life, psychological stress, and subjective ability to work. Clinically relevant changes during rehabilitation were also demonstrated for various lung function parameters, the 6MWD test, and FeNO (eMethods, eTable 3). Finally, this study underscores that using RCTs to test the effects of in-patient rehabilitation can also be implemented in the German rehabilitation system.
The differences in asthma control between IG and CG at the end of rehabilitation (adjusted mean difference [AMD] = 6.00; d = 1.69) and three months afterwards (AMD = 4.71, d = 1.21), and the improvements in quality of life are strong effects, according to common criteria. Although the broad inclusion criteria of the EPRA-RCT and the slightly different study populations make comparisons difficult, the effects reported here are mostly larger those of other intervention studies. Current RCTs on respiratory physiotherapy, for example, found effects in the ACT of 0.5 (26) and 2.0 points (27), respectively. Wong et al. (28) showed improvements of 4.6 points in the ACT directly at the end of a six-month outpatient asthma management program, which had more stringent inclusion criteria than the EPRA study. Exercise alone can also improve asthma control and quality of life, but to a lesser extent (29). Studies of only drug therapies report somewhat lower effects on asthma control and quality of life (30), similar to newer therapeutic methods such as biologics (31, 32) and bronchial thermoplasty (33). Thus, the effects of PR reported here should be regarded as strong and clinically relevant as compared to other intervention studies; therefore, PR should be seen as an additional effective treatment option for cases of uncontrolled asthma despite adequate medical treatment.
Medium to strong positive effects were also found for secondary outcomes such as dyspnoea, cough, and sputum. The effects on depression and anxiety were stronger than in studies on cognitive–behavioral interventions in asthma patients (34). Relevant improvements were also found in typical proximal outcome criteria of patient education courses (35), such as self-reported adherence, disease and medication attitudes, and self-management skills. These outcome criteria are considered to be predictors for the persistence of effects in a clinical course. In addition, there were clear effects with regard to the subjective ability to work, a relevant predictor for a successful return to work (36). As a result, PR seems to improve both the patients´ management of the illness and their participation in social life, in addition to improving the clinical symptoms.
The results of the subsequent observational study showed clinically relevant effects in primary and secondary outcomes even after one year, although for methodological reasons these observations cannot be traced back to the PR in a monocausal manner. The RCT that directly preceded it, however, showed that the differences in the values between the start of rehabilitation and three months after rehabilitation are directly attributable to the intervention. Therefore, the longer-term courses are also very likely to be (at least partially) due to the PR.
In addition, the parallel, positive course of the treatment results of CG and IG during rehabilitation (including for the lung function parameters and the 6MWD test) and in follow-up show that patients with asthma in the waiting list CG achieved the same rehabilitation effects as patients who did the PR directly (IG), which speaks for the effectiveness of the intervention itself.
The study examined the effectiveness of “complex rehabilitation”, which consists of various components, so that reliable conclusions about the contributions of individual therapeutic components are not possible, and the exact mechanism of action of the intervention cannot be derived from our data with certainty. Adjusting medication (eTable 4), improving drug compliance (MARS-D, Table 3), the positive results of smoking cessation (eTable 1), and participating in psychosocial therapy are all likely to have contributed to the positive effects. In addition, unspecific effects (e.g., sense of renewal due to the rehabilitation stay, climate factors, allergen avoidance) are possible. However, the persistence of the improvements at three months after the end of the rehabilitation in the RCT, and the persistence of the effects even up to one year after the PR for both groups, suggest that the effects are largely due to the PR.
Previous studies have shown that patient education (10, 37), physical exercise (12), and respiratory physiotherapy (11) are effective as single measures. The “PR” package of measures, however, produces stronger effects from these individual components than those reported in the literature, and this in a multitude of outcomes. It can therefore be assumed that the effects of PR can be traced back to the interaction of the multimodal therapy components.
The National Asthma Care Guideline from 2009 (38) explicitly called for RCTs to be carried out for more evidence regarding rehabilitation for patients with asthma. The German Council of Experts for the Assessment of Developments in the Health Care System (2014) also identified the lack of evidence—and in particular, the lack of RCTs—as a core problem in the rehabilitation sector. Missing RCTs are usually justified by the fact that insured persons with an approved application have a legal right to rehabilitation and therefore should not be randomly assigned to a control group without rehabilitation. EPRA shows by way of example that RCTs for testing rehabilitation effects can also be implemented within this legal framework in Germany (39).
Limitations of this study include that it is a single-center study, and therefore, its results cannot simply be transferred to all rehabilitation programs for asthma. The EPRA therapy program is intensive and comprehensive, but meets the structural guidelines of the German statutory health insurers (40). Similar prerequisites are likely to be present at other high-performance rehabilitation clinics.
While patients throughout Germany are assigned to the Bad Reichenhall Clinic through different health insurers, over 90% of the cases were assigned through the Statutory pension insurance; in other words, they were mostly patients who were not retired. In addition, individual patient groups (emergency cases, patients with follow-up rehabilitation [Anschlussheilbehandlung, AHB]) could not be included due to the design of the study. Therefore, caution is advised regarding the transferability of these results to other patient groups.
Additionally, blinding was not possible. Furthermore, the proportion of unspecific effects (due to change of location, work leave) or purely medicinal effects in the overall effect cannot be specified exactly. Finally, the results in the secondary outcomes must be interpreted exploratively.
The EPRA study shows that a in-patient pulmonary rehabilitation of 3 weeks for patients with uncontrolled asthma leads to a significant and clinically relevant improvement in asthma control up to three months after the end of rehabilitation. This effect is still detectable to a clinically relevant extent after one year. Therefore, patients whose asthma is poorly controlled despite adequate medical treatment should be referred to an appropriate rehabilitation.
We would like to thank all EPRA patients, who cooperatively filled out up to eight extensive questionnaires over a period of more than a year. We also thank the study assistants (B. Obermaier, M. Messerschmidt, and A. Klotz) and the DRV Bayern Süd, who supported the study financially. We would like to thank the Department of General Practice and Health Services Research and the Department of Internal Medicine VI, Clinical Pharmacology, and Pharmacoepidemiology of the Heidelberg University Hospital for the use of the MARS-D.
Data sharing statement
Anonymized data can be requested by other scientists for research purposes.
Conflict of interest statement
Dr. Schultz has received consulting honoraria from Berlin Chemie, Sanofi-Aventis, and GSK, reimbursement of conference registration fees and travel expenses from Boehringer, and honoraria for the preparation of scientific meetings from Novartis, AstraZeneca, Berlin Chemie, and Boehringer.
Dennis Nowak has received honoraria for lecturing activities from Berlin Chemie, Boehringer Ingelheim, GSK, Mundipharma, Novartis, Hexal, and Lilly, and consulting honoraria from Pfizer (smoking cessation).
The remaining authors declare that no conflict of interest exist..
Manuscript submitted on 23 December 2019, revised version accepted on 28 May 2020.
Translated from the original German by Dr. Veronica A. Raker.
Dr. med. Konrad Schultz
Klinik Bad Reichenhall
Salzburger Str. 8–11,
83435 Bad Reichenhall, Germany
Cite this as:
Schultz K, Wittmann M, Wagner R, Lehbert N, Schwarzkopf L, Szentes B,
Nowak D, Faller H, Schuler M: In-patient pulmonary rehabilitation to improve asthma control—a randomized controlled study (EPRA, Effectiveness of Pulmonary Rehabilitation for Patients with Asthma). Dtsch Arztebl Int 2021; 118: 23–30. DOI: 10.3238/arztebl.m2021.0003
For eReferences please refer to:
eMethods, eTables, eFigure:
Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Health Economics and Health Care Management, Comprehensive Pneumology Center Munich (CPC-M) – member of the German Center for Lung Research (DZL): PD Dr. rer. biol. hum. Larissa Schwarzkopf, Boglárka Szentes, MSc Economics, MPH
Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin, Klinikum der Universität München, Comprehensive Pneumology Center Munich (CPC-M) – member of the German Center for Lung Research (DZL): Prof. Dr. med. Dennis Nowak
Institute for Clinical Epidemiology and Biometry, Universität Würzburg: PD Dr. phil. Michael Schuler
Chair of Rehabilitation Science, Universität Würzburg, Germany: Prof. Dr. phil. Dr. med. Hermann Faller
IFT – Institut für Therapieforschung GmbH, München, Germany: PD Dr. rer. hum. biol. Larissa Schwarzkopf
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