One-year sustained and clinically meaningful outcomes following pulmonary rehabilitation in people with difficult-to-treat or severe asthma

Clinical ImplicationsLong-term sustainability of pulmonary rehabilitation outcomes in people with asthma is scarcely studied. In people with difficult-to-treat or severe asthma, we observed an array of clinically relevant outcomes reached through pulmonary rehabilitation that was consistently sustained at 1-year follow-up. Long-term sustainability of pulmonary rehabilitation outcomes in people with asthma is scarcely studied. In people with difficult-to-treat or severe asthma, we observed an array of clinically relevant outcomes reached through pulmonary rehabilitation that was consistently sustained at 1-year follow-up. Asthma is a common chronic respiratory disease affecting around 300 million people globally, and is associated with significant morbidity.1Porsbjerg C. Melen E. Lehtimaki L. Shaw D. Asthma.Lancet. 2023; 401: 858-873Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar It has been estimated that approximately 17% of people with asthma have difficult-to-treat asthma of whom approximately 4% have severe asthma.2Hekking P.W. Wener R.R. Amelink M. Zwinderman A.H. Bouvy M.L. Bel E.H. The prevalence of severe refractory asthma.J Allergy Clin Immunol. 2015; 135: 896-902Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar Although the introduction of biologicals has revolutionized severe asthma treatment, treatable traits qualifying for nonpharmacological therapies, such as dyspnea, overweight, and physical inactivity, are numerous in poorly controlled asthma and significantly impact on health status.3Janssen S.M.J. van Helvoort H.A.C. Tjalma T.A. Antons J.C. Djamin R.S. Simons S.O. et al.Impact of treatable traits on asthma control and quality of life.J Allergy Clin Immunol Pract. 2023; 11: 1823-1833.e4Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Pulmonary rehabilitation (PR) is a comprehensive intervention that addresses multiple treatable traits in an integrated care setting, aiming to improve the physical and psychological condition of people with chronic respiratory disease and to promote long-term adherence to health-enhancing behaviors.4Spruit M.A. Singh S.J. Garvey C. ZuWallack R. Nici L. Rochester C. et al.An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation.Am J Respir Crit Care Med. 2013; 188: e13-e64Crossref PubMed Scopus (2562) Google Scholar In people with asthma, favorable PR outcomes have been observed on asthma control,5Schultz K. Wittmann M. Wagner R. Lehbert N. Schwarzkopf L. Szentes B. et al.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: 23-30PubMed Google Scholar, 6Sahin H. Naz I. Comparing the effect of pulmonary rehabilitation in patients with uncontrolled and partially controlled asthma.J Asthma. 2019; 56: 87-94Crossref PubMed Scopus (22) Google Scholar, 7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar pulmonary function,5Schultz K. Wittmann M. Wagner R. Lehbert N. Schwarzkopf L. Szentes B. et al.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: 23-30PubMed Google Scholar, 6Sahin H. Naz I. Comparing the effect of pulmonary rehabilitation in patients with uncontrolled and partially controlled asthma.J Asthma. 2019; 56: 87-94Crossref PubMed Scopus (22) Google Scholar, 7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 8Miyamoto N. Senjyu H. Tanaka T. Asai M. Yanagita Y. Yano Y. et al.Pulmonary rehabilitation improves exercise capacity and dyspnea in air pollution-related respiratory disease.Tohoku J Exp Med. 2014; 232: 1-8Crossref PubMed Scopus (17) Google Scholar quality of life,5Schultz K. Wittmann M. Wagner R. Lehbert N. Schwarzkopf L. Szentes B. et al.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: 23-30PubMed Google Scholar, 6Sahin H. Naz I. Comparing the effect of pulmonary rehabilitation in patients with uncontrolled and partially controlled asthma.J Asthma. 2019; 56: 87-94Crossref PubMed Scopus (22) Google Scholar, 7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar oral corticosteroid (OCS) dose,7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar dyspnea,8Miyamoto N. Senjyu H. Tanaka T. Asai M. Yanagita Y. Yano Y. et al.Pulmonary rehabilitation improves exercise capacity and dyspnea in air pollution-related respiratory disease.Tohoku J Exp Med. 2014; 232: 1-8Crossref PubMed Scopus (17) Google Scholar exercise capacity,7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,8Miyamoto N. Senjyu H. Tanaka T. Asai M. Yanagita Y. Yano Y. et al.Pulmonary rehabilitation improves exercise capacity and dyspnea in air pollution-related respiratory disease.Tohoku J Exp Med. 2014; 232: 1-8Crossref PubMed Scopus (17) Google Scholar and quadriceps strength.8Miyamoto N. Senjyu H. Tanaka T. Asai M. Yanagita Y. Yano Y. et al.Pulmonary rehabilitation improves exercise capacity and dyspnea in air pollution-related respiratory disease.Tohoku J Exp Med. 2014; 232: 1-8Crossref PubMed Scopus (17) Google Scholar Few data are available, however, describing to what extent PR gains are sustained in the longer term. In a recent study, it has been observed that, at sea-level PR, clinically relevant improvements in asthma control and disease-related quality of life were achieved, but subsequently gradually disappeared during the year after PR.7de Nijs S.B. Krop E.J.M. Portengen L. Rijssenbeek-Nouwens L.H. de Vries D. Weersink E.J.M. et al.Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.Respir Med. 2020; 171106123Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In the Netherlands, people with difficult-to-treat or severe asthma can be referred for PR when multiple treatable traits contribute to a persisting poor asthma control (Global Initiative for Asthma symptom control score >2, “uncontrolled”) and/or when they had experienced 2 or more moderate exacerbations or 1 or more severe exacerbation in the previous year. In the present study, we set out to evaluate 1-year sustainability of PR outcomes in a cohort of people with difficult-to-treat or severe asthma. We performed a retrospective observational longitudinal study with data from people with asthma who had completed PR at Radboud University Medical Center (Nijmegen, the Netherlands) between 2017 and 2020 and who had completed 6- and 12-month follow-up. There were no exclusion criteria. Data were collected as part of usual care and were anonymized before analysis. The local Medical Ethics Committee concluded that the study was not subject to the Medical Research Involving Human Subjects Act (MEC-2021-13209). Before commencing PR, a comprehensive baseline assessment consisting of physical tests, questionnaires, and multidisciplinary consultations took place. During the 10-week PR program (inpatient, outpatient, or combined), participants received exercise training, education, and individual and group treatments/counseling consistent with international standards.4Spruit M.A. Singh S.J. Garvey C. ZuWallack R. Nici L. Rochester C. et al.An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation.Am J Respir Crit Care Med. 2013; 188: e13-e64Crossref PubMed Scopus (2562) Google Scholar The PR team consisted of pulmonologists, clinical psychologists, physiotherapists, specialized nurses, dieticians, social workers, psychomotor therapists, and creative therapists. Each participant was appointed a coach, and regular interdisciplinary team meetings, which included the participant, took place to evaluate progress. Six and 12 months after PR completion, participants were offered follow-up visits during which measurements of key outcomes were repeated. Participant characteristics were extracted from electronic patient files. For this study, we analyzed the following outcomes at baseline, at PR completion, and at 6- and 12-month follow-up: Asthma Quality of Life Questionnaire score, Asthma Control Questionnaire score, modified Medical Research Council score, FEV1, body mass index, quadriceps strength (measured on a computerized dynamometer [Biodex System 4 Pro, Biodex Medical Systems, Inc, Shirley, NY]), and physical activity (measured by 7-day home accelerometry [DynaPort MoveMonitor, McRoberts, The Hague, the Netherlands]). Also, the Nijmegen Clinical Screening Instrument (NCSI) was administered at all time points. The NCSI measures subdomains of health status (quality of life, health-related quality of life, satisfaction with relations, subjective impairments, behavioral impairments, subjective symptoms, dyspnea emotions, and fatigue) with a battery of subscales from disease-specific and generic questionnaires.9Peters J.B. Rijssenbeek-Nouwens L.H. Bron A.O. Fieten K.B. Weersink E.J. Bel E.H. et al.Health status measurement in patients with severe asthma.Respir Med. 2014; 108: 278-286Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar For each of these subdomains, normative data are available, indicating normal functioning or mild or severe problems. As outcome for the present study, the number of NCSI subdomains with severe problems was summed for each individual and was evaluated at all time points. Finally, the self-reported number of OCS bursts in the previous year was evaluated at baseline and at 12-month follow-up. Paired t tests and Wilcoxon signed-rank tests were used to analyze statistical significance where P less than .05 was considered statistically significant. Within the time frame of the study, 54 people with asthma commenced the PR program. Although all completed the program, 5 (9.3%) were lost to follow-up afterwards (2 for reasons related to comorbidities, 2 were not motivated for follow-up, 1 for unknown reason). Consequently, 49 people were included in the current study (71.4% inpatient, 22.4% outpatient, 6.1% combined). Baseline characteristics are presented in Table E1 in this article’s Online Repository at www.jaci-inpractice.org, and outcomes are presented in Figure 1. Asthma Quality of Life Questionnaire score, Asthma Control Questionnaire score, modified Medical Research Council score, body mass index, FEV1, quadriceps strength, physical activity, and number of NCSI subdomains with severe problems significantly improved during PR (all P < .001), and all these improvements were sustained at 12-month follow-up (differences between 12-month follow-up and immediately post-PR all P > .05). Number of OCS bursts was significantly lower in the year following PR compared with the year preceding PR (median [interquartile range], 1 [0-2.5] vs 2 [1-3], respectively; P = .002). Our data confirm previous studies that clinically relevant outcomes can be reached through PR in people with difficult-to-treat or severe asthma, and add further evidence that these outcomes can be sustained during at least the year following PR. Of note is that improvements during PR were realized without increasing inhaled corticosteroid dose (low/medium/high dose pre-PR n = 4/22/23 vs post-PR n = 3/23/23, P = .57), and none started biologicals during PR, illustrating the significant potential of nonpharmacological treatment modalities as delivered in an integrated care setting. Although the self-reported number of OCS bursts could have been subject to recall bias, we believe that the degree of such bias is limited, considering that participants were fully aware of the importance of exacerbations through dedicated education during PR. It should be acknowledged that the monocenter design of our study limits external validity; hence, confirmatory studies are warranted. Factors associated with sustaining or waning of PR outcomes deserve further study. We conclude that a PR program designed to encourage the participant to structurally engage in health-enhancing behavior enabled achievement of long-term improved asthma control and other clinically relevant health benefits in people with difficult-to-treat or severe asthma. Table E1Baseline characteristics of the study population (n = 49)CharacteristicValueSex: male/female, n (%)19/30 (39/61)Age (y), mean ± SD55 ± 10BMI (kg/m2), mean ± SD30.2 ± 6.6Smoking status, n (%) Ex-smoker33 (67.3) Never-smoker16 (32.7)Adult-onset asthma, n (%)26 (53)Atopy Atopic asthma, n (%)27 (55) Eczema, n (%)16 (33) Total IgE (U/mL), median (IQR)98 (32-217)Inflammation Eosinophils (×109/L), median (IQR)0.18 (0.06-0.34)Use of medication Dose of inhaled corticosteroids, n (%)Low4 (8.2)Moderate22 (44.9)High23 (46.9) Chronic use of OCSs, n (%)8 (16.3)Dose of OCSs (mg/d), mean ± SD8.4 ± 3.5 Leukotriene receptor antagonist, n (%)13 (26.5) Antihistamines, n (%)22 (44.9) Long-acting muscarinic antagonist, n (%)32 (65.3) Use of biological, n (%)5 (10.2) Nasal corticosteroids, n (%)26 (53.1) Reflux medication, n (%)24 (49)GINA treatment step, n (%) 1-34 (8) 4-545 (92)Patient-reported symptoms, mean ± SD ACQ score2.45 ± 0.92 AQLQ score4.29 ± 1.06 mMRC score1.63 ± 0.95Asthma exacerbations <12 mo No. of OCS bursts, n (%)08 (16.3)1-213 (26.5)≥328 (57.1) No. of hospitalizations, n (%)031 (63.3)≥118 (36.7)Functional characteristics, mean ± SD Post-BD FEV1 (%predicted)79 ± 22 Quadriceps strength (%predicted)63 ± 18 Daily physical activity (steps/d)6599 ± 3461No. of NCSI domains with severe problems, mean ± SD6.0 ± 1.7Comorbidities, n (%) Features of both asthma and COPD9 (18.4) Chronic rhinosinusitis16 (33) Diabetes mellitus8 (16.3) Sleep apnea8 (16.3) Thyroid problems5 (10.2) Musculoskeletal disorders8 (16.3)ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; BD, bronchodilator; BMI, body mass index; COPD, chronic obstructive pulmonary disease; GINA, Global Initiative for Asthma; IQR, interquartile range; mMRC, modified Medical Research Council. Open table in a new tab ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; BD, bronchodilator; BMI, body mass index; COPD, chronic obstructive pulmonary disease; GINA, Global Initiative for Asthma; IQR, interquartile range; mMRC, modified Medical Research Council.