In addition to exercise intolerance and a sedentary lifestyle, functional capacity, referring to an individual’s balance, mobility, and transfer abilities, is particularly altered in end-stage disease,1 conferring a high risk for disability, hospitalization, and mortality.2,3 The situation may even be worse in individuals who develop hypoxemic or hypercapnic chronic respiratory failure, that could lead to a stage of vulnerability and physical dependence called frailty.4 Frailty syndrome affects approximatively 1 in 5 patients with chronic obstructive pulmonary disease (COPD),5 with an increasing proportion of frail individuals in the most severe stages of the disease. 6,7 Frail patients with COPD are at higher risk of disability and falls, exercise intolerance, anxiety and depressive symptoms, hospitalizations, and death compared to their non-frail counterparts.6,7 Pulmonary rehabilitation (PR) is highly effective at improving dyspnea, exercise tolerance, and health status in patients with moderate to severe COPD.8-10 Although less documented, center-based PR is feasible and has shown similar benefits in COPD patients with chronic respiratory failure.11-13 However, PR attendance and completion are likely compromised in frail individuals with chronic respiratory failure,6,14 to whom a home-based intervention could help in eliminating barriers that affect PR attendance. The design of an effective PR program to prevent or delay functional decline and disability in older persons is a public health priority15 that has been addressed in multiple reviews.16,17 This question has received little attention in patients with COPD, although a few studies reported short-term effectiveness of center-based PR programs for improving balance, gait speed, and frailty syndrome in patients with moderate to severe COPD.18-20 Whether similar benefits of PR could be obtained in COPD patients with chronic respiratory failure who are at risk of altered functional status and physical frailty is uncertain. Home-based PR, using exercise and self-managing interventions tailored to each patient’s individual abilities and needs, is an attractive approach for these individuals that could further increase the program completion.21,22 Furthermore, focusing on functional status and autonomy in daily life activities and individualizing physical exercises in frail COPD patients with chronic respiratory disease could enhance the benefits of PR on functional capacity and frailty syndrome. The main objective of this prospective interventional study was to evaluate the effectiveness of an 8-week, home-based PR program with COPD patients with chronic respiratory failure. A secondary objective was to specifically evaluate the impact of frailty status on the efficacy of PR in improving functional capacity, exercise tolerance, health-related quality of life, and anxiety and depressive symptoms. Methods Participants and Study Design This was a prospective interventional study conducted in the north of France from December 2018 to October 2020. Participants were referred to the home-based PR program by their pulmonologist who was responsible for providing the clinical assessment and certifying the presence of COPD according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification system.23 Eligible patients were aged 40 years or above with a diagnosis of COPD as a main disease, and had chronic respiratory failure, defined as the requirement for either long-term oxygen therapy (LTOT) and/or non-invasive ventilation (NIV). Exclusion criteria included recent participation in PR (<12 months), poorly controlled psychiatric illness, neurological sequelae, or any bone and joint diseases preventing physical activity. The study was approved by the observational research protocol evaluation committee of the Société de pneumologie de langue Française (CEPRO, number: 2017-007) and all participants signed a written informed consent prior to the start of the program. While baseline participants’ data have been published elsewhere,7 the effects of PR reported in the present study are original. Home-based Pulmonary Rehabilitation Program All participants received a home-based PR program tailored to their individual needs as previously described.24 Briefly, the PR program consisted of a weekly supervised 90-minute home session, for 8 weeks. Physical activity training, educational, motivational, and self-management plans were designed and implemented through a collaborative process between the PR team, the patient, and his/her caregiver. The rehabilitation team was composed of 1 pulmonologist, 2 nurses, 1 dietitian, 1 physiotherapist, 2 adapted physical activity instructors and 1 sociomedical beautician. The health care team received the same standardized therapeutic education training from a licensed instructor. Details about the interventions performed during the PR program can be found in the online supplement. Apart from the weekly visit of the team member who supervised the sessions, participants were expected to perform, on their own, personalized physical training (at least 4 sessions/week) and a self-management plan the rest of the week and during the long-term follow-up period. Assessments Lung function, assessed by spirometry according to standard guidelines,25 medication, and comorbidity data were collected from the individual’s medical record provided by the pulmonologist. The burden of comorbidity was assessed using the Charlson Index calculated without adjusting for age and without including COPD in the individual score, as previously suggested.26 Participants were entirely evaluated at home at the beginning of the 8-week PR program (M0), at the end of the program (M2, short-term), and at 8 months (M8, medium-term) following study inclusion. Functional Capacity: Functional capacity was assessed with the short physical performance battery (SPPB) and timed-up and go (TUG) tests. The SPPB is composed of 3 standing balance tests, the 4-meter gait speed test (4MGS), and the 5-sit-to-stand repetitions test (5STS), which were performed according to the National Institute on Aging protocol.27 The sum of the 3 components determined the final SPPB score, with a possible range from 0 (functional impairment) to 12 (maximal functional capacity). TUG required the participant to rise from a seated position, walk 3 meters as quickly and safely as possible, turn around, walk back, and sit down in the shortest time possible as previously described.28 Physical Frailty: Physical frailty was defined using the Fried phenotype model,29 including 5 criteria: unintentional body mass loss history ≥4.5kg, self-reported exhaustion, low weekly self-reported energy expenditure using the modified Minnesota Leisure-Time Physical Activity Questionnaire, slowness measured during the 4MGS, and weakness measured with handgrip dynamometry. Patients with ≥3 criteria present were considered frail; those with 1 or 2 criteria were defined pre-frail, and those with no criteria were considered as robust. Exercise Tolerance: The 6-minute stepper test (6MST) was used to evaluate exercise tolerance at home, as previously described.30 Participants were all familiarized with the stepper prior to the test. Standardized instructions were given, advising the participant to make the maximum number of steps (defined as a single complete movement of raising one foot and putting it down) possible over a 6-minute period. No encouragement was given during the test. Symptom Burden, Health-related Quality of Life, and Anxiety and Depressive Symptoms: COPD symptom burden was assessed with the modified Medical Research Council (mMRC) breathlessness scale31 and with the COPD Assessment Test (CAT).32 Health-related quality of life was evaluated with the Clinical COPD Questionnaire (CCQ) which consists of 10 questions related to symptoms, mental state, and functional state (lower score indicates a greater health status).33 The Hospital Anxiety and Depression scale (7 items for anxiety and 7 items for depressive symptoms; lower scores indicate fewer symptoms)34 and the Fatigue Assessment Scale (FAS) (5 items reflecting physical fatigue and 5 items reflecting mental fatigue; lower score indicates fewer fatigue) were also assessed.35 Data and Statistical Analyses The primary study variable was functional capacity measured with the 4MGS test. Thus, sample size calculation was based on Kon et al19 to detect a 0.06±0.13 m/s improvement in gait speed 8 months after study inclusion, with a power of 80% and an alpha of 5%. With this method, the sample size was calculated to be 39 participants. Assuming that up to 20 % of patients may drop out during the follow-up period, we aimed at recruiting 47 participants. Comparisons of baseline variables between frail and non-frail individuals were performed using t-tests for the normally distributed quantitative variables while non-parametric Mann–Whitney tests were used for the non-normally distributed variables. To provide information on the impact of physical frailty on PR non-completion, a qualitative analysis was performed. To handle missing values for some variables with less than 50% missing data, a multiple imputations procedure (mianalyse) was used to evaluate the changes in study outcomes over time (at M2 and M8). This approach was performed to avoid the observation exclusion for statistical analyses. A monotone missing pattern regression method was performed for continuous variable. Classification variables were imputed using a logistic regression approach. We tested the adequacy of the iterations (convergence) by visual inspection of trace plots. The imputation procedure and the subsequent analyses were performed according to the Rubin’s protocol.36 Variables were expressed as mean±standard deviation or as frequencies and percentages, and were tested using Shapiro-Wilk for normality. The results were considered significant with P-values ≤0.05. All analyses were conducted using the statistical package SAS, Version 9.4 (SAS Institute Inc., Cary, North Carolina). Results A flow chart of the study participants is presented in Figure 1. From December 2018 to October 2020, a total of 57 patients were contacted. Among them, 1 died before the first visit at home, 4 declined participation and 5 did not meet the inclusion criteria. Among the 47 included patients, 4 did not complete PR, and 8 participants did not attend the 8-month follow-up.