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The presence of extra-pulmonary treatable traits increases the likelihood of responding to pulmonary rehabilitation

  • Sara Souto-Miranda
    Affiliations
    Respiratory Research and Rehabilitation Laboratory (Lab3R), School of Health Sciences (ESSUA), University of Aveiro, Aveiro, Portugal

    Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal

    Department of Medical Sciences (DCM), University of Aveiro, Aveiro, Portugal

    Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
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  • Vânia Rocha
    Affiliations
    Respiratory Research and Rehabilitation Laboratory (Lab3R), School of Health Sciences (ESSUA), University of Aveiro, Aveiro, Portugal

    Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
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  • Maria Aurora Mendes
    Affiliations
    Respiratory Research and Rehabilitation Laboratory (Lab3R), School of Health Sciences (ESSUA), University of Aveiro, Aveiro, Portugal

    Pulmonology Department, Centro Hospitalar do Baixo Vouga (CHBV) E.P.E, Aveiro, Portugal
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  • Paula Simão
    Affiliations
    Unidade Local de Saúde de Matosinhos, Matosinhos, Porto, Portugal
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  • Vitória Martins
    Affiliations
    Pulmonology Department, Hospital Distrital da Figueira da Foz, Figueira da Foz, Portugal
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  • Martijn A. Spruit
    Affiliations
    Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands

    Department of Research and Development, Ciro, Horn, the Netherlands
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  • Alda Marques
    Correspondence
    Corresponding author. Lab3R-Respiratory Research and Rehabilitation Laboratory, School of Health Sciences and Institute of Biomedicine, University of Aveiro, Agras do Crasto - Campus Universitário de Santiago, Edifício 30, 3810-193, Aveiro, Portugal.
    Affiliations
    Respiratory Research and Rehabilitation Laboratory (Lab3R), School of Health Sciences (ESSUA), University of Aveiro, Aveiro, Portugal

    Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
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Open AccessPublished:December 09, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107086

      Highlights

      • Pulmonary rehabilitation is effective in COPD but there are non-responders.
      • Identification of treatable traits may help distinguish type of response.
      • Presence of treatable traits at baseline increases the odds of good response.
      • Identification of treatable traits is a potential strategy to inform response.

      Abstract

      Introduction

      Studies suggest that people with chronic obstructive pulmonary disease (COPD) who are worse at baseline respond better to pulmonary rehabilitation (PR). Identifying treatable traits (TTs) may help to distinguish responders from non-responders. We explored the impact of PR on extra-pulmonary traits of people with COPD and whether the presence of TT influences the type of response to PR.

      Methods

      A comprehensive assessment of 9 TT including symptoms (dyspnoea, fatigue, anxiety and depression), functional capacity, deconditioning, balance, impact of the disease and health-related quality of life was conducted before and after a 12-week community-based PR programme. Pre-post differences between people with or without each TT at baseline were compared with independent samples t-tests or Mann-Whitney U tests. Proportion of responders between groups were explored with chi-square tests and odds ratio.

      Results

      102 people with COPD were included (70 [65; 75] years old, 78% male, FEV1 47 [36; 60] %predicted). They had a median of 3 (out of 9) TTs per person and each patient responded on average to 5 (out of 9) outcomes of PR. People with TT were more responsive than those without them in all outcomes (p < 0.05) except for the 1-min sit-to-stand test. The presence of TT increased 4 to 20 times the likelihood of being a good responder.

      Conclusions

      Identification of baseline extra-pulmonary TT in people with COPD showed the potential to inform on PR responsiveness and might therefore be an important strategy for patient prioritization, treatment personalisation (i.e., activation of the most suitable components) and optimisation.

      Keywords

      1. Introduction

      A treatable traits strategy has been advocated for people with chronic respiratory diseases, to personalise medicine to the individual's needs and therefore, improve outcomes of interventions [
      • McDonald V.M.
      • Fingleton J.
      • Agusti A.
      • Hiles S.A.
      • Clark V.L.
      • Holland A.E.
      • Marks G.B.
      • Bardin P.P.
      • Beasley R.
      • Pavord I.D.
      • Wark P.A.B.
      • Gibson P.G.
      Treatable traits: a new paradigm for 21st century management of chronic airway diseases: treatable Traits Down under International Workshop report.
      ,
      • Agusti A.
      • Bel E.
      • Thomas M.
      • Vogelmeier C.
      • Brusselle G.
      • Holgate S.
      • Humbert M.
      • Jones P.
      • Gibson P.G.
      • Vestbo J.
      • Beasley R.
      • Pavord I.D.
      Treatable traits: toward precision medicine of chronic airway diseases.
      ]. In general, only necessary treatments are provided according to the identified treatable traits. This strategy has been shown to be more effective than usual care in improving health-related quality of life and asthma control in patients with asthma [
      • McDonald V.M.
      • Clark V.L.
      • Cordova-Rivera L.
      • Wark P.A.B.
      • Baines K.J.
      • Gibson P.G.
      Targeting treatable traits in severe asthma: a randomised controlled trial.
      ].
      Pulmonary rehabilitation (PR) provides a unique opportunity to address various treatable traits simultaneously and to implement person-centred treatments in chronic respiratory diseases, namely chronic obstructive pulmonary disease (COPD). In fact, it is a multicomponent intervention moving towards more personalised care where ideally the best strategies are activated according to patients' needs [
      • Spruit M.A.
      • Wouters E.F.M.
      Organizational aspects of pulmonary rehabilitation in chronic respiratory diseases.
      ].
      PR has multiple benefits (e.g., less symptoms, better exercise tolerance, improved health-related quality of life) for people with COPD [
      • Rochester C.L.
      • Vogiatzis I.
      • Holland A.E.
      • Lareau S.C.
      • Marciniuk D.D.
      • Puhan M.A.
      • Spruit M.A.
      • Masefield S.
      • Casaburi R.
      • Clini E.M.
      • Crouch R.
      • Garcia-Aymerich J.
      • Garvey C.
      • Goldstein R.S.
      • Hill K.
      • Morgan M.
      • Nici L.
      • Pitta F.
      • Ries A.L.
      • Singh S.J.
      • Troosters T.
      • Wijkstra P.J.
      • Yawn B.P.
      • ZuWallack R.L.
      An official American thoracic society/European respiratory society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitation.
      ,
      • Souto-Miranda S.
      • Rodrigues G.
      • Spruit M.A.
      • Marques A.
      Pulmonary rehabilitation outcomes in individuals with chronic obstructive pulmonary disease: a systematic review.
      ]. However, there are non-responders in one or more outcomes (e.g., anxiety, fatigue, functional status) and the magnitude of response to PR has been found to be greater in people who are worse at baseline (e.g., higher symptom burden) [
      • Harrison S.L.
      • Greening N.J.
      • Williams J.E.
      • Morgan M.D.
      • Steiner M.C.
      • Singh S.J.
      Have we underestimated the efficacy of pulmonary rehabilitation in improving mood?.
      ,
      • Souto-Miranda S.
      • Mendes M.A.
      • Cravo J.
      • Andrade L.
      • Spruit M.A.
      • Marques A.
      Functional status following pulmonary rehabilitation: responders and non-responders.
      ,
      • Van Herck M.
      • Antons J.
      • Vercoulen J.H.
      • Goërtz Y.M.J.
      • Ebadi Z.
      • Burtin C.
      • Janssen D.J.A.
      • Thong M.S.Y.
      • Otker J.
      • Coors A.
      • Sprangers M.A.G.
      • Muris J.W.M.
      • Prins J.B.
      • Spruit M.A.
      • Peters J.B.
      Pulmonary rehabilitation reduces subjective fatigue in COPD: a responder analysis.
      ,
      • Spruit M.A.
      • Augustin I.M.
      • Vanfleteren L.E.
      • Janssen D.J.
      • Gaffron S.
      • Pennings H.J.
      • Smeenk F.
      • Pieters W.
      • van den Bergh J.J.
      • Michels A.J.
      • Groenen M.T.
      • Rutten E.P.
      • Wouters E.F.
      • Franssen F.M.
      Differential response to pulmonary rehabilitation in COPD: multidimensional profiling.
      ]. Additionally, despite its comprehensiveness, a recent systematic review has shown that treatable traits have been poorly addressed in PR trials [
      • Holland A.E.
      • Wageck B.
      • Hoffman M.
      • Lee A.L.
      • Jones A.W.
      Does pulmonary rehabilitation address treatable traits? A systematic review.
      ].
      Hence, identifying treatable traits might help to better personalise PR (e.g., select the most appropriate components for each treatable trait), and distinguish responders from non-responders, which could aid optimisation of the intervention in the future.
      This study aimed to explore the impact of PR on extra-pulmonary treatable traits of people with COPD and to explore the influence of the presence of these traits on being a responder or non-responder to PR.

      2. Materials and methods

      This was a retrospective study of data collected between October 2017 and November 2021 and is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [
      • Elm E.v.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gøtzsche P.C.
      • Vandenbroucke J.P.
      Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ]. The study was approved by the Ethics Committees of Administração Regional de Saúde do Centro (Ref. 73/2016, 16/2020, 85/2018), and Centro Hospitalar do Baixo Vouga (15-05-2019, 086,892). Participants needed to have a diagnosis of COPD (post bronchodilator forced expiratory volume in the first second [FEV1]/forced vital capacity <0.70), be clinically stable in the previous month (i.e., no hospital admissions, acute exacerbations or changes in medication) and have participated in PR to be included. Exclusion criteria comprised the presence of other respiratory diseases or any clinical condition that precluded participation in the assessment (i.e., signs of cognitive impairment or presence of a significant cardiovascular, neurological, musculoskeletal, immunological, or infectious disease). Eligible participants were identified during routine appointments at a hospital or primary healthcare centres. All participants provided written informed consent.

      2.1 Data collection and intervention

      A comprehensive assessment was performed. Sociodemographic (age and sex), anthropometric (height and weight to compute body mass index) and general clinical data (smoking status, comorbidities through the Charlson comorbidity index [CCI], use of long-term oxygen therapy and non-invasive ventilation, and number of acute exacerbations of COPD in the previous year) were collected. Activity-related dyspnoea was assessed with the modified Medical Research Council dyspnoea scale (mMRC), fatigue with the functional assessment of chronic illness therapy fatigue subscale (FACIT-F), and symptoms of anxiety and depression with the hospital anxiety and depression scale (HADS). Functional capacity was assessed with the 1-min sit-to-stand test (1-min STS) and deconditioning with the 6-min walk test (6MWT). Handgrip strength and quadriceps maximal isometric voluntary contraction (QMVC) were measured using a handheld dynamometer (microFET2, Hoggan Health, The best Salt Lake City, Utah and W50174, Baseline, UK, respectively). Balance was assessed with the Brief balance evaluation systems test (Brief-BESTest). Self-reported physical activity was measured with the brief physical activity assessment tool (BPAAT), the impact of disease/health status with the COPD assessment test (CAT) and health-related quality of life with the Saint George's respiratory questionnaire (SGRQ).
      People with COPD underwent a conventional 12-week community-based PR programme. The programme was not designed considering the prevalence of treatable traits. The exercise training was personalised to each person (e.g., functional and muscle strength capacity), but all patients received the same PR components. It consisted of exercise training (aerobic and resistance training) twice per week and education and psychosocial support once every 2 weeks. Each session lasted approximately 60 min. A multidisciplinary team of physiotherapists, medical doctors, nurses, psychologists, dietitians, and social workers provided the programme. Details of the programme have been published elsewhere [
      • Marques A.
      • Jácome C.
      • Rebelo P.
      • Paixão C.
      • Oliveira A.
      • Cruz J.
      • Freitas C.
      • Rua M.
      • Loureiro H.
      • Peguinho C.
      • Marques F.
      • Simões A.
      • Santos M.
      • Martins P.
      • André A.
      • De Francesco S.
      • Martins V.
      • Brooks D.
      • Simão P.
      Improving access to community-based pulmonary rehabilitation: 3R protocol for real-world settings with cost-benefit analysis.
      ].
      Extra-pulmonary treatable traits and responders and non-responders to PR were identified for each outcome measure. Nine treatable traits were defined based on previously established cut-offs and responders and non-responders to PR were defined based on published minimal clinical important differences (Table 1).
      Table 1Cut-offs and minimal important clinical differences used to define treatable traits and response to pulmonary rehabilitation in each outcome measure in people with chronic obstructive pulmonary disease.
      Treatable traitCut-off used for the treatable traitMinimal clinical important difference
      Severe dyspnoeamMRC ≥2 points [
      GOLD
      Global Strategy for Prevention, Diagnosis and Management of COPD.
      ]
      Difference in mMRC ≥1 point [
      • de Torres J.P.
      • Pinto-Plata V.
      • Ingenito E.
      • Bagley P.
      • Gray A.
      • Berger R.
      • Celli B.
      Power of outcome measurements to detect clinically significant changes in pulmonary rehabilitation of patients with COPD.
      ]
      Clinically relevant fatigueFACIT-F ≤43 points [
      • Stridsman C.
      • Müllerova H.
      • Skär L.
      • Lindberg A.
      Fatigue in COPD and the impact of respiratory symptoms and heart disease--a population-based study.
      ]
      Difference in FACIT-F ≥4.7 points
      Symptoms of anxietyHADS sub score ≥8 points [
      • Bjelland I.
      • Dahl A.A.
      • Haug T.T.
      • Neckelmann D.
      The validity of the Hospital Anxiety and Depression Scale. An updated literature review.
      ]
      Difference in HADS ≥1.5 points [
      • Puhan M.A.
      • Frey M.
      • Büchi S.
      • Schünemann H.J.
      The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease.
      ]
      Symptoms of depressionHADS sub score ≥8 points [
      • Bjelland I.
      • Dahl A.A.
      • Haug T.T.
      • Neckelmann D.
      The validity of the Hospital Anxiety and Depression Scale. An updated literature review.
      ]
      Difference in HADS ≥1.5 points [
      • Puhan M.A.
      • Frey M.
      • Büchi S.
      • Schünemann H.J.
      The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease.
      ]
      Poor functional capacity1-min STS <70% predicted [
      • Koolen E.H.
      • van Hees H.W.
      • van Lummel R.C.
      • Dekhuijzen R.
      • Djamin R.S.
      • Spruit M.A.
      • van 't Hul A.J.
      Can do" versus "do do": a novel concept to better understand physical functioning in patients with chronic obstructive pulmonary disease.
      ]
      Difference in 1-min STS ≥3 repetitions [
      • Crook S.
      • Büsching G.
      • Schultz K.
      • Lehbert N.
      • Jelusic D.
      • Keusch S.
      • Wittmann M.
      • Schuler M.
      • Radtke T.
      • Frey M.
      • Turk A.
      • Puhan M.A.
      • Frei A.
      A multicentre validation of the 1-min sit-to-stand test in patients with COPD.
      ]
      Deconditioning6MWT <70% predicted [
      • Koolen E.H.
      • van Hees H.W.
      • van Lummel R.C.
      • Dekhuijzen R.
      • Djamin R.S.
      • Spruit M.A.
      • van 't Hul A.J.
      Can do" versus "do do": a novel concept to better understand physical functioning in patients with chronic obstructive pulmonary disease.
      ]
      Difference in 6MWT ≥30 m [
      • Singh S.J.
      • Puhan M.A.
      • Andrianopoulos V.
      • Hernandes N.A.
      • Mitchell K.E.
      • Hill C.J.
      • Lee A.L.
      • Camillo C.A.
      • Troosters T.
      • Spruit M.A.
      • Carlin B.W.
      • Wanger J.
      • Pepin V.
      • Saey D.
      • Pitta F.
      • Kaminsky D.A.
      • McCormack M.C.
      • MacIntyre N.
      • Culver B.H.
      • Sciurba F.C.
      • Revill S.M.
      • Delafosse V.
      • Holland A.E.
      An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease.
      ]
      Poor balanceBrief-BESTest ≤16.5 points [
      • Jácome C.
      • Cruz J.
      • Oliveira A.
      • Marques A.
      Validity, reliability, and ability to identify fall status of the berg balance scale, BESTest, mini-BESTest, and brief-BESTest in patients with COPD.
      ]
      Difference in Brief-BESTest ≥3 points [
      • Paixão C.
      • Rebelo P.
      • Oliveira A.
      • Jácome C.
      • Cruz J.
      • Martins V.
      • Simão P.
      • Marques A.
      Responsiveness and minimal clinically important difference of the brief-BESTest in people with COPD after pulmonary rehabilitation.
      ]
      Poor health statusCAT ≥18 points [
      • Smid D.E.
      • Franssen F.M.E.
      • Gonik M.
      • Miravitlles M.
      • Casanova C.
      • Cosio B.G.
      • de Lucas-Ramos P.
      • Marin J.M.
      • Martinez C.
      • Mir I.
      • Soriano J.B.
      • de Torres J.P.
      • Agusti A.
      • Atalay N.B.
      • Billington J.
      • Boutou A.K.
      • Brighenti-Zogg S.
      • Chaplin E.
      • Coster S.
      • Dodd J.W.
      • Dürr S.
      • Fernandez-Villar A.
      • Groenen M.T.J.
      • Guimarães M.
      • Hejduk K.
      • Higgins V.
      • Hopkinson N.S.
      • Horita N.
      • Houben-Wilke S.
      • Janssen D.J.A.
      • Jehn M.
      • Joerres R.
      • Karch A.
      • Kelly J.L.
      • Kim Y.I.
      • Kimura H.
      • Koblizek V.
      • Kocks J.H.
      • Kon S.S.C.
      • Kwon N.
      • Ladeira I.
      • Lee S.D.
      • Leuppi J.D.
      • Locantore N.
      • Lopez-Campos J.L.
      • W D.C.M.
      • Maricic L.
      • Mendoza L.
      • Miedinger D.
      • Mihaltan F.
      • Minami S.
      • van der Molen T.
      • Murrells T.J.
      • Nakken N.
      • Nishijima Y.
      • Norman I.J.
      • Novotna B.
      • O'Donnell D.E.
      • Ogata Y.
      • Pereira E.D.
      • Piercy J.
      • Price D.
      • Pothirat C.
      • Raghavan N.
      • Ringbaek T.
      • Sajkov D.
      • Sigari N.
      • Singh S.
      • Small M.
      • da Silva G.F.
      • Tanner R.J.
      • Tsiligianni I.G.
      • Tulek B.
      • Tzanakis N.
      • Vanfleteren L.
      • Watz H.
      • Webb K.A.
      • Wouters E.F.M.
      • Xie G.G.
      • Yoshikawa M.
      • Spruit M.A.
      Redefining cut-points for high symptom burden of the global initiative for chronic obstructive lung disease classification in 18,577 patients with chronic obstructive pulmonary disease.
      ]
      Difference in CAT ≥2 points [
      • Kon S.S.
      • Canavan J.L.
      • Jones S.E.
      • Nolan C.M.
      • Clark A.L.
      • Dickson M.J.
      • Haselden B.M.
      • Polkey M.I.
      • Man W.D.
      Minimum clinically important difference for the COPD Assessment Test: a prospective analysis.
      ]
      Poor health-related quality of lifeSGRQ ≥46 points [
      • Smid D.E.
      • Franssen F.M.E.
      • Gonik M.
      • Miravitlles M.
      • Casanova C.
      • Cosio B.G.
      • de Lucas-Ramos P.
      • Marin J.M.
      • Martinez C.
      • Mir I.
      • Soriano J.B.
      • de Torres J.P.
      • Agusti A.
      • Atalay N.B.
      • Billington J.
      • Boutou A.K.
      • Brighenti-Zogg S.
      • Chaplin E.
      • Coster S.
      • Dodd J.W.
      • Dürr S.
      • Fernandez-Villar A.
      • Groenen M.T.J.
      • Guimarães M.
      • Hejduk K.
      • Higgins V.
      • Hopkinson N.S.
      • Horita N.
      • Houben-Wilke S.
      • Janssen D.J.A.
      • Jehn M.
      • Joerres R.
      • Karch A.
      • Kelly J.L.
      • Kim Y.I.
      • Kimura H.
      • Koblizek V.
      • Kocks J.H.
      • Kon S.S.C.
      • Kwon N.
      • Ladeira I.
      • Lee S.D.
      • Leuppi J.D.
      • Locantore N.
      • Lopez-Campos J.L.
      • W D.C.M.
      • Maricic L.
      • Mendoza L.
      • Miedinger D.
      • Mihaltan F.
      • Minami S.
      • van der Molen T.
      • Murrells T.J.
      • Nakken N.
      • Nishijima Y.
      • Norman I.J.
      • Novotna B.
      • O'Donnell D.E.
      • Ogata Y.
      • Pereira E.D.
      • Piercy J.
      • Price D.
      • Pothirat C.
      • Raghavan N.
      • Ringbaek T.
      • Sajkov D.
      • Sigari N.
      • Singh S.
      • Small M.
      • da Silva G.F.
      • Tanner R.J.
      • Tsiligianni I.G.
      • Tulek B.
      • Tzanakis N.
      • Vanfleteren L.
      • Watz H.
      • Webb K.A.
      • Wouters E.F.M.
      • Xie G.G.
      • Yoshikawa M.
      • Spruit M.A.
      Redefining cut-points for high symptom burden of the global initiative for chronic obstructive lung disease classification in 18,577 patients with chronic obstructive pulmonary disease.
      ]
      Difference in SGRQ ≥4 points [
      • Jones P.W.
      Interpreting thresholds for a clinically significant change in health status in asthma and COPD.
      ]
      mMRC: Medical Research Council dyspnoea scale (mMRC); FACIT-F: functional assessment of chronic illness therapy fatigue subscale; HADS: hospital anxiety and depression scale; 1-min STS: 1-min sit-to-stand test; 6MWT: 6-min walk test; Brief-BESTest: Brief balance evaluation systems test; CAT: COPD assessment test; SGRQ: Saint George's respiratory questionnaire.

      2.2 Data analysis

      A multivariate imputation by chained equations was performed as some variables (i.e., HADS, FACIT-F) had more than 5% but less than 30% of missing data [
      • Azur M.J.
      • Stuart E.A.
      • Frangakis C.
      • Leaf P.J.
      Multiple imputation by chained equations: what is it and how does it work?.
      ]. A sensitivity analysis with the original dataset (not imputed) was performed to check if results were similar to the ones of our main analysis.
      Descriptive statistics were used to characterise the sample. Effects of PR were explored using paired samples t-tests or Wilcoxon signed-rank tests. Differences in mean/median between people with COPD with or without the treatable trait were explored using independent samples t-tests or Mann-Whitney U tests. Responders with or without the treatable trait were compared using chi-square tests for two proportions.
      Odds ratios were computed to explore the probability of being a responder in each outcome, by having the presence of each treatable trait.
      Adherence of responders was compared with the adherence of non-responders considering the absence or presence of the treatable traits using non-parametric two-way ANOVA. Normality of residuals was explored with Shapiro-Wilk test and homogeneity of variance with Levene's test.
      All statistical analysis were performed in R (v. 4.1.2).

      3. Results

      Of the initial 140 database entries, 102 people with COPD were included. 38 entries were excluded after applying inclusion and exclusion criteria (repeated PR programmes, FEV1/FVC >70% predicted). No differences were found in the interpretation of results between imputed or non-imputed data (analysis with the original dataset provided in Supplementary material).
      Patients were mostly male (78%), had a median FEV1 of 47% predicted, and were predominantly from GOLD grades 2 and 3 (43%, 42% respectively) and group B (57%). Patients had 85 ± 14.3% adherence to the PR sessions. Full characteristics of the sample are presented in Table 2.
      Table 2Baseline characteristics and outcomes of pulmonary rehabilitation in people with chronic obstructive pulmonary disease (n = 102).
      BaselinePostMean/Mediandiff95% CIp-value
      Age, years69.5 [65.0; 75.0]N.A.N.A.N.A.N.A.
      Sex, n (%)
       Female23 (22.5)N.A.N.A.N.A.N.A.
       Male79 (77.5)N.A.N.A.N.A.N.A.
      Smoking status, n (%)
       Never smoker21 (20.6)N.A.N.A.N.A.N.A.
       Former smoker65 (63.7)N.A.N.A.N.A.N.A.
       Current smoker16 (15.7)N.A.N.A.N.A.N.A.
      Pack-years, n30.0 [9.4; 57.0]N.A.N.A.N.A.N.A.
      FEV1, % predicted47.0 [36.0; 60.0]N.A.N.A.N.A.N.A.
      GOLD grade, n (%)
       17 (7.0)N.A.N.A.N.A.N.A.
       243 (42.6)N.A.N.A.N.A.N.A.
       342 (41.6)N.A.N.A.N.A.N.A.
       49 (8.9)N.A.N.A.N.A.N.A.
      GOLD group, n (%)
       A27 (26.5)N.A.N.A.N.A.N.A.
       B58 (56.9)N.A.N.A.N.A.N.A.
       C2 (2.0)N.A.N.A.N.A.N.A.
       D15 (14.7)N.A.N.A.N.A.N.A.
      CCI, total4.0 [3.0; 5.0]N.A.N.A.N.A.N.A.
      LTOT, n (%)10 (9.8)N.A.N.A.N.A.N.A.
      NIV, n (%)13 (12.7)N.A.N.A.N.A.N.A.
      No. AECOPD previous 12 months, n0.0 [0.0; 1.0]N.A.N.A.N.A.N.A.
      BMI, kg/m226.4 ± 4.8N.A.N.A.N.A.N.A.
      mMRC, score2.0 [1.0; 3.0]1.0 [1.0; 2.0]0.0 [-1.0; 0.0]N.A.<0.001
      FACIT-F, total score36.1 ± 9.039.3 ± 8.53.2 ± 6.71.9; 4.5<0.001
      HADS, Anxiety score5.9 ± 4.15.2 ± 3.7−0.7 ± 3.2−1.3; −0.10.02
      HADS, depression score6.0 [3.0; 9.8]6.0 [3.0; 8.0]−1.0 [-3.0; 1.0]N.A.<0.001
      1-min STS, repetitions22.5 [18.3; 27.8]26.0 [21.0; 31.0]4.0 [0.0; 6.0]N.A.<0.001
      6MWT, m405.1 ± 127.3448.8 ± 123.143.7 ± 61.931.5; 55.9<0.001
      Handgrip strength, Kg34.0 [26.0; 40.0]N.A.N.A.N.A.N.A.
      QMVC, Kg/F30.7 ± 7.933.2 ± 8.42.5 ± 6.21.2; 3.7<0.001
      Brief-BESTest, score18.0 [15.0; 22.0]21.0 [18.0; 23.0]3.0 [0.0; 4.0]N.A.<0.001
      BPAAT, score0.0 [0.0; 2.8]4.0 [2.0; 6.0]2.0 [1.0; 4.0]N.A.<0.001
      CAT, total score14.7 ± 8.011.6 ± 7.1−3.1 ± 6.1−4.3; −1.9<0.001
      SGRQ, total score46.0 [28.4; 59.5]40.0 [20.1; 51.8]−7.5 [-14.3; 0.5]N.A.<0.001
      N.A. Not applicable; FEV1: forced expiratory volume in the first second; GOLD: Global initiative for chronic obstructive lung disease; CCI: Charlson comorbidity index; LTOT: long-term oxygen therapy; NIV: non-invasive ventilation; BMI: body mass index; mMRC: modified Medical Research Council dyspnoea scale; FACIT-F: functional assessment of chronic illness therapy fatigue subscale; HADS: hospital anxiety and depression scale; 1-min STS: 1-min sit-to-stand test; 6MWT: 6-min walk test; QMVC: quadriceps maximal isometric voluntary contraction; Brief-BESTest: Brief balance evaluation systems test; BPAAT: brief physical activity assessment tool; CAT: COPD assessment test; SGRQ: Saint George's respiratory questionnaire.
      Overall, PR was effective in improving all outcomes (p < 0.05) (Table 2).
      At baseline, people with COPD had a median [min-max] of 3 [0–7] extra-pulmonary treatable traits per person, and responded on 5 [0–9] outcomes of PR.
      People with the presence of treatable traits responded to a greater extent than those without treatable traits in all outcomes except for the 1-min STS (Table 3). Indeed, the pre-post mean differences of each outcome were significantly higher in those with a baseline mMRC ≥2 points (p < 0.001), FACIT-F ≤43 points (p < 0.001), HADS ≥8 points (p < 0.001 both anxiety and depression symptoms), 6MWT <70% predicted (p = 0.005) and Brief-BESTest <16.5 points (p < 0.001), CAT ≥18 points (p < 0.001), and SGRQ ≥46 points (p = 0.005). Accordingly, people with the treatable trait were more frequently responders than those without the treatable trait (Table 3 and Fig. 1). There was a significantly higher proportion of responders to mMRC (p = 0.003), FACIT-F (p < 0.001), HADS (p < 0.001, p = 0.001), 6MWT (p = 0.009), Brief-BESTest (p < 0.001), CAT (p < 0.001) and SGRQ (p = 0.003), in people with the respective treatable trait - severe dyspnoea, clinically relevant fatigue, symptoms of anxiety and depression, deconditioning, poor balance, poor health status and poor health-related quality of life - compared to those without the treatable trait at baseline (Table 3 and Fig. 1). People with the treatable traits were more likely responders than those without the treatable traits (OR = 4.25–19.95) with the exception of people with less than 70% predicted in the 1-min STS (Table 3).
      Table 3Response to pulmonary rehabilitation defined by the minimal important clinical differences of each outcome measure, according to the presence or absence of each treatable trait in people with chronic obstructive pulmonary disease (n = 102).
      Treatable traitMean/Mediandiffp-valueNon-responders, n (%)Responders, n (%)p-valueOR [95%CI]Non-responders % adherenceResponders % adherencep-valuea
      mMRC, score
       <2 points0.0 [0.0; 0.0]<0.00129 (76.3)9 (23.7)0.0034.14 [1.69; 10.15]88.0 [71.0; 92.0]100.0 [83.0; 100.0]0.182
      ≥2 points (severe dyspnoea)−1.0 [-1.0; 0.0]28 (43.8)36 (56.3)81.0 [74.0; 89.0]88.0 [75.0; 96.0]
      FACIT-F, score
      ≤43 points (clinically relevant fatigue)5.0 [0.0; 8.8]<0.00140 (48.8)42 (51.2)<0.00119.95 [2.55; 156.05]88.0 [75.0; 96.0]85.5 [72.0; 95.0]0.819
       >43 points0.0 [-3.0; 1.2]19 (95.0)1 (5.0)88.0 [77.0; 92.0]67.0 [67.0; 67.0]
      HADS, Anxiety score
       <8 points0.0 [-2.0; 2.0]<0.00150 (73.5)18 (26.5)<0.0016.67 [2.67; 16.62]88.0 [75.0; 96.0]88.0 [73.0; 94.3]0.362
      ≥8 points (symptoms of anxiety)−2.5 [-5.0; 0.0]10 (29.4)24 (70.6)79.0 [69.0; 94.3]81.0 [70.0; 89.0]
      HADS, Depression score
       <8 points0.0 [-2.0; 2.0]<0.00141 (69.5)18 (30.5)0.0014.25 [1.84; 9.82]88.0 [83.0; 96.0]88.0 [75.0; 95.0]0.767
      ≥8 points (symptoms of depression)−3.0 [-4.0; −1.0]15 (34.9)28 (65.1)79.0 [67.5; 88.0]81.0 [70.0; 95.3]
      1-min STS, % predicted
      <70% (poor functional capacity)4.0 [2.0; 7.0]0.04621 (39.6)32 (60.4)0.2451.72 [0.78; 3.78]79.0 [71.0; 88.0]88.0 [81.0; 96.0]N.A.
       ≥70%2.0 [-1.0; 5.0]26 (53.1)23 (46.9)90.0 [79.0; 96.0]83.0 [71.0; 93.0]
      6MWT, % predicted
      <70% (deconditioning)81.0 [43.5; 117.0]0.0054 (17.4)19 (82.6)0.0094.87 [1.52; 15.62]81.0 [79.0; 86.3]83.0 [71.0; 94.0]0.729
       ≥70%29.6 [2.5; 65.4]40 (50.6)39 (49.4)83.0 [74.0; 93.0]88.0 [75.0; 95.0]
      Brief-BESTest
      <16.5 points (poor balance)4.0 [3.0; 6.0]<0.0019 (21.4)33 (78.6)<0.0016.81 [2.75; 16.89]83.0 [75.0; 88.0]83.0 [71.0; 95.0]0.251
       ≥16.5 points1.0 [0.0; 3.0]39 (65.0)21 (35.0)88.0 [73.0; 92.0]92.0 [79.0; 100.0]
      CAT, score
       <18 points−1.6 ± 6.0<0.00132 (46.4)37 (53.6)<0.0018.65 [2.41; 31.03]88.0 [79.0; 97.0]88.0 [71.0; 96.0]0.281
      ≥18 points (poor health status)−6.2 ± 5.13 (9.0)30 (90.9)79.0 [77.0; 85.5]81.0 [71.0; 92.0]
      SGRQ, score
       <46 points−6.0 [-11.4; 4.0]0.00537 (72.5)14 (27.5)0.0039.27 [1.98; 43.32]92.0 [80.0; 100.0]83.0 [75.0; 92.0]0.193
      ≥46 points (poor health-related quality of life)−10.4 [-15.4; −5.1]2 (4.0)49 (96.1)91.5 [87.3; 95.8]88.0 [71.0; 95.0]
      ap-value of ANOVA for differences between responders and non-responders; no interaction effects found for all variables. Results are presented as mean ± SD, median [1st; 3rd quartile] or n (%). The presence of the treatable trait is presented in bold. mMRC: modified Medical Research Council dyspnoea scale; FACIT-F: functional assessment of chronic illness therapy fatigue subscale; HADS: hospital anxiety and depression scale; 1-min STS: 1-min sit-to-stand test; 6MWT: 6-min walk test; Brief-BESTest: Brief balance evaluation systems test; CAT: COPD assessment test; SGRQ: Saint George's respiratory questionnaire; N.A.: Not applicable.
      Fig. 1
      Fig. 1Flow of responders and non-responders to pulmonary rehabilitation with or without each treatable trait a) treatable trait – severe dyspnoea mMRC ≥2 points; b) treatable trait – clinically relevant fatigue FACIT-F ≤43 points; c) treatable trait – symptoms of anxiety HADS ≥8 points; d) treatable trait – symptoms of depression HADS ≥8 points; e) treatable trait - deconditioning 6MWT <70% predicted; f) treatable trait – poor balance Brief-BESTest <16.5 points; g) treatable trait poor health status CAT≥18 points; h) treatable trait - poor health-related quality of life SGRQ ≥46 points . Dark blue represents people with the treatable trait and light blue people without the treatable trait. Green represents responders and red represents non-responders. Percentages are represented for responders with the treatable trait and non-responders without the treatable trait.
      mMRC: modified Medical Research Council dyspnoea scale; FACIT-F: functional assessment of chronic illness therapy fatigue subscale; HADS: hospital anxiety and depression scale; 6MWT: 6-min walk test; Brief-BESTest: Brief balance evaluation systems test; CAT: COPD assessment test; SGRQ: Saint George's respiratory questionnaire.
      No significant differences were found between responders and non-responders nor in the interaction between the 2 factors (i.e., treatable trait, no treatable trait; responder, non-responder) for all outcomes (p > 0.05). A significant difference was found in adherence rates between people with or without depression symptoms (p = 0.013).

      4. Discussion

      This study showed that PR was generally effective in addressing extra-pulmonary traits of people with COPD, and that people who exhibit treatable traits at baseline are more responsive than those without the treatable traits.
      Our findings are consistent with several recent studies which demonstrated that people with COPD who are clinically worse at baseline are usually those responding better to the intervention [
      • Harrison S.L.
      • Greening N.J.
      • Williams J.E.
      • Morgan M.D.
      • Steiner M.C.
      • Singh S.J.
      Have we underestimated the efficacy of pulmonary rehabilitation in improving mood?.
      ,
      • Souto-Miranda S.
      • Mendes M.A.
      • Cravo J.
      • Andrade L.
      • Spruit M.A.
      • Marques A.
      Functional status following pulmonary rehabilitation: responders and non-responders.
      ,
      • Van Herck M.
      • Antons J.
      • Vercoulen J.H.
      • Goërtz Y.M.J.
      • Ebadi Z.
      • Burtin C.
      • Janssen D.J.A.
      • Thong M.S.Y.
      • Otker J.
      • Coors A.
      • Sprangers M.A.G.
      • Muris J.W.M.
      • Prins J.B.
      • Spruit M.A.
      • Peters J.B.
      Pulmonary rehabilitation reduces subjective fatigue in COPD: a responder analysis.
      ,
      • Augustin I.M.L.
      • Franssen F.M.E.
      • Houben-Wilke S.
      • Janssen D.J.A.
      • Gaffron S.
      • Pennings H.-J.
      • Smeenk F.W.J.M.
      • Pieters W.R.
      • Hoogerwerf A.
      • Michels A.-J.
      • van Merode F.
      • Wouters E.F.M.
      • Spruit M.A.
      Multidimensional outcome assessment of pulmonary rehabilitation in traits-based clusters of COPD patients.
      ]. This might be due to having more room for improvement in those more severe, and an absence of abnormal values in some measures or a delayed response to PR in people that are functionally better at baseline. Therefore, early identification of these patients and referral to PR considering their treatable traits seems to be of paramount importance.
      A recent study has demonstrated different stakeholders to believe that when necessary people with chronic respiratory diseases who are more symptomatic and with worse functional status should be prioritised for PR [
      • Marques A.
      • Souto-Miranda S.
      • Dias C.
      • Melo E.
      • Jácome C.
      Access, access, access: the Three A's of pulmonary rehabilitation – perspectives of patients, loved ones and healthcare professionals.
      ]. Considering these findings and the present study, it might be appropriate to prioritise patients who exhibit a higher number of treatable traits. Nonetheless, this requires further investigation.
      Overall, for most outcomes, the group of patients with absence of each treatable trait did not achieve clinically relevant benefits (within the established minimal clinical important differences) with PR. Therefore, it seems crucial to conduct a comprehensive assessment at baseline to identify the multiple treatable traits of each person and only activate the necessary PR components (e.g., exercise, education, psychological support, and/or balance training) accordingly. Indeed, designing the PR programme for each individual based on the treatable traits that need to be targeted could enhance the programme personalisation and cost-effectiveness, especially considering the lack of resources commonly available [
      • Rochester C.L.
      • Vogiatzis I.
      • Holland A.E.
      • Lareau S.C.
      • Marciniuk D.D.
      • Puhan M.A.
      • Spruit M.A.
      • Masefield S.
      • Casaburi R.
      • Clini E.M.
      • Crouch R.
      • Garcia-Aymerich J.
      • Garvey C.
      • Goldstein R.S.
      • Hill K.
      • Morgan M.
      • Nici L.
      • Pitta F.
      • Ries A.L.
      • Singh S.J.
      • Troosters T.
      • Wijkstra P.J.
      • Yawn B.P.
      • ZuWallack R.L.
      An official American thoracic society/European respiratory society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitation.
      ]. Healthcare professionals should be however aware of the need of a multidimensional assessment, as narrow baseline assessments may lead to a misinterpretation of the lack of need of PR for some patients. In fact, it is unlikely for a person with COPD to exhibit no treatable traits [
      • Cardoso J.
      • Ferreira A.J.
      • Guimarães M.
      • Oliveira A.S.
      • Simão P.
      • Sucena M.
      Treatable traits in COPD - a proposed approach.
      ,
      • Marques A.
      • Souto-Miranda S.
      • Machado A.
      • Oliveira A.
      • Jácome C.
      • Cruz J.
      • Enes V.
      • Afreixo V.
      • Martins V.
      • Andrade L.
      • Valente C.
      • Ferreira D.
      • Simão P.
      • Brooks D.
      • Tavares A.H.
      COPD profiles and treatable traits using minimal resources: identification, decision tree and stability over time.
      ], and therefore to have no need to be integrated, at least partially, in PR.
      The present study did not aim to explore the effectiveness of a treatable trait strategy for PR. Similar to a randomized controlled trial of a treatable traits strategy vs. usual care in asthma [
      • McDonald V.M.
      • Clark V.L.
      • Cordova-Rivera L.
      • Wark P.A.B.
      • Baines K.J.
      • Gibson P.G.
      Targeting treatable traits in severe asthma: a randomised controlled trial.
      ], future studies could compare conventional PR with a treatable traits based programme in terms of their effectiveness for people with COPD.
      Even though most responders were those who had the treatable traits at baseline, our findings still showed a large proportion of people with the treatable traits who did not respond to PR. We found no influence between adherence to PR and responding to the intervention, independently of the presence or absence of treatable traits. Therefore, whether these patients are truly non-responders or if a higher intensity or frequency of treatment is necessary, requires further research.
      In our sample the response in the 1-min STS was not significantly different between those with or without the treatable trait. Most of our patients were responders in this outcome and therefore this fact is likely to have impacted the group comparisons. Nevertheless, responders to PR in the 1-min STS have been found to exhibit a lower capacity at baseline than non-responders [
      • Souto-Miranda S.
      • Mendes M.A.
      • Cravo J.
      • Andrade L.
      • Spruit M.A.
      • Marques A.
      Functional status following pulmonary rehabilitation: responders and non-responders.
      ]. Therefore, similar to other outcomes, a pattern of better response to PR with the presence of poor functional capacity in the 1-min STS at baseline is expected.
      Although we identified multiple traits through a comprehensive assessment, it might also be important to identify other treatable traits that are relevant for PR, such as respiratory muscle dysfunction, lack of disease-specific knowledge, poor nutritional status, and poor social status, to decide the most suitable PR path for each patient. A recent study has provided a clinical decision tree for the quick allocation of people with COPD to a profile, which might enable a fast decision on the best treatment regimens, following the profile's treatable traits [
      • Marques A.
      • Souto-Miranda S.
      • Machado A.
      • Oliveira A.
      • Jácome C.
      • Cruz J.
      • Enes V.
      • Afreixo V.
      • Martins V.
      • Andrade L.
      • Valente C.
      • Ferreira D.
      • Simão P.
      • Brooks D.
      • Tavares A.H.
      COPD profiles and treatable traits using minimal resources: identification, decision tree and stability over time.
      ]. Future studies could also develop a PR-specific clinical decision tool to rapidly decide the PR components to be activated for each patient according to their treatable traits (based on a comprehensive treatable trait assessment).
      Our sample was mainly composed of men and elderly people. Studies have shown women to have a higher prevalence and more severe treatable traits than men with COPD, which also seem to increase with progression of disease [
      • Souto-Miranda S.
      • van 't Hul A.J.
      • Vaes A.W.
      • Antons J.C.
      • Djamin R.S.
      • Janssen D.J.A.
      • Franssen F.M.E.
      • Marques A.
      • Spruit M.A.
      Differences in pulmonary and extra-pulmonary traits between women and men with chronic obstructive pulmonary disease.
      ]. Hence, comparison of the impact of PR on the treatable traits of men versus women, and also in younger and less severe samples should be further explored. Holland and colleagues concluded that treatable traits have been poorly addressed in PR trials [
      • Holland A.E.
      • Wageck B.
      • Hoffman M.
      • Lee A.L.
      • Jones A.W.
      Does pulmonary rehabilitation address treatable traits? A systematic review.
      ]. However, most of the traits were identified based on previous literature [
      • Agustí A.
      • Bafadhel M.
      • Beasley R.
      • Bel E.H.
      • Faner R.
      • Gibson P.G.
      • Louis R.
      • McDonald V.M.
      • Sterk Peter J.
      • Thomas M.
      • Vogelmeier C.
      • Pavord I.D.
      Precision medicine in airway diseases: moving to clinical practice.
      ] and were non-relevant outcomes for PR, such as emphysema or persistent systemic inflammation. Future studies need to identify rehabilitation-specific treatable traits for which patients and clinicians can expect improvements [
      • Souto-Miranda S.
      • Vaes A.W.
      • Gloeckl R.
      • Grongstad A.
      • Spruit M.A.
      • Marques A.
      International perspectives on outcome measurement in pulmonary rehabilitation of people with COPD: a qualitative study.
      ]. Finally, the cut-offs used to define the treatable traits in this study seem to be suitable to differentiate responders from non-responders to PR, but they should be externally validated .

      5. Conclusions

      Identification of extra-pulmonary treatable traits in people with COPD showed the potential to inform on PR responsiveness and might therefore be an important strategy for patient prioritization (when/if needed), treatment personalisation and optimisation. Future trials are needed to compare the use of a treatable traits' strategy within PR (identification of each patient's treatable traits to trigger the most suitable PR components accordingly) with conventional PR.

      CRediT authorship contribution statement

      Sara Souto-Miranda: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft. Vânia Rocha: Conceptualization, Visualization, Writing – review & editing. Maria Aurora Mendes: Resources, Validation, Writing – review & editing. Paula Simão: Resources, Validation, Writing – review & editing. Vitória Martins: Resources, Validation, Writing – review & editing. Martijn A. Spruit: Conceptualization, Funding acquisition, Methodology, Supervision, Validation, Writing – review & editing. Alda Marques: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing.

      Declaration of competing interest

      None.

      Acknowledgements

      This research was funded by Fundação para a Ciência e a Tecnologia (FCT) through the European Social Fund and Programa Operacional Regional do Centro, under the PhD grant SFRH/BD/146134/2019 and by Programa Operacional de Competitividade e Internacionalização—POCI, through Fundo Europeu de Desenvolvimento Regional—FEDER (POCI-01-0145-FEDER-028806), Fundação para a Ciência e Tecnologia (PTDC/SAU-SER/28806/2017), and under the project UIDB/04501/2020. The funder had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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