Advertisement

Effectiveness of Pulmonary Rehabilitation in Interstitial Lung Disease, Including Coronavirus Diseases: A Systematic Review and Meta-analysis

Published:April 28, 2021DOI:https://doi.org/10.1016/j.apmr.2021.03.035

      Objective

      A meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of pulmonary rehabilitation on functional capacity and quality of life in interstitial lung diseases, including those caused by coronaviruses.

      Data Sources

      MEDLINE, EMBASE, SPORTDiscus, Cochrane Library, Web of Science, and MedRxiv from inception to November 2020 were searched to identify documents.

      Study Selection

      Publications investigating the effect of pulmonary rehabilitation on lung function (forced vital capacity [FVC]), exercise capacity (6-minute walk distance [6MWD]), health related quality of life (HRQOL), and dyspnea were searched.

      Data Extraction

      The data were extracted into predesigned data extraction tables. Risk of bias was evaluated with the Cochrane Risk of Bias tool (RoB 2.0).

      Data Synthesis

      A total of 11 RCTs with 637 interstitial lung disease patients were eligible for analyses. The pooled effect sizes of the association for pulmonary rehabilitation were 0.37 (95% confidence interval [CI], 0.02-0.71) for FVC, 44.55 (95% CI, 32.46-56.64) for 6MWD, 0.52 (95% CI, 0.22-0.82) for HRQOL, and 0.39 (95% CI, –0.08 to 0.87) for dyspnea. After translating these findings considering clinical improvements, pulmonary rehabilitation intervention increased predicted FVC by 5.5%, the 6MWD test improved by 44.55 m, and HRQOL improved by 3.9 points compared with baseline values. Results remained similar in sensitivity analyses.

      Conclusions

      Although specific evidence for pulmonary rehabilitation of coronavirus disease 2019 patients has emerged, our data support that interstitial lung disease rehabilitation could be considered as an effective therapeutic strategy to improve the functional capacity and quality of life in this group of patients.

      Keywords

      List of abbreviations:

      6MWD (6-minute walk distance), CI (confidence interval), CoV (coronavirus), COVID-19 (coronavirus disease 2019), ES (effect size), FVC (forced vital capacity), HRQOL (health-related quality of life), ILD (interstitial lung disease), RCT (randomized controlled trial), SARS (severe acute respiratory syndrome)
      Interstitial lung diseases (ILDs), also known as diffuse parenchymal lung diseases, are a set of chronic lung conditions characterized by exercise limitation and dyspnea.
      • Flaherty KR
      • Andrei AC
      • Murray S
      • et al.
      Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test.
      Pathologic features dominated by diffuse alveolar damage have also been reported in severe acute respiratory syndrome (SARS)
      • Tse GMK
      • To KF
      • Chan PKS
      • et al.
      Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS).
      ,
      • Li Y
      • Xia L
      Coronavirus disease 2019 (COVID-19): role of chest CT in diagnosis and management.
      and coronavirus disease 2019 (COVID-19), both diseases result from infection by viruses in the coronavirus (CoV) family. CoVs are a family of enveloped, single-stranded–RNA viruses
      • Chan KS
      • Zheng JP
      • Mok YW
      • et al.
      SARS: prognosis, outcome and sequelae.
      responsible for the 2 large epidemics in the past 2 decades, SARS and the Middle East Respiratory Syndrome.
      • Drosten C
      • Günther S
      • Preiser W
      • et al.
      Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
      • Ksiazek TG
      • Erdman D
      • Goldsmith CS
      • et al.
      A novel coronavirus associated with severe acute respiratory syndrome.
      • de Groot RJ
      • Baker SC
      • Baric RS
      • et al.
      Commentary: Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group.
      Toward the end of 2019, COVID-19 was identified as the cause of a severe respiratory illness, which was declared a global pandemic and is still spreading across the world with a growing number of confirmed cases.
      World Health Organization
      Coronavirus disease 2019 (COVID-19): situation report – 67.
      Although most individuals with COVID-19 develop mild or asymptomatic disease, approximately 14% experience severe disease and 6% become critically ill.

      European Centre for Disease Prevention and Control. Risk assessment on COVID-19. Available at: https://www.ecdc.europa.eu/en/current-risk-assessment-novel-coronavirus-situation. Accessed July 14, 2020.

      In the acute phase, severely affected patients may develop pneumonia characterized by bilateral interstitial infiltrate, acute respiratory distress syndrome,
      • Wujtewicz M
      • Dylczyk-Sommer A
      • Aszkiełowicz A
      • et al.
      COVID-19 – what should anaethesiologists and intensivists know about it?.
      and related pulmonary fibrosis that is even susceptible to lung transplantation.
      • Chen JY
      • Qiao K
      • Liu F
      • et al.
      Lung transplantation as therapeutic option in acute respiratory distress syndrome for COVID-19-related pulmonary fibrosis.
      Moreover, an increased risk of encephalopathy has been described in hospitalized patients with acute respiratory symptoms.
      • Filatov A
      • Sharma P
      • Hindi F
      • Espinosa PS.
      Neurological complications of coronavirus disease (COVID-19): encephalopathy.
      ,
      • Garg RK
      • Paliwal VK
      • Gupta A.
      Encephalopathy in patients with COVID-19: a review.
      The evolution of COVID-19 in the medium- and long-term is still uncertain; however, it appears to be similar to SARS regarding its clinical features.
      • Petrosillo N
      • Viceconte G
      • Ergonul O
      • et al.
      COVID-19, SARS and MERS: are they closely related?.
      Epidemic data of previous CoV infections show that pulmonary fibrosis may develop early in patients with SARS,
      • Antonio GE
      • Wong KT
      • Hui DSC
      • et al.
      Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
      which has shown a functional disability associated with the degree of lung function impairment that might be related to residual lung fibrosis, muscle weakness, and systemic effects of the viral illness.
      • Chan KS
      • Zheng JP
      • Mok YW
      • et al.
      SARS: prognosis, outcome and sequelae.
      ,
      • Hui DS
      • Wong KT
      • Ko FW
      • et al.
      The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors.
      Additionally, research has shown an important decrease in lung function, physical fitness, and health related quality of life (HRQOL) among patients recovering from CoV infections.
      • Ngai JC
      • Ko FW
      • Ng SS
      • et al.
      The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status.
      ,
      • Hui D
      • Joynt G
      • Wong K
      • et al.
      Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors.
      Recent clinical guidelines recommend pulmonary rehabilitation for the management of the long-term effects of critical illness associated with severe acute respiratory syndrome coronavirus 2 infection.
      • Thomas P
      • Baldwin C
      • Bissett B
      • et al.
      Physiotherapy management for COVID-19 in the acute hospital setting: clinical practice recommendations.
      Pulmonary rehabilitation is an evidence-based standard of care designed to improve the physical and psychological condition for patients with lung disease that include but are not limited to exercise training, education, and behavior change.
      • Spruit MA
      • Singh SJ
      • Garvey C
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation.
      Previous research reports have shown the effectiveness of pulmonary rehabilitation in improving fitness and HRQOL in patients with CoV or diseases with similar respiratory consequences.
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Yu X
      • Li X
      • Wang L
      • et al.
      Pulmonary rehabilitation for exercise tolerance and quality of life in IPF patients: a systematic review and meta-analysis.
      As COVID-19 is a new disease, there is a lack of data in the literature about the recovery pathway on sequelae of severely affected patients, and an optimal treatment is extremely urgent. Pulmonary rehabilitation might have an important role in improving functional capacity and the quality of life of survivors of this disease. Thus, the aim of this systematic review and meta-analysis was to synthetize the evidence about the effectiveness of pulmonary rehabilitation in health outcomes of ILDs, including those caused by CoVs.

      Methods

      This systematic review and meta-analysis followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.
      • Chandler J
      • Cumpston M
      • Li T
      • et al.
      Cochrane handbook for systematic reviews of interventions.
      The Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were used as a reporting structure for this systematic review.
      • Moher D
      • Shamseer L
      • Clarke M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      This meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration no.: CRD42020178937).

      Search strategy

      Two reviewers (S.R.-G, S.N.A.-A.) independently searched the MEDLINE (via PubMed), EMBASE (via Scopus), SPORTDiscus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science, and MedRxiv databases from inception to November 2020. Disagreements were solved by consensus or involving a third researcher (V.M.-V.). The search strategy used was: (covid OR coronavirus OR “Middle East Respiratory Syndrome Coronavirus” OR “Severe Acute Respiratory Syndrome” OR SARS-CoV OR “Acute Respiratory Distress Syndrome” OR ARDS OR “acute hypoxemic respiratory failure” OR “pulmonary fibrosis” OR “lung fibrosis” OR “interstitial lung disease” OR “interstitial pneumonia”) AND (“physical therapy” OR “respiratory muscle training” OR “respiratory rehabilitation” OR “pulmonary rehabilitation” OR exercise OR exercises). The reference lists of the articles included in this review, as well as the list of references of studies included in previous systematic reviews and meta-analyses, were reviewed for any additional relevant studies.

      Study selection

      Studies concerning the effectiveness of different pulmonary rehabilitation programs in ILD or patients with CoV were included in this systematic review. Inclusion criteria were: (1) randomized controlled trials (RCT); (2) participants who had ILD (including pulmonary fibrosis) or postacute CoV; (3) physical exercise or pulmonary rehabilitation as the intervention; (4) comparison with controls undergoing usual care or activities without physical demand; and (5) outcomes of lung function, exercise capacity, HRQOL, and dyspnea.
      The exclusion criteria were: (1) patients with mild-moderate severity of COVID-19 as they were not at risk of developing pulmonary fibrosis
      • Rogliani P
      • Calzetta L
      • Coppola A
      • et al.
      Are there pulmonary sequelae in patients recovering from COVID-19?.
      ; (2) studies comparing the same modality of exercise with different doses of time, frequency, or duration; (3) conference abstracts without a full published article; (4) studies with inconsistencies or that did not provide enough data to calculate the effect size (ES); and (5) studies published in languages other than English or Spanish.
      When more than 1 report provided data from the same sample, only the publication with the most detailed results or providing data for the largest sample size was included. Regarding HRQOL, only studies reporting a total score of a HRQOL scale were selected.

      Search and data extraction

      The main characteristics of the selected studies were summarized in an ad hoc table including information about (1) study characteristics such as year of publication, country, and sample size; (2) population characteristics such as type of respiratory disease, mean age, and time from diagnosis; (3) intervention characteristics such as duration, frequency, type, and exercise regime training; and (4) outcomes such as lung function, exercise capacity, HRQOL, and dyspnea. Disagreements in data collection were settled by consensus.

      Classification of the outcome

      Pulmonary rehabilitation program outcomes were classified according to 4 main areas: lung function, measured using forced vital capacity (FVC); exercise capacity measured using the 6-minute walk distance (6MWD); HRQOL, measured using a quality of life scale; and dyspnea measured at baseline using a dyspnea scale.

      Risk of bias assessment

      The quality of RCTs was assessed using Cochrane Collaboration's tool for assessing risk of bias.
      • Sterne J
      • Savović J
      • Page M
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ,a This tool evaluates the risk of bias according to 5 domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Overall bias was considered as “low risk of bias” if the study was classified as low risk in all domains, “some concerns” if there was at least 1 domain rated as having some concerns, and “high risk of bias” if there was at least 1 domain rated as high risk or several domains rated as having some concerns that could affect the validity of the results.
      Data extraction and quality assessment were independently performed by 2 reviewers (S.N.A.-A., S.R.-G.), and inconsistencies were solved by consensus or involving a third researcher (V.M.-V.).

      Statistical analysis

      We calculated a pooled ES of the mean differences for 6MWD using a random effects model based on the DerSimonian and Laird method.
      • DerSimonian R
      • Kacker R
      Random-effects model for meta-analysis of clinical trials: an update.
      A pooled ES of the standardized mean differences was necessary to use for FVC, HRQOL, and dyspnea outcomes because different measures or scales were reported by studies. A combined estimate was calculated when studies applied more than 1 questionnaire for reporting the dyspnea grade. Additionally, statistical heterogeneity was analyzed using the I2 statistic. Heterogeneity was considered as not important (I2, 0%-40%), moderate (I2, 30%-60%), substantial (I2, 50%-90%), or considerable (I2, 75%-100%); the corresponding P values were also considered.

      Higgins JP, Green S. Selecting studies and collecting data. Cochrane Handbook of Systematic Reviews of Interventions, Version 5.1.0. Cochrane Collaboration. 2011. Available at: https://handbook-5-1.cochrane.org/. Accessed June 7, 2021.

      Following the Cochrane Handbook recommendations, when data on the SDof change on outcomes from baseline were lacking, the estimates relied on standard errors, 95% confidence intervals (CI), and P values to calculate the SD. Finally, when studies were scaled inversely (ie, lower values indicated worse outcomes), the mean in each group was multiplied by −1.
      Random effects metaregression analyses were conducted to assess whether baseline age influenced the association of pulmonary rehabilitation and outcome related variables. Sensitivity analyses were performed by removing studies one by one to assess the robustness of the summary estimates and to detect whether any particular study accounted for a large proportion of heterogeneity among pulmonary rehabilitation ES pooled estimates.
      Finally, we used Egger's regression asymmetry test to assess publication bias.
      • Sterne JA
      • Egger M
      • Smith GD
      Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis.
      A level of <0.10 was used to determine whether publication bias might be present. Statistical analyses were performed using Stata Statistical software, version 16.0.b

      Results

      The literature search retrieved 12,214 articles, which were reviewed based on the title and abstract after discarding duplicates. Finally, 11 RCTs
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Dowman LM
      • McDonald CF
      • Hill CJ
      • et al.
      The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      met the inclusion criteria and were selected for this systematic review and meta-analysis (fig 1), including a total sample of 637 participants. Excluded studies with reasons for exclusion are available in supplementary table S1 (available online only at http://www.archives-pmr.org/).
      Fig 1
      Fig 1Flow chart for identification of trials for inclusion in the meta-analysis.
      Table 1 presents descriptive information for the 11 studies included in the review. The study data were obtained in samples from Europe,
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      ,
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      North America,
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      ,
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      ,
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      Asia,
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      ,
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      ,
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      and Australia.
      • Dowman LM
      • McDonald CF
      • Hill CJ
      • et al.
      The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
      ,
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      The age of included participants in the systematic review ranged between 35.9-72.2 years. Different pulmonary clinical entities were analyzed in the included studies: ILD was examined in 3 studies,
      • Dowman LM
      • McDonald CF
      • Hill CJ
      • et al.
      The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
      ,
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      ,
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      idiopathic pulmonary fibrosis in 6 studies,
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      ,
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      ,
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      ,
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      ,
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      ,
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      and postrespiratory CoV disease in 2 studies.
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      Additionally, different pulmonary rehabilitation interventions were examined in the studies selected, including combined exercise (aerobic with strength), combine exercise with specific respiratory exercises, and aerobic exercise with specific respiratory muscle training.
      Table 1Characteristics of the RCTs included in the meta-analysis
      Study CharacteristicsPopulation CharacteristicsIntervention
      StudyCountryRespiratory DiseaseAge (y)Time From DiagnosisMin/SessionFrequency(Times/wk)WeeksExperimental GroupControl GroupOutcomes
      Dowman et al
      • Dowman LM
      • McDonald CF
      • Hill CJ
      • et al.
      The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
      AustraliaILDEG: 69±11

      CG: 70±11
      NRNR2830 min of aerobic exercise (cycling and walking)

      Upper and lower limb resistance training (10-12 RM)
      Weekly telephone support6MWD, SGRQ-I, UCSD SOBQ, mMRC
      Gaunaurd et al
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      United StatesIdiopathic pulmonary fibrosisEG: 71±6

      CG: 66±7
      NR9021210 educational lectures,

      30 min of endurance training,

      20 min of flexibility exercises (3 sets/30s),

      25 min of strength training (2-3 sets/10-15 repetitions)
      Handouts about the educational lecturesSGRQ-I
      Holland et al
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      AustraliaILDEG: 70±8

      CG: 67±13
      NRNR2830 min of endurance training (cycling and walking)

      Upper limb endurance training

      Functional strength for lower limbs
      Weekly telephone support6MWD, mMRC
      Jackson et al
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      United StatesIdiopathic pulmonary fibrosisEG: 71±6

      CG: 66±7
      3-48 mo before screening12021215 min of educational lectures,

      30 min of endurance training (cycling and walking),

      15 min of flexibility exercises (3 sets/30s),

      15-30 min of strength training (3 sets/15 repetitions)
      Normal activities6MWD, Borg Dyspnea Index
      Jarosh et al
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      GermanyIdiopathic pulmonary fibrosisEG: 68±9

      CG: 65±10
      NRNR5-63Medical care, psychological support, breathing therapy, education.

      Endurance or interval cycle training (60% or 100% peak work rate)

      Resistance training for major muscle groups (3 sets/15-20 repetitions maximum)
      Usual care6MWD, CRDQ
      Lau et al
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ChinaRecovering from SARSEG: 35.9±9.3

      CG: 38.3±11.2
      NR60-904-5630-45 min of endurance training (limbs ergometer, stepper, or treadmill)

      Upper and lower limbs resistance training (3 sets/10-15 repetitions at maximum load)
      Educational session about exercise rehabilitation6MWD
      Liu et al
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      ChinaCOVID-19EG: 69.4±8.0

      CG: 68.9±7.6
      NR1026Respiratory muscle training (3 sets/10 breaths/60% MEP) and diaphragm muscle (30 contractions, placing a weight on the anterior abdominal wall)

      Stretching and cough exercise

      Home exercise (pursed-lip breathing and coughing training)
      Usual careFVC, 6MWD
      Nishiyama et al
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      JapanIdiopathic pulmonary fibrosisEG: 68.1±8.9

      CG: 64.5±9.1
      >3 moNR210Educational lectures

      Treadmill

      20 min of strength training for the limbs
      Usual careFVC, 6MWD, SGRQ, BDI
      Perez-Bogerd et al
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      BelgiumILDEG: 64±13

      CG: 64±8
      NR903-212-12Endurance training (cycling, treadmill, arm cranking and stair climbing) and peripheral muscle training (3 sets/8 repetitions)

      30 min of multidisciplinary treatment

      Medical care and medical follow-up
      Medical care and identical medical follow-up as EG6MWD, SGRQ
      Vainshelboim et al
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      IsraelIdiopathic pulmonary fibrosisEG: 68.8±6

      CG: 66±9
      EG: 3±3.7 y

      CG: 1.9±3.1y
      60212Regular medical care and exercise training: calisthenic and deep breathing exercises,

      30 min of aerobic training (treadmill walking, leg cycling, step climbing)

      Resistance training (1-2 sets/12-15 repetitions)

      5 min of flexibility exercises

      Encourage PA levels on other days
      Regular medical care

      FVC, 6MWD, SGRQ, mMRC
      Yuen et al
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      United StatesIdiopathic pulmonary fibrosisEG: 67.4±7.4

      CG: 72.2±8.4
      EG: 3.5±3.4 y

      CG: 3.0±4.2 y
      30 for Wii games and 30 for physical activity312Wii Fit exergames with an exercise protocol similar to that reported by Gaunaurd
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      and Vainshelboim
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.


      Additional physical activity
      Control Wii video game not requiring movement Additional physical activity6MWD, SGRQ, Borg Dyspnea Index
      NOTE. Values are presented as mean ± SD.
      Abbreviations: BDI, baseline dyspnea index; CG, control group; CRDQ, Chronic Respiratory Disease Questionnaire; EG, expermiental group; MEP, maximal expiratory pressure; mMRC, Modified Medical Research Council dyspnea scale; NR, not reported; PA, physical activity; RM, repetition maximum; SGRQ, St. George's Respiratory Questionnaire; SGRQ-I, St. George's Respiratory Questionnaire specific for idiopathic pulmonary fibrosis; UCSD SOBQ, University of California San Diego Shortness of Breath Questionnaire.
      Table S1Studies excluded after full text read with the reason for exclusion.
      Reference (Author and Year)Reason for Exclusion
      Barbier et al, 2014Conference abstract
      Bogerd et al, 2011Conference abstract
      Cohen et al, 2013Conference abstract
      De Las Heras et al, 2019Conference abstract
      Dowman et al, 2015Conference abstract
      Gaunaurd et al, 2011Conference abstract
      Gaunaurd et al, 2013Conference abstract
      Gaunaurd et al, 2014Conference abstract
      Gomez et al, 2012Conference abstract
      Gomez et al, 2013Conference abstract
      Jackson et al, 2012Conference abstract
      Jackson et al, 2014Conference abstract
      Jarosch et al, 2016Conference abstract
      Jastrzebski et al, 2017Conference abstract
      Koulopoulou et al, 2016Conference abstract
      Kramer et al, 2013Conference abstract
      Lanza et al, 2019Conference abstract
      Menon et al, 2011Conference abstract
      Nykvist et al, 2016Conference abstract
      Schneeberger et al, 2016Conference abstract
      Shen et al, 2016Conference abstract
      Stessel et al, 2015Conference abstract
      Vainshelboim et al, 2013Conference abstract
      Vainshelboim et al, 2013Conference abstract
      Vainshelboim et al, 2014Conference abstract
      Vainshelboim et al, 2015Conference abstract
      Parisien-La Salle et al, 2019Non data available for meta-analysis
      Cockcroft et al, 1981Population
      Greening et al, 2014Population
      Vainshelboim et al, 2014Same data as other included study
      Vainshelboim et al, 2016Same data as other included study
      Liu et al, 2017Other language
      Wapenaar et al, 2020Non data available for meta-analysis

      Risk of bias

      As evaluated by Cochrane Collaboration's tool for RCTs, 18.2% of the studies showed a high risk of bias,
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      ,
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      72.7% showed some concerns,
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      ,
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      ,
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      and 9.1% had a low risk of bias.
      • Dowman LM
      • McDonald CF
      • Hill CJ
      • et al.
      The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
      When studies were analyzed by individual domains, 91% had shortcomings in the selection of the reported results domain
      • Lau HMC
      • Ng GYF
      • Jones AYM
      • et al.
      A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
      ,
      • Gaunaurd IA
      • Gómez-Marín OW
      • Ramos CF
      • et al.
      Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
      • Jackson RM
      • Gomez-Marin OW
      • Ramos CF
      • et al.
      Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
      • Jarosch I
      • Schneeberger T
      • Gloeckl R
      • et al.
      Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
      • Liu K
      • Zhang W
      • Yang Y
      • et al.
      Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
      • Nishiyama O
      • Kondoh Y
      • Kimura T
      • et al.
      Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
      • Perez-Bogerd S
      • Wuyts W
      • Barbier V
      • et al.
      Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
      • Vainshelboim B
      • Kramer MR
      • Fox BD
      • et al.
      Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
      • Yuen HK
      • Lowman JD
      • Oster RA
      • et al.
      Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
      (supplementary fig S1, available online only at httP://www.archives-pmr.org).

      Meta-analysis

      The pooled ES estimates for pulmonary rehabilitation were 44.55 (95% CI, 32.46-56.64) for 6MWD, 0.52 (95% CI, 0.22-0.82) for HRQOL, and 0.39 (95% CI, –0.08 to 0.87) for dyspnea. Heterogeneity among studies was rated as not important for 6MWD (I2, 0.0%), moderate for HRQOL (I2, 50.1%), and substantial for dyspnea (I2, 71.3%) (figs 2-4). FVC data were available in 3 studies, which showed a significant effect of treatment (ES, 0.37; 95% CI, 0.02-0.71) (not shown).
      Fig 2
      Fig 2Mean difference (95% CI) of effect of pulmonary rehabilitation vs usual care on exercise capacity (measured by 6MWD) inmediately after intervention (n= 616).
      Fig 3
      Fig 3Standardized mean difference (95% CI) of effect of pulmonary rehabilitation vs usual care on health related quality of life inmediately after intervention (n= 354).
      Fig 4
      Fig 4Standardized mean difference (95% CI) of effect of pulmonary rehabilitation vs usual care on dyspnea inmediately after intervention (n= 300).
      The random effects metaregression models indicated that age (ß=0.3499, P=.489 for FVC; ß=–0.4345, P=.499 for 6MWD; ß=0.0913, P=.413 for HRQOL; and ß=0.4196, P=.117 for dyspnea) was not related to the association between the intervention and outcome-related variables (supplementary table S2, available online only at http://www.archives-pmr.org/).
      Table S2Meta-regressions analyses based on age.
      OutcomeAge
      nβp
      Lung function (FVC)30.34990.489
      Exercise capacity (6MWD)10-0.43450.499
      Health related quality of life70.09130.413
      Dyspnoea60.41960.117

      Sensitivity analysis

      The pooled ES estimates for the association between pulmonary rehabilitation and all outcome related variables were not significantly modified in magnitude or direction when individual study data were removed from the analysis one at a time. Extra sensitivity analysis was performed excluding the 2 CoV studies showing a pooled ES estimate of 42.00 (95% CI, 27.08-56.92) for 6MWD.

      Publication bias

      Egger's test revealed no significant publication bias for any pooled analyses. Funnel plots are shown in supplementary figures S2-S4 (available online only at http://www.archives-pmr.org/).
      Figure S2
      Figure S2Funnel plot showing publication bias results for exercise capacity outcome (measured by 6-MWD).
      Figure S3
      Figure S3Funnel plot showing publication bias results for quality of life outcome (measured by St. George Respiratory Questionnaire (SGRQ) or SGRQ-1 (SGRQ specific for idiopathic pulmonary fibrosis)).
      Figure S4
      Figure S4Funnel plot showing publication bias results for dyspnoea outcome.

      Discussion

      This systematic review and meta-analysis provides a synthesis of evidence supporting the effectiveness of pulmonary rehabilitation to improve lung function (measured by FVC), exercise capacity (measured by 6MWD), and HRQOL in patients with ILD, including patients with CoV. Meta-regression analysis did not find an association between the magnitude of the effect and the age of patients in the studies.
      Among nonpharmacologic interventions to treat these clinical entities, regular exercise is known to be a low-cost solution to improve health, wellbeing, and economic productivity of patients with chronic lung disease,
      • Singh SJ
      • Halpin DM
      • Salvi S
      • et al.
      Exercise and pulmonary rehabilitation for people with chronic lung disease in LMICs: challenges and opportunities.
      especially for those with ILD, in whom conventional pharmacologic treatment has shown a limited response.
      • Rafii R
      • Juarez MM
      • Albertson TE
      • et al.
      A review of current and novel therapies for idiopathic pulmonary fibrosis.
      Previous Cochrane reviews support positive effects and no adverse events of pulmonary rehabilitation in patients with ILD, showing improvements of 38.61-44.34 m for 6MWD, 0.58-0.59 for HRQOL, or –0.47 to –0.68 for dyspnea.
      • Holland AE
      • Hill C.
      Physical training for interstitial lung disease.
      ,
      • Dowman L
      • Hill CJ
      • Holland AE.
      Pulmonary rehabilitation for interstitial lung disease.
      Our meta-analysis, in line with the results of previous studies, confirms consistent clinical benefits for exercise capacity (6MWD), HRQOL, and dyspnea in patients with ILD, adding beneficial effects respect to lung function (FCV). Also, our data were similar with regard to the magnitude of change in 6MWD in patients post-CoV, probably because similar respiratory improvements have been reported in both patients with ILD and those post-CoV who are severely respiratory affected because they have interstitial pneumonia, fibrosis, or diffuse alveolar damage in common.
      • Kim EA
      • Lee KS
      • Johkoh T
      • et al.
      Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings.
      ,
      • Shi H
      • Han X
      • Jiang N
      • et al.
      Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
      Translating our research effect estimates to clinical improvements by using methods endorsed by the Cochrane Collaboration,
      • Schünemann HJ
      • Vist GE
      • Higgins JP
      • et al.
      Interpreting results and drawing conclusions.
      a pulmonary rehabilitation intervention increased the predicted FVC by 5.47%, and HRQOL improved 3.9 points with respect to baseline values. The 6MWD test improved by 44.55 m compared with baseline values.
      Functional status is extremely important for people with diffuse parenchymal lung disease, and the 6MWD test is widely recognized as a valid and reliable measuring tool.
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Small changes in six-minute walk distance are important in diffuse parenchymal lung disease.
      Additionally, the distance achieved for these patients is closely related with disease severity and mortality risk.
      • Hallstrand T
      • Boitano L
      • Johnson W
      • et al.
      The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis.
      Recent studies have reported severe disability in postacute patients with COVID-19 with poor results in this test because walk distances are below those expected for their age.
      • Curci C
      • Pisano F
      • Bonacci E
      • et al.
      Early rehabilitation in post-acute COVID-19 patients: data from an Italian COVID-19 rehabilitation unit and proposal of a treatment protocol. A cross-sectional study.
      ,
      • Daher A
      • Balfanz P
      • Cornelissen C
      • et al.
      Follow up of patients with severe coronavirus disease 2019 (COVID-19): pulmonary and extrapulmonary disease sequelae.
      In patients with diffuse parenchymal lung disease, Holland et al
      • Holland AE
      • Hill CJ
      • Conron M
      • et al.
      Small changes in six-minute walk distance are important in diffuse parenchymal lung disease.
      concluded that changes between 29-34 m may be clinically significant; thus, an increase of 44.55 m is significant for improving functional capacity in this population. Previous studies have reported similar clinical changes compared with our data, with results ranging between 38.38-48.6 m.
      • Yu X
      • Li X
      • Wang L
      • et al.
      Pulmonary rehabilitation for exercise tolerance and quality of life in IPF patients: a systematic review and meta-analysis.
      ,
      • Cheng L
      • Tan B
      • Yin Y
      • et al.
      Short-and long-term effects of pulmonary rehabilitation for idiopathic pulmonary fibrosis: a systematic review and meta-analysis.
      ,
      • Gomes-Neto M
      • Silva CM
      • Ezequiel D
      • et al.
      Impact of pulmonary rehabilitation on exercise tolerance and quality of life in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.
      Regarding FVC, the other major clinical outcome for pulmonary rehabilitation, differences between 2%-6% are suggested to be clinically relevant.
      • Du Bois RM
      • Weycker D
      • Albera C
      • et al.
      Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.
      Our pooled ES (5.47%) falls within this range of improvement.
      The HRQOL scales used in our study are considered an instrument whose validity, reliability, and responsiveness is sufficiently proven.
      • Puhan MA
      • Guyatt GH
      • Goldstein R
      • et al.
      Relative responsiveness of the Chronic Respiratory Questionnaire, St. Georges Respiratory Questionnaire and four other health-related quality of life instruments for patients with chronic lung disease.
      Additionally, they are considered appropriate to measure HRQOL that may have a predictive value for mortality in patients with ILD.
      • Furukawa T
      • Taniguchi H
      • Ando M
      • et al.
      The St. George's Respiratory Questionnaire as a prognostic factor in IPF.
      Although a 3.9-point improvement vs baseline assessment resulted in a moderate ES, this change remains under the recognized minimal clinical important difference for this value,
      • Swigris JJ
      • Brown KK
      • Behr J
      • et al.
      The SF-36 and SGRQ: validity and first look at minimum important differences in IPF.
      which is in line with previous findings.
      • Yu X
      • Li X
      • Wang L
      • et al.
      Pulmonary rehabilitation for exercise tolerance and quality of life in IPF patients: a systematic review and meta-analysis.
      Our data also show a positive, but not statistically significant, effect of pulmonary rehabilitation on dyspnea. In this sense, the direction of the association was not homogeneous between studies, probably owing to the different tools used to assess this outcome and the lack of responsiveness of some of the dyspnea measurement tools.
      • Rammaert B
      • Leroy S
      • Cavestri B
      • et al.
      Home-based pulmonary rehabilitation in idiopathic pulmonary fibrosis.
      ,
      • Jones P
      • Lareau S
      • Mahler DA
      Measuring the effects of COPD on the patient.

      Study limitations

      This study has some limitations that should be acknowledged. First, our study focused on rehabilitation of pulmonary involvement in patients with COVID-19. However, because this is a systemic disease,
      • Marini JJ
      • Gattinoni L.
      Management of COVID-19 respiratory distress.
      along with the lung damage, other comorbidities such as myopathy of femoral head necrosis
      • Zhang B
      • Zhang S.
      Corticosteroid-induced osteonecrosis in COVID-19: a call for caution.
      might have an important effect in the functional capacity of these patients. Thus, the rehabilitation treatment plan should be carried out according to the framework of the International Classification of Functioning, Disability and Health.

      World Health Organization. International classification of functioning, disability and health (ICF). Available at: https://www.who.int/standards/classifications/international-classification-of-functioning-disability-and-health. Accessed November 2, 2020.

      Second, because of the scarcity of studies, it was not possible to conduct a subgroup analysis separating those interventions that uniquely included an exercise modality from those that included a modality combining 2. Additionally, it was not possible to examine the pulmonary rehabilitation regime (intensity, duration, frequency of the exercise) because information was lacking or was presented in a heterogeneous manner across studies. Nevertheless, most studies showed the same exercise training modality, which may help the generalizability of our findings. Also, although the overall methodological quality of included trials was satisfactory, most trials lacked information regarding the selection of the reported results domain from the Cochrane Collaboration's tool for assessing risk of bias and the risk of bias was rated as “some concerns” in most. Third, the pooled estimates of this meta-analysis were calculated from studies that, in addition to pulmonary fibrosis, included other ILD-related entities, which might have influenced our findings. In this sense, disease severity may have influenced the effect of the intervention, but it was not available in most studies. Nevertheless, with respect to participants with CoV, all were hospitalized with lung lesions, and participants with mild-moderate severity symptoms were excluded. Fourth, to assess the effect of pulmonary rehabilitation on patients’ HRQOL, we only analyzed studies that provided a total score of the scale used. However, physical or mental domains provided by other scales may potentially act as confounders or mediators in this association. To overcome some of these limitations, we conducted several sensitivity analyses to provide evidence regarding the robustness of the results.

      Conclusions

      This meta-analysis revealed a positive association between pulmonary rehabilitation and lung function, exercise capacity, and quality of life in patients with ILD, including severely affected patients with CoV. We are aware that further studies are necessary to confirm the role of pulmonary rehabilitation in the management of respiratory disabilities caused by COVID-19; however, although specific evidence of the effect of pulmonary rehabilitation in patients who have survived the severe acute respiratory syndrome coronavirus 2 infection appears contradictory, our data support that this intervention improves their functional capacity and their quality of life.

      Suppliers

      • a
        RoB 2: a revised tool for assessing risk of bias in randomised trials; Cochrane Collaboration
      • b
        Stata statistical software, version 16.0; Stata Corp.

      References

        • Flaherty KR
        • Andrei AC
        • Murray S
        • et al.
        Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test.
        Am J Respir Crit Care Med. 2006; 174: 803-809
        • Tse GMK
        • To KF
        • Chan PKS
        • et al.
        Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS).
        J Clin Pathol. 2004; 57: 260-265
        • Li Y
        • Xia L
        Coronavirus disease 2019 (COVID-19): role of chest CT in diagnosis and management.
        AJR Am J Roentgenol. 2020; 214: 1280-1286
        • Chan KS
        • Zheng JP
        • Mok YW
        • et al.
        SARS: prognosis, outcome and sequelae.
        Respirology. 2003; 8: S36-S40
        • Drosten C
        • Günther S
        • Preiser W
        • et al.
        Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
        N Engl J Med. 2003; 348: 1967-1976
        • Ksiazek TG
        • Erdman D
        • Goldsmith CS
        • et al.
        A novel coronavirus associated with severe acute respiratory syndrome.
        N Engl J Med. 2003; 348: 1953-1966
        • de Groot RJ
        • Baker SC
        • Baric RS
        • et al.
        Commentary: Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group.
        J Virol. 2013; 87: 7790-7792
        • World Health Organization
        Coronavirus disease 2019 (COVID-19): situation report – 67.
        World Health Organization, Geneva2020
      1. European Centre for Disease Prevention and Control. Risk assessment on COVID-19. Available at: https://www.ecdc.europa.eu/en/current-risk-assessment-novel-coronavirus-situation. Accessed July 14, 2020.

        • Wujtewicz M
        • Dylczyk-Sommer A
        • Aszkiełowicz A
        • et al.
        COVID-19 – what should anaethesiologists and intensivists know about it?.
        Anaesthesiol Intensive Ther. 2020; 52: 34-41
        • Chen JY
        • Qiao K
        • Liu F
        • et al.
        Lung transplantation as therapeutic option in acute respiratory distress syndrome for COVID-19-related pulmonary fibrosis.
        Chin Med J (Engl). 2020; 133: 1390-1396
        • Filatov A
        • Sharma P
        • Hindi F
        • Espinosa PS.
        Neurological complications of coronavirus disease (COVID-19): encephalopathy.
        Cureus. 2020; 12: e7352
        • Garg RK
        • Paliwal VK
        • Gupta A.
        Encephalopathy in patients with COVID-19: a review.
        J Med Virol. 2021; 93: 206-222
        • Petrosillo N
        • Viceconte G
        • Ergonul O
        • et al.
        COVID-19, SARS and MERS: are they closely related?.
        Clin Microbiol Infect. 2020; 26: 729-734
        • Antonio GE
        • Wong KT
        • Hui DSC
        • et al.
        Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
        Radiology. 2003; 228: 810-815
        • Hui DS
        • Wong KT
        • Ko FW
        • et al.
        The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors.
        Chest. 2005; 128: 2247-2261
        • Ngai JC
        • Ko FW
        • Ng SS
        • et al.
        The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status.
        Respirology. 2010; 15: 543-550
        • Hui D
        • Joynt G
        • Wong K
        • et al.
        Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors.
        Thorax. 2005; 60: 401-409
        • Thomas P
        • Baldwin C
        • Bissett B
        • et al.
        Physiotherapy management for COVID-19 in the acute hospital setting: clinical practice recommendations.
        J Physiother. 2020; 66: 73-82
        • Spruit MA
        • Singh SJ
        • Garvey 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-e64
        • Lau HMC
        • Ng GYF
        • Jones AYM
        • et al.
        A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome.
        Aust J Physiother. 2005; 51: 213-219
        • Yu X
        • Li X
        • Wang L
        • et al.
        Pulmonary rehabilitation for exercise tolerance and quality of life in IPF patients: a systematic review and meta-analysis.
        Biomed Res Int. 2019; 20198498603
        • Chandler J
        • Cumpston M
        • Li T
        • et al.
        Cochrane handbook for systematic reviews of interventions.
        John Wiley & Sons, Hoboken2019
        • Moher D
        • Shamseer L
        • Clarke M
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Rogliani P
        • Calzetta L
        • Coppola A
        • et al.
        Are there pulmonary sequelae in patients recovering from COVID-19?.
        Respir Res. 2020; 21: 286
        • Sterne J
        • Savović J
        • Page M
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: l4898
        • DerSimonian R
        • Kacker R
        Random-effects model for meta-analysis of clinical trials: an update.
        Contemp Clin Trials. 2007; 28: 105-114
      2. Higgins JP, Green S. Selecting studies and collecting data. Cochrane Handbook of Systematic Reviews of Interventions, Version 5.1.0. Cochrane Collaboration. 2011. Available at: https://handbook-5-1.cochrane.org/. Accessed June 7, 2021.

        • Sterne JA
        • Egger M
        • Smith GD
        Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis.
        BMJ. 2001; 323: 101-105
        • Dowman LM
        • McDonald CF
        • Hill CJ
        • et al.
        The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.
        Thorax. 2017; 72: 610-619
        • Gaunaurd IA
        • Gómez-Marín OW
        • Ramos CF
        • et al.
        Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program.
        Respir Care. 2014; 59: 1872-1879
        • Holland AE
        • Hill CJ
        • Conron M
        • et al.
        Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.
        Thorax. 2008; 63: 549-554
        • Jackson RM
        • Gomez-Marin OW
        • Ramos CF
        • et al.
        Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation.
        Lung. 2014; 192: 367-376
        • Jarosch I
        • Schneeberger T
        • Gloeckl R
        • et al.
        Short-term effects of comprehensive pulmonary rehabilitation and its maintenance in patients with idiopathic pulmonary fibrosis: a randomized controlled trial.
        J Clin Med. 2020; 9: 1567
        • Liu K
        • Zhang W
        • Yang Y
        • et al.
        Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study.
        Complement Ther Clin Pract. 2020; 39101166
        • Nishiyama O
        • Kondoh Y
        • Kimura T
        • et al.
        Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis.
        Respirology. 2008; 13: 394-399
        • Perez-Bogerd S
        • Wuyts W
        • Barbier V
        • et al.
        Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial.
        Respir Res. 2018; 19: 182
        • Vainshelboim B
        • Kramer MR
        • Fox BD
        • et al.
        Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis.
        Eur J Phys Rehabil Med. 2017; 53: 209-218
        • Yuen HK
        • Lowman JD
        • Oster RA
        • et al.
        Home-based pulmonary rehabilitation for patients with idiopathic pulmonary fibrosis: a pilot study.
        J Cardiopulm Rehabil Prev. 2019; 39: 281-284
        • Singh SJ
        • Halpin DM
        • Salvi S
        • et al.
        Exercise and pulmonary rehabilitation for people with chronic lung disease in LMICs: challenges and opportunities.
        Lancet Respir Med. 2019; 7: 1002-1004
        • Rafii R
        • Juarez MM
        • Albertson TE
        • et al.
        A review of current and novel therapies for idiopathic pulmonary fibrosis.
        J Thorac Dis. 2013; 5: 48-73
        • Holland AE
        • Hill C.
        Physical training for interstitial lung disease.
        Cochrane Database Syst Rev. 2008; 4CD006322
        • Dowman L
        • Hill CJ
        • Holland AE.
        Pulmonary rehabilitation for interstitial lung disease.
        Cochrane Database Syst Rev. 2014; 10CD006322
        • Kim EA
        • Lee KS
        • Johkoh T
        • et al.
        Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings.
        Radiographics. 2002; 22: S151-S165
        • Shi H
        • Han X
        • Jiang N
        • et al.
        Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
        Lancet Infect Dis. 2020; 20: 425-434
        • Schünemann HJ
        • Vist GE
        • Higgins JP
        • et al.
        Interpreting results and drawing conclusions.
        Cochrane Hndbook Syst Rev Intervent. 2019; : 403-431
        • Holland AE
        • Hill CJ
        • Conron M
        • et al.
        Small changes in six-minute walk distance are important in diffuse parenchymal lung disease.
        Respir Med. 2009; 103: 1430-1435
        • Hallstrand T
        • Boitano L
        • Johnson W
        • et al.
        The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis.
        Eur Respir J. 2005; 25: 96-103
        • Curci C
        • Pisano F
        • Bonacci E
        • et al.
        Early rehabilitation in post-acute COVID-19 patients: data from an Italian COVID-19 rehabilitation unit and proposal of a treatment protocol. A cross-sectional study.
        Eur J Phys Rehabil Med. 2020; 56: 633-641
        • Daher A
        • Balfanz P
        • Cornelissen C
        • et al.
        Follow up of patients with severe coronavirus disease 2019 (COVID-19): pulmonary and extrapulmonary disease sequelae.
        Respir Med. 2020; 174106197
        • Cheng L
        • Tan B
        • Yin Y
        • et al.
        Short-and long-term effects of pulmonary rehabilitation for idiopathic pulmonary fibrosis: a systematic review and meta-analysis.
        Clin Rehabil. 2018; 32: 1299-1307
        • Gomes-Neto M
        • Silva CM
        • Ezequiel D
        • et al.
        Impact of pulmonary rehabilitation on exercise tolerance and quality of life in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.
        J Cardiopulm Rehabil Prev. 2018; 38: 273-278
        • Du Bois RM
        • Weycker D
        • Albera C
        • et al.
        Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.
        Am J Respir Crit Care Med. 2011; 184: 1382-1389
        • Puhan MA
        • Guyatt GH
        • Goldstein R
        • et al.
        Relative responsiveness of the Chronic Respiratory Questionnaire, St. Georges Respiratory Questionnaire and four other health-related quality of life instruments for patients with chronic lung disease.
        Respir Med. 2007; 101: 308-316
        • Furukawa T
        • Taniguchi H
        • Ando M
        • et al.
        The St. George's Respiratory Questionnaire as a prognostic factor in IPF.
        Respir Res. 2017; 18: 18
        • Swigris JJ
        • Brown KK
        • Behr J
        • et al.
        The SF-36 and SGRQ: validity and first look at minimum important differences in IPF.
        Respir Med. 2010; 104: 296-304
        • Rammaert B
        • Leroy S
        • Cavestri B
        • et al.
        Home-based pulmonary rehabilitation in idiopathic pulmonary fibrosis.
        Rev Mal Respir. 2011; 28: e52-e57
        • Jones P
        • Lareau S
        • Mahler DA
        Measuring the effects of COPD on the patient.
        Respir Med. 2005; 99: S11-S18
        • Marini JJ
        • Gattinoni L.
        Management of COVID-19 respiratory distress.
        JAMA. 2020; 323: 2329-2330
        • Zhang B
        • Zhang S.
        Corticosteroid-induced osteonecrosis in COVID-19: a call for caution.
        J Bone Miner Res. 2020; 35: 1828-1829
      3. World Health Organization. International classification of functioning, disability and health (ICF). Available at: https://www.who.int/standards/classifications/international-classification-of-functioning-disability-and-health. Accessed November 2, 2020.