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Respiratory rehabilitation in patients recovering from severe acute respiratory syndrome: A systematic review and meta-analysis

Background With an increase in published reports on respiratory rehabilitation (RR) in severe acute respiratory syndrome (SARS), there is a need for a meta-analysis and systematic review to measure the effects of the RR in SARS. Objective Objective of the review was to evaluate the efficacy and safety of RR in patients recovering from SARS. Methods PubMed/ MEDLINE, CENTRAL, EMBASE, and Clinical Trial Registries were systematically searched (between January 1, 2003, to July 31, 2021) to identify all patients who received RR, at least for six days, following SARS. The primary outcome was exercise capacity [6-meter walking distance (6-MWD)], and secondary outcomes were change in pulmonary function test (PFT) parameters, activities in daily livings (ADLs), and quality of life (QoL). Meta-analysis was performed by using RevMan 5.4. Results Twenty-one observational studies, including eight comparative studies, were included. Eight comparative studies participated in quantitative meta-analysis. The intervention group, who received RR, improved significantly in exercise capacity (6-MWD) [mean difference (MD):45.79, (95% CI:31.66–59.92)] and PFT parameters, especially in forced vital capacity (FVC%) [MD:4.38, (95% CI:0.15–8.60)], and diffusion lung capacity for carbon monoxide (DLCO%) [MD:11.78, (95% CI:5.10–18.46)]. The intervention group failed to demonstrate significant improvement in ADLs and QoL outcomes. No significant adverse events were reported during the intervention. Conclusion Respiratory rehabilitation can improve exercise capacity and PFT parameters in patients recovering from SARS infection. The RR does not cause serious adverse events. Clinical trials to determine the best RR program (in terms of initiation, duration, and components) in SARS and its treatment efficacy, both in the short and long- term are needed.


Introduction
Severe acute respiratory syndrome (SARS) is a serious health concern, a rapidly progressive respiratory syndrome, which is caused by severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and coronavirus-2 (SARS-CoV-2). SARS-CoV was identified as a global threat in 2003 (SARS-CoV-1) and 2019 (SARS-CoV-2). 1,2 The lung injury in SARS is caused either due to direct viral effects or immune pathogenic factors. 1 Approximately 20 to 30% of patients with SARS may require intensive care unit (ICU) treatment, including mechanical ventilation. 2 The lung damage in SARS-CoV is mainly characterized by diffuse alveolar damage, which ultimately can lead to either pleural effusion, pulmonary edema, and or consolidation/ fibrosis of the lung. 1 It is already evident from the literature that respiratory rehabilitation (RR) may improve dyspnoea, functional capacity, and healthrelated quality of life (QoL). Despite this widespread clinical acceptance and demonstration of the therapeutic potential of the RR in chronic obstructive lung diseases, there is uncertainty about the precise therapeutic efficacy of the RR in patients recovering from SARS CoV infection.
Recently many reviews, consensus reports, guidelines, expert opinions have been published on recommending RR in patients recovering from SARS-CoV infection. 3À10 However, most of these reviews are based on previous experience managing other chronic lung diseases, not on patients' research data on SARS infection. Therefore, it is essential to accumulate data for RR programs' evidence, clarify the benefit, and strengthen its rationale for incorporating standard clinical management in patients with SARS-CoV infection.
In this review, we summarised all the available literature and determined the efficacy and safety of the RR following SARS infection.

Methods
The review was performed according to the PRISMA-P 2015 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 11,12 The study protocol was registered prospectively in the International Prospective Register of Ongoing Systematic Reviews (Systematic review registration À PROSPERO 2021: CRD42021255409).

Inclusion and exclusion criteria
Observational studies of any kind [randomized controlled trials (RCT), nonrandomized clinical trials (non-RCT), studies with cohort design (prospective or retrospective), or case series (with minimum of 5 participants)], published as an article or as a pre-print, were eligible for inclusion. Duplicate studies, case series with less than 5 participants, case reports, meta-analyses, review articles, consensus documents, comments, opinion articles, and letters not presenting the original data were excluded from this review. Articles written in languages other than English were excluded.

Participants
Patients, with any age, with (1) SARS either due to SARS-CoV-1 or SARS-CoV-2 infection, (2) who underwent RR for at least six days, (3) who were admitted and treated in an inpatient hospital (irrespective of severity) for the acute management of SARS, were included in this review.

Intervention
Respiratory rehabilitation (RR) consisting of 'aerobic exercises (endurance training)' and/or 'respiratory muscle training (RMT) exercises' was considered the primary treatment for SARS-CoV infection. Respiratory rehabilitation, which was administered only after the diagnosis of SARS, was included in this review. No restriction was placed based on rehabilitation technique (components of RMT or aerobic /endurance training), exercise frequency/ schedule, exercise duration, and rehabilitation set-up (ICU/ inpatient /outpatient/ home).

Comparison
Research articles, with or without having any control group (only intervention group), were included in this review. For the quantitative meta-analysis, it was mandatory to have a control/ comparison group. Control groups involved 'any interventions other than RR (an education program/ video program)' or 'no intervention' along with standard medical care for SARS. For descriptive/narrative analysis, it was not mandatory to have a comparison group.

Selection of studies
According to the inclusion and exclusion criteria, two reviewers (A.B.and M.K.S) independently searched the articles and identified them as included, excluded, or uncertain. The full-text article was obtained and reviewed for eligibility based on the inclusion criteria in case of uncertainty.

Data extraction and management
Two reviewers (A.B. and M.K.S.) extracted the data independently with a standardized data collection form, including (1) author, year, setting (country, ICU, inpatient (IPD), Out-patient (OPD), home) (2) participants (number, mean age and gender, type of viral infections, and severity of the disease, (3) inclusion and exclusion criteria, (4) intervention (components of RR, frequency, intensity, and duration), (5) results (outcome measures, effect, significance) (6) safety (adverse events, mortality due to intervention). Any discrepancies during the selection and data collection were resolved by discussion and consensus. For studies with more than one-time point to observe and assess, the outcome data assessed at the end of intervention (RR) was included.
For continuous outcomes, mean values, standard deviation (SD), and total participants were extracted. For dichotomous outcomes, the total number of events and total participants were extracted. If mean and SD were not reported in the particular study, it was calculated manually from the reported indicators. If data were not available or written in an unusable way, the specific research was excluded from meta-analysis, and the data were presented descriptively.

Data analysis
Only comparative ('RR' versus 'No RR') studies [clinical trials and comparative observational studies] were included in the meta-analysis. Meta-analysis was performed by Review Manager software (Rev-Man 5.4) (The Cochrane Collaboration, Copenhagen, Denmark). As per the recommendation of the Cochrane handbook, during analysis, the random-effects model analysis was utilized, as there could be heterogeneity (none of the studies applied the same set of RR) among the original studies, which might not be evident in the data.

Assessment of risk of bias
The methodological quality of the comparative studies was assessed with the Newcastle -Ottawa scale (NOS), 23 which is being used to measure the risk of bias of observational (non-randomized) studies. A score >7 on NOS was considered a high-quality study. The higher the total NOS, the lower the risk of bias was. 23 Two reviewers (A.B. and M.K.S.) independently extracted data and performed the risk-of-bias assessment. Disagreements between these two reviewers were resolved by discussion with a third reviewer (J.S.).

Measurement of treatment effects
The outcome measures of interest, exercise capacity/ endurance (6-MWD), change in PFT parameters, ADL and QoL scores were presented as continuous data, and mortality events (deaths during study period) were presented as categorical data.
For quantitative meta-analysis of comparative studies (to measure the treatment effect), either 'the mean differences (MD)' or 'the standardized mean difference (SMD)' with corresponding 95% confidence intervals (CIs) was used to calculate the effect sizes of continuous outcomes measures. The significance level was fixed at P< .05.
Data from non-comparative observational studies or case series were presented and discussed narratively. In non-comparative studies, the therapeutic efficacy of RR (change in outcome) was considered significant if there was a significant change (p<0.05) following RR.
The overall efficacy of the RR was assessed according to the criteria recommended by the French Haute Autorit e de la sant e, 24 which is being used to evaluate the level of scientific proof. The levels of evidence were categorized into four classes, ranging from level-1 (wellpowered, randomized, comparative trials) to level-4 (comparative studies with marked biases and retrospective studies). 24

Results
The outcome of the electronic search A total of 4211 articles were retrieved from January 1, 2003, to July 31, 2021. After excluding the irrelevant (not matching the inclusion and exclusion criteria) and duplicate reports, 21-articles  were included in this review (Fig. 1).
Only comparative studies (8-articles) 25À32 were included for the quantitative meta-analysis. However, all observational studies (21articles)  were included for descriptive and qualitative analysis.

Characteristics of all included studies
Characteristics of all included studies where RR was undertaken have been presented in Table 1. Irrespective of the study design, 996 patients (21-articles) received RR. The mean age of the patients, who received RR following SARS, ranged from 37.1 to 70.5 years.
Each study used a different protocol for the RR (exercise schedule). Components of the RR used in each study have been presented in Table

Quantitative analysis (Meta-analysis) of comparative studies
In the quantitative meta-analysis, only eight comparative studies (334 participants received respiratory rehabilitation (RR), and 319 received 'No RR') were included.
The mean age of patients, who were included in the meta-analysis, were ranged from 37.1 years to 70.4 years. One-hundred thirtythree patients reported SARS secondary to SARS-CoV-1, and 461 reported SARS secondary to SARS-CoV-2.
The quality assessments (the risk of bias) of individual articles (included in the meta-analysis) have been presented in [ Table 2].
Thus, irrespective of inclusion or exclusion of the study by Qi Di et al., 31 the mean difference in 6-MWD between two groups (active intervention versus control) remained significantly in favor of the RR group.

Change in PFT parameters
The PFT parameters were reported in 4-articles. 25,26,29,31 Researchers expressed the PFT-parameter data in (% pred) and (absolute volume) values to examine the effect on PFT parameters. In 2articles, 29,31 the PFT parameters were expressed in (% pred) value, and in another two-articles, 25,26 PFT parameters were presented in absolute volume (liter). They (% pred and liter) were analyzed separately.

Change in activities of daily livings (ADLs)
To explore whether RR had an effect on ADL, the FIM scores were included. The FIM scores were reported in 2-articles. 26,31 The pooled data from these 2-studies 26,31 demonstrated that the MD of FIM scored 3.68 points (95% CI: -2.93 to 10.30), I 2 = 67%] ( Fig S3).

Adverse events
None of the studies reported any significant adverse events (falls, arrhythmia, severe hypertension, hypotension, syncope, ischaemic heart disease, cardiac arrest, and death) during or after the RR. No dropouts were reported due to intolerance or adverse events of RR.
No deaths were reported due to active intervention (RR). However, deaths were reported due to other causes (disease itself and comorbidities) from 3-studies. 28,31,32 Irrespective of causes, there was no significant difference in deaths in both groups ('RR' versus 'No RR') [relative risk: 0.73, (95% CI: 0.19 to 2.86), I 2 =39%] (Fig. S7), which indicated that intervention (RR) did not significantly increase or decrease the mortality rates among survivors.
Descriptive analysis of all included articles (comparative and noncomparative) The clinical outcomes of non-comparative studies (change in outcome parameters following RR) have been presented in Table 3.
However, irrespective of study designs, all studies (21-studies) were included to summarize the overall efficacy of the RR. The summary of the overall effectiveness, according to criteria recommended by the French Haute Autorit e de la sant e 24 of the RR, has been presented in Table 4.

Discussion
This study gives an idea of the efficacy of aerobic exercises/ aerobic training and RMT exercises among patients with SARS recovering from active disease. This is the first review article on a meta-analysis on SARS and respiratory rehabilitation (RR). The present meta-analysis suggested a beneficial effect of the RR following SARS infection, especially in terms of improvement in exercise capacity (6-MWD) and pulmonary function parameters (FVC%, FEV1(liter) and DLCO%).
It is already evident that severe acute respiratory syndrome, caused by SARS CoV-1 and SARS-CoV-2, causes significant lung damage (acute lung injury), along with the involvement of other organs. 34 Acute lung injury, multi-organ involvement, prolonged bed rest, ICU care, adverse drug effects, and residual disease pathology can cause B: The forest plot for included studies pooled together using a random-effects model for assessing the diffusing capacity of the lung for carbon monoxide (DLCO: % pred) immediately after intervention: comparison between respiratory rehabilitation (RR) (experiment) and control interventions. respiratory distress, dyspnoea, and palpitation during walking and daily functional activities. Respiratory distress during walking/ activities can cause significant impairment in exercise capacity (endurance) and PFT parameters. 34 Exercise intolerance, measured by exercise capacity, is one of the key features of acute and chronic lung diseases 9 and is associated with poor survival 46 and reduced QoL. 47 Self-paced 6-MWD is a validated tool to measure the exercise capacity following pulmonary diseases, 9,46 and it correlates with peak functional or aerobic capacity. 34, 48 Chan KS et al., 48 in their studies, reported a minimally important difference of 20À30 m in 6-MWD could be considered significant changes in exercise capacity (endurance) in patients with acute respiratory distress syndrome or acute respiratory failure. Our review found a mean difference of 45.79 m with 95% of 31.66 m to 59.92 m.
Previous Cochrane and non-Cochrane reviews demonstrated the positive effects of pulmonary rehabilitation programs on increasing exercise capacity and PFT parameters in chronic lung disease, 49À55 including chronic obstructive pulmonary disease and interstitial lung diseases. The American Thoracic Society/European Respiratory Society defined pulmonary rehabilitation as a patient-tailored, structured, comprehensive intervention that included patient assessment, exercise training, education, and behavior training as essential for pulmonary rehabilitation. 9 Pulmonary rehabilitation is usually being delivered over several weeks. During this review, we observed that many pulmonary rehabilitation program components, like education and behavioral treatment, were not instructed in many patients. In a few studies, the study duration was very short (1-week), and there was a lack of consistent, thorough assessment at baseline and followup visits. There were significant variations in the exercise or activity schedules, though the core components 9 of the pulmonary rehabilitation program-aerobic exercise/ endurance training and RMT exercises were included in all studies.
Any form of exercise (walking exercise, running, cycling, ergometer training, etc.) or physical activity (mobility training, treadmill training, etc.) that produces an increased heart rate and respiratory volume (to meet the increased oxygen demands in the activated muscles) is called aerobic exercise. 55 Respiratory muscle training comprises breathing exercises, airway clearance techniques, and strengthening exercises of respiratory muscles. Aerobic exercises/ endurance training cannot improve the pressure-generating capacity of the inspiratory muscles. 9,56,57 The RMT exercises, especially inspiratory muscle training (IMT), improve inspiratory muscle strength and endurance. 9,57 RMT can reduce dyspnoea and increase peak inspiratory flow. 9,58 Studies 59,60 on critically ill patients reported RMT is effective in persons with weaning failure (from mechanical ventilation). Respiratory muscle training effectively reduces the duration of mechanical ventilation and improves respiratory muscle function in ICU. 9,59,60 Ozyemisci T 32 and Li Lei 34 conducted RR training in an ICU set-up. Both 32,34 reported significant improvement in respiratory muscle function in patients recovering from active SARS following RR training.
Exercise intensity, duration, and frequency are essential factors for increasing the aerobic and RMT exercise capacities. 9,61 This review observed that in most studies, the activity schedule, duration, and intensity of exercises (RR) were planned according to each patient's oxygen saturation level, Borg dyspnoea score, body temperature, respiratory rates, and mental status.
The PFT parameters, FVC, and FEV1 largely depend on the status of the respiratory muscle function, lung compliance, and airway resistance. 55 In contrast, DLCO largely depends on lung parenchymal changes (blood flow and alveolar damage), provides information on the quantitive measurement of gas transfer in the lungs. 62 This metaanalysis could not show the consistent beneficial effects in all PFT parameters following RR training. The impact of RR is challenging to evaluate when disease (lung involvement) course, severity, and resolution of lung pneumonia are inconsistent/ variable in a particular disease.
Exercise training is the best available means of improving muscle function. 9 However, the exact mechanisms of improving exercise capacity and PFT parameters in the SARS population are still unclear. We speculate that aerobic exercises and RMT might have improved the respiratory muscle function, inspiratory volume, expiratory reserve capacity, and reduced airway obstruction, thereby reducing the dyspnoea, improving gas exchange and fatigue on physical activities, and increasing exercise capacity and PFT parameters in patients with SARS recovering from active disease.
The previous reviews, 9,42 conducted on acute and chronic lung diseases, reported that the pulmonary rehabilitation program, as a whole or every activity, is a safe intervention, does not cause significant adverse events or increase mortality. Similarly, we also noticed that none of the studies had reported serious adverse events (including death) during the training program. However, few transient events (pulse rate, dyspnoea, drop of saturation rate) related to exercises were reported from a few patients, especially those who were admitted to ICU.
However, a few aspects should be considered during the interpretation of this study's results. (1) This study included a large number of observational studies. Among them, few were retrospective studies (Level-4 evidence); (2) The search criteria were limited to English language articles only; (3) The number of studies in each pooled analysis was significantly less. Most of the findings were reported based two-three studies; (4) There was heterogeneity between the studies. Heterogeneity was probably due to different study designs and different patients' conditions. This review included patients with various severity of SARS-CoV diseases; (5) Respiratory rehabilitation was provided at different clinical set-ups (ICU, IPD, OPD, Home). The activities of RR were not uniform across the studies. Duration and composition of RR were different in each study; (6) This review evaluated only the short-term effect (1 to 6 weeks) of RR in SARS patients. The longterm efficacy of RR was not assessed; (7) During analysis, this study did not consider other comorbidities like myopathy, neurological disorders, or femoral head necrosis during outcomes assessment.

Conclusions
This systematic review demonstrated a positive association between respiratory rehabilitation and exercise capacity and PFT parameters in patients with SARS infection. Respiratory rehabilitation did not cause significant adverse events or increase mortality in the SARS population. Among the various program schedules, aerobic exercises and RMT could be used as important techniques to improve exercise capacity and lung function. However, additional RCT is needed comparing RR and conventional treatment to determine the best RR program/ schedule (in terms of initiation, duration, and components) and to measure the accurate treatment efficacy in COVID-19 patients at different set-ups, both for short and long duration.

Declaration of Competing Interest
In this study, there were no competing interests or financial benefits to the authors.