key: cord-0750098-6zfeeuy3
authors: Gloeckl, Rainer; Leitl, Daniela; Jarosch, Inga; Schneeberger, Tessa; Nell, Christoph; Stenzel, Nikola; Vogelmeier, Claus F.; Kenn, Klaus; Koczulla, Andreas R.
title: Benefits of pulmonary rehabilitation in COVID-19 – a prospective observational cohort study
date: 2021-03-11
journal: ERJ Open Res
DOI: 10.1183/23120541.00108-2021
sha: b88b884a958d67a4f806869e85ee365c84ddaa67
doc_id: 750098
cord_uid: 6zfeeuy3

BACKGROUND: The new Corona-Virus disease (COVID-19) can result in a large variety of chronic health issues like impaired lung function, reduced exercise performance, and diminished quality of life. Our study aimed to investigate the efficacy, feasibility, and safety of pulmonary rehabilitation (PR) in COVID-19 patients and to compare outcomes between patients with a mild/moderate and a severe/critical course of the disease. METHODS: Patients in the post-acute phase of a mild to critical course of COVID-19 admitted to a comprehensive three-week inpatient PR were included in this prospective, observational cohort study. Several measures of exercise performance (6-minute walk distance, 6MWD), lung function (forced vital capacity, FVC), and quality of life (36 question short-form health survey, SF-36) were assessed before and after PR. RESULTS: Fifty patients were included in the study (24 with mild/moderate and 26 with severe/critical COVID-19). On admission, patients had a reduced 6MWD (mild: 509 m [426–539]; severe: 344 m [244–392]), an impaired FVC (mild: 80% [59–91]; severe: 75% [60–91]) and a low SF-36 mental health score (mild: 49 pts [37–54]; severe: 39 pts [30–53]). Patients attended a median of 100% [94–100] of all provided PR sessions. At discharge, patients in both subgroups improved in 6MWD (mild/moderate: +48 m [35–113 m]; severe/critical: +124 m [75–145 m], both p<0.001), FVC (mild/moderate: +7.7% [1.0–17.8], p=0.002; severe/critical: +11.3% [1.0–16.9], p<0.001) and SF-36 mental component (mild/moderate +5.6 pts [1.4–9.2], p=0.071; severe/critical: +14.4 pts [−0.6–24.5], p<0.001). No adverse event was observed. CONCLUSION: Our study shows that PR is a feasible, safe, and effective therapeutic option in COVID-19 patients independent of disease severity.

Disease severity in coronavirus disease 2019 can be very heterogeneous. Forty percent of COVID-19 subjects develop mild disease (defined as symptomatic patients without evidence of viral pneumonia or hypoxia), another 40% have a moderate disease (with clinical signs of pneumonia).

Approximately 15% suffer from a severe disease (with severe pneumonia) that requires oxygen therapy and 5% develop a critical disease with complications such as respiratory failure, acute respiratory distress syndrome, thromboembolism, sepsis, and/or multiorgan failure [1, 2] . Older age, smoking, and pre-existing comorbidities have been reported to be risk factors for a more severe course of COVID-19 and an increased mortality [3, 4] .

Even two to three months after being "cured" from the severe acute respiratory syndrome corona virus type 2 (SARS-CoV-2) infection many patients are still affected with chronic, clinically relevant sequelae. Frequently reported health issues are a new illness-related fatigue (53 to 87%), breathlessness (43 to 71%), or neuropsychological impairments (47%) with a high prevalence of psychological disorders like increased levels of stress, anxiety, and depression [5] [6] [7] [8] . According to recent NICE guidelines, signs and symptoms of COVID-19 from 4 to 12 weeks after the onset of first symptoms are defined as "ongoing symptomatic COVID-19" [9] whereas COVID-19 sequelae that last longer than 12 weeks are summarized in terms like "long-COVID" or "post-COVID-19 syndrome" [9, 10] . The latter are typically more pronounced in patients that needed treatment on an intensive care unit (ICU) compared to ward patients [5] .

Based on the individual deficits in COVID-19 patients, comprehensive and multidisciplinary rehabilitation like pulmonary rehabilitation (PR) should be offered with attention for improving respiratory, physical, and psychological impairments, as suggested by various international expert groups [11] [12] [13] . Carda et al. suggested to provide PR treatment based on the content that is usually recommended in lung fibrosis since COVID-19 can also induce a restrictive lung disease [14] .

So far, only few retrospective data and case series on PR in COVID-19 have been published. Therefore, the aim of our study was to prospectively investigate the efficacy, feasibility, and safety of PR in COVID-19 patients and to compare differences in PR outcomes between patients with a mild/moderate and a severe/critical course of the disease.

COVID-19 patients with persistent impairments following their SARS-CoV-2 infection were referred to PR from the hospital (severe/critical or by their general practitioner (mild/moderate COVID- 19) . Patients admitted to a comprehensive, inpatient PR program at the Schoen Klinik Berchtesgadener Land (Schoenau am Koenigssee, Germany) were screened for eligibility to participate in this prospective, observational cohort study. Patients were recruited between November 2020 and January 2021. This study was submitted to the Clinical Trials Registry (www.clinicaltrials.gov, NCT04649918) and approved by the Ethics Committee of the Philipps-University of Marburg (approval number: 85/20). This manuscript was written according to the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) guideline.

Inclusion criteria were as follows: (a) patients in the post-acute phase of mild, moderate, severe or critical COVID-19 as defined by the world health organization [2] and (b) an obtained written informed consent. Patients unable to walk were excluded from the study.

Patients participated in a three-week comprehensive multimodal and multidisciplinary inpatient PR.

The PR program for COVID-19 patients was based on the PR content for patients with lung fibrosis (as suggested by Carda et al. [14] ) and is described in detail in panel 1. 

Exercise performance

The 6-minute walk test (6-MWT) was the primary outcome of this study. One 6MWT was performed on admission and one at discharge of PR, respectively [15] .Thirty meters is regarded as the threshold of the minimal important difference (MID) [15] .

Additionally, the following comprehensive exercise testing was performed only in the subgroup of patients with severe/critical COVID-19 to assess the complexity of severe/critical COVID-19 in more

detail.

An endurance shuttle walk test (ESWT) was performed at 85% of the maximum walking speed derived from an incremental shuttle walk test [15] . Both tests were performed on a consecutive day following the 6MWT. Physiological parameters like oxygen saturation (SpO 2 ) and heart rate were measured continuously by Sentec Digital Monitor (SenTec AG, Therwil, Switzerland). Breathing frequency was assessed by Apnea Link (ResMed, Martinsried, Germany). To compare physiological changes after PR at an equal level of exercise performance, these outcomes were analysed at baseline and ESWT isotime (= end of the shortest ESWT).

Maximum isometric knee extension force at 90° knee angle (MicroFET 2 dynamometer) and handgrip force (JAMAR hand dynamometer) were assessed by dynamometry using the best out of three tests [16] . A five-repetition sit-to-stand test was performed from a 46 cm height chair with arms crossed in front of the chest [17] and the frailty phenotype was assessed by the Fried Frailty Index [18] .

Bodyplethysmography was performed in all patients to measure forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), total lung capacity (TLC), and diffusion lung capacity for carbon monoxide (DLCO). Capillary blood gas samples to assess the partial oxygen pressure (PaO 2 ) and partial carbon dioxide pressure (PaCO 2 ) were taken at rest, breathing ambient air.

The subjective effect of breathlessness on daily activities was assessed with the modified Medical

Research Council (mMRC) [19] . -The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment (score of <26 out of a maximum of 30 points) [22] .

Due to a lack of data we did not perform an a priori sample size calculation. However, a post-hoc power calculation based on the mean and standard deviation of the improvements in the primary outcome (6MWD) showed an effect size of 1.21 for the group of 24 mild/moderate COVID-19 patients and an effect size of 1.75 for the severe/critical COVID-19 group to analyze the changes in exercise performance.

Results are presented as median and interquartile range. 

Fifty out of 58 eligible patients were included in the study. Eight patients were excluded due to the following reasons: three were too weak to perform a walk test, one refused to participate, one had language difficulties, one was isolated due to a multi-resistant infection and two had other reasons. Figure S3 ). [23] . Searching the PubMed library with the terms "pulmonary rehabilitation" AND "COVID-19" on February 7 th , 2021 yielded that only four studies have investigated the effects of PR in COVID-19 patients so far. Two studies were case series reports describing seven [24] and three [25] cases of COVID-19 PR. One study was conducted as a randomized, controlled trial in 72 patients with a severe acute course of COVID-19 [26] . However, this study provided home-based respiratory muscle training as the main content and should therefore not be considered as PR which is defined as a much more comprehensive intervention according to the current ATS/ERS PR statement [27] . Only Hermann et al. investigated the effects of a comprehensive inpatient PR similar to ours by retrospectively analyzing data from 28 patients with severe/critical COVID-19 [28] . In line with our findings, they concluded that PR following COVID-19 was effective to improve physical performance and subjective health status in these patients with severe disease.

1.0 [-1.0-2.5] 0.19 End-6MWT dyspnea, Borg scale 4 [3-5] 4 [2-6] 0 [-1-1] 5 [4-6] 5 [3-6] 0 [-2-1] 0.83 General O 2 -therapy at rest, n (%) 0 (0%) 0 (0%) 0 5 (19%) 3 (11%) -2 § (-7%) 0.16 O 2 -therapy during exertion, n (%) 0 (0%) 0 (0%) 0 8 (31%) 7 (27%) -1 § (-4%) 0.33

In our study, not only patients with severe/critical COVID-19 suffered from persistent physical impairments, but also patients with a mild/moderate course of the disease. Despite significantly improving exercise performance, mild/moderate COVID-19 patients were still discharged with an impaired 6MWD (81% predicted). From experiences with SARS-CoV-1, it is known that the 6MWD could remain significantly lower compared to normal reference values even one-year after the acute SARS-CoV-1 infection phase [29] . However, mild/moderate COVID-19 patients in our study improved 6MWD by 48m what is clearly beyond the suggested MID of 30m in patients with respiratory diseases (88% of patients exceeded this threshold) [15] . Even though a certain natural recovery effect cannot be ruled out, we suggest that these improvements seem to be related to the impact of PR because patients reached this significant increase in 6MWD only within three weeks of PR, although their acute SARS-CoV-2 infection phase was already six months ago. Furthermore, a recent study by Daher et al. in patients with severe COVID-19 has shown, that exercise performance is still severely impaired six weeks after hospital discharge in patients who did not perform a PR (6MWD median 380m) [30] . This implies a slow natural recovery in severe COVID-19 patients following hospitalization. Severe/critical Up to now, it is not clear whether COVID-19 will leave permanent lung damage and, if so, to what extent [12] . In our study, COVID-19 patients showed a restrictive lung function pattern, a severely impaired gas exchange and an increased breathing rate during exertion.

Although lung function, gas exchange, and breathing frequency improved significantly following PR, patients were discharged with a persistent impaired respiratory function. From a 2005 study in 97 SARS-CoV-1 survivors, it is known that 24% had persistent reduced lung diffusion compared to healthy control subjects even at a one-year follow-up [29] . Furthermore, 28% to 62% of SARS-CoV-1 survivors exhibited decreased lung function and increased lung fibrosis [32] . Currently, there is some evidence that suggests that the development of a fibrotic lung disease as an outcome of COIVD-19 is also a serious concern [33, 34] . Since our study was not randomized and does not contain a COVID-19 control group without PR we would like to draw an indirect comparison by using a group of idiopathic pulmonary fibrosis (IPF) patients from a former study of our working group where the same outcome measures were assessed [35] . This IPF comparison group did not perform PR and had a comparable impairment in lung function (see online supplementary material table S1 and S2).

However, at PR admission, COVID-19 patients with a severe/critical course showed even a significantly lower 6MWD and mental health summary score compared to IPF patients. COVID-19

patients were able to improve all mentioned outcomes following PR whereas IPF patients in our non-PR comparison group did not change in any of these outcomes at a two months follow-up assessment. In the lack of a COVID-19 non-PR control group, this comparison to non-PR IPF patients may give a further clue that PR in COVID-19 is beneficial beyond the natural recovery. However, although COVID-19 patients had a restrictive lung function pattern, this comparison must be interpreted with caution, since COVID-19 is an acute damage, whereas IPF is a chronic progressing disease.

About 75% of hospitalized COVID-19 patients show abnormal patient-reported outcome measures three months after symptom onset, with 33% of patients reporting at least moderate impairments in major dimensions of quality of life [36] . Consistently, patients in our study also showed impairments in physical and mental quality of life. Notably, these patients in our study with severe/critical COVID-19

course experienced even a significantly lower mental quality of life than a comparison group of IPFpatients (table S1). Within our subsample of severe/critical COVID-19 patients, 58% showed at least mild depression and 38% at least mild anxiety symptoms. Notably, this group showed much more psychological distress than comparable cohorts of severe/critical COVID-19 three months after symptom onset (24% mood-impairment) [36] or six months after symptom onset (32% anxiety or depression) [31] . We found that mental quality of life and depression improved significantly in patients with severe/critical COVID-19 (although 35% of patients were still reporting at least mild depression symptoms after PR). We acknowledge that these effects could also be interpreted as spontaneous remission. However, the patients´ symptom onset in our cohort was two months ago. Therefore, we attribute these improvements mainly to the impact of the PR program, which also included specific interventions focusing on disease management as well as on coping with COVID-19 and its sequelae.

Interestingly, PR was not associated with a change in the number of patients reporting at least mild anxiety symptoms. However, patients' anxiety scores increased slightly but significantly. Potentially, patients only began during PR to reflect on daily life challenges as a result of their COVID-19 disease.

Specifically, the increasing focus on day-to-day functioning along with patients' awareness of their persistent impairments (e.g. in cognitive function) may have resulted in higher anxiety scores. Of course, this finding needs replication before further interpretation. However, a potential area for future research could be that PR and possible interventions that take place after PR, should monitor and focus on patients´ disease-specific-and future related anxieties and help, to cope with their ongoing impairments after PR.

The most relevant limitation of our study is the absence of a randomized COVID-19 control group which was not possible due to ethical issues. However, the known COVID-19 sequelae from other studies without PR, the comparison to a non-PR group of IPF patients, and the large gains that mild/moderate COVID-19 patients reached during three weeks of PR (even six months after their acute SARS-CoV-2 infection) suggest, that these benefits are more related to PR rather than to only a natural convalescence. A second limitation of our study might be a specific selection bias because mainly COVID-19 patients with a focus on lung disease were referred to our PR program. However, it is known that there are COVID-19 patients in which neural, cardiac, renal, gastrointestinal, or coagulative disorders dominate [37] . This limits the generalizability of our findings. A third limitation might be that we did not perform a practice 6MWT.

A strength of our study is the inclusion of patients with the full spectrum of disease severity and the collection of a comprehensive data set that provides an important insight into the benefits of PR in COVID-19 patients.

Our study shows that PR is effective, feasible, and safe to improve exercise performance, lung function, and quality of life in patients with persistent impairments due to a mild to critical course of COVID-19. Further randomized controlled trials including follow-up assessments are needed to assess PR long-term benefits. 

This study was funded by own resources of the study centre (Schoen Klinik Berchtesgadener Land, Schoenau am Koenigssee, Germany) and did not receive any external funding.

All authors declare no competing interests.

A pseudonymized dataset will be made available upon reasonable request to the corresponding author. The request must include a statistical analysis plan. 

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We thank Daniel Felde (University of Giessen, Germany) for supporting data collection.

The comparison group consisted of 17 IPF patients that were recruited for a randomized, controlled trial, investigating the benefits of pulmonary rehabilitation. These 17 patients belonged to the control group and received usual care (without pulmonary rehabilitation).Results from this study were recently published by our working group (Jarosch et al. J Clin Med 2020; 9, 1567). COVID-19 patients in the current study showed restrictive lung pattern similar to patients with chronic fibrotic lung diseases. Since the current study was not a randomized, controlled trial we draw an indirect comparison by using these IPF patients as a non-PR comparison group.Description of baseline characteristics can be found in table S1. Furthermore, a comparison of changes following 3-weeks of rehabilitation in COVID-19 patients versus the outcomes of usual care in IPF patients after 2 months can be found in table S2.