Post-COVID: effects of physical exercise on functional status and work ability in health care personnel

Abstract Purpose Post-COVID fatigue significantly limits recovery and return-to-work in COVID-19 survivors. We aimed to assess the effects of physical exercising on post-COVID-19-symptoms, physical/mental capacities and workability within a workplace-health-promotion project in health-care personnel. Materials and methods Thirty-two HCWs were enrolled in two groups based on Post-COVID-Functional Scale (PCFS) scores: (1) severe (SSG, n = 11) and (2) mild (MSG, n = 21) symptoms. The participants underwent an eight week exercise intervention program consisting of two supervised resistance exercise sessions per week plus individual aerobic exercise recommendations. Primary outcome-parameter for physical fitness was VO2peak. Further, physical function (6MWT, 30 s sit-to-stand test (30secSTS)), mental health (anxiety (GAD-7), depression (PHQ-9), stress (PSS-10), fatigue (BFI), resilience (BRS)), cognitive capacity (MoCA) and workability (WAI) were assessed at baseline, after 4 weeks and after completion of exercise intervention. Results VO2peak improved significantly in the SSG by 2.4 ml/kg/min (95% CI [1.48; 3.01], adj.p < 0.001) and non-significantly in the MSG by 1.27 ml/kg/min (adj.p = 0.096). Both groups significantly improved their 30secSTS (p = 0.0236) and 6MWT (p = 0.0252) outcomes in both follow-ups (4 weeks and 8 weeks after inclusion). The SSG improved more than the MSG in VO2peak and 6MWT both after 4 and 8 weeks, respectively, although not statistically significant; findings were vice versa for the 30secSTS. 30secSTS outcomes correlated significantly with mental health outcomes and workability. Conclusions Post-COVID exercise intervention improved physical fitness, psychological outcomes and workability in HCWs. Cases with severe fatigue showed higher benefit levels compared to those with mild symptoms. The safe and highly feasible 30secSTS correlated well with physical and mental outcomes and better workability in COVID-19 survivors. Implications for rehabilitation Physical exercising showed to be an effective intervention method in the rehabilitation of COVID-19 survivors suffering from post-COVID syndrome by positively affecting both physical and mental health. In health care workers suffering from post-COVID syndrome, increases in physical performance are directly related to improvements in work ability. The 30 s sit-to-stand test (30secSTS) showed promising results as clinical assessment tool. The results of this study indicate that physical exercising will need to play a large and substantial role over the next years in the rehabilitation of COVID-19 survivors suffering from post-COVID-19-syndrome as it positively affects both physical and mental dimensions of the post-COVID-19-syndrome as well as work ability.


Introduction
The SARS-CoV-2 pandemic has kept the world in suspense for two years by now. Nearly, 230 million people around the world have contracted COVID-19 to date and nearly 6 million people have died of COVID-19 by mid of February 2022 [1]. Another 405 million COVID-19 survivors are now the focus of interest in longterm follow-ups and rehabilitative care, as it is known that surviving the disease does not necessarily equal being completely cured. Over 50 different symptoms have been associated with long-haul COVID [2]. Specifically the post-COVID-19 fatigue syndrome, which is primarily associated with physical weakness, fatigue, substantially limits full recovery and return-to-work in COVID-19 survivors [3,4]. Thirty-five percent of all COVID-19 survivors [5] and 87% of COVID-19 survivors hospitalized in the course of their illness [6] suffer from after-effects that are currently summarized as post-COVID syndrome.
Due to their higher SARS-CoV-2 exposure risk, health care workers (HCWs) have a significantly increased risk of infection [4]. Therefore, and especially considering the great importance of HCWs for the maintenance of a functioning health system during this pandemic, hospital employees who are also COVID-19 survivors are of particular interest for the investigation of the effectiveness of rehabilitation interventions [7,8].
The wide range of symptoms currently associated with post-COVID is so large, that treating each symptom separately is commonly impracticable. Hence, a systemic approach should be considered in the treatment of post-COVID symptoms [9]. Physical exercise has already shown striking potential in cancer rehabilitation of various malignancies, mediated via secretion of antiinflammatory cytokines, respectively, myokines [10,11], activation of natural killer cells (NK cells) [11], or simply due to improvement of overall metabolic risk [12] and physical function [13]. Moreover, besides cancer-rehabilitation, physical exercise has been wellestablished in medical training therapy for a number of medical conditions like cardiovascular diseases [14], metabolic diseases [15], or various other chronic diseases [16]. Its health-promoting role was just recently confirmed by the increasing the former recommendations for adults of 75-150 min to 150-300 min of exercise per week [17].
Our specialized study group hypothesized that physical exercising might bear a similar treatment outcome in patients suffering from post-COVID syndrome. We therefore aimed to assess the effects of physical exercise on post-COVID-19 fatigue and other associated symptoms, by conducting an exercise intervention trial with COVID-19 surviving HCWs working at a large COVID-19 hospital in Vienna.

Participants and group allocation
Employees of the General Hospital of Vienna and the Medical University of Vienna, Austria, who had survived a COVID-19 infection were invited to take part in a health promotion program with the aim of reconditioning after a COVID-19 infection in April 2021. According to their Post-COVID-Functional Scale (PCFS) [18] outcomes, two groups were formed: participants with a score of 0 or 1 (no or negligible impairments) were allocated to the mild symptoms group (MSG) while participants with scores of �2 were allocated to the severe symptoms group (SSG) for further analysis. The participants were blinded regarding the group allocation. Inclusion criteria were employment at the General Hospital of Vienna, Austria, regardless of position and status post COVID-19 infection. Exclusion criteria were preexisting contraindications to aerobic exercise and resistance training as well as insufficient language skills.

Exercise intervention
After evaluation of cardiovascular risk factors (echocardiography, cardio pulmonary exercise testing (CPET), blood sampling) and clearance for physical exercising, all participants -independent of group allocation -attended a supervised resistance exercise (RE) group training twice per week for eight weeks, between May and July 2021. The exercise sessions took place at the Department of Physical Medicine, Rehabilitation and Occupational Medicine of the General Hospital of Vienna, Austria, hence the hospital they were employed at. The RE program was designed as a circuit training with body weight and resistance bands and consisted of eight exercises for the whole body (squats, glute bridge, hip-abductor walks, 45 � standing back extension, push-ups, low row, planking, shoulder external rotation). Any of the eight exercises could be chosen in various difficulty levels to incorporate the different fitness levels of the participants. After a short warm-up routine, the circuit training consisted of two sessions of these eight exercises and started with 30 s of exercising alternating with 30 s of rest in weeks one and two. Progression was implemented by adding 10 s of exercise and rest time every two weeks. Therefore, the participants exercised 60 s per exercise alternating with 60 s of rest in weeks seven and eight. After submaximal exercise intensity in the first two weeks (rate of perceived exertion (RPE) 7-8 on a 10-points RPE-scale at the end of each exercise set), participants were advised to choose the difficulty level that would lead to muscular fatigue at the end of each exercise (RPE 9-10) set for weeks 3-8. This per definition represents a low intensity, high repetition RE method and could also be described as resistance training at the 30-60 s repetition maximum (30-60secRM) (reference: ISBN: 9781492501626 Essentials of Strength Training and Conditioning).
For their aerobic exercise, which the participants were instructed to perform independently, participants received an activity tracker watch (Garmin Venu SQ, Garmin, Olathe, KS) with individualized exercise zones. They were advised to perform as much aerobic exercise as feasible, but at least complete three times 20 min of moderate aerobic exercise per week, and to exercise primarily at low intensities, particularly at their ventilatory threshold 1 (VT1).

Outcome measures
The present analyses took place within the scope of the larger project "COFIT", which focuses on the effects of exercise interventions on various dimensions of the post-COVID syndrome (NCT04841759 at ClinicalTrials.gov).
Here, we present primary results focusing on the effects of the exercise intervention on the performance parameters maximum oxygen uptake (VO 2 peak), the 6-min-walk-test (6MWT), and the 30 s sit-to-stand test (30secSTS) in relation to fatigue (PCFS), workability and psychological outcomes.

Primary outcome parameter
The primary outcome parameter was VO 2 peak during the cardiopulmonary exercise testing. Sample size calculation was based on an exercise intervention study of similar duration [19]. With an estimated effect size of 0.5, alpha error probability of 0.05 and power of 0.8 a priori sample size, our calculations showed the need of at least 12 participants per group. With the need for the comparison of two groups and additional anticipated 33% for dropouts, a total of N ¼ 32 participants were included in the study.

Secondary outcome parameters
With the aim of assessing physical function, the 6MWT [20] and the 30secSTS [21] were performed. COVID-19 related fatigue was assessed with the PCFS [18]. For the assessment of mental health the following questionnaires were used: anxiety was assessed with the Generalized Anxiety Disorder 7 (GAD-7) [22], depression with the Patient Health Questionnaire 9 (PHQ-9) [23], stress with the Perceived Stress Scale 10 (PSS-10) [24], and resilience with the Brief Resilience Scale (BRS) [25]. Fatigue was assessed with the Brief Fatigue Inventory (BFI) [26]. Workability was assessed with the WAI [27] and cognitive capabilities were assessed with the Montreal Cognitive Assessment (MoCA) [28].
All outcome parameters were assessed at baseline (BL), midintervention, after 4 weeks of training (follow-up 1, FU1), and after completion of the exercise intervention (follow-up 2, FU2), except for the MoCA which was assessed at the beginning and at the end of the intervention only.

Statistical analysis
Statistical analysis was conducted in GraphPad Prism (GraphPad Prism version 9.1.0 for Windows, GraphPad Software, San Diego, CA) and SPSS (IBM Corp., Released 2020, IBM SPSS Statistics for Windows, Version 27.0, Armonk, NY).
An alpha of 0.05 was assumed to constitute statistical significance. Where appropriate, confidence intervals are reported, also using alpha ¼ 0. 05. In all cases, two-sided testing is performed. Descriptive analysis included mean (metric variables) and percentiles (scores). Graphical analysis was done by employing confidence interval plots. Hypothesis testing (for difference in medians) employed Mann-Whitney's U tests, association was estimated either via Pearson's coefficient (performance parameters, PCFS, WAI) or Spearman's Rho (vs. psychological scores) and difference in distribution was tested via modified Chi-Square tests for multiple variables. Metric variables (6MWT, 30 s STS test and rel. VO2 peak) were analyzed at different follow-up periods and in different groups (MSG vs. SSG) using repeated measures mixed effects models with Geisser-Greenhouse correction for sphericity and Sidak-corrected post hoc tests. Regression analysis on ordinal measures (PCSF, WAI) was carried out using generalized ordinal mixed effects models with repeated measures.

Compliance with ethical standards
The research protocol was approved by the ethics committee of the Medical University of Vienna, Austria (EK1181/2021) and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All participants gave their informed consent prior to their inclusion in the study.

Baseline characteristics
Mean age at inclusion was 42.9 years in the mild symptom group (MSG) and 47.4 years among those with severe symptoms (SSG). In both groups, the majority of participants were female with 60.0% in the MSG and 89% in the SSG. The average time since COVID-19 diagnosis was about one month less in the SSG than in the MSG; however, none of the demographic characteristics differed significantly at BL (Table 1).

Development of performance parameters during the trial in the MSG and SSG
Repeated measures mixed effects models were used on all performance parameters between the MSG and the SSG at BL, FU1 and FU2 with Sidak-corrected post hoc analysis. As Figure 1 shows: (1) both groups significantly improved their 30 s STS and 6MWT results in both follow-ups (middle and bottom panel). (2) The SSG also improved their relative VO 2 peak and the MSG shows a tendency towards improvement (top panel). (3) In the graphical analysis of the 95% confidence intervals of from VO2 peak and the 6MWT between BL and FU1, the SSG improved more than the MSG; findings were vice versa for the 30 s STS. Intergroup differences were only statistically significant regarding the 30 s STS (p < 0.001).

The effect of performance parameters on PCFS
Correlation of performance parameters with the PCFS corrected with the Bonferroni method shows a strong association of relative VO2 peak, 30 s STS and 6MWT at all measurement periods (Table  2). This relationship is insignificant for relative VO2 peak at BL, but turns into the strongest correlation at FU1. All three performance parameters show strong and highly significant correlations with PCFS at FU2.
The ordinal logistic mixed effects model on the effect of relative VO2 peak on the PCFS of a participant passed an Omnibus test at a p < 0.001. In this model, "sex" was statistically insignificant (p < 0.165). The model estimated an odds ratio of 0.895 (p < 0.001; Wald-Chi-Square ¼ 10.229). Translated into physical units, a participant with 10 ml higher relative VO 2 peak had twice the odds of having a one point lower PCFS score.

The effect of performance parameters on workability
At BL, none of the performance parameters showed a significant correlation with workability as measured by WAI (Table 3). The most prominent association was found between WAI and the 30 s STS test, which showed a moderate to strong and statistically significant correlation with WAI at both follow-up periods. The following model is therefore estimated using 30 s STS data rather than VO2 peak. The ordinal logistic mixed effects model on the effect of 30 s STS on the probability of having a WAI of �28, controlling for sex and age passed an omnibus test at p < 0.001. While "sex" and "age" showed no significant effect on the probability of having a WAI of �28, one more repetition in the 30 s STS had an estimated odds ratio of 0.836 (p < 0.001, Wald-Chi-Square 12.45). Accordingly, a participant with 10 more repetitions has twice the odds of having a WAI of �29.

The effect of performance parameters on psychological outcomes
At all three time points (BL, FU1, FU2), 30 s STS test showed the strongest correlation of all performance parameters with results of the psychological tests in both absolute size of Spearman's rho and statistical significance of these correlations (Table 4).
At BL, the 30 s STS test showed a moderate (0.42), significant (p ¼ 0.026) Spearman's correlation with the MoCA score at BL. None of the performance scores showed statistically significant correlation with the MoCA score at FU2.
No adverse events were registered throughout the trial.  The association is measured via Pearson's correlation coefficient (column 2) with the corresponding confidence interval (column 3) and a two-tailed p value for difference from 0 (column 4). The association is measured via Pearson's correlation coefficient (column 2) with the corresponding confidence interval (column 3) and a two-tailed p value for difference from 0 (column 4).

Discussion
The results of our study show that both higher endurance capacity as well as higher muscle strength -respectively physical function -of the lower extremity muscles are related to less fatigue, i.e., better PCFS results, and improved workability, e.g., lower risk of dropping below a critical WAI score. Moreover, the 30secSTS correlates with an improvement in all psychological outcomes, except for resilience (e.g., BRS scores). How does physical exercise mediate these potent benefits? We hypothesize that the reasons lie on the one hand within the systemic effects of physical activity. Increased activity of anti-inflammatory cytokines like interleukin 6 (IL-6), interleukin 10 (IL-10), or transforming growth factor beta (TGF-b), which inhibit the production of pro-inflammatory cytokines [29,30], the activation of NK cells [31], or the modulation of the immune system [32] are well established effects of physical exercising. This fits the pathophysiology of the post-COVID-19 syndrome, which suggests dysregulation of the immune response as one of its key characteristics [9]. On the other hand, the physical and functional decline due to physical inactivity during the acute infection phase as well as the potential involvement of various organ systems (lungs, heart, kidney, liver, pancreas, and spleen) suggest that at least some of the post-COVID-19 symptoms are associated with muscle weakness [9]. Physical exercise appears to be a powerful treatment, as it both helps to increase physical performance and functionality as well as systemically promotes an anti-inflammatory state. Furthermore, it could explain why the performance parameters analysis indicates larger effects in the SSG compared to the MSG.
A noteworthy aspect of our total participant population, was that the gender ratio of 4:1 (females to males). When differentiating between symptoms severity (i.e., MSG and SSG), this ratio increased to 9:1 in the SSG while decreasing to 1:1.5 in the MSG. This indicates a higher percentage of females suffering from (more intensive) post-COVID-19 symptoms than males. This is consistent with observations in autoimmune [33] and rheumatoid diseases [34] but also fibromyalgia [35]. This would actually explain why exercise as an immune modulating and anti-inflammatory intervention shows such promising results.
Beyond the effects on performance and functionality, the exercise intervention program also showed significant effects on four of five psychological dimensions. Anxiety, depression, stress, and fatigue outcomes were significantly improved. These results are in line with earlier research on the effects of physical exercising on anxiety and depression [36], distress [37], and fatigue [38]. However, our exercise program did not show any effect on resilience scores in our participants. This might be due to the fact, that resilience, particularly in HCWs, is affected by a number of different factors besides physical fitness [39]. Furthermore, the SARS-CoV-2 pandemic -respectively the post-COVID-19-syndrome -is a completely new and complex situation to cope with and confronts HCWs with yet unmet challenges [40]. All other psychological dimensions (anxiety, depression, stress, and fatigue) not only showed significant improvement but were also associated with physical performance, particularly 30secSTS outcomes.
The 30secSTS proved to be a diagnostically conclusive tool regarding psychological health, but also workability. This is of great clinical relevance, as this functional test does neither need large financial, personal, nor time resources; it can be easily performed in the clinical routine. Moreover, the 30secSTS directly assesses physical function and appears to reflect improvement of outcome parameters concomitant to an exercise intervention program. Our results reconfirm the findings of Hameed et al. [41] who used the 30secSTS to assess the effects of a physical therapy program on physical function in SARS-CoV-2 survivors. Moreover, with its high test-retest reliability [42], the 30secSTS has been successfully used as a physical function measurement since the early 2000s [43] and is therefore well established in clinical practice.

Strengths and limitations
A study limitation is the lack of an inactive control group. As the present study was primarily devised as a workplace health promotion project, this kind of control group was impracticable. However, when considering the extent of the improvements both of physical performance as well as the post COVID functional status within all individuals, it is safe to assume that the measured improvements directly result from the exercise intervention.
Another limitation is that we were unable to analyze the home based aerobic exercise program in detail. However, step count analysis indicated similar physical activity levels in both groups.
Further, the generalization of our study results of on the general population is limited. HCWs working in hospitals can be considered as more health-aware and better educated in handling stress than the general population, due to their job characteristics including physical fitness psychological distress, and shift-work [44]. Clinical trials testing effective treatments and rehabilitation options for post COVID are ongoing and still heterogeneous [45]. Various exercise programs, already validated for other diseases, are currently applied in the context of post COVID [46]; in this context, particularly telerehabilitation appears to be a valuable tool in improving patients' functional capacity and quality of life [47].

Conclusions
When analyzing the results of our exercise intervention program, we can safely conclude that physical exercise with its effects on both endurance and strength positively affects post-COVID functional status and post-COVID associated workability in HCWs. More severe cases of post-COVID fatigue seem to benefit more compared to those with mild symptoms. Moreover, the 30secSTS presents itself as a promising easy and practicable clinical assessment tool regarding physical and mental performance, as well as predicted workability in COVID-survivors.