Psychophysiological Adaptations to Exercise Training in COVID-19 Patients: A Systematic Review.

Introduction. Many COVID-19 patients display adverse symptoms, such as reduced physical ability, poor quality of life, and impaired pulmonary function. Therefore, this systematic review is aimed at evaluating the effectiveness of physical exercise on various psychophysiological indicators among COVID-19 patients who may be at any stage of their illness (i.e., critically ill, hospitalized, postdischarge, and recovering). Methods. A systematic search was conducted in PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar from 2019 to 2021. Twenty-seven studies, which assessed a total of 1525 patients, were included and analysed. Results. Overall, data revealed significant improvements in the following parameters: physical function, dyspnoea, pulmonary function, quality of life (QOL), lower limb endurance and strength, anxiety, depression, physical activity level, muscle strength, oxygen saturation, fatigue, C-reactive protein (CRP), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α), lymphocyte, leukocytes, and a fibrin degradation product (D-dimer). Conclusions. Physical training turns out to be an effective therapy that minimises the severity of COVID-19 in the intervention group compared to the standard treatment. Therefore, physical training could be incorporated into conventional treatment of COVID-19 patients. More randomized controlled studies with follow-up evaluations are required to evaluate the long-term advantages of physical training. Future research is essential to establish the optimal exercise intensity level and assess the musculoskeletal fitness of recovered COVID-19 patients. This trial is registered with CRD42021283087.

The coronavirus disease 19 (COVID-19) is a novel infectious illness that has caused dramatic health effects and drastically impacted economic costs worldwide [[1]]. On March 11, 2020, the WHO officially declared the COVID-19 pandemic [[2]]. COVID-19 has had a massive impact and a high death rate worldwide [[3]]. To date, COVID-19 has caused 269 million cases and 5.3 million deaths across 224 countries and territories. Since the advent of the Omicron variant, daily case numbers have surged to 0.6 million with thousands of fatalities [[4]]. Furthermore, those who recovered remain partly affected by the virus. Barriers to participation in more physical activity have increased dramatically with COVID-19 [[6]]. Patients with severe COVID-19 have significant daily activity impairments and require multimodal rehabilitation with cardiovascular and pulmonary medicine expertise [[8]]. The residual impact of hospitalization length of stay and side effects of medication among recovered patients resulted in a decline in pulmonary function and cardiorespiratory deconditioning [[9]]. Furthermore, a high prevalence of anxiety and depression has been documented post-treatment as well as anxiety in families [[11]].

The COVID-19 pandemic highlights the need for postacute care in individuals with a severe disease progression. It has been reported that after being released from the acute care unit, COVID-19 patients may not be able to return to their pre-COVID-19 functional state or baseline levels of healthcare need [[12]]. Long-term consequences are anticipated, and rehabilitation medicine is challenged in recovering physical performance and improving cognitive dysfunction [[13]]. However, much evidence indicates that COVID-19 is causing long-term effects for the survivors [[14]] and postacute syndrome manifested as shortness of breath, cognitive disturbances, fatigue, chest pain, and decreased quality of life [[15]]. Thus, immobility syndrome and physical function impairment are common in post-COVID-19 patients, even in those who are only mildly affected [[17]]. However, early rehabilitation, such as mobilization, pulmonary rehabilitation, and therapeutic training, may positively impact patient recovery following COVID-19, especially in severe cases or those at risk of developing postintensive care syndrome [[18]]. Despite this, the need for postacute care, particularly rehabilitation after severe and catastrophic COVID-19 infections, is mandatory, yet it challenges the global healthcare systems [[19]].

Although survivors with severe COVID-19 have chronic weakness and cardiorespiratory failure, the availability and potential benefit of cardiopulmonary rehabilitation and physical exercise after COVID-19 are unknown [[21]]. Moreover, in the literature, there is insufficient evidence of the effect of exercise on fitness determinants, inflammatory markers, physical function, strength, body composition, and sleep quality [[22]]. Interestingly, postrehabilitation exercise programs for people affected by COVID-19 have been discussed in the global health and fitness industry [[23]–[25]]. However, most data on the benefits of rehabilitation and physical activity as long-term care in postacute patients are unclear. The development and evaluation of effective rehabilitation programs are urgently needed [[13], [26]]. Therefore, this systematic review is aimed at determining the effectiveness of physical training among COVID-19 patients on fitness determinants, pulmonary function, and quality of life.

The protocol was registered in the international database PROSPERO with the registration number CRD42021283087. Before the registration in PROSPERO, we carried out a formal screening of searches in PubMed, Scopus, ScienceDirect, Google Scholar, and Web of Science to check whether there were adequate studies related to our study or to ensure that no other systematic reviews on the same topic had been conducted, which is a requirement before the registration in PROSPERO.

The study is aimed at determining the effectiveness of physical activity on the quality of life and physical function in COVID-19 patients. The study adhered to the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P 2016). Patients were selected based on the "PICOS" (participants, interventions, comparisons, outcomes, study design) process with the criteria as follows: P (population) = COVID-19 patients; I (intervention) = physical training; C (comparison) = control; O (outcome) = improvement in physical function, QOL, CRP, IL6, and pulmonary function; and S (study design) = clinical studies.

(1) The Primary Outcomes. The primary outcome included physical function (walking distance and muscle strength), dyspnoea, and pulmonary function among critically ill, hospitalized, postdischarge, and recovering COVID-19 patients.

(2) The Secondary Outcomes. Secondary outcomes included quality of life (QOL), lower limb endurance and strength, anxiety, depression, physical activity intensity level, oxygen saturation, fatigue, C-reactive protein (CRP), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α), lymphocyte, leukocytes, and D-dimer.

Five databases, including PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar, were searched. Three independent authors (S.B.A., B.O.K., and H.A.) conducted an electronic literature search using keywords combined with the Boolean operations OR and "AND" to find relevant literature (Table 1). The search strategy involved a combination of subject terms and free words and was finalized after repeated checks. The keywords were ("physical activity $\ast$ " OR "exercise" OR "pulmonary rehabilitation" OR "telerehabilitation" OR "Respiratory rehabilitation" OR "training" OR "fitness") AND ("Covid-19" OR "SARS-CoV-2" OR "2019-nCoV").

Table 1 Search strategy.

A literature search was carried out to identify experiments that investigated the impact of exercise on COVID-19 patients published between 2019 and 2021. Three authors (S.B.A., Y.W., and H.A.) used the PICOS strategy to examine the extensive texts of the remaining papers and define the inclusion and exclusion criteria. The judgment of a fourth author (A.B.) was employed to settle disagreements.

This study involved COVID-19 patients with varying severity levels, including mild, moderate, and severe/critical cases. The study also considers the presence or absence of comorbidities and other underlying diseases, with no age limit, publications with no language limitation and with full text available, any structured physical exercise (aerobic training, resistance training, combined aerobic and resistance training, physical activity, or pulmonary rehabilitation exercise), and any relevant clinical experimental studies (RCT, pre-post study design, and non-RCT). Exclusion criteria were case reports, review articles, letters, commentaries, short communications, and studies with unclear data.

Three authors, A.A.I., A.B., and H.A., evaluated the selection and exclusion of articles based on a linear assessment of names, abstracts, and full texts (in cases of doubt). The remaining papers were evaluated entirely based on the qualifying criteria before making a final selection. This method was used independently, with the assistance of a fourth author, M.G., in the case of any conflicts or doubts.

After reading the full article, three authors (H.A., S.A.B., and M.G.) conducted independent sampling and data extraction from qualifying studies. Specifically, information on the first author, journal name, population, year of publication, gender, and type of intervention (exercise mode, duration, intensity, sets, repetition, and exercise duration), study duration, and outcome measures was extracted.

The assessment of the risk of bias was previously described [[27]]. In summary, we checked the risk of bias based on the Cochrane Handbook for Systematic Reviews of Interventions (Figures 1 and 2) [[28]].

Graph: Figure 1 Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005179.pub3/full).

Graph: Figure 2 Risk of bias summary: review authors' judgments about each risk of bias item for each included study (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005179.pub3/full).

The Cochrane Collaboration's Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence of the included studies. The GRADE system provides four levels of quality, with randomized trial evidence being the highest. It might be degraded to moderate, low, or even extremely poor-quality evidence [[29]] (Table 2).

Table 2 Summary of finding using GRADE quality assessment.

1 aThe included studies recorded a small sample size for both the control and intervention groups. bThere is considerable heterogeneity in the studies. cParticipants and assessors were not blinded. dThe assessors were not blinded. ${}^{\ast }$ Not stated. APS = a prospective interventional study; RCT = randomized control trial; PCS = pilot control clinical study; RS = retrospective study; OS = observational study; QM = a quasiexperimental repeated measure.

Figure 3 depicts the consort diagram of the study in which a total of 13,806 studies were retrieved. After identifying duplicate articles, 12,263 studies were screened for further selection. After reading the article's title and abstract, a total of 12,219 were excluded according to the inclusion and exclusion criteria. Thus, 44 articles proceeded for further selection by reading the full texts, out of which 17 were excluded. The remaining 27 articles that met the eligibility criteria were used for data extraction.

Graph: Figure 3 PRISMA flowchart for search strategy.

Table 3 summarizes the major features of the studies included in this systematic review. The studies selected were carried out in different countries during various time durations. Each of the included studies was published in a good, reputed journal. The technical characteristics were population, type of exercise, duration of the training, intensity, sets, repetition, the timing of the intervention, duration of the activity, and outcome measures.

Table 3 Characteristics of the included studies.

In the included studies, a total of 1525 patients were clinically assessed. The duration of the training was approximately one to eight weeks. In these studies, COVID-19 patients were introduced to the combination of various exercises like aerobic exercise (AE) [[30]]; motor training [[31]]; Liuzijue exercise (breathing exercise) [[32]]; telerehabilitation program [[33]]; a combination of AE, resistance training (RT), and breathing exercise (cardiopulmonary rehabilitation) [[21]]; rehabilitation program consisting of passive or active range of motion exercises [[34]]; respiratory rehabilitation programs [[12], [22], [26], [35]–[49]]; and AE and RT [[50]].

(1) Walking Distance. A significant improvement in the physical function of patients undergoing respiratory rehabilitation [[13], [22], [26], [35]–[38], [40], [42]–[45], [47]–[49]], AE and RT [[50]], and following Liuzijue exercise [[32]] was reported. Lack of significant differences was reported in physical function after AE and RT [[51]], after respiratory rehabilitation [[12]], and following AE, strength training, and breathing exercises [[21]] in COVID-19 patients.

(2) Muscle Strength. There were significant improvements in physical activity intensity levels following the respiratory rehabilitation [[43], [51]], while no significant difference following the Rb program consisting of passive or active range of motion exercises was observed [[34]].

(3) Dyspnoea. There was a significant improvement in dyspnoea in COVID-19 patients following respiratory rehabilitation [[12], [26], [36], [38], [46]], while no significant differences in dyspnoea postrespiratory rehabilitation were observed [[37], [42]].

(4) Pulmonary Function. There was a significant improvement in pulmonary function following respiratory rehabilitation [[13], [37], [40], [48]] and following Liuzijue exercise [[32]]. At the same time, few studies reported no significant difference in pulmonary function following respiratory rehabilitation [[12], [22], [35], [47]].

(1) QOL. There was a significant improvement in QOL following respiratory rehabilitation [[22], [35], [39]–[41], [43], [47]] and following the Liuzijue exercise [[32], [46]]. No significant difference in QOL was reported following the respiratory rehabilitation in COVID-19 patients [[37]] and following the Rb program consisting of passive or active range of motion exercises [[34]] and progressive muscular relaxation training [[33]].

(2) Peripheral Muscle Performance of Lower Limb. There were significant improvements in the peripheral muscle performance of the lower limb following the respiratory rehabilitation [[22], [38], [44], [47]], while one study reported no significant improvements following the respiratory rehabilitation [[48]].

(3) Anxiety. There were significant improvements in anxiety following respiratory Rb [[39]–[41]], after motor training [[31]], and following progressive muscular relaxation training [[33]].

(4) Depression. There were significant improvements in depression following respiratory Rb [[39]], after motor training [[31]], and following progressive muscular relaxation training [[33]].

(5) Physical Activity Intensity Level. There were significant improvements in physical activity levels following the respiratory rehabilitation [[38], [44]].

(6) Oxygen Saturation. There were significant improvements in oxygen saturation following the respiratory rehabilitation [[22], [26]], while no significant difference was observed following the respiratory Rb [[37]] and AE, strength training, and breathing exercise [[21]].

(7) Fatigue. There were significant improvements in fatigue following the respiratory rehabilitation [[12], [26]].

(8) CRP, IL6, and TNF-α. There was a significant improvement in CRP following respiratory rehabilitation [[26], [46]] and AE and RT [[50]]. At the same time, few studies reported no significant difference in CRP [[37], [49]], following respiratory Rb, and following passive or active range of motion exercises [[34]]. One study reported a significant reduction in IL6 and TNF after AE [[30]].

(9) Lymphocyte. There was a significant improvement in lymphocytes following respiratory rehabilitation [[46]] and AE [[30]]. There was no significant difference in lymphocytes following AE and RT [[50]], passive or active range of motion exercises [[34]], and respiratory rehabilitation [[49]].

(10) Leukocytes. There was a significant improvement in leukocytes following AE [[30]], while there was no significant difference following the respiratory rehabilitation [[37]].

(11) D-Dimer. There was a significant improvement in D-dimer following respiratory rehabilitation [[37]] and AE and RT [[50]], while no significant difference in D-dimer was observed following passive or active range of motion exercises [[34]], as well as respiratory rehabilitation [[49]].

The quality of trial evidence was mainly very low, and only a few had moderate certainty. There was a low or unclear risk of bias for most trials in most domains, and there is no evidence of selective reporting bias. In the original research and subsequent review, a lack of proper random sequence generation could lead to treatment effect bias in the original trial and the subsequent review. Very low to moderate heterogeneity was found in the studies, indicating that the overall quality of the evidence supporting this review, as determined by the GRADE method, ranges from very low to moderate quality.

For additional details, we searched many databases without language restrictions and checked all the reference lists to identify all the relevant studies. We cannot declare with absolute certainty, however, that we have identified all the articles in this field. All selected papers met all criteria for inclusion, and no bias was introduced throughout the review process. Secondary citations were verified, and each study underwent a thorough examination.

This study is aimed at determining the effectiveness of physical exercise among COVID-19 patients. The obtained review findings proved to be interesting in terms of public health, considering the impact of the epidemic period on COVID-19 patients. To the best of our knowledge, this is the first systematic review that investigated the effects of different types of physical exercise on COVID-19 patients. However, prior research examined the impacts of pulmonary rehabilitation using various study methodologies but did not encompass diverse forms of exercise intervention [[52]–[55]].

We observed significant improvements in the following parameters: physical function including walking distance and muscle strength, dyspnoea, pulmonary function, QOL, peripheral muscle performance of lower limb, anxiety, depression, physical activity level, oxygen saturation, fatigue, CRP, IL-6, TNF-α, lymphocyte, leukocytes, and D-dimer. These findings aligned with the previous studies [[53], [56]–[58]]. Interestingly, Cuenca-Zaldivar et al. [[56]] delved into the impacts of four physiotherapy interventions, namely, strength exercises, seated exercises, cardiovascular exercises, and balance and walking exercises. Their research revealed notable enhancements in physical fitness and reductions in frailty through the implementation of multicomponent exercise programs.

In the included RCTs, the results revealed significant differences in health outcomes within the intervention group. However, there was no significant difference in the control group. This could be attributed to the beneficial effects of exercise on immune function, respiratory health, and overall well-being, which might have been more pronounced among those actively engaging in physical activity.

However, the current review included different types of exercise, and some of them showed no significant improvement in physical function following AE and RT [[51]], respiratory rehabilitation [[12]], and AE, strength training, and breathing exercises [[21]] in COVID-19 patients. The use of different measures in the studies, the multivariate nature of QOL, exercise type, duration and intensity, a lack of high-quality research, or differences in study populations might all contribute to the insignificant improvement of these measures.

Despite a considerable improvement in exercise performance, mild/moderate COVID-19 patients were released with a degraded 6-minute walk distance (81% pred). In some reports, even a year after the COVID-19 acute phase, it has been shown that the 6-minute walking distance test may be markedly below typical reference values [[59]]. However, mild to severe COVID-19 patients in the same trial increased the 6-minute walking distance by 48 m, significantly above the recommended minimal significant difference of 30 m in patients with respiratory illnesses (88% of patients surpassed this threshold) [[60]]. Despite that, the patient was in a six-month post-SARS-CoV-2 infection phase, and a significant increase in six-minute walking distance within three weeks of pulmonary rehabilitation was reported. This suggests that the impact of pulmonary rehabilitation cannot be completely ruled out. It seems that referring COVID-19 patients to pulmonary rehabilitation following the illness's acute phase may enhance exercise capacity recovery. Despite this significant improvement, patients with severe/critical COVID-19 still only attained 70.5% of their anticipated 6MWD after pulmonary rehabilitation. Considering that patients' quadriceps strength returned to normal (99.6% pred) at the end of pulmonary rehabilitation, this could be connected to the enduring respiratory capacity limitations rather than to skeletal muscle weakness [[37]].

Most of our included studies showed significant improvement in dyspnoea, but few reported no significant difference in dyspnoea postrespiratory rehabilitation [[37], [42]]. The exact mechanisms underlying this low impact of respiratory rehabilitation should be investigated explicitly in dedicated studies. The low effect of respiratory rehabilitation might be due to the severity and long-term impact of COVID-19 infection or usual symptoms for far longer than expected [[61]]. The duration of the intervention should also be considered when conducting respiratory rehabilitation among COVID-19 patients. Therefore, one of our included studies reported no significant difference in dyspnoea after four weeks of intervention, but the follow-up of six weeks showed significant improvements in dyspnoea postrespiratory rehabilitation in COVID-19 patients [[47]]. A previous study reported significant improvement in dyspnoea, respiratory function, quality of life, and anxiety among the patients who participated in the study rehabilitation program [[57]].

Three months after the beginning of symptoms, 33% of COVID-19-hospitalized patients exhibit aberrant patient-reported outcome measures, with 33% reporting at least substantial impairments in critical quality domains [[62]]. However, most of our included studies showed significant improvement in QOL. At the same time, few reported no significant difference in QOL following respiratory rehabilitation in COVID-19 patients [[37]], following a passive or active range of motion exercise rehabilitation program [[34]], and following a telerehabilitation program of muscular relaxation training [[33]]. This might be due to the use of various quality-of-life scales and the variances in the type, duration, and intensity of exercise, a scarcity of high-quality research, or discrepancies in study populations [[63]]. Usually, COVID-19 patients have psychological distress [[16]]. This review showed significant improvement in anxiety and depression following physical training. Therefore, we primarily attributed these improvements to the effects of physical training, including targeted interventions concentrating on disease management and coping with COVID-19 and its aftereffects.

Some of our included studies reported no significant difference in pulmonary function following respiratory rehabilitation [[12], [22], [35], [47]]. A previous study assessed the impact of rehabilitation on 29 studies involving COVID-19 patients and showed a decrease in the severity and progression of COVID-19-related disorders and an improvement in pulmonary function and quality of life [[65]].

The most relevant limitation of our study is the inclusion of only a few randomized controlled trials. Some of the included studies consisted of COVID-19 patients without a control group due to ethical issues of withholding a known effective treatment. Another limitation of the current study was the heterogeneity of included studies, which included different types of physical training. Apart from this, there was no such limitation for the review process.

Our study showed that exercise training is a practical, feasible, and safe way to improve physical function, dyspnoea, pulmonary function, QOL, peripheral muscle performance of lower limbs, anxiety, depression, physical activity intensity level, muscle strength, oxygen saturation, fatigue, CRP, IL-6, TNF-α, lymphocytes, leukocytes, and D-dimer in COVID-19 patients. Therefore, promoting physical training early in the stage of recovery is recommended to mitigate the negative consequences of the disease. The results of this review could be considered in the context of clinical findings. Additional studies, however, are suggested to enhance the understanding of the appropriate training parameters and exercise prescriptions to enhance the physical and psychological condition of patients recovering from COVID-19.

More randomized controlled studies with follow-up evaluations are required to evaluate the long-term advantages of physical training. Future research is essential to establish the proper exercise intensity level and to assess the musculoskeletal fitness of recovered COVID-19 patients. Additionally, research on COVID-19 and other respiratory illnesses should be compiled concerning aerobic and resistance training. Finally, robust evidence based on high-quality trials and effort is required to support nonpharmaceutical intervention to enhance the health and well-being of individuals recovered from COVID-19 [[66]].

All data are available by the corresponding author upon reasonable request.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.