Physical exercise as a treatment for persisting symptoms post-COVID infection: review of ongoing studies and prospective randomized controlled training study

Subsequent to the health problems of the acute phase of SARS-CoV-2 infection, the long-term consequences of SARS-CoV-2 infection are affecting large numbers of patients worldwide. Estimates of patients affected by persisting or new symptoms post-COVID reach from 6 to 28 percent of the infected population [1]. To date, no evidence-based treatment is available for persisting symptoms post-COVID infection. The most common symptoms post-COVID are fatigue, muscle weakness, and sleep difficulties [2]. Fatigue in particular is associated with a significantly reduced quality of life [3]. There is a strong overlap in the spectrum of the symptoms post-COVID and the chronic fatigue syndrome / myalgic encephalomyelitis, which is characterized by post-exertional fatigue and persistent symptoms related to cognitive and autonomous dysfunction [4]. Various triggers including viral infections (e.g. with the Epstein–Barr virus) are discussed for chronic fatigue syndrome [5].

The molecular mechanisms causing the symptoms post-COVID are not completely understood and are likely multi-factorial. A summary of these mechanisms is depicted in Supplemental Fig. 1. Physical exercise is well established to exert anti-inflammatory, vasculo-protective, and anti-aging effects [6‐8].

Based on the potential mechanisms contributing to the persisting symptoms post-COVID and the potential effects of physical exercise on these pathologies we hypothesized that physical training may be associated with beneficial effects for patients with persisting symptoms post-COVID. However, in addition to the assessment of potentially positive effects, it is important to establish the safety of exercise post-COVID. Physical exercise has negative effects in mice with myocarditis [9]. In athletes, myocarditis is the underlying cause of sudden cardiac death in about 10 percent of cases [10].

We, therefore, performed a systematic search of the literature for training studies in patients post-COVID to review the available information on the safety and efficacy of physical exercise for these patients. The systematic review of the literature revealed a shortage of prospective, randomized training studies and a lack of information on safety. Therefore, we designed and performed a prospective study to test the effects of supervised personalized strength endurance training for 4 weeks or usual care on safety, fatigue, and quality of life.

The study shows that physical exercise is safe in patients with persisting symptoms post-COVID. Exercise improved endurance capacity, oxygen pulse, and strength compared to control. The self-reported quality of life and fatigue improved over time in both groups. In the follow-up period, the exercise group was more active and the MFI-20 improved more than in the control group. The physical training was not associated with additional effects on questionnaires or subdomains of fatigue compared to the patients randomized to the control group.

Our systematic search of the ongoing trials investigating exercise in post-COVID patients identified 107 records. Six records were removed due to duplication in different databases. Ultimately, 15 studies were found reporting a randomized design with an exercise intervention and a control group that underwent no intervention. Most of the studies (n = 13) use a combined exercise intervention. An endurance-only intervention and a resistance-only intervention are planned in one trial each. The sample size, comparator types, blinding, and supervision of the ongoing RCTs are summarized in Supplemental Table 1. A detailed summary of the characteristics of each study can be found in Supplemental Tables 2–4. An overview of primary outcomes sorted into the groups defined by the potential mechanisms is shown in Supplemental Fig. 3. In comparison to other trials, our trial was the only one to use a supervised combined training regimen and follow-up for 5 months after the intervention ended. Although supervising exercise during an ongoing pandemic (as in our study) can be challenging, it is well established that supervised exercise yields a better result compared to unsupervised training programs [17]. Supervision also improves the safety of patients. Most studies identified by the systematic search of the literature use a combined training regimen. Combined exercise interventions target a wide spectrum of physiological dimensions of exercise capacity but conclusions about specific aspects of exercise that are effective are hard to draw. Combined exercise interventions may be more effective on submaximal exercise capacity and quality of life compared to isolated endurance exercise [18]. Therefore, a careful evaluation and studies of the effective training modality are needed to tailor a possible training intervention to the needs of patients post-COVID infection.

One major limitation compared to the other studies is the shorter duration of our training intervention.

The improvement in quality of life and fatigue post-COVID over time is supported by the literature [19]. Several potential limitations and explanations may contribute to the lack of an additional effect of physical exercise on fatigue: All training studies face a selection bias because only patients willing to participate in a training study can be randomized. These individuals may have a better prognosis reducing the additional effect of any intervention. Specifically, the subgroup of fatigue patients dominantly affected in the reduced motivation dimension of the MFI-20 may be under-represented. In our population, this dimension was the least affected.

Additionally, we found a higher daily activity in the exercise group in the follow-up period which is supportive of the under-representation of persons with reduced motivation. On the other hand, this greater activity can also be discussed as the cause of the improvement in the MFI-20 in the follow-up period.

The duration of the intervention may have been too short, however, we observed marked improvements in cardiovascular capacity in the intervention group. In one trial investigating exercise as a treatment option, the duration was 8 weeks compared to 4 weeks in our study. This study found effects in some fatigue-associated questionnaires, but the MFI-20 questionnaire was not used [19]. The sample size is too low for the identification of a subgroup potentially benefitting from exercise. However, there is no larger randomized training study in patients post-COVID published. The expected intra-group variability in physical performance, as well as fatigue symptoms at baseline, may be concealing effects. Another explanation may relate to the endpoint fatigue which is a very difficult-to-treat symptom. It is possible that the underlying pathologies of fatigue are not susceptible to physical exercise. Interestingly, fatigue does not correlate with the severity of the initial COVID infection, serum markers of inflammation or cardiovascular biomarkers, or cell turnover or echocardiographic findings [20, 21].

The symptoms post-COVID are characterized by physical fatigue, reduced activation, and impaired motivation. Our study shows that an individually planned and structured training regimen is highly effective in improving cardiovascular capacity, e.g. the maximum oxygen uptake and the oxygen pulse, in this patient population. Training effects have been consistently associated with a reduction of cardiovascular as well as all-cause mortality [22, 23].

In addition to the assessment of potentially positive effects, the safety of exercise post-COVID needs to be established. Physical exercise can promote sudden cardiac death in patients with myocarditis [24]. Sudden cardiac death has been reported in non-hospitalized patients with COVID-19 infection and mild symptoms [25]. However, dysrhythmias and cardiac arrest are rare in non-hospitalized individuals compared to hospitalized individuals with COVID-19 and also the presence of myocarditis in the athlete population post-COVID seems to be low [26]. Patients with persisting myocarditis should not be included in exercise programs according to international sport cardiology guidelines [27, 28]. Exercise aggravates myocarditis in animals [9]. Pro-arrhythmic effects of exercise in myocarditis are well established [29]. Myocarditis is a common cause of sudden cardiac death in athletes [10] and myocarditis is a frequent underlying cause of sudden cardiac death in physically active persons [30]. Our study, therefore, provides important reassurance that patients post-COVID without elevation of troponin and signs of cardiac diseases can safely perform physical exercise.

In conclusion, an individualized exercise program is a safe and well-tolerated treatment option in patients with persisting symptoms post-COVID. These patients significantly improve in physical performance after 4 weeks compared to patients without exercise intervention and these positive effects persist after the intervention ended. Exercise had no beneficial effect on fatigue symptoms or quality of life in our study. Additional results from longer or different exercise interventions on quality of life and fatigue are eagerly awaited.