A Review Article on Exercise Intolerance in Long COVID: Unmasking the Causes and Optimizing Treatment Strategies

Background

VIRUS-RELATED MECHANISM OF THE PATHOPHYSIOLOGY OF ME/CFS:

Of particular interest for this article is the symptomatic manifestation of decreased physical capacity following the acute COVID-19 phase, which has been associated with virus-induced physiological effects, such as pulmonary dysfunction and physical inactivity as consequences of environmental restrictions such as quarantine, social distancing, and isolation. Current research furthermore indicates that the observed intolerance to physical activity in PASC patients is strongly connected to musculoskeletal symptoms, chronic fatigue syndrome (CFS), or so-called myalgic encephalomyelitis (ME) [8]. Chronic fatigue (ME/CFS) is a persistent feeling of tiredness that lasts for more than 6 months and cannot be relieved by rest or sleep, and is a common symptom after recovery from an acute illness [10].

Although many people consider long-lasting fatigue a common and inevitable symptom of their busy lives or a stress response, studies demonstrate increased fatigue syndrome symptoms associated with post-COVID syndrome [1,2,11–19].

The cause of chronic fatigue after COVID-19 has yet to be fully understood. However, it may underly various mechanisms related to the enduring effects of inflammation in the body and weakening of the immune system. While ME/CFS can also be caused by long-term exposure to factors such as anxiety, depression, or insomnia, infections are among the most common triggers [20].

While almost all viral infections can lead to post-viral fatigue, studies have attributed the state of prolonged exhaustion mainly to acute systemic infections, such as viral, bacterial, or protozoal pathogens, including Epstein-Barr virus (EBV), dengue virus, chikungunya virus, Ebola virus, Coxiella burnetii (the cause of Q fever), and Giardia lamblia or Candida [21]. The spontaneous course of persistent fatigue is often slow. In patients overcoming acute infection, it tends to be a common and often debilitating symptom that can persist for up to 6 months following the acute phase and longer in 10–35% of adolescents or adults [11]. Patients often cannot report the last time they felt energetic or well. Such profound exhaustion usually develops over time, making it difficult to pinpoint when it started [22].

IMPORTANCE OF TREATMENT STRATEGIES:

In clinical and research settings, it is crucial to delineate the nature of symptoms and specific difficulties to reach a reliable diagnosis of the underlying causes. For example, the subjective experience of fatigue, like somatic pain, could also be an automated mental construction according to the patient’s underlying brain processes incorporating subjective perception, emotions, and cognition [23].

Notably, according to the estimates used in the USA, Komaroff and Bateman (2021) have predicted that the number of new cases of ME/CFS is expected to increase globally and exceed 10 million patients [17]. Accepting that PASC has overlapping clinical features and symptomatology with ME/CFS, it can be anticipated that incorporating existing knowledge on ME/CFS will benefit post-COVID treatment [24].

Post-COVID-Associated Intolerance to Physical Activity

SYMPTOMOLOGY OF INTOLERANCE TO PHYSICAL ACTIVITY:

Symptoms of intolerance to physical activity (IFA) overlap those of PEM. Similar to ME/CFS, symptoms such as reduced daily activity, malaise after exertion, and prevalent feelings of fatigue or intolerance to physical activity (IFA) commonly manifest in patients with COVID-19 [18]. The inability to return to the same activity level as before the illness is one of the first indicators of a long-term problem, and accompanying symptoms such as chronic fatigue, pain, and malaise often develop gradually. A significant proportion of patients report that even a minor physical activity attempt leads to significant worsening of fatigue and other symptoms. These patients report coping by resting or avoiding physical activity [10]. The prognosis of different groups of patients with ME/CFS varies, and patients often experience alternating periods of remission and relapse.

PATHOPHYSIOLOGY OF INTOLERANCE TO PHYSICAL ACTIVITY:

Interestingly, studies have identified frequent EBV reactivation during the acute phase of patients hospitalized with COVID-19. This is important since EBV infection, similar to SARS-CoV-2, is accompanied by long-lasting and reoccurring episodes of fatigue [27].

A significant factor impacting the duration and course of the disease is the time spent in bed during hospitalization, often in combination with perceived levels of family stress and subjective psychological difficulties. Furthermore, during the first months after recovery from the acute phase of infectious mononucleosis, adolescents more severely limited by fever and a more challenging course of illness were more prone to develop ME/CFS [15]. Nevertheless, the prognosis of CFS in adolescents appears to be better than that of adults. A study showed that adolescents who met the CFS criteria 6 months after overcoming the disease could perform physical activity to the same extent as the recovered control group. However, more significant differences emerged in autonomic symptomatology, analytics involving cytokine biomarkers, and psychological risk factors [28].

The growing body of research on post-acute sequelae of SARS-CoV-2 recognizes this syndrome as one of the possible triggers of exercise intolerance. A cohort study of patients with a confirmed positive PCR COVID-19 test result examined the prevalence of various PASC symptoms using the metabolic equivalent score (MET) for exercise tolerance. The results demonstrated that a significant proportion of patients in the study group suffered from exertional dyspnea of varying degrees. Fatigue, shortness of breath, and anxiety were also frequently reported in the acute post-COVID phase, up to 12 weeks after the illness. In the chronic grade of PASC, over more than 12 weeks, fatigue was the most common symptom [29].

Regarding the mechanisms underlying IFA, cardiac and peripheral autonomic dysregulation appears to create a vicious cycle of altered exercise capacity in PASC patients. In a study of COVID-19-recovered patients with no cardiopulmonary sequelae of the disease, the sample showed a significant reduction in peak CO2 from peripheral but not central cardiac limits and an exaggerated hyperventilation response during exercise [30]. However, the study did not report individuals’ baseline physical activity levels or physiological states before COVID-19. Therefore, these results must be interpreted with caution. According to the results of a systematic review, 41% of patients with acute lung injury had reduced aerobic capacity 3 months after the disease. Feelings of weakness in this group persisted in 14% of COVID-19 patients for twelve months and likely contributed to their reduced daily activity. It remains to be explored whether cardiac abnormalities contribute to exercise intolerance [31]. Other research findings suggest that according to laboratory and clinical parameters, the prothrombotic state persists in PASC patients, suggesting that a hypercoagulable state in these patients also endures. The latter may be associated with endothelial dysfunction and microthrombi in the capillary blood flow in large muscles, causing oxygen capacity reduction during exercise and leading to anaerobic respiration and fatigue [32].

Significantly, symptoms of IFA also overlap with symptoms of cognitive decline or chronic stress, including anxiety, depression, and loss of physical fitness during illness and social isolation [12].

THE ROLE OF A COMPLEX INTERVENTION IN PASC-RELATED SYMPTOMS:

When a patient manifests symptoms of post-COVID fatigue and IFA, it is essential to consider possible comorbidities that might interfere with their condition. The diagnostic process, therefore, requires an interdisciplinary and holistic approach. The proposed treatment plan for energy management may include a gradual return to exercise, an appropriate diet, or other individualized interventions. Although the pathogenesis of ME/CFS has been linked to many fundamental processes, including immune dysregulation, hyperinflammatory states, oxidative stress, and autoimmunity, the etiology of PASC is likely to be more complex, and research in this area is still ongoing. However, as in ME/CFS, inflammatory states and dysregulated immune responses play a significant role in PASC pathology, suggesting that treatments tailored to ME/CFS may be effective. Hence, a therapeutic plan considering patients’ activity thresholds and implementing daily energy expenditure management to support a healthy lifestyle may reduce symptom recurrence [24].

Potential Mechanisms Underlying Post-COVID-Associated Fatigue

OXIDATIVE STRESS:

One line of evidence suggests that as in patients with ME/CFS, abnormal mitochondrial function and oxidative stress can be caused by inflammation and the production of pro-inflammatory cytokines in patients with PASC. Oxidative stress is associated with ME/CFS by decreased levels of antioxidants and increased oxidative damage. A study of ME/CFS patients that observed their post-exertional condition suggested excessive production of reactive oxygen species (ROS), classified as free radicals. This was confirmed by detecting an alteration between resting states of oxidants and antioxidants in the patients’ blood and associated muscle fatigue symptoms [33]. Another study suggested that ME/CFS results from a chronically activated immune response related to oxidative stress, and stress-induced hyperglycemia was correlated with a pro-inflammatory immune response and ROS production [34].

Mitochondrial myopathy in patients with exercise intolerance in ME/CFS involved increased reliance on anaerobic metabolism, increased production of free radicals, or decreased oxygen extraction [35]. As in ME/CFS, the exact mechanism may be involved in patients after COVID-19 recovery exhibiting symptoms similar to those associated with chronic fatigue syndrome. Several recent studies have suggested that the severity of SARS-CoV-2 is associated with a “cytokine storm”, an uncontrolled cytokine cascade produced by the immunity system of the host after the invasion of viral particles [36]. It has been demonstrated that the energy metabolism and oxidative processes in the mitochondria influence the response of innate and adaptive immunity to SARS-CoV-2. Acute inflammation, oxidative stress, elevated interleukin-6 (IL-6) levels, and tumor necrosis factor alpha (TNFα) have been consistently reported in patients affected by SARS-CoV-2. Therefore, it is hypothesized that disrupted mitochondrial function and mitochondrial mutations, which contribute to muscle degeneration, fatigue, and metabolic changes, lead to immune cell failure and the severity of COVID-19 disease [12].

ALTERED ENERGY METABOLISM:

Astin et al (2023) reviewed physiological changes that underly post-COVID conditions and discussed their similarities with ME/CFS. They concluded that the shared pathophysiological mechanisms might include dysregulated energy metabolism, exercise-induced plasma metabolome alterations, dysbiosis, and immune cell dysfunction [37].

According to current evidence, exercise intolerance in post-COVID patients is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests of volitional exertion, showing higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di-, and tri carboxylates (eg, pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine), and taurine. The result indicates an altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism, consistent with mitochondrial dysfunction during exercise [38].

Results from energy metabolism research in patients with chronic fatigue show that cultured skeletal muscle cells are limited in utilizing carbohydrates during exercise. Moreover, the inability of CFS patients’ cells to use glucose oxidation to the same extent as healthy controls’ cells results in decreased mitochondrial respiration at both basal and maximal levels, which may partly explain why CFS patients suffer from post-exertional malaise. The fact that CFS skeletal muscle cells can utilize galactose and fatty acids to the same extent as healthy controls suggests that the dysfunction is localized between the steps of glycolysis and the TCA cycle [39].

GUT MICROBIOME DYSBIOSIS:

Alterations in the gut microbiome have been linked to neurocognitive disorders. In addition, research shows a correlation between the microbiome’s state, the immune system’s functionality, and the pathology of ME/CFS [40]. Increased gut permeability leads to the translocation of bacteria and, as a result, to microbial fermentation products, directly and indirectly affecting various cells, their mitochondria, local and systemic metabolism, and thus, systemic immunity [41].

The consequences of gut microbiome alterations due to SARS-CoV-2 may also include detrimental effects on systemic immunity and the gut environment [42]. Disrupted microbiota of the host favors dissemination of opportunistic microorganisms, including Candida [21], which may prevent the gut microbiome from restoring a healthy balance after COVID-19. The microbiome of COVID-19 patients was characterized by significantly reduced diversity of gut bacteria, depletion of beneficial and commensal bacteria, and expansion of microbial diversity by opportunistic pathogens such as Clostridium, Actinomyces viscosus, and Bacteroides [43].

Research on the gut microbiota provides an opportunity to fully understand its role in the host immune response in the context of SARS-CoV-2 infection. In addition, understanding the effects of changes in the gut microbiota on the pathophysiology of post-COVID infection should be a target for further development of innovative therapies, such as psychobiotics [13].

Therapeutic Approaches

PHYSICAL ACTIVITY:

Existing research provides strong evidence across 29 ethnic groups that obesity and high body mass index (BMI) are significant risk factors for more severe COVID-19 outcomes [45]. In addition to dietary habits, physical activity prevents obesity and supports immune functioning and overall physical and mental health. Physical exercise also mediates the bidirectional relationship between the gut and the brain through changes in the microbiome. These changes include, for example, increased numbers of serotonin-producing bacterial strains, which may cause a reduction in stress-related symptoms such as anxiety and depression [46]. Physical activity improves physical fitness, immune health, and quality of life in ME/CFS patients [47].

Conversely, loss of independence and physical inactivity due to PASC symptoms have been associated with mental health symptoms such as depression [48]. A sample of individuals who increased or maintained their physical activity levels during the lockdown of the COVID-19 pandemic reported better mental health scores compared to a group that did not keep their physical activity levels. Lower physical activity levels were also correlated with increased anxiety levels in the study group [49]. A systematic review of longitudinal studies with university students during the COVID-19 pandemic concluded that lifestyle changes, including increased sedentary behaviors, time spent studying individually, internet use, and decreased physical activity levels, are significant risk factors in students’ mental health status [50]. Physical activity and exercise also promote the regulation of neurotransmitters such as dopamine, norepinephrine, and serotonin, which can support brain health, mitochondrial biogenesis, stronger psychological resilience [51], and a positive relationship with oneself [52].

An appropriate form of physical activity can reduce the risk of infectious diseases by reducing systemic inflammation [53]. Thus, regular exercise could contribute to healthy immune system functioning. Research further shows that relapses in ME/CFS patients can be partially induced by excessive exercise and other physical or mental activity that causes stress [54]. Some infections can trigger inflammation in the patient’s body, causing muscle weakness or pain, which may prevent physical activity engagement. Physical activity and exercise depend on the balance between oxygen supply, oxygen consumption, and the ability to eliminate toxic metabolites. These processes depend on the cardiovascular and respiratory systems for optimal exercise performance. Pneumonia, sepsis, and respiratory infections, such as COVID-19 disease, can cause damage to the lungs and other body organs, triggering a cascade of exercise intolerance symptoms in patients [30].

Thus, a gradual return to physical activity can reduce inflammatory markers, encourage overall fitness, and reduce the patient’s fatigue. This approach could include a combination of cardio exercise, weight training, and stretching exercises, depending on the patient’s ability and condition [18].

Future research should aim to provide a better understanding of the risks and associations concerning chronic fatigue and limited physical activity, thereby preventing chronic fatigue syndrome symptoms in COVID-19 patients. In addition, developing individualized exercise and physical activity programs could mitigate the negative health consequences of physical inactivity.

REDOX-BASED SUPPLEMENTATION:

Antioxidant supplementation can help regulate oxidative stress in ME/CFS patients, promoting quality of life in individuals suffering from PASC. CoQ10 is an essential lipid-soluble antioxidant that reduces reactive oxygen species (ROS). There is evidence of a significant correlation between increased CoQ10 concentration and reductions in oxidative stress and fatigue [32,47]. In addition, low CoQ10 levels have been linked to reductions in oxidative stress in ME/CFS patients [14].

In a non-randomized clinical trial, Cash et al investigated the effects of anhydrous enol oxaloacetate (AEO) capsules in ME/CFS patients and patients with chronic fatigue after SARS-CoV-2 infection with improvements in fatigue from baseline after adding 500 and 1000 mg of AEO over 6 weeks [55]. The positive effects of oxaloacetate include mitochondrial biogenesis activation, which leads to mitochondrial growth and increased mitochondrial density. In addition, oxaloacetate is a potent antioxidant that protects mitochondrial DNA from damage [56].

Glutathione is an important antioxidant that plays a role in reducing inflammation and protecting cells from impairment. Compared to an uninfected control group, COVID-19 patients are severely deficient in glutathione, with increased oxidative stress and oxidative damage in all age groups [57]. Supplementation with a combination of glycine and N-acetylcysteine, a glutathione precursor, is highly effective in correcting glutathione deficiency, thus reducing oxidative stress in HIV patients [57]. An identical form of therapy could improve similar deficiencies manifested in patients with COVID-19.

Other small studies reported ubiquinol, cysteamine, sulforaphane, nicotinamide, melatonin, selenium, vitamin C, vitamin D, vitamin E, melatonin plus pentoxifylline, disulfiram, ebselen, or corticosteroids as potential treatments targeting the redox balance [58].

Omega-3 fatty acids have anti-inflammatory and antioxidant properties and have been associated with many positive health effects, including reducing the risk of heart disease [59]. In addition, several studies suggested that omega-3 fatty acids are an essential nutrient that should be supplemented when treating symptoms of depression [60], anxiety [61], or chronic fatigue [62], and omega-3 PUFAs and/or their biologically active metabolites have beneficial effects on immunity, inflammation, oxidative stress, and psychoneuroimmunity in various stages of SARS-CoV-2 infection [63]. They can also promote clearance of chronic inflammation and restore tissue homeostasis, thus offering a promising strategy for PASC patients [64].

PULMONARY REHABILITATION:

Contreras-Briceño et al proposed pulmonary rehabilitation with movement training focused on aerobic exercise ECC (eccentric contractions characterized by the lengthening of the muscle during its muscular contraction) as an alternative to conventional pulmonary rehabilitation with CONC (concentric contractions where muscle groups shorten). However, traditional CONC programs can increase cardiopulmonary workload in patients, thus inducing higher ventilation, worsening dyspnea, and increasing oxidative stress. Hence, traditional CONC may affect central pathophysiological mechanisms involved in developing functional limitations in patients with moderate to severe damage associated with SARS-CoV-2 infection and subsequent prolonged hospital stay [65]. On the contrary, evidence suggests that ECC is a well-tolerated exercise that increases muscle mass gain without significant cardiopulmonary stress, thereby improving the functional capacity of the musculoskeletal system [66].

OTHER POTENTIAL THERAPEUTIC APPROACHES:

Apart from symptom-relief medication, recent progress in pharmacological treatment targets specific molecular or cellular disorders associated with ME/CFS, focusing on autoantibodies, immune dysregulation, and mitochondrial dysfunction. This approach also included medications affecting particular proteins involved in either the initiation or development of ME/CFS symptoms.

Oxygen therapy can help improve breathing and reduce fatigue in severe oxygen deprivation. Therefore, hyperbaric oxygen therapy (HBOT) has been investigated as a potential treatment for chronic fatigue [67], including ME/CFS [68]. Beneficial effects include reduced fatigue and pain, improved cognitive function, increased energy levels, improved fitness and physical performance, and positive changes in the patient’s overall quality of life. Furthermore, HBOT is a promising treatment option for post-acute sequelae of SARS-CoV-2 [69]. In addition, HBOT in PASC patients is suggested to alleviate psychiatric symptoms (depression, anxiety, and somatization), pain interference symptoms, and fatigue levels [70].

Cognitive behavioral therapy (CBT) for patients with PASC aims to identify levels of psychological distress and reduce dysfunctional beliefs, emotions, and behaviors, thereby alleviating patients’ symptoms of psychological distress [71]. However, a reanalysis of CBT studies of ME/CFS patients reported that CBT did not lead to objective improvements in physical performance or restore their ability to work [72].

Among mind-body practices, meditation is an effective concomitant treatment for post-viral symptoms of ME/CFS. Meditation can help PASC patients by balancing pro-inflammatory and anti-inflammatory effects and reducing excessive sympathetic activation by triggering a relaxation response. Positive immunomodulatory impacts have also been reported [73].

Molecular hydrogen therapy has demonstrated efficacy in the treatment of COVID-19. Research shows that regular 14-day inhalation of molecular hydrogen (H2) positively affects physical and respiratory functions in patients with SARS-CoV-2 infection [74]. Molecular H2 can suppress inflammatory cytokines, induce cytoprotective heat shock proteins, and improve mitochondrial bioenergetics. The existing research reports no evidence of molecular H2 toxic effects, even at very high levels [75].

Furthermore, there is evidence of the positive effects of EECP (enhanced external counterpulsation) in PASC patients who showed improvements in fatigue, shortness of breath, brain fog, and overall quality of life. Sathyamoorthy et al suggested including EECP treatment based on evidence that post-acute sequelae of SARS-CoV-2 appear as a disease of endothelial dysfunction and endothelins, as in patients with angina pectoris, where EECP has led to improvements in markers associated with morbidity [76].

Electromagnetic therapy promises to improve numerous health problems, particularly multiple sclerosis. Pulsed electromagnetic field (PEMF) therapy directs small amounts of energy toward a specific part of the body, penetrating body tissue via a specialized magnetic device. PEMF has been used to treat acute and chronic pain by reducing inflammation. In addition, this therapy has recently been successfully applied to manage post-acute sequelae of SARS-CoV-2. However, more clinical sham-controlled studies are needed to evaluate this [77].

Photobiomodulation is another promising approach for treating patients with PASC. It has been shown to reduce inflammation levels and promote control of exacerbated responses caused by SARS-CoV-2 in the lungs. In addition, this treatment has been beneficial for patients with systemic disorders due to its action at the cellular and mitochondrial level [78] and in preventing thrombosis [79]. Photobiomodulation can support rehabilitation and appears to be a suitable method for controlling a severe disease course. Nevertheless, research evidence regarding the effects of this treatment in SARS-CoV-2 infection is limited, which offers future directions for clinical trials.

Future Directions

Various biochemical mechanisms have been proposed to explain the body’s energy depletion, including increased levels of oxidative stress and microbial dysbiosis, but further research is needed to understand this condition better and develop effective treatment strategies.

Several therapeutic approaches have been proposed to treat PASC symptoms, including malaise after exertion or IFA. Lifestyle interventions such as exercise and diet modifications may benefit patients with PASC. These approaches should be tailored to individual patients and their specific symptoms to help stabilize patients’ energy levels during rehabilitation and to promote recovery.

Conclusions

Intolerance to physical activity is a commonly reported symptom of PASC. This limiting condition prevents individuals from engaging in physical activity or exercise due to persistent symptoms or complications after overcoming an infectious disease. These symptoms include fatigue, shortness of breath, chest pain, and muscle weakness. A growing body of research suggests that individuals who recovered from COVID-19 tend to have reduced exercise capacity, muscle weakness, increased levels of inflammation, and oxidative stress compared to a healthy control group, which may present essential factors contributing to intolerance to physical activity. A predisposing suboptimal mitochondrial phenotype resulting from comorbidity, age, and/or previous poor lifestyle leads to reduced mitochondrial function and health status disruptions. Research suggests that a previously suboptimal or virus-altered mitochondrial function could contribute to morbidity in SARS-CoV-2 infection. Therefore, improving mitochondrial health could be vital in preventing and treating patients with PASC. Approaches such as restricting caloric intake, incorporating appropriate physical activity, regular antioxidant supplementation, or photobiomodulation therapy are possible forms of treatment that suppress inflammatory pathways or promote antioxidant processes and may positively impact homeostasis in these patients [80].