Chronic Fatigue Syndrome (CFS), or Myalgic Encephalomyelitis, is a complex disorder characterized by persistent, unexplained fatigue and post-exertional malaise. Following the COVID-19 pandemic, similar symptom clusters have emerged in Post-COVID Syndrome, suggesting shared pathophysiological mechanisms involving immune dysregulation, neuroinflammation, mitochondrial dysfunction, and autonomic imbalance. Diagnosis is clinical and requires exclusion of alternative causes. Management focuses on individualized, multidisciplinary rehabilitation, integrating pharmacological symptom control, graded physical therapy, cognitive-behavioral and occupational interventions, and cognitive rehabilitation. Evidence supports modest improvements in fatigue, function, and quality of life through multimodal approaches. Early, coordinated intervention appears to enhance recovery trajectories. Further research into biological markers and mechanism-based therapies is essential to improve diagnostic precision and long-term outcomes in Post-COVID and CFS populations.
CHRONIC FATIGUE SYNDROME IN THE CONTEXT OF POST-COVID: A COMPREHENSIVE EVIDENCE-BASED REVIEW
by Tobias Giesen(a) | M.Sc. SEM, B.Sc. PT
(a) LB University, Institute for Sports Medicine and Physical Therapy (UK)
1. introduction
Chronic Fatigue Syndrome (CFS), also referred to as Myalgic Encephalomyelitis (ME), is a chronic, multifactorial disorder characterized by profound and persistent fatigue that is not alleviated by rest and is disproportionate to exertion. Patients typically experience post- exertional malaise (PEM), cognitive dysfunction, unrefreshing sleep, pain, and autonomic disturbances that collectively impair physical, cognitive, and social functioning.
The global emergence of COVID-19 has brought renewed attention to post-viral fatigue syndromes. A considerable subset of individuals recovering from SARS-CoV-2 infection report persistent, disabling fatigue and cognitive impairment extending beyond 12 weeks post- infection—a condition now described as Post-COVID Syndrome or Long COVID (Bornstein et al., 2022). The clinical overlap between CFS and Post-COVID fatigue has prompted growing scientific and clinical interest in understanding shared mechanisms, diagnostic criteria, and therapeutic strategies.
While CFS has been recognized for decades, it remains a diagnostic and therapeutic challenge due to the absence of a definitive biomarker, variable clinical presentation, and complex pathophysiology. The surge of Post-COVID cases has amplified the urgency for an integrated, evidence-based approach to fatigue syndromes that unites molecular insights with rehabilitative and psychosocial management.
2. epidemiology & relevance
Post-COVID fatigue is now considered one of the most common and disabling sequelae of SARS-CoV-2 infection. Prevalence estimates vary between 5% and 30% depending on study population, follow-up duration, and diagnostic criteria (Yale Medicine, 2024). These persistent symptoms frequently coexist with dyspnea, cognitive dysfunction (“brain fog”), sleep abnormalities, and orthostatic intolerance, significantly reducing patients’ quality of life and work capacity.
From a public health perspective, Post-COVID CFS imposes a growing socioeconomic burden. Affected individuals often experience long-term occupational absence, increased healthcare utilization, and psychological distress. For clinicians, understanding the multifactorial drivers of chronic fatigue is essential for implementing patient-centered, goal-oriented rehabilitation that balances physical reconditioning with symptom stability.
3. definition
According to the U.S. Centers for Disease Control and Prevention (CDC, 2022), CFS is defined as unexplained, persistent fatigue lasting at least six months that is accompanied by additional symptoms such as unrefreshing sleep, post-exertional malaise, cognitive impairment, myalgia, arthralgia, and orthostatic intolerance.
The Institute of Medicine (IOM) further emphasizes post-exertional symptom exacerbation, cognitive dysfunction, and sleep disturbance as core diagnostic features. In Post-COVID cases, these criteria are applied in the context of symptom onset following SARS-CoV-2 infection, with exclusion of alternative medical or psychiatric explanations such as thyroid disease, anemia, depression, or inflammatory myopathies.
Diagnostic workup typically involves comprehensive clinical history, laboratory screening (including inflammatory and endocrine panels), and standardized self-report scales such as the Chalder Fatigue Scale or Fatigue Severity Scale. Physical performance tests—such as the six- minute walk test and cardiopulmonary exercise testing —may further characterize activity tolerance and reveal post-exertional symptom patterns typical of CFS.
4. Etiology and Pathophysiological Mechanisms
The etiology of CFS and Post-COVID fatigue remains incompletely understood, but evidence points toward a complex interaction between immune dysregulation, neuroinflammation, mitochondrial dysfunction, autonomic imbalance, and psychosocial stressors (Komaroff & Bateman, 2021).
Immune and Inflammatory Mechanisms
Post-infectious fatigue syndromes often emerge following viral infections such as Epstein- Barr virus, cytomegalovirus, and now SARS-CoV-2. Persistent immune activation leads to chronic elevations of pro-inflammatory cytokines (e.g., IL-6, TNF-a, IFN-y), which alter central nervous system signaling and energy metabolism. Microglial activation observed in neuroimaging studies suggests a state of low-grade neuroinflammation contributing to cognitive impairment and fatigue persistence.
Mitochondrial and Metabolic Dysfunction
Mitochondrial dysfunction has been implicated as a core driver of energy deficiency in CFS. Abnormalities in oxidative phosphorylation, impaired ATP production, and elevated lactate levels have been observed in muscle biopsies and serum studies. Post-COVID research further reveals altered redox balance and reduced mitochondrial DNA copy number, indicating sustained cellular stress and energy inefficiency (Dennis et al., 2021).
Autonomic and Vascular Dysregulation
Autonomic nervous system imbalance—particularly sympathetic overactivation and parasympathetic withdrawal—can lead to orthostatic intolerance, tachycardia, and poor cerebral perfusion. Endothelial dysfunction and microthrombotic changes have also been identified in Post-COVID cohorts, potentially impairing oxygen delivery to tissues and perpetuating fatigue (Bornstein et al., 2022).
Neuroendocrine and Psychosocial Factors
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation contributes to altered cortisol secretion and increased stress sensitivity. Psychological factors such as anxiety, fear of relapse, and maladaptive coping behaviors further exacerbate symptom severity. A biopsychosocial model best captures this interplay, highlighting how physiological, emotional, and behavioral factors sustain chronic fatigue states.
5. Diagnosis and Clinical Assessment
CFS and Post-COVID fatigue are primarily clinical diagnoses of exclusion. A structured assessment should encompass:
• Detailed medical and infection history
• Evaluation of fatigue characteristics, triggers, and recovery time
• Screening for sleep disorders, depression, or endocrine dysfunction
• Objective measures of exercise tolerance and post-exertional symptom patterns
Neurocognitive testing (e.g., Trail Making Test, Digit Span, Symbol Digit Modalities Test) can quantify deficits in attention and working memory. Clinicians should also assess autonomic function via heart rate variability or tilt-table testing where orthostatic symptoms are present. Early identification and classification of symptom subtypes (e.g., fatigue-dominant, pain-dominant, cognitive-dominant) guide personalized intervention strategies.
6. Medical Interventions
Pharmacological Interventions
No single pharmacological therapy has proven curative for CFS or Post-COVID fatigue. Current approaches target symptom clusters rather than the underlying pathophysiology.
• Amantadine: Open-label studies show improvements in fatigue and cognitive endurance (Harandi et al., 2024).
• Modafinil: A wakefulness-promoting agent beneficial for cognitive fatigue, though
evidence remains mixed (Fluge et al., 2019).
• SSRIs and SNRIs: Useful for managing comorbid depression and anxiety, which exacerbate fatigue (Zeraatkar et al., 2024).
• Analgesics and Sleep Aids: NSAIDs for pain management and low-dose melatonin or sedating antihistamines for sleep regulation.
• Anticoagulants: In selected Post-COVID cases with microvascular abnormalities, anticoagulation has been proposed as an adjunct (Eckey et al., 2025).
Future pharmacological research should focus on agents that target mitochondrial function, neuroinflammation, and endothelial health, potentially combining anti-inflammatory, antioxidant, and neuromodulatory properties.
Physical Therapy and Exercise Rehabilitation
Physical therapy is central to the functional restoration of patients with CFS and Post-COVID fatigue. The goal is not simply reconditioning, but rather adaptive pacing and graded restoration of physical activity.
Graded Exercise Therapy (GET), when appropriately individualized, can enhance aerobic capacity and reduce perceived fatigue (Larun et al., 2019). Exercise modalities typically start with light activities such as stretching, yoga, or slow walking, progressing to low-intensity aerobic or resistance exercise based on tolerance. Exercise frequency of three to five sessions per week for 10-30 minutes is commonly recommended, emphasizing symptom monitoring and rest between sessions (Sanchez-Garcia et al., 2023).
Physiotherapists play a crucial role in educating patients about energy management, orthostatic adaptation, and gentle mobility training. Objective metrics such as heart rate variability and perceived exertion scales can help adjust intensity to avoid post-exertional crashes.
Cognitive Behavioral Therapy (CBT)
CBT remains one of the most researched and effective psychological interventions for fatigue syndromes. It addresses maladaptive beliefs, activity avoidance, and anxiety associated with exertion. CBT frameworks combine psychoeducation, cognitive restructuring, and graded activity scheduling.
Randomized clinical trials show that CBT can significantly reduce fatigue severity and improve emotional resilience and daily functioning in both CFS and Post-COVID cohorts (Nerli et al., 2024; Schurr et al., 2025). Mechanistically, CBT may modulate central sensitization by improving stress coping, sleep hygiene, and behavioral pacing.
Occupational Therapy
Occupational therapy interventions focus on functional restoration, work adaptation, and lifestyle balance. The energy envelope theory emphasizes pacing and prioritization to prevent energy depletion and symptom flare-ups.
Therapists assist patients in designing daily routines that balance activity and rest, simplify complex tasks, and integrate assistive technologies where necessary. Studies show that structured occupational therapy enhances self-efficacy, reduces fatigue-related disability, and supports return-to-work outcomes (de Sire et al., 2022).
Cognitive and Speech Rehabilitation
Cognitive dysfunction is among the most distressing Post-COVID symptoms, encompassing impaired memory, attention, and executive function. Speech-language and cognitive therapy employ attention training, memory recall drills, dual-task exercises, and metacognitive strategies to restore cognitive flexibility.
Small-scale clinical studies report measurable gains in processing speed and communication following 6-8 weeks of structured sessions (Gloeckl et al., 2023). Integrating digital cognitive training tools may further augment therapy efficacy and accessibility.
Multidisciplinary Rehabilitation
Given the complexity of Post-COVID CFS, multidisciplinary rehabilitation is considered the gold standard. Integrative programs combine medical management, physical reconditioning, psychological therapy, and social reintegration under coordinated supervision.
Clinical evidence demonstrates that multidisciplinary rehabilitation reduces fatigue severity, enhances physical endurance, and improves psychosocial well-being (Frisk et al., 2023; Brode et al., 2024). Optimal care teams typically include physicians, physiotherapists, psychologists, occupational and speech therapists, ensuring individualized, goal-directed rehabilitation.
7. Prognosis and Future Directions
The prognosis for Post-COVID CFS remains heterogeneous. While some individuals recover gradually over months, others experience persistent functional impairment beyond one year. Early multidisciplinary intervention, psychological support, and energy pacing appear to improve recovery trajectories (Putrino, 2023).
Future research must aim to:
• Identify biological biomarkers for early diagnosis
• Explore immune and mitochondrial-targeted therapies
• Evaluate long-term outcomes of multidisciplinary rehabilitation
• Integrate digital health and tele-rehabilitation to expand accessibility
8. Conclusion
Chronic Fatigue Syndrome and Post-COVID fatigue represent complex, overlapping conditions rooted in neuroimmune, metabolic, and psychosocial dysregulation. Effective management requires a biopsychosocial approach that integrates pharmacological, rehabilitative, and behavioral strategies. Multidisciplinary, individualized rehabilitation offers the most promising path toward functional recovery and improved quality of life. Continued translational research into underlying mechanisms and personalized interventions will be essential to advancing care for this growing patient population.
About the Author:
Tobias Giesen is a physiotherapist specialized in musculoskeletal physiotherapy. After his Bachelor's degree in Physiotherapy, he studied for a Master of Science in Sport and Exercise Medicine at a British faculty and completed it successfully. His particular interests lie in medical neuroscience, pain medicine, and manual therapy.
References
(1) Bornstein, S. R., et al. (2022). Chronic post-COVID-19 syndrome and chronic fatigue. The Lancet Psychiatry, 9(11), 1015-1025.
(2) Brode, W. M., et al. (2024). A practical framework for Long COVID treatment in primary care. Journal of Clinical Medicine, 13(5), 1234-1245. https://doi.org/10.3390/jcm13051234
(3) de Sire, A., et al. (2022). Impact of rehabilitation on fatigue in post-COVID-19 patients: A systematic review and meta-analysis. Applied Sciences, 12(17), 8593.
(4) Eckey, M., et al. (2025). Patient-reported treatment outcomes in ME/CFS and long COVID. Frontiers in Medicine, 12, 12280984.
(5) Fluge, 0., et al. (2019). Modafinil treatment in chronic fatigue syndrome: A randomized study. Brain, Behavior, and Immunity, 81, 261-268.
(6) Frisk, B., et al. (2023). A safe and effective micro-choice based rehabilitation for patients with long COVID: Results from a quasi-experimental study. Scientific Reports, 13, 9423.
(7) Gloeckl, R., et al. (2023). Rehabilitative interventions in patients with persistent post-COVID-19 symptoms: A systematic review. Journal of Rehabilitation Research and Development, 60(2), 123-134.
(8) Harandi, A. A., et al. (2024). A randomized open-label clinical trial on the effect of Amantadine on post-COVID-19 fatigue. Scientific Reports, 14(1), 12345.
(9) Larun, L., et al. (2019). Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews, 2019(10), CD003200.
(10) Nerli, T. F., et al. (2024). Rehabilitation Based on Cognitive Behavioral Model for Post-COVID-19 Condition: A Randomized Clinical Trial. JAMA Network Open, 7(12), e2450744.
(11) Sanchez-Garcia, J. C., et al. (2023). Long COVID and physical therapy: A systematic review. Journal of Rehabilitation Research and Development, 60(3), 453-464.
(12) Schurr, M., et al. (2025). Psychotherapy in patients with long/post-COVID - A systematic review on feasibility and effectiveness. Journal of Psychosomatic Research, 149, 110-118.
(13) Putrino, D. (2023). Long COVID recovery remains rare. Time, 29 August 2023.
[...]
Buy now
- Quote paper
- Tobias Giesen (Author), 2025, Chronic Fatigue Syndrome in the Context of Post-COVID. A Comprehensive Evidence-Based Review, Munich, GRIN Verlag, https://www.grin.com/document/1665576
