Why Does Long Covid Cause Fatigue?

Written By Shannon Burford

Long COVID, a condition where symptoms persist for months or even years after a SARS-CoV-2 infection, affects millions globally, with fatigue being one of its most debilitating hallmarks. Up to 50% of Long COVID patients report extreme tiredness that disrupts daily life, work, and mental health. Why does this fatigue linger? Drawing on the latest research as of May 2025, I explore the 11 key mechanisms behind Long COVID fatigue, shedding light on this complex condition and what it means for those affected.

1. Chronic Inflammation: Immune System’s Overdrive

One of the leading culprits of Long COVID fatigue is chronic inflammation. After the initial infection, the immune system may remain in overdrive, releasing pro-inflammatory cytokines like TNF-α, IL-6, and IL-8. These molecules, meant to fight infection, can persist, draining our energy and causing exhaustion. Studies show elevated monocyte levels and low cDC1 cells in Long COVID patients, signaling ongoing immune activation that saps vitality (Frontiers in Immunology, 2024). This relentless immune response mimics chronic fatigue syndrome, leaving us feeling perpetually drained.

2. Oxidative Stress: Cellular Damage at Play

Oxidative stress, an imbalance between harmful reactive oxygen species and protective antioxidants, is another key player. I often see elevated C-reactive protein, nitric oxide, and reduced levels of zinc, selenium, and glutathione in Long COVID patients. This oxidative damage impairs our cellular function, particularly in energy-hungry tissues like muscles and the brain, leading to fatigue. Research highlights how this stress contributes to a cellular energy deficit, making even simple tasks feel monumental (Vollbracht & Kraft, 2022).

3. Microvascular Dysfunction: Starving Tissues of Oxygen

Microclots and impaired blood flow are significant contributors to Long COVID fatigue. Fibrin amyloid microclots, found in many patients, block tiny blood vessels, reducing oxygen delivery to tissues. This hypoxia causes muscle weakness and exhaustion, as our cells struggle to function without adequate oxygen. Studies like Kruger et al. (2022) show these microclots trap pro-inflammatory molecules, worsening the cycle of fatigue and systemic inflammation.

4. Mitochondrial Dysfunction: Powerhouse Failure

Mitochondria, our cells’ energy factories, are prime targets of SARS-CoV-2. The virus can disrupt mitochondrial function, reducing ATP (energy) production. This creates an “energy debt” that manifests as profound fatigue. Research, including ongoing clinical trials (ClinicalTrials.gov, NCT05152849), suggests parallels with other viral infections like Ebola, where mitochondrial damage leads to lasting tiredness. Oxidative stress further exacerbates this dysfunction, compounding our energy crisis (Wood et al., 2021).

5. Transcriptional Dysregulation: Genes Gone Awry

Persistent changes in gene expression, or transcriptional dysregulation, contribute to fatigue by altering immune and metabolic pathways. Studies show 446 genes differentially expressed 24 weeks post-infection, with upregulated alarmins like S100A8 driving immune activation. This prolonged molecular imbalance disrupts energy metabolism, leaving exhaustion even without physical exertion (Nature Communications, 2023).

6. Viral Reactivation: Old Viruses, New Problems

Long COVID can reactivate latent viruses like Epstein-Barr virus (EBV) or cytomegalovirus, which are linked to chronic fatigue syndrome. This reactivation triggers additional immune responses, further depleting energy reserves. Research by Rohrhofer et al. (2023) highlights how EBV reactivation correlates with fatigue in Long COVID, adding another layer to the condition complexity.

7. Neuroinflammation: Brain Fog and Beyond

Inflammation in our central nervous system, or neuroinflammation, contributes to both fatigue and cognitive issues like “brain fog.” This inflammation disrupts neural signaling, making mental and physical tasks exhausting. Studies (Tate et al., 2022) suggest that SARS-CoV-2’s impact on the brain creates a persistent state of neurological fatigue, affecting concentration and stamina.

8. Autonomic Dysfunction: Nervous System Out of Sync

The autonomic nervous system, which regulates heart rate, breathing, and other automatic functions, can become dysregulated in Long COVID. This leads to a state of sympathetic dominance, akin to being stuck in “fight or flight” mode, causing exhaustion. Research links this to mast cell activation and systemic inflammation, amplifying fatigue (Weinstock et al., 2021).

9. Impaired Waste Clearance: Toxic Buildup

Prolonged immune exhaustion can hinder the body’s ability to clear metabolic waste from muscles and tissues. This toxic buildup contributes to muscle fatigue and brain fog, as noted in studies (PMC, 2023). Poor waste clearance exacerbates feelings of heaviness and sluggishness, making recovery slow and challenging.

10. Sleep and Hormonal Imbalances: Disrupting Recovery

Disrupted sleep and hormonal imbalances are common in Long COVID experience, contributing to post-exertional malaise (PEM), where even mild activity triggers severe fatigue. Poor sleep quality and altered hormone levels, like cortisol, impair the body’s ability to recover, perpetuating exhaustion (Springer, 2016). These disruptions create a vicious cycle, as fatigue worsens sleep, and poor sleep intensifies fatigue.

11. Vascular and Muscle Tension Issues: Oxygen Starvation

Inflammation of the blood vessels and chronic muscle tension, often from prior injuries or lifestyle factors, can restrict oxygen delivery. This vascular dysfunction, combined with muscle tension, exacerbates fatigue by limiting tissue oxygenation. Research (Translational Medicine, 2024) suggests that these factors increase vulnerability to Long COVID’s exhausting effects.

The Road Ahead

While these 11 mechanisms explain why you may feel so fatigued with Long COVID, no single treatment fully addresses them yet. Current approaches, like rehabilitation programs and antioxidants, offer partial relief, but ongoing research is crucial for targeted therapies. Understanding these causes empowers me to advocate for better care and fuels hope for recovery.

A holistic and functional medicine approach most definitely has an important role in the successful support of patients struggling with Long covid. Take control now and schedule your appointment.

Shannon Burford
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