Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating multi-system disease affecting an estimated 17–24 million people in the USA and 0.3–2.8% of the global population. It is characterized by:

• Post-Exertional Malaise (PEM): The pathological hallmark — worsening of symptoms 24-72h after physical or cognitive exertion
• Profound fatigue: Not relieved by rest, unrelated to activity level
• Cognitive impairment ("brain fog"): Memory deficits, processing speed reduction
• Autonomic dysfunction: POTS, orthostatic intolerance, reduced HRV
• Unrefreshing sleep: Altered REM/Stage 3 architecture
• Pain: Central sensitization, myalgia, headache

The disease frequently follows viral infections (EBV, HHV-6, SARS-CoV-2, enteroviruses), establishing it as a post-infectious syndrome with persistent immune activation and metabolic dysregulation.

Viral persistence / Immune activation
    ↓
IFN-γ ↑ (Th1/NK)
    ↓
PDK1 ↑ (Pyruvate Dehydrogenase Kinase 1)
    ↓
PDH ↓ (Pyruvate Dehydrogenase — phosphorylated/inhibited)
    ↓
Pyruvate → Lactate (instead of Acetyl-CoA → TCA cycle)
    ↓
↓ NADH → ↓ Complex I → ↓ ATP synthesis
    ↓
ATP Deficit → Fatigue + PEM (anaerobic threshold ↓)

This "Warburg-like" metabolic shift in immune/muscle cells was confirmed by:

• Fluge et al. (2017) JCI Insight: metabolic profiling
• Naviaux et al. (2016) PNAS: CDe metabolomics
• Tomas et al. (2017) PNAS: metabolite profiling

1. Triggering Events & Viral Persistence — EBV, HHV-6, SARS-CoV-2, enteroviruses, latent reservoir
2. Innate Immune Activation — TLR3/4/7/9, cGAS-STING, IRF3, NLRP3 inflammasome, NK cells, macrophages
3. Adaptive Immune Dysregulation — T cell exhaustion, B cell dysfunction, autoantibodies (β2AR, M1R)
4. Cytokine Network — IL-6, TNF-α, IFN-γ, TGF-β, CXCL10, cytokine dysregulation
5. Mast Cell Activation (MCAS) — MC degranulation, tryptase, histamine, leukotrienes, prostaglandins
6. HPA Axis & Neuroendocrine — CRH, ACTH, hypocortisolism, GR resistance, circadian disruption
7. Autonomic Nervous System — POTS, orthostatic intolerance, HRV reduction, RAAS, small fiber neuropathy
8. Mitochondrial Dysfunction — PDH/PDK1, Complex I-IV, ROS, ATP deficit, NAD+ pool, PGC-1α
9. Neuroinflammation & CNS — Microglial activation, TSPO, BBB disruption, central sensitization, kynurenine pathway
10. Post-Exertional Malaise (PEM) — Anaerobic threshold ↓, Day-2 CPET, immune flare, metabolic collapse
11. Clinical Endpoints & Biomarkers — FSS, SF-36, CPET VO2max, NK cytotoxicity, morning cortisol, HRV RMSSD
12. Drug PK/PD — LDN, Pyridostigmine, Rituximab, BC007, NAD+ precursors, Rintatolimod, Aripiprazole, IVIG

1. Patient Profile — Disease overview, radar chart, symptom burden timeline, pathophysiology table
2. PK Profiles — LDN, Pyridostigmine, Rituximab, NAD+ pool kinetics
3. Immune & Cytokines — IL-6, TNF-α, IFN-γ, NK cells, T cell exhaustion, autoantibodies, MCAS
4. Mitochondria & Energy — PDH activity, ATP state, ROS, metabolic cascade visualization
5. Neuroinflammation/CNS — NI index, cognitive function, HPA axis, ANS, kynurenine pathway
6. Clinical Endpoints — FSS fatigue score, PEM sensitivity, HRV, cortisol, outcome table at 6 months
7. Scenario Comparison — Multi-treatment comparison with fatigue, ATP, NI, PEM outcomes
8. Biomarker Dashboard — Bar chart vs. healthy reference, drug target table, response heatmap

See mecfs_references.md for 62 PubMed-cited references organized by:

• Foundational & Epidemiology (6 refs)
• Viral Triggers & Pathogen Persistence (5 refs)
• Immune Dysregulation (6 refs)
• Autoantibodies & Autonomic Dysfunction (5 refs)
• Mitochondrial Dysfunction & Energy Metabolism (7 refs)
• Neuroinflammation & CNS (6 refs)
• HPA Axis & Neuroendocrine (3 refs)
• Post-Exertional Malaise (4 refs)
• MCAS & Mast Cells (3 refs)
• Pharmacological Treatments (9 refs)
• QSP & Systems Biology (7 refs)

Date: 2026-06-28 | QSP Library — ME/CFS Model