Integrated Immune and Metabolic Dysfunction in POTS and Long COVID

• Mechanistic Framework for Clinical Understanding

• Dr Graham Exelby May 2025

Overview:POTS and Long COVID share a complex clinical phenotype marked by fatigue, orthostatic intolerance, neurocognitive dysfunction, and multisystem sensitization. Increasing evidence supports a unifying model based on immune–metabolic dysfunction: chronic immune activation and neuroinflammation disrupt cellular energy production, redox balance, and autonomic stability.

Immune Dysregulation:

• TLR4 and RAGE activation in response to viral debris, extracellular DNA, and oxidative stress maintains low-grade inflammation.

• NF-κB and STAT3 signalling amplify cytokine expression (IL-6, TNF-α, CCL2), which sustains microglial priming, endothelial activation, and mast cell reactivity.

• Persistent antigen presentation or latent viral reactivation (e.g., EBV, HHV-6) may perpetuate the immune loop.

• Mast cell activation contributes to vasodilation, histamine overload, and neuroimmune cross-talk.

Metabolic Consequences:

• Pyruvate dehydrogenase (PDH) inhibition from inflammation, oxidative stress, and low NAD⁺ shunts metabolism toward anaerobic glycolysis.

• Mitochondrial dysfunction reduces ATP output, elevates lactate, and depletes buffering capacity.

• NAD⁺ depletion impairs sirtuin activity, DNA repair, and redox resilience.

• Malate–aspartate shuttle dysfunction in low-aspartate states leads to poor mitochondrial metabolite handling.

• CoQ10, magnesium, and carnitine deficiency impair electron transport chain efficiency and membrane stability.

Neuroimmune-Metabolic Looping:

Mitochondrial failure → increased ROS → activates TLR4/RAGE → further inflammation.- Microglial activation → excitotoxicity (↑glutamate, ↓GABA) → central sensitization.- Dysautonomia → poor cerebral perfusion → exacerbates neuroinflammation and energy deficits.

Mast cell–glial–endothelial interaction amplifies symptom response to minor stressors.

Clinical Implications:

• Patients often show low urinary aspartate, GABA, lysine, and ethanolamine with elevated glutamate

• Symptom clusters include PEM, sensory overload, brain fog, and orthostatic tachycardia.

• Interventions should target both immune stabilization and metabolic recovery: 

  • LDN, telmisartan, quercetin – immune modulation    • Nicotinamide riboside/NMN, ALA, carnitine, CoQ10 - mitochondrial repair   

• B-complex, magnesium, taurine – membrane and redox buffering

Summary:

POTS and Long COVID are not isolated syndromes but represent a failure of immune–metabolic homeostasis. Chronic inflammation, neuroimmune sensitization, and mitochondrial compromise drive a self-reinforcing loop. Integrated treatment requires targeting both arms of this dysfunction to restore energy availability, autonomic tone, and immune tolerance.