Chronic Phase Pathways in Long COVID and POTS - for GPs and Patients

Integrating Immune–Metabolic and Neurovascular Mechanisms in Long COVID and POTS: A Synthesis of Emerging Evidence and Clinical Observations.

Dr Graham Exelby November 2025, with translational directions from Dr Valerio Vittone.

Preface / Source Note

This paper synthesises findings from a wide body of peer-reviewed research, including recent work in Nature, Science, PNAS, JCI, Frontiers, and related journals. It integrates published evidence on hypoxia signalling, STAT3 dysregulation, RAGE–TLR4–NF-κB–CCL2 loops, and astrocyte–pericyte dysfunction with translational observations from clinical cohorts (Vittone & Exelby, 2024) and evolving data on echocardiography, amino acid profiling, and DNA mutation analyses in patients with Long COVID and POTS.

We acknowledge that aspects of these pathways remain under debate and that consensus is still developing. The purpose of this work is not to present a definitive model, but rather to provide a structured framework that links molecular mechanisms to clinical findings and highlights potential therapeutic targets for further study.

Summary

Long COVID and POTS share a chronic immune–metabolic lock-in centred on RAGE, NF-κB, STAT3, and NLRP3. These pathways reinforce one another, driving persistent inflammation, endothelial leak, and mitochondrial dysfunction. A key consequence is hypoxia and PDH blockade, which traps cells in inefficient glycolysis, causing fatigue, post-exertional malaise, and cognitive dysfunction.

The neurovascular unit is particularly affected: astrocytes and pericytes lose regulatory function, glymphatic clearance fails, and excitotoxicity emerges. Microglia remain primed, driving central sensitisation, while mast cell activation contributes to BBB strain, fibrosis, and vascular stiffness. Clinically, this manifests as multi-organ inflammation and cognitive decline in Long COVID, and orthostatic intolerance, tachycardia, and upright head pressure in POTS.

Management requires a layered approach. Foundation therapy includes H1/H2 antihistamines and LDN. Anchors such as telmisartan (immune–vascular stabilisation) and tirzepatide (metabolic reset) are potentially central. Mitochondrial support with NR, ALA, magnesium and taurine helps restore PDH activity.

Adjuncts (HBO, nattokinase, plasmapheresis, peptides) and lifestyle measures (MLT, sleep/glymphatic hygiene, pacing, diet) complete the scaffold. Symptoms reflect biology, not psychiatry, and need multi-pronged stabilisation.

Diagram 1: The Chronic Pathway of POTS and Long COVID

Source: Exelby, G 2025

Simplified explanation

1. The System Gets Stuck in “Inflammation Mode”

After the initial viral infection, the body’s immune system should settle back to normal. In Long COVID and POTS, however, a set of pathways (RAGE, NF-κB, STAT3, NLRP3) lock the system into a state of chronic low-grade inflammation. Instead of resolving, the immune system keeps firing.

2. Hypoxia and Energy Blockade

Because blood vessels and mitochondria are stressed, oxygen delivery is impaired. Energy production becomes blocked, forcing cells into “survival metabolism,” where energy is made inefficiently (glycolysis). This PDH block creates a “glycolytic trap,” leading to lactate build-up, fatigue, and post-exertional malaise.

3. Ongoing Immune Recruitment

The body keeps calling immune cells into tissues via signals like CCL2. This creates constant neuroinflammation and vascular remodelling—meaning blood vessels and nerves are repeatedly irritated and reshaped.

4. Brain and Nerve Dysfunction

• Astrocytes and Pericytes (support cells around brain vessels) lose their normal balance. This disrupts the “glymphatic” waste-clearing system and leads to upright head pressure, brain fog, and poor sleep.

• Microglia (immune cells in the brain) stay “primed,” causing central sensitisation, pain, and mood changes.

• Mast cells leak small amounts of chemicals, straining the blood–brain barrier and worsening symptoms.

  
  

5. Lock-in of Chronic Damage

• The inflammasome (NLRP3) keeps producing inflammatory messengers (IL-1β, IL-18), which perpetuate immune attack.

• STAT3 and NF-κB act like “master switches” keeping the system stuck in autoimmunity, fibrosis, and even cancer risk.

  
  

6. What This Means Clinically

• In Long COVID: widespread multi-organ inflammation, fatigue, brain fog, autoimmunity risk, and clotting abnormalities.

• In POTS: preload failure and venous congestion add to this loop, leading to poor brain blood flow, tachycardia, upright head pressure, dizziness, and fatigue.

  
  

7. Therapeutic Principles

Therapies are experimental and chosen according to phenotype; these represent possible avenues rather than prescriptive treatment protocols.  The goal is to unlock the system by:

• Calming the inflammatory loops (telmisartan, LDN, antihistamines).

• Restoring energy metabolism (NR, ALA, Mg).

• Supporting vascular and glymphatic function (MLT, sleep strategies, positional care).

• Anchoring metabolic reset (tirzepatide in selected phenotypes).

In short: the body gets stuck in a self-perpetuating cycle of inflammation, poor oxygen use, and vascular/brain dysfunction. This explains why patients feel exhausted, foggy, and unwell for months to years, and why both Long COVID and POTS share so many features.

Discussion

In both Long COVID and POTS, the body remains trapped in a state of immune–metabolic lock-in. What begins as an appropriate antiviral response fails to switch off, leaving a persistent loop involving RAGE, NF-κB, STAT3, and the NLRP3 inflammasome. These molecular switches reinforce one another, driving endothelial leak, mitochondrial stress, and neurovascular strain.

A major feature of this loop is hypoxia and metabolic blockade. In POTS, preload failure and venous congestion reduce brain blood flow. In Long COVID, microvascular inflammation impairs oxygen delivery. In both cases, cells shift into inefficient glycolysis. This so-called “glycolytic trap” arises because PDH is switched off by HIF-1α and PDK activation. The result is energy starvation, lactate accumulation, and the familiar pattern of fatigue and post-exertional malaise.

The neurovascular unit (NVU) is central to the clinical picture. Astrocytes and pericytes lose their normal regulatory role: aquaporin-4 polarity is disturbed, glymphatic clearance falters, and glutamate excitotoxicity emerges. Microglia remain primed in a state of heightened sensitivity, contributing to central sensitisation, chronic pain, and mood-cognitive symptoms. At the same time, mast cells release small amounts of mediators that strain the blood–brain barrier, worsen inflammation, and, through enzymes like collagenase, promote fibrosis and vascular stiffness.

Clinically, these mechanisms manifest differently but are closely related. In Long COVID, the result is multi-organ inflammation, autoimmunity, clotting abnormalities, and cognitive decline. In POTS, the same pathways amplify orthostatic intolerance, tachycardia, upright head pressure, dizziness, and brain fog. Both conditions reflect the same biological trap—only expressed through different systemic vulnerabilities.

From a management perspective, therapy must be layered rather than singular. Immune stabilisation with H1/H2 antihistamines and low-dose naltrexone provides a foundation. Telmisartan is potentially a key anchor, dampening RAGE and supporting endothelium and pericytes, while tirzepatide may offer systemic metabolic reset in selected patients. Nicotinamide riboside, alpha-lipoic acid, magnesium and taurine help restore mitochondrial metabolism and PDH function.

Adjuncts such as hyperbaric oxygen, nattokinase, plasmapheresis, and investigational peptides may be required in refractory cases. Finally, lifestyle measures—in POTS, electrolytes, stockings, manual lymphatic therapy, sleep and glymphatic hygiene, exercise pacing, and dietary control of AGEs, histamine, or glutamate—complete the framework.

The key point for GPs is that persistent symptoms in Long COVID and POTS are not psychiatric but arise from this chronic immune–metabolic lock-in. Recognising the underlying biology allows a more structured, multi-pronged approach, rather than symptomatic trial-and-error.  Persistent symptoms in Long COVID and POTS arise from chronic immune–metabolic lock-in. These are biological disorders, not psychiatric, and require layered, multi-pronged stabilisation strategies.

Table 1 Comparison POTS and Long COVID in chronic pathways

Pathway/ Driver	Shared Mechanisms	Long COVID	POTS
Hypoxia & PDH Dysfunction	Hypoxia and blocked PDH lead to reliance on inefficient glycolysis, causing fatigue and PEM	Systemic hypoxia from microvascular inflammation, mitochondrial exhaustion, PDH inhibition; drives PEM and fatigue	Cerebral hypoperfusion from preload failure, venous congestion, impaired oxygen delivery; PDH inhibition central to fatigue
RAGE–NF-κB–STAT3 Loop	Sustains chronic inflammation, fibrosis, vascular stress, and immune suppression	Sustains chronic inflammation, fibrosis, immune suppression; links to malignancy and autoimmunity	Drives vascular leak, autonomic plexus stress, orthostatic intolerance, upright head pressure
CCL2/CCR2 Chemotaxis	Persistent immune recruitment fuels neuroinflammation and vascular remodelling	Chronic immune recruitment driving multi-organ inflammation and vascular remodelling	Immune traffic contributes to autonomic nerve sensitisation and vascular tone abnormalities
Astrocyte–Pericyte Dysfunction	NVU instability leads to glymphatic failure, excitotoxicity, and cognitive dysfunction	Contributes to glymphatic failure, brain fog, upright head pressure, cognitive decline	Loss of AQP4 polarity and pericyte detachment worsen upright cognitive dysfunction, sensory hypersensitivity
Mast Cell-Glia Axis	Mast cell activation adds to BBB leak, fibrosis, and chronic symptom flares	Mast cell degranulation amplifies neuroinflammation, allergic responses, BBB leak	Low-grade mast cell activity produces orthostatic vasodilation, fibrosis, symptom flares
NLRP3 Inflammasome	Pyroptosis perpetuates autoimmunity, fibrosis, chronic pain, and neurodegeneration	Pyroptosis promotes autoimmunity, fibrosis, neurodegeneration, chronic pain	IL-1β/IL-18 perpetuate neuroinflammation, dysautonomia, autoimmunity in POTS subtypes
Key Activators	Viral infection, immune priming, metabolic stress, mechanical triggers	Viral persistence (SARS-CoV-2, EBV), spike protein, AGE burden, metabolic dysfunction, immune priming	Viral triggers (COVID, EBV), trauma (neck, T8 rotation, thoracic outlet, jugular/azygous obstruction), pregnancy/ECM shifts, mould, vaccination

Long COVID and POTS share an underlying immune–metabolic lock-in. These are biological, not psychiatric conditions, and require multi-pronged stabilisation strategies.