Therapeutic Interventions in Long COVID: Phase-Specific Strategies for Family Physicians

Author: Based on original work by Dr Graham Exelby, with contributions from Dr Valerio Vittone (PhD) Date: September 05, 2025

Purpose: This summary adapts the complex therapeutic proposals for Long COVID for family physicians, who often manage these multisystem cases across specialties. It provides a broad, understandable overview of the 3-phase model, symptoms, and practical interventions, emphasizing early recognition and multidisciplinary approaches to support primary care.

Family physicians are generally tasked with treating Long COVID, but are ill-equipped with the knowledge of how.   It crosses multiple specialty areas, making the family physician the key person to manage these.   The interventions in the acute phase, despite not well-known have been effectively proven.   The use of other medication remains research-orientated, and their use carefully weighed up against patient risk.

Abstract

Long COVID is a progressive condition involving ongoing inflammation, low oxygen (hypoxia), and metabolic changes, not just post-viral fatigue. This paper outlines a 3-phase model: acute (inflammation storm), transition (ongoing stress), and chronic (hypoxia and scarring). Key drivers include overlapping pathways (e.g., STAT3, CCL2, RAGE, NLRP3) creating self-sustaining cycles.

Proposed treatments target phases: tirzepatide for metabolism/fibrosis, telmisartan for blood flow/inflammation, peptides for repair. Adjuncts like antihistamines, low-dose naltrexone (LDN), hyperbaric oxygen (HBOT), and manual lymphatic therapy (MLT) support. Genetics (e.g., mutations in CCL2, PEMT, APO E4) may guide personalization.

For family physicians: View Long COVID as treatable with staged strategies. Use symptoms and simple tests for phasing. This shifts from symptom relief to breaking cycles, potentially preventing long-term issues like organ damage.

Introduction

Long COVID impacts millions with symptoms like extreme fatigue, PEM (worsening after activity), brain fog, heart rate instability (dysautonomia), stiff tissues, and head pressure. It's not random—it's a phased disorder from initial immune overdrive to chronic hypoxia and scarring, overlapping with POTS, ME/CFS, and fibromyalgia.

The 3-phase model:

1. Acute: Cytokine storm, mast cell activation, vessel leaks.

2. Transition: Persistent inflammation, mitochondrial (energy) issues, early brain drainage problems.

3. Chronic: Low oxygen drives inefficient energy use, inflammation loops, fibrosis (scarring).

These are fuelled by redundant hubs (e.g., STAT3/CCL2 for inflammation, HIF-1α for hypoxia, NLRP3 inflammasome as amplifier). Single treatments fail due to backups; need combined approaches.

For physicians: Patients may present across phases—acute resolves quickly, chronic is harder. Genetics (e.g., inflammation-prone mutations) explain variability. Urgency: Untreated risks neurodegeneration or increased malignancy.

Early Phase: Inflammation-Driven Response

Mechanisms: Virus triggers immune sensors (TLRs), releasing cytokines (IL-6, TNF-α) and histamine from mast cells, causing leaks and brain inflammation. Symptoms: Fatigue, fog (early signs).

Treatments:

• Antivirals first (e.g., Paxlovid if acute).

• Adjuncts:

  • Metformin: Cuts Long COVID risk ~40% if started early; reduces virus/inflammation.

  • H1 blockers (e.g., fexofenadine, cetirizine): Calm mast cells, may block virus entry.

  • Famotidine (H2 blocker): Reduces signalling.

  • LDN: Blocks TLR4, lowers cytokines, modulates glia.

Physician tip: Effective in mild/early cases; loses impact later. Screen post-COVID patients at 4 weeks; combine with rest/hydration.   Both H1 and H2 blockers (famotidine only) usually need twice daily usage.   Watch for QT prolongation, add magnesium to reduce risks.

Transition Phase: Chronic Inflammation and Metabolic Stress

Mechanisms: Cytokines persist (IL-6, CCL2), causing mitochondrial fatigue and early brain waste buildup. Shift to harder state with hypoxia hints.

Therapeutic Strategies (target STAT3/CCL2/RAGE):

• Nicotinamide riboside (NR): Boosts energy (NAD+), improves mitochondrial function

• Magnesium: Supports energy, calms nerves.

• Alpha-lipoic acid (ALA): Antioxidant, energy restore.

• Fenofibrate: Lipid/inflammation modulator; not for acute, Omega 3 if not severe

• Dapagliflozin (SGLT2 inhibitor): Reduces fluid retention, aids clearance, metabolism; useful with metabolic issues.

• Vitamin C and Iron (Fe): Vitamin C and iron play a supportive but important role in Long COVID management. Together they act as cofactors for enzymes that help break down HIF-1α, the key protein that drives hypoxia and fatigue when it builds up. Vitamin C keeps iron in its active form, while iron itself is needed for proper enzyme activity. Without them, low oxygen signalling becomes “locked on,” worsening tissue scarring and energy problems. Patients with low stores of either nutrient may benefit from replacement—Vitamin C (oral or IV in selected cases) and iron (guided by ferritin and transferrin saturation)—to help stabilise connective tissue, support energy metabolism, and improve the effect of other treatments. These are not disease-modifying on their own, but correcting deficiencies can make anchor therapies (like telmisartan or tirzepatide) more effective.

Physician tip: For patients 1-3 months post-infection with lingering fatigue. Check blood sugar/lipids; consider if overlapping diabetes.   Persistent elevation D-Dimer may respond to Nattokinase and Fenofibrate (research still- see original paper)

Chronic Phase: RAGE-Driven Disease

Mechanisms: Hypoxia stabilizes HIF-1α, upregulating RAGE/TLR4, shifting to inefficient energy (glycolysis), lactate buildup, fibrosis. NLRP3 inflammasome central (releases IL-1β/IL-18); others like AIM2/NLRC4 may contribute. Loops cause PEM, scarring, risks (e.g., cancer).

Amplifiers: Persistent damage signals, succinate, oxidative stress.

Therapeutic Targets:

• Tirzepatide: Shifts metabolism, reduces inflammation/fibrosis; emerging for fatigue/fog.

• Telmisartan: Improves brain flow, anti-inflammatory; crosses BBB.

Adjuncts:

• Fenofibrate: Antifibrotic, aids clots; combine with nattokinase/nigella sativa if clots suspected.

• High-purity omega-3s (EPA/DHA with polyphenols/vitamin D3): Balance ratios, reduce inflammation; safer long-term alternative to fenofibrate.

• Manual lymphatic therapy: Boosts brain/lymph drainage, reduces metabolites.  Strong evidence of fascial changes causing lymphatic dysfunction

• HBOT: Oxygenates tissues, suppresses HIF-1α; improves fatigue/fog.

• Plasmapheresis: Removes mediators; preliminary benefits (experimental).

• Continue H1/H2, LDN if needed.

Physician tip: For >3 months symptoms. Use imaging (SPECT) if available; monitor for fascial change/fibrosis

Potential Therapeutic Interventions

Anchor on tirzepatide/telmisartan; adjuncts per phase. Personalize by genetics (e.g., ApoE4 for neurodegeneration risk).  Peptides repair, but limited by lack of human safety data, and which ones should be used, and method of delivery (eg BPC157 not effective orally and limited value nasally)

Table: Phase-Specific Approaches

Phase	Key Issues	Main Treatments	Adjuncts
Acute	Cytokine storm, mast cells	Antivirals, metformin, H1/H2 blockers	LDN
Transition	Persistent cytokines, mitochondrial dysfunction	NR, magnesium, ALA, dapagliflozin (experimental)	Fenofibrate (especially if elevated D Dimer)
Chronic	Hypoxia, fibrosis, NLRP3	Tirzepatide, telmisartan	HBOT, MLT, high purity omega 3, (peptides experimental), (plasmapheresis experimental)

Therapeutic Implications

Prioritize anchors; adjuncts for support. Research-level, but mechanistic. Trials needed for validation.

Physician note: Off-label uses (e.g., tirzepatide) require informed consent. Combine with lifestyle (pacing, diet).

Conclusion and Management Tips for Family Physicians

Long COVID is modifiable—disrupt loops early to prevent chronicity. Family physicians bridge specialties: Screen broadly, phase patients by duration/symptoms.

Practical Advice:

• Diagnosis: History (PEM, fog), exclude mimics (bloods: inflammation, thyroid).

• Management: Start supportive (pacing, hydration). Phase-based: Early—antihistamines/LDN; Chronic subject to symptom load

• Referrals: MRI brain venography especially if pulsatile tinnitus, head pressure.  Others depending on symptom load

• Monitoring: Track symptoms, biomarkers. Watch mental health. Check D-Dimer, fibrinogen.  Complement C3 and HS-CRP usually suppressed and useful to gauge immunological status.  Lymphocyte subpopulations valuable.

• Patient Education: Explain phases; it's biological, not "in your head." Encourage support groups.

• Future: DNA results linked to targeted metabolic solutions valuable when you are proficient at them.

This is theoretical—consult evidence-based guidelines, but these are lagging behind reality. References available on original paper.