Long COVID in 2025: Why You Keep Crashing – and Why There’s Hope

Dr Graham Exelby December 2025

“Long COVID is much more than a classic ‘post-viral syndrome”

It is a condition in which the acute-phase inflammatory program never fully switches off — and remains easily re-triggered months or years after the initial infection.

Figure 1: Simplified Immune Pathways

The Two Phases of COVID Never Separate

For millions worldwide (conservatively 1–3% of those infected), SARS-CoV-2 leaves behind:

• persistent spike protein and/or viral RNA in subsets of severely affected patients

• microvascular injury

• primed innate immunity

This keeps the acute-phase pathway — TLR2/4 → NF-κB → IL-6/STAT3 → CCL2 → NLRP3 — accessible long after recovery. Minor triggers such as a cold, reinfection, stress, vaccination, mould exposure, menstruation, heat, or altitude can reactivate:

• TLR4–RAGE danger sensing

• NLRP3 bursts

• acute cytokine cascades

• mast-cell activation

• spike-sensitised endothelial leak

Stacked upon a chronically injured microvasculature, these produce the classic crash:

“I was finally improving. One week later I’m back at zero.”

This relapse pattern is the signature of Long COVID.    It is not psychological — it is biochemistry repeating itself.

What Makes Long COVID Unique

Most viral illnesses progress from acute activation → resolution → tissue recovery.

In Long COVID:

• the acute phase never fully resolves,

• the chronic phase locks in place, and

• both phases can continue or fire simultaneously months or years later.

This is why Long COVID so closely resembles POTS, ME/CFS, fibromyalgia, MCAS, migraine, and dysautonomia: they represent different manifestations of the same hypoxia–inflammation loop.

The Core Mechanism: Pericyte Injury + Brainstem Hypoxia

A growing body of evidence indicates that the earliest and most decisive injury in Long COVID occurs in the microcirculation, especially the pericytes that regulate capillary tone, endothelial integrity, and regional oxygen delivery.

Pericytes are vulnerable to:

• spike protein

• ROS and mitochondrial stress

• TLR4 and RAGE activation

• inflammatory monocyte signalling

• mast-cell mediators

• microclots and fibrin–amyloid deposits

• hormonal fluctuations

• biomechanical venous congestion

When pericytes detach:

• capillaries leak

• the neurovascular unit destabilises

• preload falls on standing

• brainstem oxygenation drops

• glymphatic flow slows

This explains the hallmark symptoms:

• head pressure

• dizziness

• air hunger

• tachycardia

• PEM

• cognitive dysfunction

• sensory overload

• fragmented sleep

Long COVID is a circulatory and neurovascular disorder, not a psychological one.

Figure 2 The Neurovascular Unit

Pericyte injury appears to be one of the earliest and most critical events in Long COVID and in many cases of post-infectious ME/CFS and POTS.

Source: Thomas Daubon, Audrey Hemadou, Irati Romero Garmendia, and Maya Saleh, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

The Pericyte Switch: Acute Activation → Chronic Disease

In Long COVID, the sequence begins with spike protein, viral RNA, or mitochondrially-derived danger signals (mtDAMPs) activating TLR4 and RAGE, which directly injure pericytes, the capillary gatekeepers. Early pericyte detachment destabilises the neurovascular unit, producing capillary leak, impaired oxygen extraction, and regional hypoxia.

This hypoxic environment stabilises HIF-1α (acute, easily re-triggered) and HIF-2α (chronic, persistent), which further amplify RAGE, STAT3, CCL2, and NLRP3 signalling. The result is a self-reinforcing inflammatory–hypoxic loop in which pericytes cannot reattach, and microvascular rarefaction progressively develops.

Sequence: Spike/RNA/mtDAMPs → TLR4/RAGE → pericyte injury → capillary leak → local hypoxia → HIF-1α (acute) + HIF-2α (chronic) → STAT3/CCL2 → NLRP3 → sustained pericyte dropout → microvascular rarefaction → brainstem hypoperfusion → POTS/PEM/cognitive dysfunction.

This sequence reflects three key facts:

1.     Pericyte injury happens early — via spike protein, ROS, mitochondrial dysfunction, mast-cell mediators, microclots, and biomechanical venous congestion.

2.     Hypoxia signalling (HIF-1α → HIF-2α) then locks in, preventing pericyte reattachment and stabilising a chronic microvascular failure state.

3.     RAGE–STAT3–CCL2–NLRP3 operate as a feed-forward loop, meaning even minor triggers re-activate the acute inflammatory programme on top of a chronically injured microvasculature.

When this loop stabilises, the symptoms become persistent:

• orthostatic intolerance

• fatigue

• PEM

• cognitive dysfunction

• chest pressure

• migraine

• sensory hypersensitivity

• widespread autonomic instability

Genomic vulnerabilities — including variants in TLR4, RAGE, STAT3, PEMT, COMT, MTHFR, TRPM3, ApoE4, CCL2 — determine whether the loop resets or becomes chronic (Exelby & Vittone 2025).

Why Long COVID Patients Keep Relapsing

Because the acute-phase machinery remains loaded and easily re-triggered.   Persistent spike protein or ongoing release of mitochondrially-derived danger signals (mtDAMPs) keeps:

• TLR4 sensitised

• RAGE primed

• NLRP3 “armed”

• CCL2 elevated

• STAT3 phosphorylated

• mast cells hyper-responsive

• microglia in a standby activated state

• pericytes unable to reattach

This is why Long COVID patients deteriorate with:

• stress

• exertion

• infection

• menstruation

• chemical triggers

• heat or dehydration

• altitude

• poor sleep

Each trigger reactivates an acute-phase burst on top of chronic microvascular injury.

Acute COVID: The On-Switch

During infection SARS-CoV-2 activates:

• TLR2/4 and MyD88 → NF-κB

• ROS generation

• IL-6 → STAT3

• CCL2 → CCR2 monocyte recruitment

• NLRP3 inflammasome

• mast-cell activation

• PDH shutdown

• HIF-1α stabilisation

• early astrocyte/glymphatic dysfunction

This is the blueprint for the chronic state — unless the system fully de-escalates.

The Chronic Loop: Why Long COVID Doesn’t Switch Off

The same innate pathways needed in acute infection become self-perpetuating:

• RAGE sensing of AGEs, oxidised lipids, fibrin amyloid, spike fragments

• STAT3 remains active

• CCL2 stays elevated

• NLRP3 keeps priming

• HIF-2α maintains hypoxic reprogramming

• pericytes remain detached

• brainstem perfusion remains impaired

• glymphatic clearance remains limited

This produces the symptom constellation labelled:

• POTS

• ME/CFS

• MCAS

• Fibromyalgia

• Dysautonomia

• Chronic migraine

• Cognitive dysfunction

• Sleep disruption

• Sensory hypersensitivity

• Exertional crashes

Different tissues — same mechanism.

The Transition from the Acute to Chronic HIF Activation -from virus to hypoxia

In Long COVID, the shift from acute HIF-1α activation to chronic HIF-2α signalling is not a handover but a persistent overlap. Acute HIF-1α can be re-triggered at any time by stressors such as exertion, infection, heat, menstruation, or chemical exposures, while HIF-2α continues to drive chronic hypoxic reprogramming in the background.

This dual accessibility explains why the body behaves as if it is still in the acute phase years later — and why the core H1/H2 anchors may remain essential to stabilise metabolic function, vascular tone, and pericyte integrity long after the initial SARS-CoV-2 infection.

Table 1: The HIF Overlap Model: Why Acute COVID Never Fully Switches Off

HIF-1α (acute hypoxia sensor)	HIF-2α (chronic hypoxia and iron/redox sensor)
Rapid response- within 0-2 hrs	Slower induction (4–24 hours)
Drives glycolysis, Pyruvate dehydrogenase (PDH) inhibition (via PDK1), glutamate accumulation, NO uncoupling, metabolic shutdown	Maintains sustained hypoxic reprogramming
Strongly induced by ROS, RAGE, NF-κB, mitochondrial dysfunction	Upregulates VEGF, EPO, erythropoiesis gene
Dominant in microvascular collapse	Drives persistent inflammation, endothelial dysfunction, vascular leakage, pericyte dropout

Preload Failure: The Bridge Between Long COVID and POTS

Supine to standing echocardiography in Long COVID cohorts consistently shows:

• reduced stroke volume

• impaired diastolic filling

• blunted RAAS activation

• tachycardia as compensation

• vertebral venous congestion

• reduced brainstem perfusion

Long COVID often layers an easily re-triggered acute-phase inflammatory state on top of the same mechanical–vascular preload defects seen in severe POTS.   This combination explains why Long COVID is more volatile and relapse-prone than classic POTS.

Why This Matters

When clinicians and patients understand that Long COVID = acute-phase reactivation + chronic hypoxic microvascular disease, everything snaps into place:

• symptoms make sense

• relapses make sense

• comorbidities make sense

• treatment pathways become clearer

The full scientific, physician, and patient-level series — including preload signatures, RAAS physiology, pericyte biology, genomic risk clusters, and therapeutic frameworks — will be released in early 2026.

For the first time, Long COVID has a coherent and testable biological mechanism — and with it, a realistic and increasingly reproducible path toward recovery for many patients.