Long Covid: Dysfunction, Not Damage — Theory and Treatment Concepts

While Long Covid brings about a lot of bad news, the good news is that there is not a single type of organic damage found across all Long Covid sufferers which could explain even a fraction of the complex and evolving symptoms. This indicates Long Covid is due to dysfunction and not damage, making it easily treatable with the right understanding. While there is organic damage found, there is nothing causative and it only seems to be a side product of another process.
The Dysfunction, Not Damage Theory is that the acute phase of COVID19 causes a number of metabolic shifts, pushing the body into metabolic states which are stable but cause dysfunction. Combined with a small amount of (reversible) damage to the mitochondrial membranes, dysfunction of iron homeostasis and an unbalanced microbiome — this seems it can explain all of the complex and evolving symptoms of Long Covid.
Dysfunction, Not Damage Theory:​
  • An acute oxidative event causes iron mobilization into the brain and other tissues, causing auto-oxidation, which produces massive oxidative stress and destroys cellular lipids, antioxidants and DNA. The bodies DNA repair system, PARP activates but due to oxidative conditions depletes NAD+and its building blocks, this triggers what I refer to as the “Niacin Sink Trap”.
  • At the same time, the production of vitamin B12 is interrupted, because the cobalamine building block is oxidized, triggering the “Methyl Trap”. Both the Niacin Sink Trap and Methyl Trap are stable metabolic dysfunction which cause a variety of evolving and complex symptoms.
  • The iron which was mobilized causes oxidative damage to cell membranes and DNA, since the body doesn’t have a mechanism to regulate extra iron well and is bound in the form of ferritin and possibly other compounds. These leak iron due to the bodies pro-inflammatory state and causes evolving and complex symptoms.
  • The mitochondrial membranes that got oxidized stick around as they get complexed with proteins, causing fatigue and lower bioenergetic functioning as they can not function properly.
  • The microbiome gets remodeled due to iron absorption, triggering microbial community changes, growth of more pathogenic microbes and disruption of gut/brain axis.
  • In some people, the oxidative stress/damage will reactivation dormant neurotrophic viruses like EBV and oxidized cell membranes will harbor any dormant Lyme disease pathogens. Parasites may overgrow due to the iron mobilization and oxidative stress as well as the microbiome remodeling.
Any one or more of these things happen together, many of them playing off each-other in feedback loops, with the resulting symptoms depending on the deficiencies in the vitamin co-factors and genetic predisposition at the time of oxidative assault, as well as any dormant infections.
Analysis based on symptom time progression research:​
A recent study which surveyed thousands of participants all over the world regarding their disease progression and symptoms, then used statistical analysis and natural language processing found that there are three clusters of symptom progression over time which are highly correlated. This indicates that there are three main mechanisms in long covid and an analysis of the three graphs below indicates the mechanisms are coupled together.
Looking at the clusters below, it appears the three clusters correlate to:
Cluster 1 — Dysbiosis of the Microbiome
Cluster 2 — Niacin Sink Trap and Methyl Trap, Metabolic Dysfunction
Cluster 3 — Iron Mobilization and Dysfunction

This validates the “Dysfunction not Damage” theory of Long Covid and a further analysis of the symptoms and how they correlate to each of these mechanisms paints a very strong picture of the driving mechanisms behind Long Covid.


Senior Member
First off, I don't really see any point in the differentiation of dysfunction and damage since one thing goes with the other. In ME patients, we see structural damages/changes, in organs and intracellularly. Many conditions that are classified as damage are just structural changes that are considered irreversible. They are irreversible within the current standard of care. But they might be reversible with novel treatments. Even Alzheimer's might be reversible.

This is why I find the terminology not fitting for this theory. What stands out in this theory in my eyes is the iron mobilization. I'd call it "iron mobilization theory". This is the part I'd be interested to discuss and how consistent it is with the current observational evidence on ME pathophysiology.

The theory within itself appears to be consistent. How much evidence is there on iron mobilization and how could patients verify it themselves? How could it be treated?


Senior Member
The paper says

"...MRI with an educated technician can determine brain iron accumulation based on specific signal characteristics. "

so presumably the appropriately setup MRI with a trained technician ought to be able to determine if iron has accumulated in the brain. I have had an MRI of my brain and they found nothing of note but also they weren't looking for iron accumulation and would it show up in a normal scan that is looking for tumors and other big anomalies?


Senior Member
MRI of neurodegeneration with brain iron accumulation (2020) [10.1097/WCO.0000000000000844]

Purpose of review
The diagnosis of neurodegeneration with brain iron accumulation (NBIA) typically associates various extrapyramidal and pyramidal features, cognitive and psychiatric symptoms with bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance images, reflecting the alteration of iron homeostasis in this area. This article details the contribution of MRI in the diagnosis by summarizing and comparing MRI patterns of the various NBIA subtypes.

Recent findings
MRI almost always shows characteristic changes combining iron accumulation and additional neuroimaging abnormalities. Iron-sensitive MRI shows iron deposition in the basal ganglia, particularly in bilateral globus pallidus and substantia nigra. Other regions may be affected depending on the NBIA subtypes including the cerebellum and dentate nucleus, the midbrain, the striatum, the thalamus, and the cortex. Atrophy of the cerebellum, brainstem, corpus callosum and cortex, and white matter changes may be associated and worsen with disease duration. Iron deposition can be quantified using R2∗ or quantitative susceptibility mapping.

Recent MRI advances allow depicting differences between the various subtypes of NBIA, providing a useful analytical framework for clinicians. Standardization of protocols for image acquisition and analysis may help improving the detection of imaging changes associated with NBIA and the quantification of iron deposition.

MRI isn't the only marker the author suggests.

Ferritin and full iron panel, research shows the ideal ferritin range is below 100. High ferritin puts you at risk but iron can mobilize and deposit even with low ferritin. Again, ferritin and other iron levels do not indicate the amount of iron stored in your nervous system or other tissues but can show if you have large amounts of stored iron that may be “leaking”, and can indicate if its safe to try and chelate iron.

8-OHdG, a DNA damage biomarker, may be most relevant and will be elevated if you have iron releasing from tissues causing oxidation.

High homocystein has been correlated to iron overload disorders although it is also expected to be elevated due to the methyl trap.

Serum copper and Ceruloplasmin enzyme levels can indicate if you have deficiencies in your iron transport system and would be important to understand and may have led to iron redistribution.

Observation of ferritin based Fleischer Rings in the eyes, in some visible under blacklight.

Transcranial sonography can be used to detect changes in some parts of the brain in brain iron accumulation disorders.
For my part, I have inconsistent results, namely in that my trans-/ferritin/iron levels in the blood are too low or at the lower boundaries. But I agree with the author that the blood markers aren't suited because they don't correlate with tissue iron.

None of the other proposed markers is specific enough, either, except for the Fleischer Rings. A brain MRI might be the only specific one.

I know of one hemochromatosis case in my own family. This is what makes this theory particularly interesting to me. So this might stick out in the DecodeME study as a predisposing factor if iron storage plays a role in the pathophysiology.

Having ocular issues as well, I might go and let an ocular specialist check if I have Fleischer Rings. I've met three ocular specialists so far and no one has checked this.

What I don't understand: How has the author got to this idea in the first place? Is there a patient (group) where this was checked? It seems like a coincidence that this turned out to be associated with different aspects of the long-hauler condition.

T2 hyperintensities of white matter is one of the most common reported MRI findings in those that are suffering from long covid and a paper on iron storage disease states, “T2 hyperintensities in white matter have been reported in most NBIA (Neurodegeneration with Brain Iron Accumulation) subtypes”.
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