Review Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, 2025, Komaroff et al.

[Jesse]

Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome​

Anthony L. Komaroff, Robert Dantzer

Abstract
Debilitating symptoms for many years can follow acute COVID-19 (“long COVID”), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60–400 million individuals, globally.

Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms.

In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats—sickness behavior and torpor—responses mediated by specific, recently discovered neural circuits. These neural circuits constitute a symptom-generating pathway, activated by neuroinflammation, which may be targeted by therapeutics to quell neuroinflammation.

Many factors cause the symptoms to become chronic, including persistent infectious agents (and/or their nucleic acids and antigens) and the fact that many of the underlying biological abnormalities reinforce each other, creating ongoing physiological vicious cycles.

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[DMissa]

"Although acute and chronic infection require and consume considerable ATP, people with both long COVID and ME/CFS have a reduced capacity to generate ATP from oxygen, glucose, fatty acids, and amino acids."

Citation: prior review where they have a table of very broadly combined evidence from many studies undertaken over several decades. Studies using different criteria, types of sample and assays and showing pretty diverse sets of specific results.

No conclusive effect has been seen in a particular tissue or even systemically. Even among mitochondrial studies "reduced ATP synthesis" is absolutely nowhere near a consistent effect seen. Nor, to my knowledge, is diet- and activity-independent wasting a feature of these syndromes and it could be the first thing one might expect as a consequence. Nor does the clinical presentation of known primary mitochondrial diseases seem to match ME/CFS.

We are a long way from having the evidence needed to make the claims being put forward, and I don't really see how it fits the symptoms.

 

[Jonathan Edwards]

We are a long way from having the evidence needed to make the claims being put forward, and I don't really see how they fit the symptoms.

I agree. I think the general idea that symptoms are mediated by immune signals impacting on hind brain is reasonable but the detailed analysis looks very unconvincing, both in terms of invoking 'neuroinflammation' and metabolic shut down.

I don't see how neuroinflammation can be a useful concept for explaining why you feel terrible within minutes of pyrognic substances getting in to the circulation. Symptoms clearly depend on responses through things like TNF, prostanoids and TLR4 in the hypothalamic region but that has nothing to do with inflammation as such, or with the sort of generalised microglial activation that Nakatomi suggested but then never materialised.

And invoking the same mechanism as depression (which is Dantzer's field) doesn't work because the symptoms in ME/CFS are independent of any accompanying depressive reaction. They caannot be the same process.

 

[Hoopoe]

Now that I'm able to be more active, I've put on muscle and look fit. Yesterday, after a walk on even ground that was too long, I ended up with an urge to lie down and rest and fell asleep from the stress and exhaustion of the walk. This appears to be a manifestation of difficulty tollerating upright posture, even if during the walk there were barely any symptoms and it would have been hard to notice anything wrong from the outside. It's as if the body is able to compensate for the intolerance of upright posture for some time, and endure it, but eventually really needs a period rest in a quiet room in horizontal position.

The most notice of the subtle signs that something was wrong was probably a hint of a stressed and pained expression on the face. This is sometimes misinterpreted, usually as negative reaction to some social interaction or dynamic. Another things is becoming more withdrawn, and participating less in conversation. This is interpreted by others as disinterest which is half right... it feels like a desire to withdraw somewhat from conversations... to reduce the exposure to the activity of socialization, but isn't because the topic is not of interest to me or because I wouldn't be interested in a conversation.

 

[Jesse]

And invoking the same mechanism as depression (which is Dantzer's field) doesn't work because the symptoms in ME/CFS are independent of any accompanying depressive reaction. They caannot be the same process.

I don't know how common it is but (especially severe) PEM does make me feel very depressed. I don't struggle with depression at all outside of PEM.

Then again it's somewhat similar to the depressed feeling I sometimes get when I'm very sick, so maybe it fits more with that theory.

 

[Hoopoe]

I don't know how common it is but (especially severe) PEM does make me feel very depressed. I don't struggle with depression at all outside of PEM.

I can also get depressive mood during PEM but it seems to depend on the cause. If the overexertion was mental, PEM can be accompanied by feelings of hopelessness, despair, negativity out of proportion, etc. If the overexertion was mainly due to physical activity, mood can be normal.

This change in mood is a reaction to the activity/exertion/stimulation not to a negative event. This can be seen clearly when it is overwhelmingly positive and exciting events that lead to a massive crash. Presumably strong positive feelings are associated with increased brain activity, which then contributes to PEM.

 

[Jonathan Edwards]

I don't know how common it is but (especially severe) PEM does make me feel very depressed.

I am not surprised but the fact that you separate the two aspects surely just confirms that they are not just the result of the same process. People like Dantzer want to claim that neuroinflammation explains the 'biological' type of depression where you are not depressed by something else but just have an abnormal brain state for no other reason. If it was the same neuroinflammationn as ME/CFS then all people with biological depression would have PEM and OI and all the other stuff.

 

[Jesse]

I am not surprised but the fact that you separate the two aspects surely just confirms that they are not just the result of the same process. People like Dantzer want to claim that neuroinflammation explains the 'biological' type of depression where you are not depressed by something else but just have an abnormal brain state for no other reason. If it was the same neuroinflammationn as ME/CFS then all people with biological depression would have PEM and OI and all the other stuff.

Agreed! I made a slight update to my comment which you might not have seen yet.

 

[Simon M]

Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms.

I don't think many have been found with much confidence. So this approach is likely to be chasing shadows.