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.

 

[Dolphin]

Why do symptoms linger in some people after an infection? A conversation on post-acute infection syndromes

Long COVID and ME/CFS, both post-infection illnesses, are now being more studied as part of a broader group called post-acute infection syndromes (PAISs). A new Q&A with Dr. Anthony Komaroff highlights research showing shared biological roots and potential treatment paths for these often...

www.eurekalert.org

News Release 1-Aug-2025

Why do symptoms linger in some people after an infection? A conversation on post-acute infection syndromes​

Peer-Reviewed Publication
Massachusetts General Hospital


In recent years, doctors and scientists are increasingly studying long-lasting illnesses that begin after someone recovers from an infection. Two of the most well-known examples are long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

It has been estimated that 400 million people, globally, may have Long COVID, and nearly half of them meet criteria for ME/CFS.

These conditions were often misunderstood or overlooked in the past, but that is starting to change. Researchers are now studying them as part of a larger group of illnesses called post-acute infection syndromes, or PAISs.

A new review by Mass General Brigham investigator Anthony L Komaroff, MD, and Robert Dantzer, MD, of the MD Anderson Cancer Center in Houston, published in Cell Reports Medicine, and a new review by Dr. Komaroff in the Proceedings of the National Academy of Sciences (PNAS), brings together decades of research and new discoveries to help explain what causes these illnesses and how they might be treated. Dr. Dantzer is one of the world’s experts on how animals respond to infection.

Their review highlights that long COVID and ME/CFS share many of the same biological problems such as inflammation in the brain, issues with how cells produce energy, and problems with the immune system.

They also introduce the idea that certain brain circuits that evolved to help the body respond to serious illness, may be stuck in the "on" position after the body has cleared the infection and could be causing many of the ongoing symptoms people experience.

In this Q&A, Dr. Komaroff shares what motivated this research and what it could mean for how we understand, diagnose, and treat these complex conditions.

Q: What Inspired You to Study the Field of Long Covid and other Post-Acute Infection Syndromes?​

My interest in ME/CFS began more than 40 years ago, when I met patients who never fully recovered from what seemed like a routine viral illness.

At the time, their symptoms couldn’t be explained by standard medical tests, which all came back normal. That led some to conclude the symptoms were psychologically based.

A small group of us around the world began to study if there were, in fact, underlying objective biological abnormalities that might be causing the long-lasting symptoms, perhaps in people with a genetic vulnerability.

Over the past 40 years, it became clear that this is the case. The symptoms are associated with multiple underlying abnormalities, involving multiple body systems.

In both reviews, we postulate that Long COVID and ME/CFS fall under a broader category called post-acute infection syndromes.

This helps highlight the biological similarities between them and opens the door to more targeted treatments.

​

In the review we asked two questions: what causes the symptoms, and why do the symptoms persist for years?

What causes the symptoms?

We identified a range of biological abnormalities common to both ME/CFS and long COVID that can directly cause symptoms.

These include:

• Neuroinflammation: Activation of the brain’s immune system
• Mitochondrial dysfunction: A reduced capacity to generate adenosine triphosphate (ATP), the primary energy source for cells, leading to a decrease in body- and brain-based metabolism.
• Immune dysregulation: This can include persistent inflammation, reactivation of latent viruses (like Epstein-Barr virus), and the presence of autoantibodies targeting neural tissues.
• Endothelial dysfunction: Disruption of blood flow and the blood-brain barrier, contributing to cognitive and cardiovascular symptoms.
• Gut dysbiosis: An imbalance in the gut microbiome that may perpetuate system inflammation
• Oxidative stress: An imbalance between the production of free radicals and the body's ability to neutralize them, leading to cellular damage and disease

Could "sickness behavior" be underlying these symptoms?

Our review focuses on another possible cause of the symptoms that has not previously been considered.

We think it is likely that these symptoms may be driven by evolutionarily-conserved responses to vital threats that are seen in all animals that have been studied.

Infection leads to symptoms, and the symptoms lead to behavior changes called sickness behavior. Infection also leads to changes in metabolism. Together, the behavioral and metabolic changes help preserve the body’s energy supply, its ATP, for the fight against the infection.

We suspect these behavioral and metabolic changes may be caused by recently discovered groups of dedicated brain cells (neurons) when they are stimulated by an infection or other cause of brain inflammation.

We present evidence that many of the underlying abnormalities that produce symptoms persist in some people, including the infectious agent or pieces of the infectious agent.

In addition, we point out that many of the different underlying abnormalities can reinforce each other, leading to ongoing vicious cycles that maintain the symptoms.

​

The pandemic has been a turning point. In 2020, we published a paper predicting that COVID-19 would lead to a surge in ME/CFS-like conditions, and that has happened.

Long COVID has brought visibility to post-infectious syndromes, because its cause is a specific infectious agent.

This has given credibility to the claim of many ME/CFS patients that their illness began following an acute infection—one in which no infectious agent was tested for.

It also gives credibility to similar syndromes following well-documented acute infections like Lyme disease and West Nile virus.

The scale of long COVID’s impact—both in terms of affected individuals and societal costs—has accelerated research and shifted the public discourse.



Q: What are the most interesting biological similarities between ME/CFS and long COVID?

The symptom overlap between ME/CFS and long COVID is well recognized. What our publications have cataloged is the many striking parallels in the underlying abnormalities.

These biological parallels include:

• Brain abnormalities, as seen by various types of brain imaging.
• Autonomic nervous system dysfunction affecting heart rate, breathing, and digestion.
• Immune system dysregulation and autoantibodies
• Impaired energy metabolism leading to fatigue and exercise intolerance.
• Cardiovascular issues, especially involving the lining of blood vessels (the endothelium).

These similarities suggest a shared pathophysiological foundation, reinforcing the case for unified research and treatment strategies.

Q: What are the current treatments for post-acute infection syndrome, and why have some failed to be effective?​

Currently, there are no FDA-approved treatments for ME/CFS or long COVID. However, evidence shows that early antiviral treatment and vaccination against SARS-CoV-2 can reduce the risk of developing long COVID.

Our review proposes that neuroinflammation—immune activation within the brain—is one key driver of symptoms. It stimulates the specific neural circuits that produce sickness behavior and metabolic changes.

Therefore, targeting neuroinflammation and the molecules by which it stimulates the neural circuits could lead to more effective therapies. Multiple novel therapies that target neuroinflammation are under investigation.

While promising, these treatments are still in experimental stages and not yet available to clinicians

Q: What are the most important research questions that need to be addressed to better understand and treat ME/CFS and long COVID?​

Two major questions stand out:

1. Cross-condition biological parallels: Do other post-infection syndromes—like post-Lyme disease, post-Ebola, and post-West Nile virus—share the same biological abnormalities as ME/CFS and long COVID? Systematic studies are needed to confirm this.
2. Therapeutic targeting of neuroinflammation: There are 10–20 experimental approaches currently being tested in lab models to reduce neuroinflammation. Determining which, if any, are effective in humans is a critical next step.

These questions are central to advancing treatment and understanding the broader category of post-acute infection syndromes

Finally, it's important to raise awareness.

The idea of post-acute infection syndromes is still relatively new and not yet widely recognized in medical practice. Promoting this framework can help improve how we diagnose, study, and treat these long-lasting illnesses.

---

Journal​

Cell Reports

DOI​

10.1016/j.xcrm.2025.102259

Article Title​

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

Article Publication Date​

25-Jul-2025

 

[Ariel]

"early antiviral treatment and vaccination against SARS-CoV-2 can reduce the risk of developing long COVID" (my bolding)

Is this true? I haven't seen discussion or evidence about this.

 

[Yann04]

As far as I remember the vaccine evidence wasn’t strong either way but I guess it really really depends what exactly you’re measuring as “post covid”.

 

[Ariel]

As far as I remember the vaccine evidence wasn’t strong either way but I guess it really really depends what exactly you’re measuring as “post covid”.

Yes, I remember that discussion. But I don't remember a discussion or conclusion about the antivirals. Again I imagine it depends what you measure as "long covid". But still, it's interesting that this is being claimed and I was wondering if there was any evidence for it.

 

[Hoopoe]

Is this true? I haven't seen discussion or evidence about this.

From what I remember, there were many papers on this. There was a small reduction in risk in some studies, in others there was no difference.

 

[rvallee]

From what I remember, there were many papers on this. There was a small reduction in risk in some studies, in others there was no difference.

IIRC it was mostly reductions in the, let's say, non-ME type of issues. Or not necessarily ME/not ME, but what's usually categorized as neurological symptoms is what had no differences, while the rest generally saw a slight reduction.

 

[Sly Saint]

In recent years, doctors and scientists are increasingly studying long-lasting illnesses that begin after someone recovers from an infection. Two of the most well-known examples are long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

It has been estimated that 400 million people, globally, may have Long COVID, and nearly half of them meet criteria for ME/CFS.

These conditions were often misunderstood or overlooked in the past, but that is starting to change. Researchers are now studying them as part of a larger group of illnesses called post-acute infection syndromes, or PAISs.

A new review by Mass General Brigham investigator Anthony L Komaroff, MD, and Robert Dantzer, MD, of the MD Anderson Cancer Center in Houston, published in Cell Reports Medicine, and a new review by Dr. Komaroff in the Proceedings of the National Academy of Sciences (PNAS), brings together decades of research and new discoveries to help explain what causes these illnesses and how they might be treated. Dr. Dantzer is one of the world's experts on how animals respond to infection.

Their review highlights that long COVID and ME/CFS share many of the same biological problems such as inflammation in the brain, issues with how cells produce energy, and problems with the immune system.

They also introduce the idea that certain brain circuits that evolved to help the body respond to serious illness, may be stuck in the "on" position after the body has cleared the infection and could be causing many of the ongoing symptoms people experience.

In this Q&A, Dr. Komaroff shares what motivated this research and what it could mean for how we understand, diagnose, and treat these complex conditions.

Q: What inspired you to study the field of long covid and other post-acute infection syndromes?

My interest in ME/CFS began more than 40 years ago, when I met patients who never fully recovered from what seemed like a routine viral illness.

At the time, their symptoms couldn't be explained by standard medical tests, which all came back normal. That led some to conclude the symptoms were psychologically based.

A small group of us around the world began to study if there were, in fact, underlying objective biological abnormalities that might be causing the long-lasting symptoms, perhaps in people with a genetic vulnerability.

Over the past 40 years, it became clear that this is the case. The symptoms are associated with multiple underlying abnormalities, involving multiple body systems.

In both reviews, we postulate that Long COVID and ME/CFS fall under a broader category called post-acute infection syndromes.

This helps highlight the biological similarities between them and opens the door to more targeted treatments.

Q: What did you find in this review?

In the review we asked two questions: what causes the symptoms, and why do the symptoms persist for years?

What causes the symptoms?

We identified a range of biological abnormalities common to both ME/CFS and long COVID that can directly cause symptoms.

These include:

• Neuroinflammation: Activation of the brain's immune system
• Mitochondrial dysfunction: A reduced capacity to generate adenosine triphosphate (ATP), the primary energy source for cells, leading to a decrease in body- and brain-based metabolism.
• Immune dysregulation: This can include persistent inflammation, reactivation of latent viruses (like Epstein-Barr virus), and the presence of autoantibodies targeting neural tissues.
• Endothelial dysfunction: Disruption of blood flow and the blood-brain barrier, contributing to cognitive and cardiovascular symptoms.
• Gut dysbiosis: An imbalance in the gut microbiome that may perpetuate system inflammation
• Oxidative stress: An imbalance between the production of free radicals and the body's ability to neutralize them, leading to cellular damage and disease

Could "sickness behavior" be underlying these symptoms?

Our review focuses on another possible cause of the symptoms that has not previously been considered.

We think it is likely that these symptoms may be driven by evolutionarily-conserved responses to vital threats that are seen in all animals that have been studied.

Infection leads to symptoms, and the symptoms lead to behavior changes called sickness behavior. Infection also leads to changes in metabolism. Together, the behavioral and metabolic changes help preserve the body's energy supply, its ATP, for the fight against the infection.

We suspect these behavioral and metabolic changes may be caused by recently discovered groups of dedicated brain cells (neurons) when they are stimulated by an infection or other cause of brain inflammation.


We present evidence that many of the underlying abnormalities that produce symptoms persist in some people, including the infectious agent or pieces of the infectious agent.

In addition, we point out that many of the different underlying abnormalities can reinforce each other, leading to ongoing vicious cycles that maintain the symptoms.

Unraveling the mysteries of post-acute infection syndromes

In recent years, doctors and scientists are increasingly studying long-lasting illnesses that begin after someone recovers from an infection.

www.news-medical.net

 

[V.R.T.]

Does the idea that its caused by neuroinflammation and will need new anti-inflammatory drugs to treat carry weight with anyone round here? It sort of seems like a shrug type response to me...

 

[Utsikt]

Does the idea that its caused by neuroinflammation and will need new anti-inflammatory drugs to treat carry weight with anyone round here? It sort of seems like a shrug type response to me...

I’d ask them to show me the tissue damage if they want to talk about inflammation. Something wrong in the brain has by no means been ruled out, but that doesn’t have to be inflammation.

 

[V.R.T.]

Our review proposes that neuroinflammation—immune activation within the brain—is one key driver of symptoms. It stimulates the specific neural circuits that produce sickness behavior and metabolic changes.

Therefore, targeting neuroinflammation and the molecules by which it stimulates the neural circuits could lead to more effective therapies. Multiple novel therapies that target neuroinflammation are under investigation.

While promising, these treatments are still in experimental stages and not yet available to clinicians

Q: What are the most important research questions that need to be addressed to better understand and treat ME/CFS and long COVID?​

Two major questions stand out:

1. Cross-condition biological parallels: Do other post-infection syndromes—like post-Lyme disease, post-Ebola, and post-West Nile virus—share the same biological abnormalities as ME/CFS and long COVID? Systematic studies are needed to confirm this.
2. Therapeutic targeting of neuroinflammation: There are 10–20 experimental approaches currently being tested in lab models to reduce neuroinflammation. Determining which, if any, are effective in humans is a critical next step.

I don't feel like the authors provide any evidence that neuroinflammation is the cause. And also is the definition that its 'immune activation within the brain' accurate?

But the idea of targeting the sickness behavior itself rather than the cause of it is kind of intriguing. I guess time will tell if there's any merit to it...

 

[V.R.T.]

I’d ask them to show me the tissue damage if they want to talk about inflammation. Something wrong in the brain has by no means been ruled out, but that doesn’t have to be inflammation.

Precicely i feel like they are talking about something that isnt neuroinflammation. These new drugs they are talking about are intriguing but I don't find it particularly compelling as a hypothesis.