Insights from ME/CFS May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome - Komaroff, Lipkin 2021

Trends in Molecular Medicine
Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome
Anthony L. Komaroff, W. Ian Lipkin

Highlights


• In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.

• Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.

• ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.

• The US and other developed nations have committed considerable support for research on post-COVID illnesses.

Abstract:

SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.

 

Nice overview. Not sure what to say about it otherwise.

 

The full text is now open access.

 

Emotional stress can be like kryptonite here.

 

The problem is, that it doesn't really explain anything. How are the "non-essential energy-consuming processes are throttled down"?

 

Very much agree.

To me the key error here is muddling an explanation of what happens normally with an explanation of what happens in disease. It is similar to the story of 'molecular mimicry'.

The story for molecular mimicry is: the immune system has a sophisticated mechanism for leaving self proteins alone and reacting to foreign proteins. Autoimmunity is when the immune system mistakes self for foreign. The trouble is that this explains nothing. The mechanisms of the immune system explain why most people do not have autoimmunity. They do not explain why some people do. My work on autoimmunity was about showing that there is a much more direct way of explaining it. Specific parts of the mechanism have a predictable capacity to engage loops where negative feedback is replaced by positive feedback.

So while I agree that a hypothalamic or brainstem centre misbehaving might explain ME/CFS it is not going to be explained by the way it normally works because most people do not get ME/CFS.We must be looking for a completely new mechanism that kicks in rarely and changes all the rules.

I am also sceptical about the broad brush teleological account in terms of 'sickness response' or cell danger response or neuroinflammation or redox - all tried buzzwords that allow people to waffle without specifics.

If this hypothalamic nucleus is there to respond to danger signals then it will do it without itself being inflamed so neuroinflammation seems a red herring.

The thing that makes least sense to me is this idea of energy conservation during sickness. The cardinal sign of acute illness, whether infection or to a lesser extent trauma or stroke or whatever is FEVER. Fever is a state where energy stores are being burnt overtime. I don't think the systemic fever response has anything to do with a cell response to danger to itself that might shut down metabolism.

And again I agree that the evidence is NOT robust.

 

These sorts of articles don’t help our case. Anyone looking at the evidence objectively would conclude that it just isn’t there.

 

Thank you for this Jonathan.

I've been meaning to highlight that

• Chris Armstrong and Robert Phair are looking for bistabilities/traps in amino acid metabolism and the TCA cycle;
• Robert Phair is working with Jonas Bergquist and his colleagues looking for traps in their vicious-cycle model of thyroid hormone metabolism in chronic disease.

 

What about a hypothetical circulatory "danger response" that has the function of lowering circulation through capillaries, with the purpose of restricting pathogens and inflammatory debris from causing problems in the periphery?

 

I don't see how reducing circulation through capillaries would stop pathogens embolising (which is a pretty unusual situation anyway). I would have thought it would be better to open up the capillaries to encourage bacteria to be washed right through and on into the spleen. I am not sure that inflammatory debris is a problem. If it arises from inflammation fed by the systemic circulation it tends to get filtered out in the lung (which it has to go through before it can access systemic capillaries again.

And I am not aware of any such shut down response. There may be shut down in septicaemia shock but in that situation I think you have loss of blood volume from permeability changes.

Some tissues will use less energy during illness - muscles if you are lying down. But in general during illness metabolic rate increases with fever. It just looks like sloppy muddling up of buzzword concepts to me.

 

Dr. Anthony Komaroff has written a summary of the paper:

Center for solutions for ME/CFS: ME/CFS Research: State of the Art, State of the Science

Quote:
In summary, the recent article summarizes in some detail what is known about the underlying biology of ME/CFS. It also highlights the fact that understanding a disease sometimes awaits the development of new scientific technologies. The article also emphasizes why physicians should never dismiss an illness just because they don’t understand it. With dedication, new tools and an open mind, the answers are coming.

 

Trial By Error: Medical Societies and new Komaroff-Lipkin Paper Highlight Long COVID and ME/CFS Links

"In the research realm, two well-known ME/CFS investigators have co-authored a useful overview of possible overlaps between ME/CFS and Long-COVID. In the paper published last month by the journal Trends in Molecular Medicine, Harvard’s Anthony Komaroff and Columbia’s Ian Lipkin cover a range of immunological, metabolic, neurological and other abnormalities identified in studies of these illnesses, and pose questions for future research. Dr Komaroff has presented a useful summary of the paper in a recent blog post."

https://www.virology.ws/2021/07/20/...-paper-highlight-long-covid-and-me-cfs-links/