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

Discussion in 'BioMedical ME/CFS Research' started by Kalliope, Jun 7, 2021.

  1. Kalliope

    Kalliope Senior Member (Voting Rights)

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    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.
     
  2. Grigor

    Grigor Senior Member (Voting Rights)

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

    Dolphin Senior Member (Voting Rights)

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    The full text is now open access.
     
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  4. Forbin

    Forbin Senior Member (Voting Rights)

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  5. Hutan

    Hutan Moderator Staff Member

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    I don't think it's complete enough to say the physical stressors are exercise and prolonged upright position. Lots of people with ME/CFS don't do any formal exercise. It's physical activity that is the problem.

    I don't know that we have evidence that emotional stressors produce a worsening of the illness. In my experience, if they do, they act via the issues with activity and cognitive stress. In my experience, having an emotional stressor (being concerned for a child; being angry about something) can help me function at a higher level for a while.
     
    Last edited: Jun 12, 2021
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  6. Amw66

    Amw66 Senior Member (Voting Rights)

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    Emotional stress can be like kryptonite here.
     
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  7. Hutan

    Hutan Moderator Staff Member

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    I don't think either of those statements can be made with such certainty. Reading this paper, I'm left with the feeling that we have got to get some decent replication of studies to confirm (or disprove) the assumptions about ME/CFS that some ME/CFS experts state so confidently and that are the basis for decisions about further studies.

    The authors seem a lot more confident.


    This is a proposed mechanism - damage to a hypothesised nucleus of neurons in the hypothalamus that are sensitive to neuroinflammation and switch on the 'sickness behaviour' symptoms in order to allow the body to deal with an infection or other stressor.
     
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  8. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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

    Hutan Moderator Staff Member

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    I'm not sure that I've registered the term 'redox imbalance' before. The authors have suggested that redox imbalance 'may be a marker for systemic inflammation'. It sounds as though its about overproduction of ROS and reactive nitrogen species.

    So, the theory goes - infection or other stressor >> redox imbalance/inflammation >> triggering of a hypothalamus nucleus >> sickness behaviour.

    https://pubmed.ncbi.nlm.nih.gov/15365815/

    Yes, the problem is that lots of people have inflammation, often a lot more than what can be found in people with ME/CFS. But not all of them develop ME/CFS. And free radicals have been blamed for just about every chronic illness.

    From the Komaroff and Lipkin paper:
    "Redox imbalance [78, 103]:
    Increased levels of pro-oxidants: Peroxides and superoxides, correlating with severity of symptoms [104]; isoprostanes, both at rest and after exercise [105]

    Decreased levels of antioxidants: Decreased levels of α-tocopherol [106]; thiobarbituric acid reactive substances, or TBARS, that correlate with severity of symptoms [107]

    Increased nitrosative stress: Increased levels of inducible nitric oxide synthase (iNOS), possibly secondary to increased production of NFκB [108]; increased nitric oxide (NO), peroxynitrite and nitrate, particularly following exercise [109]

    Brain magnetic resonance imaging (MRI) has shown elevated levels of ventricular lactic acid consistent with oxidative stress [110, 111]."​

    It looks as though a key reference is still in the works:
    Here's the rest.
     
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  10. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    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.
     
  11. Sid

    Sid Senior Member (Voting Rights)

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

    Hutan Moderator Staff Member

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    I agree. But, at the same time, a lot of people don't look very deeply at the evidence behind the statements.

    I think papers like this one probably do convince quite a lot of people that there is a huge stack of robust research on a wide range of biological anomalies. And those people aren't just patients desperate for signs of progress as they read popularised versions of the papers in blogs. Lipkin has a pretty high profile. I would not be surprised if Lipkin and the paper helps sway some politicians and medical professionals towards seeing ME/CFS and Long Covid as issues that need funding.
     
  13. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    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.
     
  14. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    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?
     
  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    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.
     
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  16. Kalliope

    Kalliope Senior Member (Voting Rights)

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    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.
     
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  17. Andy

    Andy Committee Member (& Outreach when energy allows)

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    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/
     
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