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

[Kalliope]

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.

 

[Grigor]

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

 

[Dolphin]

The full text is now open access.

 

[Forbin]

It is too early to know the ultimate health impact of post-COVID chronic illnesses; however, senior economists have estimated that the cumulative future costs in the United States may be as high as $4.2 trillion [90].

 

[Hutan]

Two physical stressors, exercise and prolonged upright position, as well as cognitive and emotional stressors, typically produce a worsening of all of the symptoms of the illness, a condition called post-exertional malaise.

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.

 

[Amw66]

Emotional stress can be like kryptonite here.

 

[Hutan]

Several of the abnormalities appear to be affected by the duration of the illness, with more pronounced abnormalities seen in the first three years followed by a tendency for the abnormalities to subside—a phenomenon that suggests an exuberant immune response at the onset of the illness that may then become exhausted, or attenuated by counter-regulatory mechanisms, as the illness becomes more chronic.

Many ME/CFS patients have autoantibodies that target adrenergic and muscarinic cholinergic receptors

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.

In summary, while the findings we have summarized regarding the underlying pathology of ME/CFS are robust, they also raise questions that require further investigation,

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.

ME/CFS may represent the unchecked persistence of a response that occurs when various stressors (e.g., infection, injury, cold temperatures, lack of sufficient nutrients) threaten the viability of a cell or of an organism. At the cellular level it is called the cell danger response (CDR) [74]. At the level of the organism, such as in the extreme case of a hibernating animal, it has been called the integrated stress response (ISR) [75]. In both the CDR and ISR, non-essential energy-consuming processes are throttled down, allowing the available energy molecules to be used for processes essential to maintaining viability.

A hypothalamic “torpor” nucleus (a group of neurons dedicated to a particular function) has been identified in rodents [76]; we speculate that such a nucleus also may mediate the ISR. We speculate that a similar nucleus of neurons may be implicated in human sickness symptoms and associated physiologic phenomena, like fever. The nucleus may be triggered by neuroinflammation. Neuroinflammation can occur directly through injury to or infection of the brain. It also can occur indirectly, in response to humoral and retrograde neural signals generated by inflammation elsewhere in the body [77] or by autoantibodies against specific neural or immune system targets.

The redox imbalance that is a central feature of ME/CFS [78] may be a marker for systemic inflammation in response to infection or injury.

 

[Snow Leopard]

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.

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

 

[Hutan]

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.

Substantial evidence implies that redox imbalance attributable to an overproduction of reactive oxygen species or reactive nitrogen species that overwhelm the protective defense mechanism of cells contributes to all forms of Parkinson's disease. Factors such as dopamine, neuromelanin, and transition metals may, under certain circumstances, contribute to the formation of oxygen species such as H(2)O(2), superoxide radicals, and hydroxyl radicals and react with reactive nitrogen species such as nitric oxide or peroxinitrite.

Mitochodrial dysfunction and excitotoxicity may be a cause and a result of oxidative stress. Consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage, and interference of reactive oxygen species with signal transduction pathways. These consequences become even more harmful when genetic variations impair the normal degradation of altered proteins. Therefore, therapeutic strategies must aim at reducing free-radical formation and scavenging free-radicals.

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:

78.Paul, B. et al. (2021) Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Nat Acad Sci USA, In press.

Here's the rest.

103. Nijs, J. et al. (2014) Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev 20, 94-116.

104. Maes, M. et al. (2011) Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit 17 (4), SC11-5.

105. Robinson, M. et al. (2010) Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand J Med Sci Sports 20 (2), 282-90.

106. Miwa, K. and Fujita, M. (2009) Increased oxidative stress suggested by low serum vitamin E concentrations in patients with chronic fatigue syndrome. Int J Cardiol 136 (2), 238-9.

107. Fenouillet, E. et al. (2016) Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl MEd 14 251.

108. Morris, G. and Maes, M. (2014) Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol 12 (2), 168-85

109. Suarez, A. et al. (2010) Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt) 19 (6), 1073-7.

110. Natelson, B.H. et al. (2017) Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity. J Neurol Sci 375, 411-416

111. Shungu, D.C. et al. (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25 (9), 1073-87.

 

[Jonathan Edwards]

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.

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.

 

[Sid]

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

 

[Hutan]

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

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.

 

[FMMM1]

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.

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.

 

[Snow Leopard]

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.

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?

 

[Jonathan Edwards]

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.

 

[Kalliope]

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.

 

[Andy]

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/