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Research Review: What is causing Long Covid?

The Neurobiology of Long Covid by Michelle Monje1,2 and Akiko Iwasaki 3,4

  1. Department of Neurology, Stanford University
  2. Howard Hughes Medical Institute, Stanford University
  3. Department of Immunobiology, Yale University
  4. Howard Hughes Medical Institute, Yale University

This is one of the most comprehensive and impressive reviews of findings from all the different neurological research studies that are trying to find the cause of Long Covid. The connection to ME/CFS is acknowledged:

“A subset of PAIS [post-acute infection syndromes] patients develop myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic and debilitating condition with neurological and immunological symptoms accompanied by chronic fatigue that is not relieved by sleep or rest”.

Not surprising, almost all of the main neurological and immunological findings to be reported so far are very similar to what we already know about causative factors for ME/CFS. In particular:

— Involvement of the autonomic nervous system – causing symptoms such as orthostatic intolerance and PoTS

— Structural changes in brain anatomy

— The possibility of cytokine-mediated neuroinflammation

— Downregulation of the hypothalamic-pituitary-adrenal axis leading to lowered levels of the hormone cortisol (which is produced in the adrenal glands)

— On-going immune system activation

— An autoimmune component – with production of potentially harmful auto-antibodies

— Defective mitochondrial function and muscle energy metabolism

— Reactivation of dormant herpesvirus infections – such as Epstein-Barr virus

— Overlap with mast cell activation syndrome

But there are a couple of findings which are probably directly related to COVID-19 infection:

— First is the possible involvement of small blood clots (micro-clots) in the tiny blood vessels (capillaries)

— Second is the way in which some people with Long Covid report a significant improvement in symptoms after vaccination whereas people with ME/CFS often experience an exacerbation of symptoms following a vaccination. However, people with ME/CFS are seldom given a vaccination against the infection that triggered their condition.

And it's important to note that that as Long Covid involves a specific infection (COVID-19) that can affect almost any organ and tissue in the body there are a significant proportion of people with Long Covid who have symptoms that are directly related to damage involving the lungs, heart, kidneys, liver etc.

Overall, these research findings help to confirm what we have been pointing out at the MEA since May 2020 – that there are important clinical and pathological overlaps between ME/CFS and Long Covid

If Long Covid researchers had acknowledged this fact and collaborated with the ME/CFS research community from the very start this would have been to the advantage of people with both conditions

Dr Charles Shepherd,
Trustee and
Hon. Medical Adviser
to the ME Association.
Member of the 2018-2021 NICE Guideline Committee.
Member of the 2002 Independent Working Group on ME/CFS.

Dr Charles Shepherd
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