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Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID 2022 Yavropoulou et al

Discussion in 'Long Covid research' started by Andy, Oct 2, 2022.

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  1. Andy

    Andy Committee Member

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    Abstract

    About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic–pituitary–adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID.

    We suggest that the inability of hypothalamic–pituitary–adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

    Open access, https://www.sciencedirect.com/science/article/pii/S1521661622002145
     
  2. Arnie Pye

    Arnie Pye Senior Member (Voting Rights)

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    The phrasing of this suggests to me that they didn't expect depression and anxiety to be increased with low cortisol. I wonder why?
     
  3. Hutan

    Hutan Moderator Staff Member

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    [Preprint] Distinguishing features of Long COVID identified through immune profiling, 2022, Iwasaki et al
     
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  4. Hutan

    Hutan Moderator Staff Member

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    These authors have jumped on the low cortisol finding in Long Covid of the Iwasaki paper and put it together with the IOM report supposedly saying that low cortisol levels are a feature of ME/CFS:
    Reference #10: Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness
    JAMA, 313 (2015), pp. 1101-1102 ( I can't access the IOM paper to see what it says.)

    These authors assume that people have a stress-induced burn-out of cortisol production, and then when a virus comes along, there is an inability to produce increased levels of cortisol, resulting in the immune system going berserk.
    Screen Shot 2022-10-03 at 10.12.53 am.png


    It sounds all so neat and all the HPA axis proponents want it to be true. The only problem is that the evidence for the idea is so poor. We've tracked the papers about cortisol here, and they together don't add up to low cortisol being a feature of ME/CFS. There have been prospective studies, and if it was as simple as low cortisol and chronic stress prior to an infection, that would have been identified.
     
    Last edited: Oct 3, 2022
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  5. Arnie Pye

    Arnie Pye Senior Member (Voting Rights)

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    I've got extremely confused about what is being said in this thread so this reply is probably irrelevant and pointless, but I would assume that low white blood cell levels would lead to a poor response to infection. I'm unclear how cortisol comes into this at all, unless the authors are suggesting that some people don't respond well to stress and/or can't produce sufficient cortisol for their needs?

    If the suggestion is that some people don't respond well to stress then no doubt it will be used to support the idea that the "patient is emotionally / psychologically / mentally ill and just needs CBT and exercise".

    I'm assuming that CRH is corticotropin-releasing hormone. I looked up what wikipedia has to say about CRH and ACTH.

    I find it ironic that this paper mentions ACTH. It almost never gets measured when inadequate cortisol is suspected. If you look at pages 68 - 70 in this document :

    http://imperialendo.co.uk/Bible2018.pdf

    it gives the protocol for a Short Synacthen Test. In reality, the ACTH part of the test is very rarely done because "Oh, that's really rare", and as a result, in real life, secondary and tertiary adrenal insufficiency can't actually be diagnosed.
     
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  6. boolybooly

    boolybooly Senior Member (Voting Rights)

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    OK inconsistent evidence I can believe ... but low cortisol has been discussed before and I think if true the depletion paradigm is overly simplistic and probably presumptious. I think the alternative might be an adaptive response, maybe for some individuals or subtypes, which primarily reduces immunosuppression in the situation where there is an immune response ongoing.

    As I mentioned in my blog long ago.
    https://boolyblog.blogspot.com/2010/12/calming-mental-overactivity-in-me.html

     
    Last edited: Oct 3, 2022
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  7. Shadrach Loom

    Shadrach Loom Senior Member (Voting Rights)

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    If there are valid grounds to suspect primary, secondary or tertiary adrenal insufficiency, they will do SSTs and ACTH testing at the drop of a hat, even if cortisol is only mildly depressed.

    But, yeah, endocrinological resources are tightly controlled and they don’t act on patient (or primary care) suspicion unless bloods or scans tell them to. I’ve yet to meet an endocrinologist who has any interest at all in “fatigue”, and I’ve met quite a few now.
     
    Last edited: Oct 3, 2022
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  8. Arnie Pye

    Arnie Pye Senior Member (Voting Rights)

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    I often read a thyroid forum. Cortisol issues are common with thyroid disease. Patients have huge difficulty getting an SST which includes getting ACTH tested. Several have said "I asked my doctor to test for secondary or tertiary adrenal insufficiency" and they refused saying it was "really rare" implying the patient wasn't worth the effort and the expense. Thyroid patients are treated better than ME patients generally because many people with thyroid disease can be treated if their disease is actually recognised, but overall they have a lot in common. Most patients are female and they are told their problems are caused by one or more of the following :

    1) You've just gone through puberty. You'll be fine when your hormones settle down.
    2) You've just had a baby. You'll be fine when your hormones settle down.
    3) You're going through the menopause. You'll be fine when your hormones settle down.
    4) You're only tired because you've just had a baby and you are working too. What else do you expect?
    5) Patient complains about fatigue, memory problems, muscle pains... Doctor says "You're over 50, what else do you expect?
    6) There's nothing wrong with you.
    7) Your TSH is only just over the range but we don't treat until TSH is over 10, so you have a long way to go before your thyroid is really in trouble.
    8) T3 is a waste product of thyroid metabolism. It doesn't matter if it is low. [It is actually the active thyroid hormone required by every cell in the human body.]
    9) Thyroid hormones are addictive. You only want them to help you get through your housework quicker. [Yes - an actual quote from an endocrinologist.]
    10) All thyroid hormones do is give you a feeling of well being. [What's wrong with feeling well?]
    11) Don't read thyroid forums. They write a lot of dangerous rubbish.
     
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  9. bobbler

    bobbler Senior Member (Voting Rights)

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    Personally I do not think that you can measure cortisol in something like ME the way they assume they can for others - due to the exertion involved with just getting to the blood test. This needs to be something that is flagged to be borne in mind. The only thing I can really think of to get definitive ideas of what you are actually measuring (and even then - is it, given PEM?) would be to look at peak cortisol post ACTH injection. Otherwise what point of a huge exertion or PEM cycle are you measuring it?

    If they think as far as saying 9am for others - partly because of the cycle meaning this should be 'at a certain point' (even tho it is pulsatory anyway) - and probably that gives some consistency that most wont have just run a marathon or had a sensory overload implicit within that, then how relevant is methodology for those with ME?

    This would present a validity issue where the assumption of a 9am test is that is 9am cortisol when actually it is almost peak cortisol due to the physical stress of getting oneself to the appointment itself. Plus maybe any other phenomena associated with prior PEM not being able to be isolated.

    This sort of thing is why I'd like workwell to focus on the PEM stuff next ie what happens in PEM or from turning up (and resting) right the way through. We sort of need to know surely if we are looking at these important things, what approx these things look like?
     
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  10. bobbler

    bobbler Senior Member (Voting Rights)

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    When I first heard of this type of thing (2011) it was very much emphasised that the term stress was being used for physical - in a 'load' sense, or 'exertion' (cumulative included) which did very much equate to ME (and wasn't someone saying it that way as a soft soak/con when they really meant 'anxiety). The big difference between then and now seems to be the BACME and others' focus on trying to rewrite the term stress into meaning anxiety-type predominantly.

    This warping of vocab is a real issue for our area because in the truest sense our condition is indeed one of exertion and the stress that places on the body, but the last thing we want is that basic getting lost due to others who either have an agenda or an intelligence issue and confuse the two (EDIT for clarity : anxiety and stress).
     
    Last edited: Oct 3, 2022
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  11. Hutan

    Hutan Moderator Staff Member

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    There was a study of cortisol levels in hair, possibly more than one study. The advantages of that approach is that it gives you a great time series, the sampling can be done at home without exertion and it gets around issues with the timing of peak cortisol to give an idea of total cortisol. I'm not aware of abnormal levels of cortisol in hair being found, on average, for people with ME/CFS.

    I managed to get an ACTH challenge test, and it was normal. If the results of an ACTH challenge test aren't normal, then the patient has a (treatable) reason for their symptoms. That would suggest to me that an earlier diagnosis of ME/CFS should be withdrawn, at least until cortisol levels are normalised.
     
  12. bobbler

    bobbler Senior Member (Voting Rights)

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    Have they suggested that normalisation of cortisol levels in the examples above will relieve the participants of having long covid? And what would normalisation look like vs what it is currently if they've only taken the above measures?

    Or would it make them more like the others with long covid who have normal cortisol levels? or just relieve them a bit of the symptoms specifically related to that issue? or some other unexpected happening long term? We don't know until the methodology and longitudinal follow-up is there?

    The hair one sounds like an interesting data point agreed. How finely grained are the time series possible these days, what would it be showing (is it averages or by day/hr etc)?

    Given cortisol is supposed to be related to exertion in normal people (among other things), wouldn't better exertion data would be a useful pair to correlate it to? If we don't/can't measure 'exertion' in PwME (as a walk to the toilet vs turning over in bed might equate to similar impact to a jog in healthy controls, and they've tried to use 9am to anchor that for the tests for a reason) then what 'cortisol' are we measuring - just like many other things trials might take measures for without knowing how much PEM someone is in or how much exertion getting to the test took? So I'm intrigued by this for LC and considering what it 'means'/relates to as a measure.

    I was under the impression that cortisol was one that had found some variation across PwME already (but again what does that really mean given what our bodies go through), and that for some steroids are part of their POTS management, but without having found a fix for the underlying disease as yet, and that steroids (and stimulants etc) aren't straightforward because of the PEM issue with going over energy threshold inadvertently. I may well be inadvertently putting my foot in it as I'm neither suggesting averages nor that it is a driving underlying mechanism for all ME/LC, as surely even bad medicine might have noticed PEM and all the rest of symptoms disappearing with steroids by now (if rituximab was spotted), but it's perhaps a bit to unpick if we are ever going to get near homogenity in trial/research conditions for other things?

    I think this is a useful one to study - in the right way (the hard bit) - as others will, using presumptions about certain theories. ME is such a hard one to study as the heterogeneity can be down to types, wellness at time of individual systems (which could be down to different ways in which it could be 'live' or 'flaring' or 'under exertion', PEM, severities, different stages, different 'weaknesses' that might get worsened/hit and different environments) and we have chicken or egg questions going on within this.

    LC may in some or may not be similar in some to the ME in others (we don't know) but the one thing it has going for it is seeing how a challenged system progresses over time with things such as this. It also stands a chance of at least some of those with it (certainly those under experimental conditions) possibly having adjustments and tools (heart rate measurement) to see more consistency of knowing about their exertion vs their results over that time frame.

    Lots of diseases/issues cause further knock-on effects, some necessary adjustments trying to find some sort of new 'balance' others just getting knocked off kilter or downstream 'damage' of some kind. Like a bad knee either getting progressively more gnarly due to whatever is underlying that or causing a bad ankle or a bad hip or a bad other knee or a bad shoulder (from leaning on something) and so on. It makes sense that over time the variability may increase across different bodies and picking up the 'hows', and those reasons would be insightful given so little is known longitudinally about 'post'-viral in general it seems.

    I'm guessing it will be investigated in LC so if got right with really clever methodology it might provide some useful bits that could be insightful for the general area (which again might have some relevance for some with ME, or indeed be a jigsaw piece puzzle that doesn't elicit symptoms in all but can be controlled for - I don't know what the right term is).

    And if the part associated with that is treated in some who have it then I don't know but would be intrigued to see how different that makes them to the others who had LC without it in the first place over time, or indeed those who aren't treated. Yet more questions I guess
     
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  13. Sean

    Sean Moderator Staff Member

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    They also do it in conflating GET with pacing.
     

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