Distinguishing features of Long COVID identified through immune profiling, 2022, Klein, Iwasaki et al

[Hutan]

This study is interesting in relation to the question of how quickly cortisol responses to activity levels might change:
Stressor-Induced Temporal Cortisol Deficiency as a Primary Trigger for Adaptation to Stress, Latour et al 2022
These were Polish rowers, at a 6 week training camp. They did an exertion test at the beginning and end of the camp. At the beginning, cortisol levels reduced during exertion (these people still would have been "fit" compared to the average person), and increased during the recuperation period. After 6 weeks of intensive training, the rowers managed the exertion without any significant change in cortisol levels. Their baseline production of cortisol had increased.

That all makes complete sense. When (relatively) untrained, the rowers were unable to produce enough cortisol to maintain a steady level during a physical stress, and so there was a bounce back with an increased production after the exertion. After 6 weeks of training really hard, the rower's bodies had increased their baseline cortisol in order to meet the (now) routine physical stress. If the body isn't having to routinely cope with physical stress, it doesn't need as much cortisol and can use resources for other things; if there is routine physical stress, the body adapts, including by increasing baseline cortisol.



They also found that cortisol levels and changes were associated with body fat, and noted that there are other factors that affect cortisol levels including age. It is clear from this 2022 paper that it's complicated.

The literature on the question of cortisol levels in people with ME/CFS (and LC) taken in its entirety does not suggest that cortisol levels are markedly different from healthy people. It seems likely that any differences found are a result of changes in activity levels and other lifestyle changes. And it seems that the body adapts to different levels of stress quite quickly - probably less than 6 weeks.

Like others, I'm concerned that this team, which has the capacity to do useful work, is being distracted by a red herring. There's enough variation in the cortisol levels of people with LC/ME/CFS, and enough overlap with levels of healthy controls to suggest that any differences in the average cortisol levels in any particular study are not causative or diagnostic.

 

[Kalliope]

Science Blood abnormalities found in people with Long Covid

Quote:
An ambitious study of people with Long Covid, the mysterious, disabling symptoms that can trail a SARS-CoV-2 infection, has turned up a host of abnormalities in their blood. The clues add to a body of evidence hinting at drivers of the condition and potential treatments worth testing. They also suggest that, as many scientists and patients have suspected, Long Covid shares certain features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another condition thought to follow an infection.

 

[Jonathan Edwards]

An ambitious study of people with Long Covid, the mysterious, disabling symptoms that can trail a SARS-CoV-2 infection, has turned up a host of abnormalities in their blood.

Like others, I'm concerned that this team, which has the capacity to do useful work, is being distracted by a red herring.

Do we know much about their capacity though? Conducting 'science' via Twitter with gossip columnists at what were once respectable journals lapping it up when all the authors can come out with is some age old mantras that look as if they don't go very far even here - I don't see anything here that would register a twitch on my 'interestometer'.

 

[bobbler]

They also found that cortisol levels and changes were associated with body fat, and noted that there are other factors that affect cortisol levels including age. It is clear from this 2022 paper that it's complicated.

The literature on the question of cortisol levels in people with ME/CFS (and LC) taken in its entirety does not suggest that cortisol levels are markedly different from healthy people. It seems likely that any differences found are a result of changes in activity levels and other lifestyle changes. And it seems that the body adapts to different levels of stress quite quickly - probably less than 6 weeks.

Have they evidenced any of these?

I was still doing a pretty physical job (despite being moderate) when I had a synacthen a decade ago and had to change roles. I've been severe for a number of years when I had one more recently. The results were pretty much identical. I highly doubt my body fat has increased between those two times.

I know that is a sample of one but these experiences of mine make me wonder whether it is assumptions like when I collapse medics say 'were you scared or have you not eaten' yet when male relatives have very different explanations are reached for. I don't think the inability of people to realise these presumptions they've had drilled in from somewhere that isn't fact are different from science is a big problem - which dogs conditions like ME. How many people get such tests before they become ill?

Maybe (and I'm not even sure) if they've come up with these for one-offs in otherwise healthy people it comes up with something for them to say, but isn't that a problem of functional fixedness/not being able to see past certain things to learn other patterns too? 'stress' isn't even something they can measure without maybe cortisol - given it is stress on the body and worse the mind can over-ride people listening to their body on physical stress (hence is a problem rather than a help when taught wrong ideas by certain models or attitudes), so is the opposite to what I ever seem to have seen written about it of recent years.

Re the last line: It would not cause illness (which we have all seen with our eyes, and no CBT doesn't stop overwork/overexertion) if 'the body adapts' to 'whatever', that seems to be a dangerous fallacy/myth being pushed for situations where unsafe levels of stress exertion are involved. Ask anyone who has colleagues leave and ends up with more work, or takes on other committments like caring responsibilities I'm pretty sure they just get more drained and body less well over time when it might have survived just about with adrenaline for the short term? So how have they concluded that?

 

[Sly Saint]

article on the paper

Blood abnormalities found in people with Long Covid
Study implicates lack of key hormone, battle-weary immune cells, and reawakened viruses

An ambitious study of people with Long Covid, the mysterious, disabling symptoms that can trail a SARS-CoV-2 infection, has turned up a host of abnormalities in their blood. The clues add to a body of evidence hinting at drivers of the condition and potential treatments worth testing. They also suggest that, as many scientists and patients have suspected, Long Covid shares certain features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another condition thought to follow an infection.

The new study, posted as a preprint last week, was modest in size, examining just 99 people with Long Covid. “But it went very deep, it went into granular aspects of the T cells, the antibody response,” says Eric Topol, director of the Scripps Research Translational Institute, who was not involved in the work. “This is exploratory, but it’s the foundation for much bigger studies.”

https://www.science.org/content/article/blood-abnormalities-found-people-long-covid

 

[Hutan]

Re the last line: It would not cause illness (which we have all seen with our eyes, and no CBT doesn't stop overwork/overexertion) if 'the body adapts' to 'whatever', that seems to be a dangerous fallacy/myth being pushed for situations where unsafe levels of stress exertion are involved. Ask anyone who has colleagues leave and ends up with more work, or takes on other committments like caring responsibilities I'm pretty sure they just get more drained and body less well over time when it might have survived just about with adrenaline for the short term? So how have they concluded that?

Just to be clear, my post above was talking about another paper, the Latour et al paper, in order to start to answer the question someone asked above about whether levels of cortisol at rest change in response to regular physical activity. That paper shows they do; the rowers had slightly higher cortisol levels at rest after 6 weeks of becoming accustomed to intense physical activity.

So, my point is that it would not be at all surprising if people with Long Covid, who now are just mostly pottering around at home, would have a slightly lower baseline cortisol level than the average person, some of whom are working full-time, going for a jog every morning and a spin class and a yoga class once a week and playing football with the children. Cortisol levels that are within normal ranges but tend, on average, to be a bit lower than normal would be in line with what we might expect to find in people with Long Covid. All that a slightly lower average tells us is that the Long Covid group on average aren't routinely as active as healthy people. Which is not a revelation, or useful.

Do we know much about their capacity though?

Well, they are well-educated, well-resourced, well-funded, have access to Long Covid patients. They should be able to do something useful. I don't understand why they haven't looked at the cortisol literature more critically. (It was the study of the Polish rowers that I found interesting.)

 

[bobbler]

Just to be clear, my post above was talking about another paper, the Latour et al paper, in order to start to answer the question someone asked above about whether levels of cortisol at rest change in response to regular physical activity. That paper shows they do; the rowers had slightly higher cortisol levels at rest after 6 weeks of becoming accustomed to intense physical activity.

So, my point is that it would not be at all surprising if people with Long Covid, who now are just mostly pottering around at home, would have a slightly lower baseline cortisol level than the average person, some of whom are working full-time, going for a jog every morning and a spin class and a yoga class once a week and playing football with the children. Cortisol levels that are within normal ranges but tend, on average, to be a bit lower than normal would be in line with what we might expect to find in people with Long Covid. All that a slightly lower average tells us is that the Long Covid group on average aren't routinely as active as healthy people. Which is not a revelation, or useful.


Well, they are well-educated, well-resourced, well-funded, have access to Long Covid patients. They should be able to do something useful. I don't understand why they haven't looked at the cortisol literature more critically. (It was the study of the Polish rowers that I found interesting.)

Yes, sorry didn't make it clear I wasn't questioning that so to speak - my question was more about it feels a big jump that they have made to infer that ongoing that is accustomisation that is good and follows any set pattern without continuing to monitor. And certainly agree that getting people with the right level of curiousity and who might be capable of a good approach looking at it isn't a waste of time as long as they are open to ruling out as well as ruling in based on findings so the literature goes forward on this question one way or another.

6 weeks is a standard time a normal person could cope with some upswing in stress, before it often then begins to harm so it seems begging evidence and explanation to suggest the 'after' e.g. that this 'sets them up for a year's time' and to potentially generalise beyond the context. I'm no expert on cortisol but get the impression from what I know that the medium term increase is quite a different situation re: body impact to beyond that, and that you start having other patterns that come through if 'turned on' over longer time periods etc. So I'm curious about the next bit almost more than that initial 6 weeks.

Overtraining for example can lead to reductions in cortisol and increased ACTH.

Athletic training has a careful balance where I believe the ideal is to get the body to 'withstand' the 'surge' needed, but also there are discussions you find of reducing cortisol as it interferes with other important factors if 'consistently high'. I'm not sure it is such a complete truism that high resting cortisol is and should be higher in all athletes etc: https://www.researchgate.net/public..._Athletes_and_Nonathletes_A_Systematic_Review

Agree that it might not be surprising/is feasible in the opposite direction if people seem to objectively do less (but then pain and other things relate to cortisol/might make such externally objective ratings 'relative' ie a task harder on a sick body), but I'm wondering what would be good/possible methodology on the 'doing less'. Ill health, infections, injuries etc can lead to increased ACTH and cortisol. I think that cortisol itself in certain patterns over time can then have impacts on the body as well as potentially the HPA system itself showing different patterns over the longer time periods (and of course all these things interact due to the various cycles and balances involved). So at least ACTH seems relevant to be measured alongside and the potential for longitudinal patterns etc.

 

[Kalliope]

Article today about the study where Research Director Signe Flottorp from the Norwegian Institute for Public Health (FIH) comments.

Google translated quote:

The head of research at FHI is not surprised by what emerges in the American study,

- It is interesting, but not surprising, says Flottorp.

The findings in the study have several things in common with the illness chronic fatigue syndrome.

This is something researchers have suspected for a long time because the symptoms have several similarities and because it is suspected that both diseases occur after an infection.

In addition to low levels of cortisol, it was also discovered that several of the patients in the study had a poor ACTH response, another important hormone in the body.

- Low cortisol and poor ACTH response is a consistent finding in many ME studies, and in general in long-term stress, says Flottorp.

She therefore believes that research into the late effects of corona can also provide important answers about other diseases.

- This knowledge can probably also be relevant for understanding and treating the late effects of other types of infections, says Flottorp.

https://www.tv2.no/nyheter/15026080/

 

[Jonathan Edwards]

I have an increasing impression that the world now revolves around people who have tweeted enough times about nothing of importance to be treated as if they have something important to say.

Here we have Mrs Floptop again giving her humble opinion on something she has no particular expertise on as far as I know.

Astronomers talk of things called black holes - into which anything that is sucked never returns. I the world being sucked into a twittering of ignorance?

 

[Ariel]

I have an increasing impression that the world now revolves around people who have tweeted enough times about nothing of importance to be treated as if they have something important to say.

Please get on twitter? Desperate times!

 

[ahimsa]

Why do Some People Develop Long COVID?

6 October 2022 by Gertrud U. Rey

https://www.virology.ws/2022/10/06/what-causes-long-covid/

 

[Hutan]

The most interesting observation in this study was that compared to control groups, long COVID participants had about 50% lower levels of the steroid hormone cortisol. Because cortisol is a potent anti-inflammatory agent, it is feasible that a shortage of cortisol would lead to persistent inflammation and the long-term tissue damage associated with inflammation. In line with this reasoning, cortisol levels were highest in healthy, vaccinated, uninfected controls (group 1 controls); lower in healthy, unvaccinated, previously infected individuals without persistent symptoms (group 2 controls); and lowest in long COVID participants. Using machine learning methods, the authors determined that cortisol deficiency was the single most significant predictor of a long COVID diagnosis. Low cortisol has also been implicated in ME/CFS, and treatment with hydrocortisone can provide some relief from symptoms.

I've got to say, it's disappointing to have this analysis in Virology blog. There's no context, no discussion of the issues with cortisol testing (a single moment versus daily; the interplay between timing of collection and waking time and lifestyle in general; findings in ME/CFS that contradict this finding; the overlap in levels in Long Covid and healthy controls). The way the paragraph is written, it makes it sound like cortisol levels were lower in every person with Long Covid - there's no mention of 'average'. The rest of the article isn't bad though.

@dave30th, I don't think this is the first 'not quite right' article on Long Covid in Virology Blog (not yours, yours are fine of course). If we can't ensure good articles in Virology Blog, what hope do we have for doing that elsewhere? Perhaps there could be a policy that any author writing about ME/CFS or Long Covid is given the suggestion to come here to review content relevant to their article before finalising it? Who proofreads the articles? As I've said before, if researchers or journalists want private comment from members on articles/papers before they are published, the forum would be happy to facilitate that (a private forum, identifying one or two members with relevant expertise who are willing to put time to it).

Who is Gertrud Rey and why did she choose to write about this issue?

 

[ahimsa]

Thanks, @Hutan!

I appreciate folks who are able to analyze and make comments on posts about research. It's not something I'm able to do.

Who is Gertrud Rey and why did she choose to write about this issue?

I can't answer that question, but here's her twitter profile, which has a link to her youtube channel.

https://twitter.com/GertrudRey

And here's a list of other posts she has made on Virology Blog (same link as the original post)

https://www.virology.ws/author/rey/

 

[Hutan]

Just looking at this again, aside from the cortisol issue. This is useful:

Importantly, there were also no baseline differences in the prevalence of anxiety (Fisher’s Exact p = 0.5978 (OR: 1.232 [0.6171 - 2.425]) or depression (p = 0.8339 (OR: 1.192 [0.5394 - 2.607])) across aggregated participant medical histories.

Yet more evidence that pre-existing mental health issues are not risk factors for post-infection fatigue syndromes.

 

[Hutan]

I've been meaning to come back to this study, to see how strong findings other than the cortisol result look.
CC are healthy convalescent controls; HC are never-infected healthy controls

Immune phenotyping of circulating cell populations from Long COVID participants demonstrated specific elevations in both inflammatory and anti-viral immune responses

Non-classical monocytes increased
They suggest that numbers of nonclassical monocytes (CD14lo CD16hi) were elevated in the Long Covid participants: (mean 1.14% LC vs. 0.74% CC vs. 0.86% HC) - LC is in purple in Fig. 2A:



There's a lot of overlap between the groups, but there could be a difference for a subset of the Long covid group . They say that "Non-classical monocytes are frequently associated with anti- inflammatory response programs; however, they are also engaged in maintenance of vascular homeostasis, Th1 anti-viral response polarization, regulation of immune complex deposition, and various chronic inflammatory and autoimmune conditions."

Some background on non-classical monocytes:
Human monocytes are divided in three major classes; classical (CD14+CD16−), non-classical (CD14dimCD16+), and intermediate (CD14+CD16+). Each of these is distinguished from each other by the expression of distinct surface markers and by their functions in homeostasis and disease. There are subsets within the broad categories.

Non-classical monocytes are involved in complement and Fc gamma-mediated phagocytosis and adhesion.They are said to maintain vascular integrity by slowly patrolling the endothelium, reacting to inflammatory signals, and clearing cell debris.
from Nonclassical Monocytes in Health and Disease, 2019

Nonclassical monocytes display a distinct motility and crawling pattern along the vasculature and hence have acquired the nickname patrolling monocytes (18, 19, 21, 78). Patrolling monocytes survey the luminal side of vascular endothelium in an LFA-1- and integrin-α4-dependent manner.
Studies by Geissmann and colleagues have shown that nonclassical monocytes recognize and clear dying endothelial cells in a TLR7-dependent manner to maintain vascular homeostasis (78, 79). Thus, during homeostasis, nonclassical monocytes appear to be sentinels and caretakers of the vascular tissue.

One study found that there were less CD36, CD64, CCR2, CD11b, and CD33 surface markers, but more CD45, CD11c, and HLA-DR expression in non-classical monocytes than in classical and intermediate monocytes.

CD16+ cells (as the non-classical monocytes are) have been found to express higher levels of CX3CR1 which explains the fact that they migrate and adhere more than CD16− cells to fractalkine-secreting endothelium.

Whereas classical monocytes utilize carbohydrate metabolism as their energy source, the non-classical monocytes don't. They have antigen processing capabilities. They are involved in wound healing processes and anti-virus responses. They promote neutrophil adhesion at the endothelial interface via the secretion of TNF-α and do not reach the classical monocyte production levels of pro-inflammatory cytokines. A role for the SLAN+ subset of non-classical monocytes in TNF overproduction in viraemic HIV-infected patients has been proposed, suggesting that they might be considered as a major actor in the immune hyperactivation of the disease.

Numbers of non-classical monocytes are increased with obesity; fasting reduces the numbers of non-classical monocytes. So, one question would be, is there a relationship between BMI and the levels of nonclassical monocytes? Could a high BMI and related comorbidities, perhaps new comorbidities such as T2 diabetes, explain some of the persistent symptoms in the Long covid group?

Numbers of non-classical monocytes are reported to be increased in sepsis, arthritis and multiple sclerosis.

There is an emerging focus on the not yet well explored nonclassical monocytes that maintain vascular integrity by slowly patrolling on the endothelium, reacting to inflammatory signals, and clearing cell debris. In this manner, they are not only crucial for vascular homeostasis but also play a vital role in wound healing and resolution of inflammation by linking innate to adaptive immune response. Although they have been shown to be protective, yet they are also associated with inflammatory disease progression.

Increased abundance of non-classical monocytes expressing HLA-DR

Abundance of maturing (CD15+), MHC Class II (HLA-DR) expressing, non-classical monocytes were similarly elevated (HLA-DR+ mean 5.02% LC vs. 1.22% CC vs. 2.60% HC; CD15+ mean 30.16% LC vs. 22.45% CC vs. 17.59% HC) (Fig 2A). Significant decreases in circulating populations of cDC1 subsets, typically involved in cross-presentation to CD8+ T cells and Th1 response polarization42,43, were also noted among Long COVID participants (Fig. 2B).

Levels of other circulating granulocyte populations (neutrophils, eosinophils, classical and intermediate monocytes, plasmacytoid dendritic and cDC2 populations) were not significantly different between groups, with significant heterogeneities noted among participants with Long COVID (Fig. S2A).

It's pretty much the same story with the percentage of the non-classical monocytes that are expressing HLA-DR+. There is an overlap, but a subset of the Long Covid group does have a higher percentage.



Monocytes presenting HLA-DR+ present antigens to T-cells. Low levels of HLA-DR+ seem to indicate immunosuppression - but, with, on average, higher numbers of non-classical monocytes, and, on average, a higher percentage of those cells expressing HLA-DR+, there's no indication of immunosuppression here, quite the opposite. Patients with sepsis have low levels of HLA-DR+, with patients having more normal levels having a higher chance of survival. Low levels of HLA-DR+ are also associated with acute Covid severity. But here we are seeing high levels.

I found it quite hard to find examples of situations where high levels of HLA-DR+ monocytes are a problem whereas there are lots of examples where low levels are associated with disease. I found one study where people with acute intestinal bacterial infections had higher levels of HLA-DR+ monocytes, than controls, while people with ulcerative colitis and Crohn disease had lower levels.


Increased abundance of non-classical monocytes expressing CD15+
And it's also the same story with the percentage of the non-classical monocytes that are expressing CD15+. That is, an overlap between the groups, but a substantial proportion of the Long covid group has a higher percentage.




CD15 (also called Sialyl LewisX) is a molecule found on the surface of cells. Non-classical monocytes move through the blood stream then tether themselves to the endothelial wall, rolling along it to get to sites of vascular inflammation. So, that's an interesting connection with endothelial dysfunction.


Monocytosis in general is a sign of many different medical conditions including infectious disease like EBV infection and autoimmune diseases like lupus. But, it doesn't look like there was generalised monocytosis.
It would be interesting to know more about subsets within the Long Covid group in this study, and the interactions between the findings in each person.

It would also be interesting to see if there are any studies reporting on non-classical monocytes in ME/CFS. If there isn't, this would be a good thing to look at.

 

[Hutan]

Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) ..., 2021, Patterson et al (in prep)
Bruce Patterson's team actually also found increased levels of non-classical monocytes:

The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection.

They found that the non-classical monocytes contained a Covid protein in people with Long Covid.

 

[Wyva]

So are these non-classical monocytes included in your typical blood test when it tests for monocytes? Because my monocytes have always been elevated since my EBV infection more than 6 years ago, without exception. That's the only value that is off for me. The value is not as high as it was during the mono but sometimes comes quite close. I asked the endocrinologist I visited at Semmelweis University if my Hashimoto's thyroiditis (an autoimmune disease) can cause it and he said no, it must be some other immune problem. I'm also not overweight. Not one doctor paid attention to this value though. My GP's reasoning was that we don't know if it was the same level even before the mono (I'm pretty sure it wasn't, but I don't have my old lab results to prove it).

So I'm wondering if I'm similar to those people with long covid and this is some sort of manifestation of that or not. Mine sounds more like more or less low(er)-grade monocytosis or whatever and if they didn't have the general monocytosis, then maybe it is unrelated.

 

[Hutan]

I think I have seen that the non-classical subset of monocytes is typically 10% of the total number of monocytes (classical + intermediate + non-classical). So the non-classical subset could be increased, with or without the total number of monocytes necessarily appearing abnormal. I'm pretty sure normal blood tests just report the broad category of 'monocytes'.

So, you might have a high level of non-classical monocytes, but it also might be, as you say, a generalised monocytosis. Either way, it's interesting though.

 

[Hutan]

Another thought on the cortisol finding:

This recent paper reported on prescriptions given to people from two very large databases, reporting the odds ratios for people having had a Covid infection in the previous two years or so.
Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative 2023 Zang et al
There were higher odds of previously infected people being prescribed these drugs:
hydrocortisone 1.2
budesonide 1.57
fluticasone 1.38
prednisone 1.35

These are all corticosteroids.

Pharmacokinetic and pharmacodynamic analysis of budesonide 9 mg treatment for 3 weeks in 19 patients with PBC showed significantly lower morning plasma cortisol and urinary cortisol levels in late-stage PBC (cirrhosis) compared with early-stage PBC

Budesonide is Pulmicort turbo inhaler - used to prevent asthma symptoms, irritation of the lungs, used in Covid-19.

With repeated dosing across a dose range of 250-1000 micrograms twice daily, fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol.

Adrenal suppression by inhaled corticosteroids in patients with asthma: A systematic review and quantitative analysis

From analysis of 64 studies identified in the review, the strongest dose-response urinary cortisol suppression was observed in patients treated with beclomethasone (8.4% per 100 μg; p = 0.029), followed by fluticasone (3.2% per 100 μg; p < 0.001), and budesonide (3.1% per 100 μg; p = 0.001).

I think the problem is that "Long covid" is such a mix of conditions. Finding the "distinguishing features of heterogeneous conditions - twitchy lungs and lingering coughs; ME/CFS; heart issues; anosmia; and more - isn't really possible.

So I think what has happened instead is that at least two things are favouring the lower average cortisol. One is the issue I've already posted about - people with post-covid ME/CFS have, on average, a lower activity than the controls, so their bodies have adjusted the level of cortisol down a bit. The other issue I think might be at work here is that some of the people with lingering symptoms are taking various corticosteroids which is suppressing their endogenous cortisol. There might also be a residual effect from steroid treatments during the acute covid-19 infection for people who had severe acute illnesses - these people are probably more likely to still have symptoms.

I haven't looked into the latter much, so I may be wrong. But I reckon it's worth thinking about.
Edit to add: I did see this exclusion for the selection of participants

immunosuppression equivalent to or exceeding prednisone 5 mg daily

But, that's just prednisone.


I think the higher IL-8 levels that were reported may also be indicative of lung injury than post-Covid ME/CFS.
The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome, 2022

crucial role of IL-8 in lung inflammation and disease pathogenesis

We really need these researchers to re-analyse their data, with the Long Covid people stratified into groups according to their symptoms. And researchers in general to stop using Long Covid, and be specific about symptom groups.

 

[Hutan]

More on that exogenous corticosteroid possibility:
Is there a safe and effective way to wean patients off long-term glucocorticoids?, 2020

In a systematic review of studies measuring adrenal function following systemic glucocorticoid exposure, Joseph and colleagues found that a median of 37% (interquartile range 13–63%) patients had adrenal insufficiency.20 Adrenal insufficiency occurred even with low dose (<5 mg prednisolone equivalent) and short duration (<4 weeks) glucocorticoid treatment and following tapered withdrawal. It persisted in 15% patients retested 3 years after glucocorticoid withdrawal. In a separate review, Broersen and colleagues found that there was no administration form, dosage, treatment duration or underlying disease for which adrenal insufficiency could be excluded, although increased dose and duration of treatment were associated with increased risk.21

I haven't looked closely to see if that is likely to be true, but it does sound concerning.