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

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.

 

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.)

 

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?

 

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

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

 

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

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

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.

Increased abundance of non-classical monocytes expressing HLA-DR

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.

 

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:

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

 

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.

 

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.

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

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

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

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

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.

 

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

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