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This is the second in a series of blogs on the IACFS/ME 2022 International Conference on ME/CFS (and long COVID). The last one focused on David Systrom’s Keynote address. This one focused on an hour-long talk that kicked off the keynote session.

Top Immunologist Featured in Keynote Session

Akiko Iwasaki

Akiko Iwasaki PhD jumped on long COVID early.

The IACFS/ME really scored when they got Yale immunologist Akiko Iwasaki to start off the keynote session. Iwasaki’s co-leading the Yale COVID-19 Recovery Study, as well as multiple other studies, and is developing animal models for the disease. She was recently featured in a Wired piece on brain fog and long COVID, and has given updates on long-COVID research to the American Medical Association. In short – she’s right in the middle of things – just the person to get us up to date on some exciting new research – which she proceeded to do in her hour-long talk on the “Immunology of long COVID”.

Animal Models

With the reinvigorated Simmaron Research team using an animal model to uncover some potentially fascinating aspects of ME/CFS, animal models are in the air. Given the central role they play in medical research, it’s not surprising at all to see Iwasaki quickly turn to one. Iwasaki and Michele Monje at Stanford produced an animal model to test one of four major immunological possibilities believed to be driving the central nervous system issues in long COVID.

Four long COVID hypotheses

Four long-COVID hypotheses. (from Choutka 2022)

They include an infection in the central nervous system, autoimmunity, tissue damage, inflammation produced in the body by an infection or other means. They tested the last hypothesis by inserting the ACE-II receptor the virus uses to infect cells in humans into the lungs of the mice and then infecting them with the coronavirus. Having the ACE-II receptor be only present in the lungs meant there was no chance of central nervous infection.

Seven days later, an upregulation of the cytokines in the cerebral spinal fluid indicated that the inflammation in the lungs had made it to the central nervous system. Those cytokines remained elevated over the 7 weeks of the study. Interestingly, a chemokine called CCII – which has been found in another long-COVID study – was elevated as well.

Even in mice with mildly COVID-reactivated microglia – long thought to be the source of neuroinflammation in ME/CFS – were found. These findings fit with those from Iwasaki’s long-COVID autopsy study which found increased microglial activity in the white matter surrounding the nerves. The hippocampus – a part of the limbic system involved in encoding memories – was particularly hard hit with a reduction in nerve generation found and a significant loss of the oligodendrocytes that protect the nerves and support the production of the myelin that covers the nerves. A significant reduction in myelinated axons, which would surely impair communication in the brain, was also found.

The conclusion: a direct infection of the central nervous system is not needed for significant damage to occur – even with mild COVID. An infection or inflammation in the periphery (the body) is all that is needed.

The Gist

  • The second IACFS/ME Conference blog covers Iwasaki’s immunology presentation, which started off the keynote session. Iwasaki is an accomplished immunologist who, with David Putrino, jumped on long COVID early.
  • A mouse study found that a mild COVID infection in mice that does not reach the brain produces significant central nervous system damage including microglial activation, neuroinflammation, and damage to the myelin coverings of the nerve axons, particularly in the hippocampus region of the limbic system. Some evidence of myelin problems and neuroinflammation has been found in ME/CFS. 
  • She relayed the results of an unpublished study that assessed long-term long-COVID patients who had been sick for an average of 400 days. 
  • A large study of long-COVID patients who’d been sick for well over a year found numerous immune aberrations including high levels of monocytes, exhausted T-cells, and the presence of double-positive T-cells.
  • High levels of anti-coronavirus antibodies indicated that even after all this time, the patients’ immune systems were still responding to the virus – either because it or parts of it were still present, or because an autoimmune or inflammatory response to it remained.
  • The coronavirus wasn’t the only virus the immune system was responding to – high antibody levels and markers of activation suggested that herpesviruses, in particular, EBV and varicella-zoster, have become reactivated and were possibly having major effects. 
  • The factor that REALLY differentiated the long-COVID patients from the healthy controls, though, was low cortisol. Iwasaki called the low cortisol levels “highly predictive” and noted that they alone were enough to determine who had long COVID and who was healthy.
  • Low cortisol levels were also predictive of severity: the lower the cortisol levels – the worse off the long-COVID patient was. Normal ACTH levels left the reason for the low cortisol levels a mystery. Autoantibodies that are whacking the hypothalamus/pituitary are a top hypothesis and she is looking for them now. 
  • The cortisol and EBV findings fit very well with ME/CFS. They also fit well with what we know of overtraining syndrome in which a plethora of endocrine abnormalities including reduced cortisol and hypometabolism have been found. Low cortisol has also been found in fibromyalgia. 
  • This is the second major long-COVID study to find evidence of low cortisol and EBV reactivation. 
  • Iwasaki is interested in doing a similar ME/CFS study but doesn’t have funding for it.

 

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Chronic Fatigue Syndrome (ME/CFS) Connection?

We’ve heard a lot about microglial cells in ME/CFS (see Renz-Polster’s paper for a review) and fibromyalgia, but what about the oligodendrocytes that create the myelin sheaths that protect and support the long axonal sheaths that reach from one nerve to the other. Without healthy axons, the nerves can’t communicate with each other. Have problems with oligodendrocytes and reductions in white matter (axons) shown up in ME/CFS/FM?

In “The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure“, Renz-Polster and friends point out that reduced white matter volume and impaired myelination have been found in ME/CFS, but the findings have been inconsistent. Time will tell with that.

Hugely Predictive Factor Found

That was intriguing – what came next was kind of mind-blowing. When you search back through the history of ME/CFS research, you find two themes that dominated research in the early years – herpesviruses and the HPA axis: both came up big-time in this mammoth study. How right it was that it was at an ME/CFS conference that Iwasaki first shared their results.

Iwasaki noted that she can Dave Putrino have been collaborating for two years on the Mt Sinai-Yale Long-COVID study; i.e. as soon as long COVID hit – they were on it. Like Iwasaki, Putrino’s been featured in several media articles and podcasts on long COVID.

He was recently featured on Science Friday with Ira Flatow where he underlined how little the message about long COVID has gotten out: People with ME/CFS have been watching with dismay as officials like Anthony Fauci failed to warn the public in a timely manner about the dangers of long COVID.

“I think that from the outset, long COVID has been treated more like a shadow pandemic and less like an actual pandemic. People have not been giving it the level of attention it deserves as a mass disabling event in the United States. And the current sort of switch away from safe practice across the nation should be cause for alarm for everybody.”

 

“Long COVID is very much a continuing issue that we need to be strongly concerned about. And we still need to strongly get out the message that death is not the only serious outcome of COVID, especially non-hospitalized COVID cases– these so-called mild cases of COVID. There’s nothing mild about an acute case of COVID right now.”

He also underscored the very interesting and troubling finding that people can get through their coronavirus infection without any symptoms at all – and still come down with long COVID.

“We know for a fact that your chance of contracting long COVID is not correlated with the initial severity of your symptoms. So we have certainly seen many individuals who had an asymptomatic course of COVID-19 infection go on to develop long-COVID symptoms, which is incredibly alarming when we consider the fact that it’s hard enough right now to get insurers and other care providers to take long COVID seriously when you have a known case of COVID.”

Back to the Study

Iwasaki and Putrino (and a huge team of collaborators) appear to have thrown just about everything they could (electronic medical records, flow cytometry, antibodies, peptide metabolomics) at their long-COVID patients. They ended up measuring thousands of parameters and assessed hundreds of immune cells for each participant.

T-cell exhaustion

T-cell exhaustion has been found in both long COVID and ME/CFS.

These weren’t newbie long -COVID patients they were studying, either. This wasn’t one of those studies focused on patients who had had long-COVID for 1 month or 3 months. With the average time since infection averaging 410 days, long COVID had had ample time to settle in and do its work. These patients came the closest we’ve seen yet to approximating an ME/CFS patient.

Monocyte levels were up (Dr. Patterson would probably like that), dendritic type 1 cells were reduced, and activated B cells were still up.

Reduced levels of CD4 T memory cells suggested that the immune system was having trouble raising the alarm. The presence of “double positive T-cells” which function as both helper and cytotoxic T-cells suggested something strange was indeed going on. The exhausted T-cells suggested that an important part of the immune system had been overwhelmed.

Immune exhaustion has become something of a theme in ME/CFS. First came exhausted NK cells in ME/CFS. Next, there was a glimmer of evidence that the T-cells were exhausted as well. Now – as evidenced by Liisa Selin’s fascinating talk – exhausted T-cells look like they might be a pretty big thing in ME/CFS.

High levels of Anti-SARS IgG antibodies suggested that something somewhere – whether it was the virus itself, a piece of it, or an autoimmune reaction to it, was keeping the immune system activated. On that note, some cytokines (Il-2, IL-4, IL-6) were also elevated.

“Hugely Predictive Factor”

low cortisol

Low cortisol levels were “hugely predictive” for long COVID.

But then came the “hugely predictive” factor – reduced cortisol. Of all the factors, abnormally low cortisol levels were the factor that really differentiated the long-COVID patients from the healthy controls. Iwasaki noted that another long-COVID study found reduced low cortisol after 2-3 months, but their study – done after 18 months – found even more reduced cortisol – suggesting that cortisol levels had continued to drop.

Low cortisol, as well as high chemokines and lectins, were also the factors most associated with increased disease severity. Why the cortisol was so low – about half normal – was a mystery as the levels of its trigger, ACTH, were completely normal.

Machine-learning, an analytic process that Dr. Patterson used with his long-COVID patients, was very accurate at predicting long COVID. It indicated, again, that cortisol was the number one factor distinguishing long-COVID patients from healthy controls. That was followed by alterations in T-cells, EBV antibodies, and reactivity to EBV. Decreased cortisol alone is able to efficiently distinguish long COVID.

Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Connection

Interest in the HPA axis – which regulates the production of cortisol – in ME/CFS dates back 30 years. While the cause of the low morning salivary cortisol was never identified, several problems in the HPA axis did pop up over time.

Several factors made the HPA axis and cortisol an obvious early choice. Cortisol’s regulation of the stress response, metabolism, the sleep-wake cycle, and in suppressing inflammation means it has the potential to affect many of the processes at play in ME/CFS and long COVID. While HPA axis work declined over time, in ME/CFS it never really stopped. One intriguing 2018 ME/CFS study linked epigenetic modifications in T-cells to an impaired response to glucocorticoid hormones, such as cortisol, in a subset of patients. Dr. Klimas’s model-generated protocol for Gull War Illness (GWI) and ME/CFS includes both an immune modulator (etanercept) and drug (mifepristone) that she hopes will reset the HPA axis.

Powerful Models Accurately Predict Response to Exercise and Treatments in ME/CFS

Low cortisol has also been found in fibromyalgia as well as prolonged critical care illness – which may be a close cousin to ME/CFS. A 2022 fibromyalgia study found that low salivary cortisol was associated with cognitive issues.

Cognition II: Cortisol, Fibromyalgia, ME/CFS … and Functional Cognition Disorder (?)

Epstein-Barr Virus (EBV) Pops Up Again

Research into EBV stretches even further into the history of ME/CFS – and continues today, as well, with studies regularly popping up.

The virus ME/CFS has been associated with more than any other has already popped up in a couple of long-COVID studies. One review suggested it might even be knocking off the mitochondria. This study found high elevations of antibodies to EBV, suggesting that it had become reactivated. Iwasaki highlighted one very interesting – to her – correlation: increased EBV reactivity was correlated with a T-cell measure (which I missed). The tight connection suggested EBV reactivation might be playing a strong role in the immune abnormalities seen. Another herpesvirus – varicella-zoster – was also found.

In his Science Friday interview, Putrino echoed what Dave Patterson found – it’s not just EBV – all sorts of past viruses are getting reactivated in long COVID.

“So many people who previously had Lyme disease, but it’s been quite dormant for some time, can experience worsening of Lyme symptoms. Epstein-Barr Virus is another very common virus that people are experiencing reactivations of. And the list goes on. There are many, many previous viruses that can be reactivated by the immune sequelae of long COVID.”

Q&A

A fascinating question concerned whether Iwasaki would consider replicating the work of Goebel et al. which found that putting IgG antibodies from fibromyalgia patients into mice gave them FM.  Goebel found the autoantibodies were attacking the dorsal root ganglia – which regulates the sensory signals entering the spinal cord. Iwasaki said she is finding some autoantibodies against neurons and has something similar in the works. Let’s hope she can do it and Goebel can get an ME/CFS study done.

Study Suggests Something in the Blood is Causing Fibromyalgia

She also agreed with Ray Perrin that the glymphatic drainage that clears toxins from the brain could be backed up in long COVID. Her group is now measuring salivary cortisol several times a day in long-COVID patients. She is hearing from a “significant number of people” who reported long-term health problems after vaccination. She wants to study these patients in the future as the immune analyses they use are incredibly sensitive. She agreed that autoantibodes to the hypothalamus or pituitary could be causing the low cortisol and that that was one of the top hypotheses they’re testing right now.

With regard to doing a similar ME/CFS study, she said she was trying to do a similar study but didn’t have funding for it. She said she was extending analyses, though, to ME/CFS with the help of Amy Proal and Michael Van Elzakker.

Conclusions

A mild COVID infection in mice that does not reach the brain produces significant central nervous system damage including microglial activation, neuroinflammation, and damage to the myelin coverings of the nerve axons, particularly in the hippocampus region of the limbic system.

A large study of long-COVID patients who’d been sick for well over a year found numerous immune aberrations including high levels of monocytes, exhausted T-cells, and the presence of double-positive T-cells.

High levels of anti-coronavirus antibodies indicated that even after all this time the patients’ immune systems were still responding to the virus – either because it, or parts of it, were still present or because an autoimmune or inflammatory response to it remained. The coronavirus wasn’t the only virus the immune system was responding to – high antibody levels and markers of activation suggested that herpesviruses, in particular, EBV and varicella-zoster, have become reactivated.

The factor that REALLY differentiated the long-COVID patients from the healthy controls, though, was low cortisol. Iwasaki called the low cortisol levels “highly predictive” and noted that they alone were enough to determine who had long COVID and who was healthy. They were also predictive of severity: the lower the cortisol levels – the worse off the long-COVID patient was. Normal ACTH levels left the reason for the low cortisol levels a mystery. I don’t think anyone thinks low cortisol levels are “it” in long COVID and ME/CFS – these are complicated multisystemic diseases – but it sure showed up big time in this study.

The cortisol and EBV findings fit very well with ME/CFS. They also fit well with what we know of overtraining syndrome in which a plethora of endocrine abnormalities (blunted and late GH (growth hormone), reduced cortisol and prolactin responses to a central stimulation test, reduced testosterone), as well as hypometabolism, have been found.

Novel Insights into Overtraining Syndrome Suggest Chronic Fatigue Syndrome (ME/CFS) Connection

Encouragingly, they also appear to fit well with Deeks’s massively complex 2021 long-COVID study which also highlighted low cortisol and EBV reactivation\.

Major Long COVID Study Brings Autoantibodies and Epstein-Barr Virus to the Fore

Iwasaki warned that more studies need to be done to confirm her findings, but it’s very good to see two such complex studies come to similar conclusions – and to have those conclusions match what we’ve seen in MECFS and fibromyalgia.

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