Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Shanti1

Moderator
Messages
1,798
Likes
4,275
Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Stanculescu D, Bergquist J. Front Med (Lausanne). 2022 Mar 8

We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS.

Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.
Discussion
Hypoperfusion and endotheliopathy, intestinal injury, pituitary suppression, and low thyroid hormone function are each central to prolonged critical illness regardless of the nature of the initial severe injury or infection (101, 173, 195, 196). We propose that, similarly, these mechanisms and their reciprocal relationships with inflammation could underlie ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins or other) (Table 1). Moreover, the severity of ME/CFS may be a function of the strength of these mechanisms...
1650154255461.png


Conclusion
Decades of research in the field of critical illness medicine have demonstrated that in response to the stress of severe infection or injury, the vascular system, intestines, endocrine axes and thyroid hormone function experience profound alterations. Self-reinforcing interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation may perpetuate illness irrespective of the initial severe infection or injury. Without excluding possible predisposing genetic or environmental factors, we propose that the pathological mechanisms—and the interlinkages between them—that prevent recovery of some critically ill patients may also underlie ME/CFS. This initial proposal is in line with and complements several existing hypotheses of ME/CFS pathogenesis. If this hypothesis is validated, past treatment trials for critical illness may provide avenues for a cure for ME/CFS. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved understanding of not only both conditions, but also PICS, long-COVID, PACS, and fibromyalgia.

This paper is a sequel to and builds on this earlier Jan 2021 paper:

Stanculescu D, Larsson L, Bergquist J. Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Med (Lausanne). 2021 Jan

Discussed here on PR: https://forums.phoenixrising.me/thr...elitis-chronic-fatigue-syndrome-me-cfs.82761/
 
Messages
11,115
Likes
26,495
a brief interlude of Googling on the topic of treating post ICU illness.....it doesn't sound like they really know how to treat it at all. Places treating such things- it sounds like a GET and CBT type approach to fighting your way back.
 

Shanti1

Moderator
Messages
1,798
Likes
4,275
a brief interlude of Googling on the topic of treating post ICU illness.....it doesn't sound like they really know how to treat it at all. Places treating such things- it sounds like a GET and CBT type approach to fighting your way back.
The paper authors don't seem to be GET/CBT proponents, but they also don't offer many solutions. This is what they have to say on treatment:
Relevance of Critical Illness Treatment Trials for ME/CFS
Although prolonged critical illness remains unresolved, early treatment trials—such as the reactivation of the pituitary, or interruption of the vicious inflammatory cycles centered around either gut injury or low thyroid hormone function—may provide therapeutic avenues for ME/CFS (19). Longitudinal studies of (spontaneous) recovery from critical illness may also give clues about prerequisites for recovery from ME/CFS. Researchers have, for example, found that “supranormal TSH precedes onset of recovery” from prolonged critical illness (96) and that metabolic rate rises > 50% above normal in the recovery phase (213).

I saw this paper get picked apart on s4me
I think the paper makes some connections that are interesting to consider, but I was left trying to follow the threads of the paper to something that was tied together more conclusively. It feels like the authors were trying to make the science conform to a pre-decided hypothesis, but are missing pieces and evidence to make it convincing instead of tenuously held together.

I debated posting, but the authors touch on several aspects of ME and try to relate them to each other, which is what we are all trying to do. I tend to think that most people with Post-Intensive Care Syndrome (PICS) have a different etiology than people with ME/CFS, but in both cases, the body has been destabilized and this is reflected in the commonalities outlined by the authors.
 
Messages
819
Likes
1,441
I wonder how those anecdotal (and clinical case study) reports of increasingly higher dose T3 therapy leading to remissions fit into here.. I made a thread about them months ago and nobody seemed interested.!


Also would larazotide (and perhaps repairative peptides such as BPC-157) play any role in resolving the intestinal barrier problem? I tried BPC but it just made me feel wired and wore me down into a flare by overdoing it. I didn't take it orally though.

@mitoMAN did you find any ME benefits from larazotide? Or only reduced gluten sensitivity. Maybe it needs long term ongoing treatment for the barrier functions to slowly correct. Perhaps in combination with trying to fix the microbiome and promoting/supplementing butyric acid/butyrate?
 
Messages
11,115
Likes
26,495
The paper authors don't seem to be GET/CBT proponents, but they also don't offer many solutions. This is what they have to say on treatmen
I was noting that places which advertise as where you go to Recover from an ICU intense event: its shrinks, PTs, respiratory therapist (many were on ventilators and having lung issues), a nurse, ...and one person on the "team" sounds like- , maybe a doctor.

so thats the team that address the problems. Not many are doctors.
 

SWAlexander

Senior Member
Messages
1,119
Likes
2,684
Jonas R. Kunst Twitter:
A new #LongCovid paper argues that COVID19 may trigger the "production of superoxide instead of nitric oxide leading to a self-perpetuating cycle of oxidative stress with the potential to impair numerous metabolic processes and damage multiple organs."

Abstract
Mucormycosis is a rare but life-threatening opportunistic fungal infection caused by a group of molds that belong to Zygomycetes of the order Mucorales. These fungi are found in the environment such as soil, decaying vegetation, and organic matters. Sporangiospores present in the environment enter the human body through inhalation or direct skin inoculation by trauma or ingestion and result in pulmonary, cutaneous, and gastrointestinal mucormycosis, respectively, in immunocompromised hosts. Patients with uncontrolled diabetes, hematological malignancies, high-dose glucocorticoid therapy, iron overload, and organ transplantation are at high risk of acquiring mucormycosis. The second wave of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] affected India severely with the highest number of cases and deaths compared to all other countries. Additionally, the country was affected by emergence of rare but life-threatening mucormycosis. Currently, many coronavirus disease 2019 patients with underlying risk factors such as uncontrolled diabetes, high-dose steroid therapy, and exposure to mechanical ventilation have developed mucormycosis. Inhalation is the most common mode of transmission that results in colonization of sporangiospores in the nose. In immunocompromised host, sporangiospores germinate, and subsequently form hyphae. These hyphae invade into tissues, and produce tissue infarction, necrosis, and thrombosis. Angioinvasion causes hematogenous dissemination to many organs, predominantly to brain, that result in rhino-orbital-cerebral mucormycosis. Clinical characteristics, radio imaging, fungal culture, histopathology, and molecular techniques are the key diagnostic methods. Surgical intervention and aggressive antifungal therapy are the main management strategies. Amphotericin B is the drug of choice for treatment of mucormycosis, whereas posaconazole or isavuconazole is used for step-down therapy and salvage therapy.
https://pubmed.ncbi.nlm.nih.gov/35433396/
 
Messages
819
Likes
1,441
Jonas R. Kunst Twitter:
A new #LongCovid paper argues that COVID19 may trigger the "production of superoxide instead of nitric oxide leading to a self-perpetuating cycle of oxidative stress with the potential to impair numerous metabolic processes and damage multiple organs."

Abstract
Mucormycosis is a rare but life-threatening opportunistic fungal infection caused by a group of molds that belong to Zygomycetes of the order Mucorales. These fungi are found in the environment such as soil, decaying vegetation, and organic matters. Sporangiospores present in the environment enter the human body through inhalation or direct skin inoculation by trauma or ingestion and result in pulmonary, cutaneous, and gastrointestinal mucormycosis, respectively, in immunocompromised hosts. Patients with uncontrolled diabetes, hematological malignancies, high-dose glucocorticoid therapy, iron overload, and organ transplantation are at high risk of acquiring mucormycosis. The second wave of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] affected India severely with the highest number of cases and deaths compared to all other countries. Additionally, the country was affected by emergence of rare but life-threatening mucormycosis. Currently, many coronavirus disease 2019 patients with underlying risk factors such as uncontrolled diabetes, high-dose steroid therapy, and exposure to mechanical ventilation have developed mucormycosis. Inhalation is the most common mode of transmission that results in colonization of sporangiospores in the nose. In immunocompromised host, sporangiospores germinate, and subsequently form hyphae. These hyphae invade into tissues, and produce tissue infarction, necrosis, and thrombosis. Angioinvasion causes hematogenous dissemination to many organs, predominantly to brain, that result in rhino-orbital-cerebral mucormycosis. Clinical characteristics, radio imaging, fungal culture, histopathology, and molecular techniques are the key diagnostic methods. Surgical intervention and aggressive antifungal therapy are the main management strategies. Amphotericin B is the drug of choice for treatment of mucormycosis, whereas posaconazole or isavuconazole is used for step-down therapy and salvage therapy.
https://pubmed.ncbi.nlm.nih.gov/35433396/
The link was wrong, he updated it in a response

https://www.sciencedirect.com/science/article/pii/S0306987722000822
 
Messages
11,115
Likes
26,495
the way this is described sounds very much like Valley Fever.

I posted something from China on a long covid thread here last week and it never even surfaced: the chinese have found a cure. Gut fix.

You would think that medicine could identify a fungus is growing in your nose.
 
Messages
11,115
Likes
26,495
Im officially confused by the two links...but I can' t read this today anyway, reading not allowed.

these seem to be differing topics- one about fungus. one about oxidate stress....?
 
Messages
819
Likes
1,441
I wonder how those anecdotal (and clinical case study) reports of increasingly higher dose T3 therapy leading to remissions fit into here.. I made a thread about them months ago and nobody seemed interested.!


Also would larazotide (and perhaps repairative peptides such as BPC-157) play any role in resolving the intestinal barrier problem? I tried BPC but it just made me feel wired and wore me down into a flare by overdoing it. I didn't take it orally though.

@mitoMAN did you find any ME benefits from larazotide? Or only reduced gluten sensitivity. Maybe it needs long term ongoing treatment for the barrier functions to slowly correct. Perhaps in combination with trying to fix the microbiome and promoting/supplementing butyric acid/butyrate?
@Learner1, what do you think, maybe this could be the mechanism? You asked on the T3 thread how it could all boil down to T3 for those patients.

Maybe there's a "low thyroid hormone function" issue going on, that is overcome by flooding the system with increasing amounts of T3. This slowly corrects physiological issues and the support can be slowly weaned off of..?

I don't think this has ever been tested but it's interesting that there are all of those anecdotal and physician reports on treating ME/CFS/FM in this way.. Perhaps more should trial it.
 

Shanti1

Moderator
Messages
1,798
Likes
4,275
I wonder how those anecdotal (and clinical case study) reports of increasingly higher dose T3 therapy leading to remissions fit into here.. I made a thread about them months ago and nobody seemed interested.!
I think it is beneficial to get a full thyroid workup (TSH, total and free thyroid hormones, thyroid antibodies) and I'm in favor of using T3 when someone has "low T3 syndrome", however, I question the use of T3 monotherapy to induce supraphysiological levels of T3. We only have anecdotal evidence that T3 monotherapy yields benefit, but we have good clinical evidence that hyperthyroid, both overt and subclinical, takes a toll on the bones and heart. This includes thyroid hormone medication that over-suppresses TSH.

I think I am somewhat biased because I have spoken with several practitioners trying Dr. Wilson's approach (which is basically to use sustained-release T3 mono-therapy to increase the temperature to 98.6, regardless of lab numbers) at the AARM conference where Dr. Wilson is a frequent speaker. The main challenge practitioners seemed to have was trying to get people's temperature up without making them tachycardic:wide-eyed:. People with high T3 due to taking too much thyroid hormone typically experience anxiety and or heart symptoms, but not everyone. Some people are just happily more energetic. However, in this latter group, does that mean that it is safe to assume that it isn't hurting their bones or hearts?

As a side note, it is normal for people taking T3 to test slightly above the T3 reference range if they took their medication a couple hours before the test. This is due to the shorter half-life of T3 and a quicker rise and drop. What I'm talking about is a higher and more sustained T3 elevation above the reference range.

My thought is that some people feel better in a hyperthyroid state because it is overriding some of the body's fatigue mechanisms. I also suspect that when T3 doses are ramped up beyond physiological normal in a slow, deliberate way, the body will profoundly downregulate receptors, helping people to tolerate the therapy.

One of the authors of the above paper (Stanculecu) also wrote this blog post on Health Rising on T3 supraphysiologic mono-therapy. While there are preliminary papers demonstrating that thyroid hormone conversion, uptake, and cell sensitivity, may be partially regulated at a tissue level, I'm not sure we can extrapolate that this means people should be given supraphysiological t3.

I'm not saying that this approach has never helped anyone, or that there aren't people for whom it may be appropriate. The theory hasn't been proven to be false or true. I just think that if people try it it should be with the awareness that the science lags behind the theory and that there may be a tradeoff for having t3 blood levels far above the normal range. I also get that many of us are willing to assume some risk to regain some function. I do wonder, though, if this type of high dose thyroid could push someone into a crash.

I have to admit that I didn't take to the blog piece listing the shared symptomologies between ME/CFS and hypothyroid as evidence that ME/CFS is a thyroid issue when there are many things that can cause these types of non-descript symptoms. Sure, thyroid is a part of the picture for many people, by my sense is that for most people, it isn't the keystone.

I'm definitely open to other perspectives, but that is where mine lands at the moment.
 
Last edited:
Messages
819
Likes
1,441
Thanks @Shanti1, I share your concerns. Purportedly the patients Myhill (and perhaps others?) treated didn't have any hyper symptoms, they just improved their ME more and more, sometimes to remission.. I'm not sure what to make of it but it seems like it should be tested and explored more perhaps.?
 

Shanti1

Moderator
Messages
1,798
Likes
4,275
I agree, it warrants more investigation and exploration as a therapy. Also, a "kick start" approach with short term use seems more reasonable than long term supraphysiologic therapy, which is moreso what concerns me. From what I gather, Myhill uses more of a short-term approach? I would just say proceed with caution, start low, go slow. T3 is finicky and side effects from too much can be scary, but I think it can be trialed safely if done right, as evidenced by docs like Myhill. Lord knows I've trialed some interesting things myself.
 
Messages
245
Likes
605
For me the CIRS model provides a nearly complete scientific explanation of my disease experience, similar to what this paper tries to do, I haven't done the correct tests yet though to prove whether I have mold toxicity but it seems highly likely. Its all explained in the book on Amazon by Dr Neil Nathan. In regards to the 'leaky gut' they claim its due to changes in the hormones or other natural chemicals that are altered in biotoxin cases, ( hypothalamus and pituitary is affected ) when that happens it can cause autoimmunity, but its a downstream effect not the cause of the disease.
 
Messages
819
Likes
1,441
For me the CIRS model provides a nearly complete scientific explanation of my disease experience, similar to what this paper tries to do, I haven't done the correct tests yet though to prove whether I have mold toxicity but it seems highly likely. Its all explained in the book on Amazon by Dr Neil Nathan. In regards to the 'leaky gut' they claim its due to changes in the hormones or other natural chemicals that are altered in biotoxin cases, ( hypothalamus and pituitary is affected ) when that happens it can cause autoimmunity, but its a downstream effect not the cause of the disease.
I saw elevated IL-6 produces gap junction issues (forgot if that's the right name sorry), hence leaky gut. So really any constant "drip" infection could cause it I'd think.
 
Messages
245
Likes
605
I rarely go into 'severe' but I was able to predict it this time based on weird symptoms in the past few months that were more neurological ( I started to wonder if I was getting a new disease not CFS ), these symptoms seemed to come on in response to stress and exposure to a known very bad room with unknown triggers. Random sharp pains in fingers, weird sensations in the brain on some exertion types, tension in the back, weird chest pains. Reading some things here it made me think about the mold toxicity or other biotoxin ( Dr Markov theory ? ). I was struggling last week but not terribly, energy levels were still ok, a few days ago we did a campfire in a woods that I didn't feel comfortable in ( mold ? ) it was a sort of damp wood with a lot of old material that nobody really goes into, day after that I walked a few hundred metres at 2 different places, again no great symptoms, that night though breathing became more difficult, felt like a barrier in between lungs and blood, next day energy levels dropped to severe and cognition also a lot worse. Noticeable hard red patch appearing on my finger ( this seems to often correlate with a dramatic worsening ), I speculate this is secondary effect and its due to an overwhelmed immune system, so viruses or something are getting free reign all of a sudden at my fingers. I want to do the Great Plains lab test soon if possible.
 
Messages
11,115
Likes
26,495
Noticeable hard red patch appearing on my finger ( this seems to often correlate with a dramatic worsening ),
my husband gets bumpy flairs on his hands which he says are some virus type reaction when he is stressed or run down.

I rarely go into 'severe' but I was able to predict it this time based on weird symptoms in the past few months that were more neurological
things "feel more neurological"...when I worsen here lately, too.

not mold in my case