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Is SIRS, CARS, MARS - and now PICS - causing the "CHAOS" in ME/CFS?

Could ME/CFS be the post-SIRS “immune paralysis” state of Compensatory Anti-Inflammatory Response Syndrome (CARS)? Or Mixed Antagonists Response Syndrome (MARS)?

The evidence we have about ME/CFS and the striking similarities between the illnesses provide a compelling argument that ME/CFS is a form of Systemic Inflammatory Response Syndrome (SIRS) as evidenced by a recent gene expression study which has so far revealed the disease as the closest resemblance to ME/CFS.

Further analysis of mRNA gene expression, in a study led by Dr. Lipkin and Dr. Mady Hornig, showed that the disease with the closest resemblance to ME/CFS is SIRS.

If this theory can be proven it would have enormous implications for funding ME/CFS research by casting a wider net to seek treatment for critically ill patients, not only for ME/CFS but for complications arising from concussion, burns, surgery, organ replacements and serious infections such as Pneumonia. The very syndromes only discussed in Surgical ICU’s that have challenged physicians for over 40 years could be the very same syndrome that has challenged ME/CFS practitioners all this time.

http://www.meaction.net/2017/02/20/is-sirs-cars-mars-and-now-pics-causing-the-chaos-in-mecfs/
 
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2,158
I tried reading that article but gave up. I found it very confusing and my scientific/medical knowledge is not up to it. Are they saying ME is a form of sepsis?

I seem to remember the Melbourne group comparing some of the metabolic findings to sepsis and to starvation, whereas Naviaux compared it to hibernation. For me these are simply indicators that the metabolism isn't functioning normally. If by making parallels, new and fruitful avenues of research and treatment are opened up, that's good.
 

ljimbo423

Senior Member
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United States, New Hampshire
From the article above-

It is fair to assume a few severe SIRS patients and certainly many Sepsis patients may not survive 6 months if it wasn’t for medical intervention, but what about a patient with mild SIRS and even perhaps mild sepsis with symptoms only just missing the diagnosis criteria and without any identifiable or treatable pathogen? There are after all no biomarkers yet for SIRS, Sepsis or ME/CFS, and all three are diagnosed by symptomatic observation.

Bolding mine.

Chris Armstrong said this-

Well we all experience a bacteremia when we exercise. The type of bacteria that enter your bloodstream are usually quite controllable by your immune system but if your gut is further compromised they may release more bacteria into your blood or more pathogenic species or your immune system may already be depleted. This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM.

Stanford University Medical Center paper-

Further analysis of mRNA gene expression, in a study led by Dr.
Lipkin and Dr. Mady Hornig, showed that the
disease with the closest resemblance to ME/CFS is Systemic Inflammatory Response Syndrome (SIRS). These
two studies provide objective evidence that that ME/CFS is indeed an inflammatory disease.
https://med.stanford.edu/content/dam/sm/chronicfatigue/documents/MECFSNewsletter_Spring_2015.pdf

Sepsis causes systemic inflammatory response syndrome (SIRS). Notice that Chris Armstrong uses the term "chronic sepsis", meaning ongoing. Also, the article above says "There are after all no biomarkers yet for SIRS, Sepsis or ME/CFS, and all three are diagnosed by symptomatic observation."

Chris Armstrong also thinks it's the (mild) sepsis that causes Immune system activation and oxidative stress, causing mitochondrial dysfunction. I think the oxidative stress also causes methylation dysfunction as well. It just makes sense to me (after 10 years of reading, research and thousands of dollars in supplements-lol) that a leaky gut is causing my symptoms. In my case the leaky gut was caused primarily by 30-40 courses of anti-biotics (EDIT-over many years) leading to severe dysbiosis and a leaky gut (mild sepsis).
 
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Jonathan Edwards

"Gibberish"
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5,256
To be honest I gave up as well. One of the reasons for posting was in the hope that some our more scientifically minded and less brainfogged members could critique it for me. :)

ME is not like a systemic inflammatory response. Perhaps the most interesting finding from Mady Hornig is that IL-6 tends to be low - which would fit with ESR being low. I am afraid this is a hodge podge of all the usual trendy theories rolled into a quattro stagioni pizza. The one thing ME is not is sepsis.
 

Countrygirl

Senior Member
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UK
http://cfstreatment.blogspot.co.uk/2015/04/guts-bugs-and-slow-sepsis-in-mecfs.html?m=1

This article refers to Dr Bell's view that ME could be described as a 'slow sepsis'

Slow Sepsis

Dr. David Bell proposed that patients with ME/CFS have what he called "slow sepsis." In his monograph, Cellular Hypoxia and Neuro-Immune Fatigue, he suggests that ME/CFS is a slow, chronic form of septic shock. The sequence of events in septic shock is: 1) a serious infection, 2) production of cytokines, 3) increased nitric oxide, and 4) interference with the production of cellular energy. In severe cases of septic shock, the loss of cellular energy is so profound that it can be fatal.

Dr. Bell suggests that a similar sequence takes place in ME/CFS, but more gradually. In ME/CFS there is: 1) an initiating infection or toxic exposure, which 2) leads to immune activation, increasing the production of cytokines, 3) the increase in cytokines leads to the production of increased nitric oxide (NO), 4) NO increases peroxynitrite and superoxide, which leads oxidative stress, and interferes with mitochondrial function, 5) the cell becomes hypoxic (oxygen-starved), and 6) vasculopathies, neuropathies, and autoimmune processes develop.

While Dr. Bell does not propose that this sequence of events can be initiated by leaky gut, there is absolutely no reason to assume that it can't. The destruction of the tight juncture between the cells of the intestinal lining has a host of causes. Any infection in the intestines (e.g. enteroviruses, parasites), drugs (e.g. NSAIDs. steroids), viral infections, radiation therapy for cancer, nutrient deficiencies (e.g. zinc), inflammatory conditions, toxins, and antibiotics can lead to the production of excess NO (oxidative stress), compromising the integrity of the gut lining (Wu et al, 2002). Given the high level of oxidative stress found in people ME/CFS it is likely that the majority of patients will develop leaky gut.
 

kangaSue

Senior Member
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Slow sepsis could fit the bill as opposed to your typical doctor's assumption that sepsis has to be full blown and draw a powerful systemic response that can easily be identified through common blood work. Something which Maes has touched on in regard to ME/CFS that can't be ruled out until such time as there has been more extensive testing is that mesenteric lymphatics is a system that can spread bacteria which can spread to the blood circulation. It needs invasive laparotomy to get mesenteric lymphatic samples so not something that would fit into routine screening.

Intestinal ischaemia/reperfusion injury and barrier failure are generally implicated in the development of multiple organ failure as a major cause of SIRS in the critical care arena be it as a consequence of serious injury or post-operative complications. Researchers using more sensitive means has found that the mesentery lymph system can spread bacteria that is not detected in typical blood cultures.

Though widely reported in the medical literature, it is even lesser known that chronic intestinal (mesenteric) ischemia can occur with chronic GI dysfunction in an outpatient population in a wide variety of conditions including IBS and IBD, something which could be a means to infect mesenteric lymphatics. This ischemia is often microvascular in nature which also is very hard to establish as there is no gold standard test for detecting it.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067918/
[Many of these infections are initiated by translocation of intestinal bacteria and usually result in bacteremia and, in more severe cases, sepsis [42]. Bacterial translocation can be demonstrated by analysis of mesenteric lymphatics or portal vein blood samples. It is important to point out here that, in a classic study, portal vein sampling in trauma patients undergoing laparotomy did not provide evidence for bacterial translocation by blood cultures [43]. Subsequent studies with trauma patients confirmed that blood cultures generally failed to show bacterial growth [44, 45]. However, more sensitive methods, such as immunostaining for E. coli beta-galactosidase [44] or electron microscopy [45], provided direct evidence for bacterial translocation to mesenteric lymph nodes (MLNs) in most patients. While the presence of bacteria in MLNs as a pathological event has been debated [46, 47], multiple studies have shown that positive cultures from MLN samples obtained from laparotomy patients occurred in 10–15 % of patients, which correlated with an increased risk of postoperative sepsis [48, 49] or postoperative infection [50].]

One Maes study found that "loosening of the gut barrier may allow poorly invasive Gram-negative bacteria to translocate from the gut into the mesenteric lymph nodes and sometimes into the blood stream. Once translocated, the LPS is recognized by the Toll-like receptor 4 (TLR4) complex, which primes immune cells and consequently activates inflammatory and Oxidative & Nitrosative Stress pathways."
https://www.ncbi.nlm.nih.gov/pubmed/19112401
 

Jonathan Edwards

"Gibberish"
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5,256
There is no such thing as slow sepsis, any more than there is slow high blood pressure. High blood pressure is not slow or quick, it is high. If the blood pressure is normal it is not high. Sepsis is the presence of high numbers of viable bacteria in blood (a tiny number get into blood in all of us) and high levels of LPS-responsive cytokines (we all have some cytokine circulating). In ME, blood cultures are negative and the relevant cytokines are NORMAL or LOW, so there cannot be 'sepsis'. Dr Maes has 'shown' nothing. He has merely speculated, based on some pretty unconvincing data not replicated by anyone else as far as I know.

The whole idea seems a bit like homeopathy - there is nothing there but it is wickedly powerful stuff.
 

ljimbo423

Senior Member
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There is no such thing as slow sepsis

I agree that there isn't such a diagnosis yet. There are however, 3 different levels of sepsis that are already recognized, sepsis, severe sepsis and septic shock - link

Here is a study from 2015 -

Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain. In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance.

Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation. To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined.

Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.

These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

Edited to break up paragraphs.

There seems to be a significant correlation here to increased bacterial translocation in cfs patients after exercise and the PEM window of up to 3 days (72 hours), for many people with cfs.

This is a link to the full paper.
 
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barbc56

Senior Member
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3,657
@ljimbo423

If you break up the longer paragraph, it makes for easier reading.

Thanks.:)

Edit. It's a good idea to mention that you've done this lest someone think you've done some "creative editing". :rolleyes:
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I agree that there isn't such a diagnosis yet. There are however, 3 different levels of sepsis that are already recognized, sepsis, severe sepsis and septic shock - link

Here is a study from 2015 -

There seems to be a significant correlation here to increased bacterial translocation in cfs patients after exercise and the PEM window of up to 3 days (72 hours), for many people with cfs.

This is a link to the full paper.

Yes I am familiar with that paper, but it does not actually say that ME patients have more bacteria than normals after exercise, as far as I am aware. It reports some differences between specific types of bacteria but who knows if these are important.

In any case this is not sepsis. We all have bacteria in the blood. I am pretty sure this study measured bacterial DNA, so there is no indication that the bacteria are alive. We need to be precise about this. When live bacteria in the blood make people feel ill the CRP level is sky high due to IL-6 production. In ME IL- 6 is not high, yet people feel terrible. It does not add up.
 

kangaSue

Senior Member
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Location
Brisbane, Australia
There is no such thing as slow sepsis
Fair enough, one can accept a medical expert's opinion that it is the wrong use of medical jargon to call it slow sepsis but splanchnic circulation is considered a major factor in spreading bacterial infection in the sepsis process however it is not fully elucidated how the sepsis process works even in an acute situation so, as that is where all the research focused, the possibility that it can occur by similar mechanism in chronic conditions too hasn't got a look in yet.

The physiological response is to prioritise blood flow to vital organs at the expense of the splanchnic circulation thus activating intestinal ischemia when the right conditions are met (likely to be microvascular ischemia which isn't fully understood either) and there are two hypotheses around the flow on effects of that, the ‘gut starter’ and the ‘gut motor’ hypotheses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2020573/
The ‘gut starter’ hypothesis is also called the ‘two hit model of MODS’ and focuses on the role of the neutrophil. Neutrophils are primed as they pass through the mesenteric circulation during reperfusion of the ischaemic intestine. They continue to circulate around the body in this primed yet inactive state until they are provoked by a second insult such as exposure to endotoxin 20. Priming of the neutrophil is initiated by mesenteric lymph rather than portal blood and it is the lipid fraction generated by phospholipase A2 that appears to be most important in priming neutrophils 21. Neutrophils primed in this way exhibit an increased oxidative burst, augmented release of proteases and cytokines 22, and reduced apoptosis 23 so becoming potent mediators of distant organ dysfunction when activated.

The ‘gut motor’ hypothesis focuses on the role of the intestinal barrier in the development of SIRS and MODS. When this barrier is disrupted the luminal content invades the portal venous and lymphatic systems. This translocation activates immune cells downstream from the intestinal mucosa, i.e. Peyers patches, macrophages in the lamina propria of the gut, mesenteric lymph nodes and Kuppfer cells in the liver. These activated immune cells release inflammatory mediators that drive the onset of SIRS and MODS even though a focus of infection may not be evident].

Is it possible then that PEM cause a diversion of blood flow from splanchnic circulation to preserve skeletal muscle and does that then lead on to the spread of bacteria in mesenteric lymphatics which can be activated into circulation by other insult.
 
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If ME isn't sepsis, could it be Post-Sepsis Syndrome? I ask this since I imagine, unlike sepsis, PSS isn't characterized by high numbers of bacteria in the blood.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
If ME isn't sepsis, could it be Post-Sepsis Syndrome? I ask this since I imagine, unlike sepsis, PSS isn't characterized by high numbers of bacteria in the blood.

I am not sure what post sepsis syndrome is but I suspect it is the sustained catabolic state that can follow a large number of insults to the body, like surgery or trauma. That is not specific to sepsis and I cannot see the point in bringing in sepsis if we have good evidence that there is none in ME.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Chronic sepsis is just sepsis lasting along time, so it still has to be defined in terms of an increase in the number of live bacteria in the blood and an acute phase response via the LPS or related pathways. In ME we have clear evidence that these are not present. So it cannot be sepsis, whether acute, chronic, slow or quick.

Grumbling sepsis in bronchiectasis will produce a CRP level of 10 with the person feeling just slightly tired or off colour. With the level of symptoms in ME that confine people to bed one would expect a CRP of 50 if the problem was due to sepsis. And that is not the case. As I understand it PEM is a set of symptoms- an effect, not a cause. If sepsis were involved I would expect it to cause the PEM, not the other way around.

Whichever way one looks at it, ME is not sepsis.
 

lansbergen

Senior Member
Messages
2,512
Chronic sepsis is just sepsis lasting along time, so it still has to be defined in terms of an increase in the number of live bacteria in the blood and an acute phase response via the LPS or related pathways. In ME we have clear evidence that these are not present. So it cannot be sepsis, whether acute, chronic, slow or quick.

Grumbling sepsis in bronchiectasis will produce a CRP level of 10 with the person feeling just slightly tired or off colour. With the level of symptoms in ME that confine people to bed one would expect a CRP of 50 if the problem was due to sepsis. And that is not the case. As I understand it PEM is a set of symptoms- an effect, not a cause. If sepsis were involved I would expect it to cause the PEM, not the other way around

Whichever way one looks at it, ME is not sepsis.

Period
 

ME3

Messages
11
Chronic sepsis is just sepsis lasting along time, so it still has to be defined in terms of an increase in the number of live bacteria in the blood and an acute phase response via the LPS or related pathways. In ME we have clear evidence that these are not present. So it cannot be sepsis, whether acute, chronic, slow or quick.

Grumbling sepsis in bronchiectasis will produce a CRP level of 10 with the person feeling just slightly tired or off colour. With the level of symptoms in ME that confine people to bed one would expect a CRP of 50 if the problem was due to sepsis. And that is not the case. As I understand it PEM is a set of symptoms- an effect, not a cause. If sepsis were involved I would expect it to cause the PEM, not the other way around.

Whichever way one looks at it, ME is not sepsis.

As a person diagnosed with CFS over 10 years ago, my consultants in different specialities now believe I have had major episodes of sepsis. I have all the criteria of sepsis but never understood the difference between the 2 conditions. I have no medical background. Please could you advise me as to how I find out the difference. Each episode has been related to infection but caused confusion before symptoms were recognised. Due to 30 years ago being placed in a psychiatric ward with no tests done I've been treated as mental health as opposed to critical care. The psychiatrists at the time said they didn't know what was wrong and found no evidence of mental illness so called it an affective disorder.

In 2014 I was again admitted to a mental health ward to discover I'd had an e coli infection which caused the symptoms of sepsis. Again no testes were done for infection at the time. The psychiatrist said what I had was very rare and he called it 'brief psychosis' but he said others may call it something different. He said it was undoubtedly caused by the infection.

I had a kidney infection after youngest daughter was born 36 years ago but got antibiotics and sepsis symptoms definitely present on that occasion, with no confusion.

Each following episode my temperature drops well below 36 e.g. 34.5 last year but got antibiotics which cleared it before things became worse.

I know now that I have had infections each time and TIA with a throat infection, but not sure if that was connected just to the vascular problems. No confusion.

I don't understand the explanations above so wondered if you can help in layman's terms please Jonathan?