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Revisited - Does ME/CFS more closely resemble an autoimmune disease or a chronic infection?

Jesse2233

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This seems to be a seminal question with profound implications for treatment. The answer of course is likely more nuanced, may involve both, and is probably better covered by terms like "immune dysfunction." We also do not yet have enough good replicated research to definitively answer the question.

Still there are clearly defined autoimmune diseases (e.g. lupus) and clearly defined chronic infections (e.g. hepatitis C) with quite disparate treatment protocols. You wouldn't treat HIV with Rituxan, and you wouldn't treat Sjögren's syndrome with Valcyte. And yet patients with ME/CFS can recover (or significantly improve) using either treatment.

Of course there are likely subsets, and yet there are unifying ME/CFS symptoms (PEM, non-refreshing sleep).

Case for autoimmunity:
  • Aberrant autoantibodies (e.g. anti-cardiolipin, adrenergic, muscarinic)
  • Decreased fequency of acute infections
  • Decreased body temperature
  • Female prevalence
  • Inter-familial prevalence
  • Waxing and waning of severity with occasional spontaneous remission
  • Biphasic frequency of teenage / middle age onset
  • Comorbidity with other autoimmune disorders, sensitivities, and allergies
  • Pregnancy linked remission
  • Cases without clearly defined infectious triggers (slow / staged onset)
  • Patient response to prednisone, rituximab, plasmapheresis, cyclophosphamide, Staph vaccine, LDA/LDI
  • Existence of other post-infectious autoimmune conditions (GBS, PANDAS/PANS, Sydenham's Chorea, Rheumatic fever)
  • Findings by Fluge / Mella, David Kem, Alan Light, Jonas Bergquist, Carmen Scheibenbogen

Case for chronic infection:
  • Acute infectious onset
  • Low grade fevers
  • Sore throat
  • Swollen lymphs
  • Discovery of virus DNA / RNA / viral particles in body tissue
  • Elevated IgG titers to various pathogens (e.g. herpes viruses, enteroviruses, Lyme, mycoplasma)
  • Geographically defined outbreaks
  • Patient response to Valtrex, Valcyte, ARVs, antibiotics, interferon alpha/gamma, Ampligen
  • Findings by John Chia, Jose Montoya, Melvin Ramsay, John Richardson, Byron Hyde, Garth Nicolson, Daniel Peterson, Kenny De Meirleir

Case for either / both:
  • Abnormal cytokine levels
  • Low NK cell function
  • Clonal T-cell expansion
  • Patient response to IVIG, HBOT, rapamycin, LDN, aggressive rest therapy
  • Orthostatic intolerance
  • Onset linked to chronic stress
  • Neuroinflammation
  • Hormonal irregularities
  • Findings by Robert Naviaux, Chris Armstrong, Sarah Myhill, Nancy Klimas, Ron Davis, Mark Davis, Jarred Younger, Masaaki Tanaka
 
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Jesse2233

Senior Member
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I can be good to use the search function before starting new threads. This topic has been discussed several times before. Here is one example:

http://forums.phoenixrising.me/inde...more-autoimmune-than-chronic-infection.37545/

Thanks I've read many of those threads. I thought it would be useful to revisit this topic given recent developments (cytokine paper, metabolomics, t-cell expansion, cyclophosphamide / rapamycin response, Jarred Younger good day / bad day findings, Lipkin microbiome, lack of CDC enterovirus replication), and with an organized list of factors for either case at the top
 

A.B.

Senior Member
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3,780
  • Acute infectious onset
That could be consistent with autoimmunity triggered by an infection as well.

  • Low grade fevers
  • Sore throat
  • Swollen lymphs
That just means the immune system is activated, no?

  • Discovery of virus DNA / RNA in body tissue
  • Elevated IgG titers to various pathogens (e.g. herpes viruses, enteroviruses, Lyme, mycoplasma)

Everybody has viruses. Finding viral DNA/RNA just means patients are no exception. Or do you have something specific in mind?

I understand that IgG antibodies just mean that the body has encountered a particular pathogen before and is keeping these antibodies around in case the pathogen visits again.

  • Geographically defined outbreaks

That could be consistent with autoimmunity triggered by an infection as well.

  • Patient response to Valtrex, Valcyte, ARVs, antibiotics, interferon alpha/gamma, Ampligen
  • Findings by John Chia, Jose Montoya, Melvin Ramsay, John Richardson, Byron Hyde, Garth Nicolson, Daniel Peterson, Kenny De Meirleir

Yes we do have doctors who think infections are the problem, but: they can't agree which infectious agent is to blame, and there isn't any convincing published research. I would say that the fact that after decades we still have so little convincing evidence infections are playing an important role besides triggering the illness suggests this idea could be a dead end, or that it applies only to a subset of cases.

A big problem with the infectious hypothesis is also that old people don't seem to get this illness, when they are more susceptible to infections.
 
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Jesse2233

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Southern California
Thanks @A.B. this is what I was in part hoping someone would do... debunk the chronic infection possibility so as to make the autoimmune case more viable.

But what doesn't fit is the response to antibiotics / antiviral drugs, and the normalization of stomach biopsies (previously found to contain enteroviruses) in Dr Chia's interferon studies.

I suppose one could argue that the anti inflammatory properties of those drugs could calm an autoimmune response, and that either the stomach biopsies normalized because the attenuated immune system could now effectively clear an irrevelant infection, or the study sample was too small.

I'm thinking of Dr Chia, Dr Hyde, and Dr Richardson's brain, stomach, and muscle biopsies when I refer to the viral RNA findings as well as Dr Peterson's cerebralspinal detection of HHV PCR. @halcyon and @Hip will know those details better than I do
 
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Yes to what @A.B. said. The raised antibodies to EBV etc., could also be due to an immune abnormality. Remember that you're not measuring the actual viral load, only the body's production of antibodies to it, so if immune system is out of control, these may go up too.
 
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Jesse2233

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Location
Southern California
A big problem with the infectious hypothesis is also that old people don't seem to get this illness, when they are more susceptible to infections.

That's an interesting angle. A higher rate of acute infections in the elderly makes sense but what about chronic infections? Are there higher rates of Hepatitis C and HIV for seniors.

I suppose longitudinal HIV susceptibility would be difficult to ascertain in the elderly given its usual transmission through unprotected sexual contact. I would imagine on balance that seniors do that less frequently although I've read it's surprisingly common in nursing homes.

Edit:

AB's point on the elderly holds true for HIV as per the paper below
As a person ages, involution of the thymus occurs, and resultant thymic volumes are significantly lower in persons 45 years and older as compared to younger persons (Kalayjian et al 2003). Moreover, the production of naïve T cells declines with increasing age and thymic output is only minimal after age 55 (Naylor et al 2005). Increased age is further associated with diminished T cell functionality, reduced memory T cell populations, and fewer numbers of properly functioning CD8+cytotoxic T cells (Effros 2004). These factors may explain why elderly persons are more prone to new infections, demonstrate less than optimal response to immunizations, or manifest anergy to skin tests such as with purified protein derivative (PPD).

In addition, thymic function and production of naïve T cells may be inhibited by HIV infection (Douek et al 1998). Because these changes in the immune system are very similar to aging effects, progression of HIV infection in the elderly may be more pronounced

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682378/#!po=5.41667
 
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A.B.

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3,780
But what doesn't fit is the response to antibiotics / antiviral drugs, and the normalization of stomach biopsies (previously found to contain enteroviruses) in Dr Chia's interferon studies.

The evidence for response to antibiotics and antivirals is weak and contradictory. Where are the clinical trials demonstrating efficacy? It's mainly hearsay.

Dr Naviaux also wrote that response to antibiotics / antivirals could be due to their effect on cell metabolism: https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/

He also had something to say about antibodies:

Third, latent and reactivated viral and bacterial infections can occur, but in the case of ME/CFS that has lasted for more than 6 months, this may be the exception rather than the rule. Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA. We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased. This is a functional kind of immune deficiency that causes an unbalanced increase in antibodies.

Dr Chia's work isn't widely accepted. Is it because of strong prejudice or because nobody can replicate it? I don't know why. Surely testing stomach biopsies for enteroviruses can't be that difficult? Gastroduodenoscopies are made every day and are uncomplicated. I had one myself. It wouldn't take much for a doctor to hand the samples over to a researcher to look for enteroviruses. At least that are my thoughts.

It could very well be that infections play an important role in a subset but the evidence just doesn't seem to be there. Maybe it will materialize or maybe it will turn out that this was an incorrect hypothesis.
 
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Jesse2233

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I'd forgotten Naviaux's comment on antibiotics/antivirals altering cellular metabolism, that's very interesting. Has that finding been replicated?

To play devil's advocate there's the Montoya Valcyte trials, Hemispherx Ampligen trials, Lerner Valtrex trials, and the Vermeulen azithromycin retrospective. ME clinicians (e.g. Montoya, Meirleir, Kaufman, Peterson, Jardain, Dentini) tend to swear by those drugs (albeit largely without published results).

There's also Dr Chia's, Dr Deckoff-Jones' and Dr Weir's purportedly successful use of ARVs
 

dreampop

Senior Member
Messages
296
Or neither. Life is complicated, there could be many other possibilities. This particular debate was what put me off PR in the first place. You can find a study saying just about anything, and take some tiny finding from ME/CFS to tie into various papers and convince yourself on either. I enter this thread at my own risk.

I always thought outbreaks represented a particularly virulent mutation of an infection that led to high CSF cytokine activity ( a la the dubbo study) and therefore more ME/CFS. But iiirc, many of the patients in outbreaks recovered over time, and least in greater numbers than those with CFS, so I see the outbreaks as triggering the ME/CFS process, but most don't have the ME/CFS predisposition of genetics and other factors. They may be separate entirely, and the outbreaks more akin to post-ebola syndrome.

As for antibiotics/antivirals - they have not been convincingly demonstrated to be effective, neither has Ampligen. Many of them possess anti-inflammatory effects. Valcyte, for example, calms the microglia which may benefit a particular patient, explaining the antecdotal response, but not treat the actual illness.

Things like swollen lymph nodes. low grade fever, sore throat are pretty ambiguous (Many people with lupus experience reoccurring, low-grade temperatures that do not reach 101).

Montoya recently said that, although he thinks chronic viral infections may play a role in some patients, they are not the main thing. Garth Nicholson has gone off the deep end in serious quack territory.

And ME/CFS behaves unlike any infection I have ever heard of - the explanations for this I find unconvincing. Here is Defoe who is bedridden and unable to move really. And yet none of the ways by which an infection induces symptoms is abnormal in him. Nor can they be consistently found in quality studies. So how exactly is an infection doing that. If it's not producing an immune response and a person is that ill, how can you argue the infection is doing anything even if you could find it - which no one can despite looking for 15 years.

Look at your own list - it speaks for itself. I'm not convinced CFS is an auto-immune disease, but I put the chances of it being a chronic infection at 5%. It's probably neither, some flaw in our biology that we don't even know about yet.
 

Jesse2233

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Location
Southern California
@dreampop good points and it's certainty possibly it's something we currently have no concept of

And I agree extrapolating huge theories on tiny data sets is problematic

I still have a hard time wrapping my head around the major responses to Ampligen in an autoimmune context (Klimas, Bateman, Peterson have all said it's the most effective drug they've ever seen, although Enlander was less enthusiastic)

For the sake of discussion, if it's not a chronic infection or an autoimmune condition, then what are some things it might be?
 

pattismith

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3,925
A big problem with the infectious hypothesis is also that old people don't seem to get this illness, when they are more susceptible to infections.

Is it that old people don't get the disease, or is it that it is considered as normal aging consequences for old people to suffer from pain and fatigue and cognitive dysfunctions...

I guess the second point is more likely to be right....
 
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pattismith

Senior Member
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3,925
@dreampop good points and it's certainty possibly it's something we currently have no concept of

And I agree extrapolating huge theories on tiny data sets is problematic

For the sake of discussion, if it's not a chronic infection or an autoimmune condition, then what are some things it might be?

Enzyme blocages by toxic triggers like lead or organophosphates?
 

A.B.

Senior Member
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3,780
To play devil's advocate there's the Montoya Valcyte trials, Hemispherx Ampligen trials, Lerner Valtrex trials, and the Vermeulen azithromycin retrospective. ME clinicians (e.g. Montoya, Meirleir, Kaufman, Peterson, Jardain, Dentini) tend to swear by those drugs (albeit largely without published results).

Yes, but how good were the results? They aren't good or reliable.
 

dreampop

Senior Member
Messages
296
@dreampop good points and it's certainty possibly it's something we currently have no concept of

And I agree extrapolating huge theories on tiny data sets is problematic

I still have a hard time wrapping my head around the major responses to Ampligen in an autoimmune context (Klimas, Bateman, Peterson have all said it's the most effective drug they've ever seen, although Enlander was less enthusiastic)

For the sake of discussion, if it's not a chronic infection or an autoimmune condition, then what are some things it might be?

Jesse, man if I knew...

I have seen a couple CFS doctors, and while earnest, I believe they wildly exaggerate the results they get with whatever their preferred ammunition is, and I've become quite jaded on what they say works in their clinic. I know people swear they get better on Ampligen, but given my experience I have to trust the studies.
 

A.B.

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3,780
Right, my understanding is that they were generally mediocre (in comparison to Fluge / Mella's Phase 2 rituximab trial) but still statistically significant

A look at the Ampligen RCT primary endpoint:

The table with results is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/table/pone-0031334-t001/

After 40 weeks, the Ampligen group improved their treadmill exercise duration from 576 to 672 seconds (+96).
The placebo group improved from 588 to 616 seconds (+28).

So there is some effect but it's not much. Instead of walking 10 minutes they can now walk 11 minutes (68 seconds advantage over a placebo).
 

Hip

Senior Member
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17,771
Everybody has viruses. Finding viral DNA/RNA just means patients are no exception. Or do you have something specific in mind?

But not everyone has chronic enterovirus infections in the brain tissues, as autopsies find ME/CFS patients have, with the "healthy" controls being free of this virus in the brain. And not everyone has chronic enterovirus infections of the muscle tissues, as numerous British studies dating back the 1970s find ME/CFS patients have, but with much less prevalence of such muscle infections in healthy controls.

Everybody has viruses, but infections are not just about whether you have caught the virus and have antibodies to it, but which particular organs in your body the virus infects. That makes all the difference in terms of the diseases the virus precipitates. For example, many people have coxsackievirus B in their body as a latent infection, but most of those people will not have chronic coxsackievirus B myocarditis, because the infection has not entered their heart muscle tissues.

Likewise, many people with have coxsackievirus B1 or coxsackievirus B4 in their body (the two coxsackieviruses that are linked to the autoimmune condition of type 1 diabetes), but most of these people will not have T1D, because these viruses have not infected the insulin-producing beta cells of their pancreas, which is thought necessary in order for the virus to trigger T1D (some studies suggest that coxsackievirus B causes T1D by directly infecting and killing these beta cells by lysis, as well as triggering and autoimmune attack which also kills the beta cells).



Yes we do have doctors who think infections are the problem, but: they can't agree which infectious agent is to blame, and there isn't any convincing published research.

There are literally dozens of British studies since the 1970s that found a much higher prevalence of coxsackievirus B in the blood, brain and muscle tissues of ME/CFS patients compared to healthy controls. Dr Chia's more recent research just replicates and advances this original research, but there is a long history of ME/CFS enterovirus studies dating back decades before.

Generally in the US, this British research has been ignored, because historically the US found it difficult to replicate the British studies (with of course the notable exception of Dr Chia's excellent work), and the US has tended to focus more on the herpes family virus connection to ME/CFS.



The evidence for response to antibiotics and antivirals is weak and contradictory. Where are the clinical trials demonstrating efficacy? It's mainly hearsay.

Coxsackievirus B-associated ME/CFS often responds to ribavirin and/or interferon, as several published studies have indicated, but there are reasons why these cannot be used as long term treatments. Nevertheless, the improvements and remissions these treatments produce indicate that treating the underlying infection works in principle.

Of course, if the infections in ME/CFS are triggering or exacerbating autoimmunity or some other immune dysfunction that causes ME/CFS, and since we don't have at present any good antivirals that can fight off these infections, it makes sense to try to treat the immune dysfunction directly, by means of rituximab for example, if that results in improvements in the illness.
 
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