Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[Woolie]

Could you fill us in a bit on the nature of your remissions and relapses. I have some questions, if I may:

(1) How long do your remissions and relapses typically last, or is this quite variable? Are we talking months or years? Do the remissions last for around the same length of time as the relapses?

Don't have them so clearly anymore, but in the past, anything from 2 weeks to 3 months. The remissions were always longer than the relapses.

(2) Have you noticed anything that seems to trigger a relapse or remission?

I always suspected it was viral infections. Obviously not exertion - the cycling and skiing would have induced a huge relapse in that case.

(3) How much difference in your symptoms do you see between the remission state, and the relapsed state? During the remissions, are you more or less free of any symptoms? I am just trying to get a sense of how different the remission state is from the relapsed state. Are these really chalk and cheese?

Remission was normal. Symptom free. Relapse was unbelievably awful. Yes, chalk and cheese.

(4) What the severity level of your ME/CFS during the relapsed state, mild, moderate or severe? (Descriptions of what mild, moderate or severe ME/CFS means can be found in this post).

Severe. Often unable to speak or lift my head from the pillow.

(5) Compared to other people on this forum, is your ME/CFS different in any way, in terms of symptoms? I am just trying to get an idea if relapsing-remitting ME/CFS might be symptomatically different to the more constant form of ME/CFS. Do you have OI symptoms for example? Do you get PEM? Is there anything at all usually about your ME/CFS symptoms (apart from the relapsing-remitting course).

Yes, it is. No OI symptoms. No neurological symptoms. Yes, I get PEM now and in the past too if I tried to do too much on the wrong day. But on the right day, no. Its pretty constant now, as I said, the pattern has changed.

Oh, the trigger was a severe viral infection which lasted months. It was mono-like, but I never tested EBV positive.

 

[leokitten]

You are presenting your own personal speculations as if they were fact. You, nor anyone else, has any evidence that the Royal Free outbreak was due to virally-induced autoimmunity.

More personal speculations presented as if they were fact. What's more, your speculations are wrong: Chia writes in his study: "No commercial funding is currently available for a placebo controlled study [on the interferon treatment]". So that is the reason he has not done a RCT on interferon treatment for ME/CFS.

You want to know how many posts I read by you and for example @halcyon where you present your own personal speculations as fact? With very very shaky evidence?

You just have your own pet ideas and are stuck in your own ideology when it comes to this disease.

If you read my posts I'm not stuck with any position, I used to think that this disease was infectious and in the past would've agreed with you but sorry the research just hasn't panned out for the majority of PWME.

Yes you are right I agree there is probably a subset that has an infectious component but I think it is smaller and less significant than you think.

I still think that even with a significant percentage of the infectious group it is a secondary effect because the root cause which is some type of immune system problem over time didn't properly control intracellular pathogens which when allowed to be active over time cause all their own additional issues and symptoms. So just because people get better with interferon treatment doesn't mean that it has any effect on the root cause, it could only be showing improvements due to secondary infectious issues.

You've shown it to yourself the therapy that Dr Chia has done doesn't tackle the root cause, the moment the take away the treatment everything comes back meaning that there is some underlying immune system problem that is not controlling these infections in their own. Everybody has these viruses but most people don't have a problem keeping them under control.

The root cause I believe in the majority of PWME is some combination of atypical immunodeficiency with autoimmunity that as a result doesn't properly control intracellular infections. And yes if the patient doesn't take treatment for the infections then after a while they will make cause all their own problems which with therapy will show improvement but it doesn't prove that the root cause is the infection itself.

 

[Hip]

@Woolie
Wow that really is quite amazing!

So in a given year, you might have several switches between the remission state and the relapsed state, and during the remission state, I presume you could for example do lots of physical exercise without problem, but during the relapsed state, you are barely able to lift your head off the pillow, and too mentally shattered to even speak.

It is quite extraordinary that there could be so much difference.


By the way, when you say you have no neurological symptoms, what are you defining as neurological symptoms?

 

[Woolie]

By the way, when you say you have no neurological symptoms, what are you defining as neurological symptoms?

Brain fog, working memory problems, poor concentration, OI and POTS too if you like. I get none of these, never understood why.

My main symptoms are crushing fatigue, severe headache, swollen and sore glands, low-grade fever, flu-like malaise, sweats, shakes and heart palpitations.

I'm not too mentally shattered to speak at these times, I'm too physically shattered to speak! (takes a lot of energy when you feel that bad!)

 

[Woolie]

@leokitten, I'm bothered by some of these things as well. It seems the whole thing is more complex than just persistent infection. It what's enabling that persistent infection to, er, persist (and even to reestablish itself after its been brought under control pharmacologically), there's where the big problem lies.

 

[leokitten]

Well if you speak to Jonathan Edwards, he will tell you that he has not seen any convincing evidence of infections triggering autoimmunity.

Well he's not always right...

Infections and autoimmunity: the multifaceted relationship

The role of infections in autoimmune disease

Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs

Mechanisms for the induction of autoimmunity by infectious agents

A Potential Link between Environmental Triggers and Autoimmunity

Scientists prove link between viral infection and autoimmune disease

And the list of papers goes on and on...

 

[Hip]

You want to know how many posts I read by you and for example @halcyon where you present your own personal speculations as fact? With very very shaky evidence?

I am usually careful to distinguish between speculations, weak evidence, strong evidence, and proven beyond all doubt evidence, and careful to distinguish between causes and associations.

Of course I may have slipped up on some occasions, but I am happy for anyone to point these out so that I can correct my errors.

I still think that even with a significant percentage of the infectious group it is a secondary effect because the root cause which is some type of immune system problem over time didn't properly control intracellular pathogens which when allowed to be active over time cause all their own additional issues and symptoms. So just because people get better with interferon treatment doesn't mean that it has any effect on the root cause, it could only be showing improvements due to secondary infectious issues.

There could well be an immune weakness in at least some ME/CFS patients which underpins why they cannot properly clear viral infections. It would still the viral infection causing the ME/CFS symptoms though, even if it is the immune weakness that facilitates the infection.

You've shown it to yourself the therapy that Dr Chia has done doesn't tackle the root cause, the moment the take away the treatment everything comes back meaning that there is some underlying immune system problem that is not controlling these infections in their own. Everybody has these viruses but most people don't have a problem keeping them under control.

I agree. There seems to be a dynamic equilibrium between enterovirus and the immune response, and even if you alter this balance using interferon, which clears up much of the viral infection, afterwards the system slowly returns to that same dynamic equilibrium. It returns to the same stalemate position. What we need to understand is what is preventing the immune from clearing out the virus.

The root cause I believe in the majority of PWME is some combination of atypical immunodeficiency with autoimmunity that as a result doesn't properly control intracellular infections.

If there were some atypical immunodeficiency, we might question why did that atypical immunodeficiency not show up earlier in the patient's life. If we take the case of patients who developed ME/CFS in their 30s, which is one of the peak age ranges for getting ME/CFS, why wasn't their earlier life blighted with lots of problems with childhood infections that they struggled to clear?

I have to admit that I had lots of tonsillitis problems as a child, and eventually had a tonsillectomy, but generally was able to brush off infections including things like food poisoning quite robustly.


Why are you postulating a combination of atypical immunodeficiency and autoimmunity together, by the way, as your hypothesis of why ME/CFS patients do not properly control intracellular infections?

 

[halcyon]

You want to know how many posts I read by you and for example @halcyon where you present your own personal speculations as fact? With very very shaky evidence?

I don't understand why you feel the need to personally attack me like this. To the best of my knowledge I don't make statements as fact that can't be backed up by some source. If I am speculating I will say "I believe" or "perhaps" or "maybe". I'm sorry that the evidence that I reference doesn't pass muster for you, but this is all we have to work with.

You just have your own pet ideas and are stuck in your own ideology when it comes to this disease.

I take offense to this as well. Earlier in the thread I suggested that we review any evidence so far that would be incompatible with a viral cause. Nobody has replied yet.

You've shown it to yourself the therapy that Dr Chia has done doesn't tackle the root cause, the moment the take away the treatment everything comes back meaning that there is some underlying immune system problem that is not controlling these infections in their own. Everybody has these viruses but most people don't have a problem keeping them under control.

That is one interpretation, the other is that the therapy isn't able to completely eradicate the virus and so viral loads increase again after treatment is stopped and cause symptoms. Without a drug that can 100% eradicate the virus, it will likely be hard to determine which interpretation is correct.

 

[leokitten]

I am usually careful to distinguish between speculations, weak evidence, strong evidence, and proven beyond all doubt evidence, and careful to distinguish between causes and associations.

Of course I may have slipped up on some occasions, but I am happy for anyone to point these out so that I can correct my errors.

Understood, thank you for being fair and kind. I think we all need to realize this is a forum medium with short statements and responses and we don't always spend the time to write everything up even though we do have evidence because it would take a lot of time to construct every single post.

There could well be an immune weakness in at least some ME/CFS patients which underpins why they cannot properly clear viral infections. It would still the viral infection causing the ME/CFS symptoms though, even if it is the immune weakness that facilitates the infection.

Yes that is plausible and a good theory.

I agree. There seems to be a dynamic equilibrium between enterovirus and the immune response, and even if you alter this balance using interferon, which clears up much of the viral infection, afterwards the system slowly returns to that same dynamic equilibrium. It returns to the same stalemate position. What we need to understand is what is preventing the immune from clearing out the virus.

Yes when we discover this I believe this will find the root cause of ME/CFS.

If there were some atypical immunodeficiency, we might question why did that atypical immunodeficiency not show up earlier in the patient's life. If we take the case of patients who developed ME/CFS in their 30s, which is one of the peak age ranges for getting ME/CFS, why wasn't their earlier life blighted with lots of problems with childhood infections that they struggled to clear?

I would say our youth, higher levels of hormones, and a younger stronger immune system makes up for some underlying flaw in our immune system. When we hit our mid to late 30s the youth masking this flaw is not there anymore. I know this doesn't sound very scientific but that's how it's felt for me.

It could also be that by the time we hit our mid 30s our infection load gets to a point that it reveals this underlying flaw in our immune system. See the article links I mentioned in another post here how infections are related to and trigger autoimmunity.

Why are you postulating a combination of atypical immunodeficiency and autoimmunity together, by the way, as your hypothesis of why ME/CFS patients do not properly control intracellular infections?

Well we have clearly seen that in a significant portion of PWME autoimmunity is driving the disease. And actually researchers have been slowly discovering that autoimmunity and immunodeficiency are really intertwined. Autoimmunity is just a form of immunodeficiency.

 

[leokitten]

I don't understand why you feel the need to personally attack me like this. To the best of my knowledge I don't make statements as fact that can't be backed up by some source. If I am speculating I will say "I believe" or "perhaps" or "maybe". I'm sorry that the evidence that I reference doesn't pass muster for you, but this is all we have to work with.

Apologies, sometimes as I said to @Hip we write posts that aren't worded perfectly and I think people need to understand this is a online forum and in this medium most posts are written quickly with opinion and speculation even if we don't always explicitly put the words "perhaps" "I believe" etc.

That is one interpretation, the other is that the therapy isn't able to completely eradicate the virus and so viral loads increase again after treatment is stopped and cause symptoms. Without a drug that can 100% eradicate the virus, it will likely be hard to determine which interpretation is correct.

Your immune system should be able to handle a small amount of ubiquitous virus, if we need to eradicate everything 100% then there is a bigger problem @halcyon because after eradicating it you will likely pick up the virus again from someone in just a week or so and then the problem starts again. You are just proving my point that the root cause is not the virus but the immune system itself.

 

[leokitten]

@Hip and @halcyon look what Jonathan Edwards just wrote coming back from the IiME conference:

Everyone was very pleased with the three days of meetings this year. The Friday tends to be a repeat of material the researchers have discussed on the previous days and I hope it was a good mix for patients and carers in the audience. I thought Olav Mella's final review of the Norwegian rituximab story was particularly impressive. This is science as good as it gets, very creative but an insistence on top quality methodology.

Honestly I think we are going to see that autoimmunity is a much bigger part of the root cause than infection. If infections were the root cause then 2/3rds of CCC/ICC PWME wouldn't get better. Yes maybe part of the 1/3rd that don't respond might have some significant infection driving symptoms, but at least finally for once someone is getting somewhere with a large subset of PWME.

Here's what someone else wrote about their talk:

Dr. Oystein Fluge, Professor Olav Mella:
As usual, a significant proportion of the audience had left the building (doubtless of necessity) by the time the headline act hit the stage. They talked us through the history of the Rituximab findings, how it came about, and the state of play with the Rituximab study.

Quite a bit of new unembargoed info in this presentation, I think. The study will be unblinded in summer of 2017 (assuming all proceeds according to plan in the next few months). The long delayed Phase II follow-up study on Rituximab should hopefully be published in PloS One in 2-3 weeks – it required 3 years observation time (post-treatment) before publication, that’s why it’s been so much delayed.

Most exciting to me (because I’ve bought into their hypothesis that it’s an antibody to the epithelium that we’re looking for, ultimately) they can already say with confidence that their sub-study on endothelial dysfunction is confirming the findings from the Dundee researchers: they, too, are finding measurable endothelial dysfunction in their patients. It also looks to them like the degree of endothelial dysfunction correlates with the degree of disability – which potentially makes it an important finding, and (I’m speculating here) they might be able to publish on this subject before the main trial completes.

The rigour of their methodology for the Rituximab trial impressed everyone present. They’ve started their approved Phase II study on the much cheaper Cyclophosphamide, with 40 patients diagnosed by CCC with illness duration >2 years. If the response is good and toxicity data is OK, they plan a second phase of this study for 20 severe and very severe patients.

Professor Mella said they’ve been to IiME for 5 years and this conference was “the best so far” – they were especially impressed by the research colloquium. Most ideas come from patients, he said: “It’s a good thing for doctors to listen to patients, because what they tell us is the truth…what they tell us is in fact what is happening to them, so it’s up to us to find a cause…”

These guys have done more for ME/CFS research and knowledge than anyone else in the history of this disease and they've done this in just 6 years.

The endothelial dysfunction they are finding is very real, it's exactly what is happening to me and perpetuating my illness. There is very likely some kind of undiscovered autoantibody to our vessel epithelium. I am certain this is where the breakthrough will occur and it explains all the ME/CFS symptoms.

 

[Hip]

Yes when we discover this I believe this will find the root cause of ME/CFS.

Have you read about RNAse L in CFS? The chopped up form of this enzyme in CFS prevents it from properly destroying the viral RNA in our cells.

 

[halcyon]

Your immune system should be able to handle a small amount of ubiquitous virus, if we need to eradicate everything then there is a bigger problem @halcyon because after eradicating it you will likely pick up the virus again from someone in just a week or so and then the problem starts again. You are just proving my point that the root cause is not the virus but the immune system itself.

Yes, definitely possible. It's my belief (based only on personal observation) there are probably at least two subgroups here, those with pre-existing subtle (or not so subtle) immune deficiency and those with temporary immune suppression proximal to ME onset (another infection, surgery, immunization, physiologic stress, etc). Some here have IgG subclass deficiencies, low CD4 counts, low NK count/function, others don't seem to have these same markers. I could be way off base here though and both groups could share some other critical deficiency/dysfunction that existed before ME onset that doesn't show up on standard immune tests.

 

[leokitten]

Yes, definitely possible. It's my belief (based only on personal observation) there are probably at least two subgroups here, those with pre-existing subtle (or not so subtle) immune deficiency and those with temporary immune suppression proximal to ME onset (another infection, surgery, immunization, physiologic stress, etc). Some here have IgG subclass deficiencies, low CD4 counts, low NK count/function, others don't seem to have these same markers. I could be way off base here though and both groups could share some other critical deficiency/dysfunction that existed before ME onset that doesn't show up on standard immune tests.

I totally agree, I think my entire life I've had some atypical immune deficiency that didn't become evident until my late 30s. I believe I had active intracellular infections and autoimmunity for a long time before I finally fell ill with ME/CFS, it just had to reach a tipping point before it became noticeable.

 

[duncan]

It might be easier to resolve the debate and figure out if it's a corrupted immune mechanism vs autoimmune vs.continued infection if so many researchers weren't unprincipled sacks of shit, willing to dispense misinformation like pez pellets.

Thankfully there are some good ones trying for us. Or trying simply to get the Science right because that is what scientists are supposed to do.

I fear, though, that unless a whistle blower steps up to the plate and reveals malfeasance or fraud or whatever, tainted findings and rigid dogma will continue to hamper progress. There are bad guys out there, and I have no reason to think they are going to stop anytime soon.

In my opinion, the best way to tell about the authenticity and merit of a given effort is to be part of it. To enroll in it. Participate - those of us that are healthy enough - in studies and report back with results and insights. Most of us must glean our clues from a distance, and assume a certain propriety was observed. But this is third-party sleuthing on our parts. To get closer to the research itself, it would help if we were embedded in studies

We are driven to review theories and sift through them, and try to exercise enough reason and logic to generate a plausible opinion based in large measure on those studies. If we can help by crossing out one theory through enrolling in study, and that source of misinformation withers, perhaps as a consequence another theory would be propped up. And then we will be one less lie closer to the truth.

I know many from this forum are doing that. I just want to point out it is just as important to expose ugly and dangerous findings, as it is to embrace findings we contributed to that we find ourselves agreeing with.

 

[leokitten]

It might be easier to resolve the debate and figure out if it's a corrupted immune mechanism vs autoimmune vs.continued infection if so many researchers weren't unprincipled sacks of shit, willing to dispense misinformation like pez pellets.

Thankfully there are some good ones trying for us. Or trying simply to get the Science right because that is what scientists are supposed to do.

I fear, though, that unless a whistle blower steps up to the plate and reveals malfeasance or fraud or whatever, tainted findings and rigid dogma will continue to hamper progress. There are bad guys out there, and I have no reason to think they are going to stop anytime soon.

In my opinion, the best way to tell about the authenticity and merit of a given effort is to be part of it. To enroll in it. Participate - those of us that are healthy enough - in studies and report back with results and insights. Most of us must glean our clues from a distance, and assume a certain propriety was observed. But this is third-party sleuthing on our parts. To get closer to the research itself, it would help if we were embedded in studies

We are driven to review theories and sift through them, and try to exercise enough reason and logic to generate a plausible opinion based in large measure on those studies. If we can help by crossing out one theory through enrolling in study, and that source of misinformation withers, perhaps as a consequence another theory would be propped up. And then we will be one less lie closer to the truth.

I know many from this forum are doing that. I just want to point out it is just as important to reveal the ugly and dangerous findings, as it is to embrace findings we contributed to that we find ourselves agreeing with.

@duncan read my earlier post with snippets about Fluge and Mella's talk at IiME this year. These guys are making a real difference and pushing us into a new era of ME/CFS research!

 

[halcyon]

Honestly I think we are going to see that autoimmunity is a much bigger part of the root cause than infection.

Let me be clear about what you're saying here so I understand. It seems like the term autoimmunity is used in a lot of different ways, a number of which I don't fully understand and some that seem contentious. Your belief is that ME is a "true autoimmunity", with production of self autoantibodies by B cells that are causing tissues to be damaged thus causing the symptoms of ME?

 

[leokitten]

Let me be clear about what you're saying here so I understand. It seems like the term autoimmunity is used in a lot of different ways, a number of which I don't fully understand and some that seem contentious. Your belief is that ME is a "true autoimmunity", with production of self autoantibodies by B cells that are causing tissues to be damaged thus causing the symptoms of ME?

Yes I believe that a significant subset of PWME have autoimmunity, either via autoantibodies or other b-cell mediated autoimmune interactions.

For my ME I believe what Fluge and Mella are finding with endothelial dysfunction is spot on. They think there is some undiscovered autoantibody to our vascular epithelium causing this dysfunction and I for certain by my symptoms believe this is what's happening to me.

 

[Hutan]

The idea of autoantibodies to vascular epithelium is interesting and I look forward to hearing more about the Fluge and Mella study on that.

Maybe it fits with the gradual development of POTS symptoms some six months after the onset of what was presumably the trigger (viral) illness in my son and I.

What kind of markers would be expected though? Wouldn't there be commonly-tested-for inflammatory markers in the blood if the vascular endothelium is being affected? I have consistently high CRP and low albumin that could perhaps fit with the hypothesis. But not everyone with ME/CFS has that. My son doesn't. He does have consistently lowish white cell, neutrophil, lymphocyte and platelet counts. (Possibly reactivated previously latent infections muddy the waters).

So positive ANA wouldn't be necessary for such an autoimmune problem?

 

[lansbergen]

That is one interpretation, the other is that the therapy isn't able to completely eradicate the virus and so viral loads increase again after treatment is stopped and cause symptoms.

I agree.

@leokitten I would not be suprised when they find epithelium dysfunction is part of the disease process.