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

[halcyon]

I have not been able to find any info regarding how much normal functionality of a cell remains once it hosts a chronic non-cytolytic enterovirus infection. Though might the fact that these infections have been observed to last many years indicate that the cell must be functioning reasonably well?

It seems to be established, at least in animal models, that non-cytolytic infections likely disturb the differentiated functions of the cell without disturbing the vital functions. See here.

 

[Hip]

See here.

In that link you provided, which is to the book: Can a Virus Cause Schizophrenia?: Facts and Hypotheses, I like the following statement about how non-cytolytic viral infections could be present in the brain of those with schizophrenia, and possibly cause this disease, yet not show any of the normal hallmarks of viral infection:

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The same statement would presumably apply to ME/CFS as well.​

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[Hip]

Although the vagus nerve innervates vagal paraganglia, and so would activate sickness behavior if there were an infection in the paraganglia, after some Googling I have found no indications whatsoever that vagal paraganglia or the glomus cells they contain can host any infection, be it viral, bacteria, fungal or protozoal.

And whereas the medical term gangliitis (inflammation of the ganglion) exists, the word paragangliitis does not (it returns zero results in Google), presumably indicating that the paraganglia never get infected or inflamed.

So the paraganglia are not looking good at all as potential hosts of an infection triggering chronic sickness behavior.

 

[Jonathan Edwards]

It seems like there are a lot of different viruses that have been documented with tropism for nervous tissue, including several of the ones implicated in ME, so it seems relevant to me. Do herpes nerve infections cause known structural pathology when they reactivate?

Yes, they produce blistering of the lips (Herpes simplex) or skin (Herpes zoster).

 

[duncan]

"Sickness behavior behavior." I'm hoping that second 'behavior' was in error. Regardless, I think it reflects, albeit only lightly, on the perils of describing sickness with "behavior', in particular with behavior that can be tied into motivation.

There are those in the psych camp of ME/CFS that would gladly embrace this terminology, irrespective of its origins purportedly in a DVM's writings.

 

[Eeyore]

It's was mentioned in passing in one post in this thread, I have been asking myself the same question:

Are there any autoimmune diseases where patients also tend to have chronic issues with intracellular pathogens?

If such exist then this to me is more proof that this is not necessarily an infectious disease?

There are diseases where the body has an impaired ability to handle intracellular infections, but they are not autoimmune (other than iatrogenic). They are usually genetic in nature - some portion of the cellular immune response is not functioning normally, but can also be acquired. HIV is an acquired immune deficiency (CD4 cells, so not specific to cellular immunity). I've generally read/heard more about diseases with impaired humoral than cellular immunity, but there are certainly both.

Autoimmune disease generally involves the body mounting an immune response against itself. Autoimmunity is not, generally, an immune deficiency, although many autoimmune patients are immunocompromised due to treatments that suppress the immune system.

Some genetic factors may represent more of a predisposition than a pathological state. For exsample, there is a polymoprhism in the IL28 gene (or receptor, can't remember which) which is very important in determining response to Hep C virus. The normal allele is far more common. People who lack the normal IL28 gene have much higher rates of hep C, more complications, and greater difficulty in clearing the disease. It also has effects on other viruses as well - HSV and VZV have been studied as well, and it does affect susceptibility.

So in general, no, I don't believe there is an autoimmune disease that impairs, by itself, the body's ability to suppress intracellular pathogens.

Diseases that are not immune in nature (like cystic fibrosis - which is a genetic mutation in the CFTR gene, which codes for a chloride channel) make mucus hard to liquefy, and as a result secretions are inhibited in many exocrine glands, including the pancreas, sweat glands, etc. This causes problems with intracellular pathogens because natural, mechanical barriers to infection (such as removal of "crud" in the lungs by action of the cilia lining the respiratory tract is impaired by the thickened mucous. This is not autoimmune either though.

Immune diseases are very different from autoimmune diseases. The first is a problem with the body's ability to defend itself, generally one where it's weakened, or partially so. Autoimmune diseases are more of a regulatory issue where the body's immune system is capable of fighting invaders, but is targeted incorrectly at itself.

 

[Hip]

"Sickness behavior behavior." I'm hoping that second 'behavior' was in error. Regardless, I think it reflects, albeit only lightly, on the perils of describing sickness with "behavior', in particular with behavior that can be tied into motivation.

There are those in the psych camp of ME/CFS that would gladly embrace this terminology, irrespective of its origins purportedly in a DVM's writings.

Thanks for pointing out the duplicate word, I have corrected it.

Those who want to propose an "all in the mind" psychogenic origin of ME/CFS are certainly not going to be embracing sickness behavior etiologies, because sickness behavior is the term used to describe the metabolic (eg, rise in body temperature) and behavioral (eg, going off somewhere to hide and lay low) responses animals including humans mount when they contract a significant infection. Implicit in the term sickness behavior is the understanding that these metabolic responses and adaptive behaviors are directly caused by an infection.

 

[Eeyore]

I have not been able to find any info regarding how much normal functionality of a cell remains once it hosts a chronic non-cytolytic enterovirus infection. Though might the fact that these infections have been observed to last many years indicate that the cell must be functioning reasonably well?

Non lytic infections generally are entirely inactive, waiting for an opportunity to reactivate. The cell carries on activities much as normal, and is fully functional. When the virus then triggers lytic infection, the cell is destroyed. In the process though, other cells are infected. This is how EBV works as well - the B-cells it infects are destroyed, but then it invades and lays dormant in other B-cells, eventually reactivating. The low level of infection is not a cellular distinction, but a body-wide distinction. i.e. It's either all or nothing per cell - the infection in a cell is active and will lead to immune response and lysis, or the infection is dormant. The concept of a low level infection is that only a small percentage of cells contain active replicating virus at any given time - so the infection is "low grade." The cells themselves are not experiencing a "low grade" infection in EBV.

Low level non-cytolytic infections may well cause symptoms and disease, because they are associated with chronic coxsackievirus B myocarditis and dilated cardiomyopathy (and also more tenuously linked to type 1 diabetes).

Coxsackie B infections usually only last a matter of weeks. According to Medscape, they have isolated live coxsackie B as long as 3 weeks after initial infection in respiratory tissue and as long as 8 weeks after infection in the GI tract. The damage to the pancreas is and heart are from acute infection, and longer term damage after viral clearance is probably autoimmune / inflammatory and a reaction to the viral infection after it has passed. The short, acute infection can cause a lot of damage, which can then be worsened by the immune system's overactivity. Many people with coxsackie B myocarditis are sick for years - but the infection only lasts weeks most of the time - if longer, it indicates a certain amount of immune dysfunction that prevents viral clearance. Coxsackie B myocarditis or IDDM is generally not a relapsing remitting condition - it gets worse, stabilizes and gets better (or just goes to death). The pattern is quite different from ME.

Some researchers think chronic CVB myocarditis may provide a useful model to help understand the chronic coxsackievirus B infections found in ME/CFS.

I don't think this is accurate. If in fact there is chronic coxsackie B infection in ME patients, that implies an immune deficiency. Coxsackie B is a hit and run phenomenon in general, not a long term chronic infection. In mice, if we deplete CD8 suppressor t cells, we can see infections last longer, as long as 2 months or so. The cellular immune response appears to be more important in coxsackie virus infection than the humoral response.

Though if we consider chronic hepatitis C infection, and my guess that this cytokine, when detected by the vagus nerve, may be largely responsible for the sickness behavior symptoms present in hep C. Yet these cytokines do not result in the elimination of this virus.

Cytokines regulate immune response, they don't, in and of themselves, clear infection. Some viruses are more able to create chronic infection - hep c is well known to do so, especially in people with defective IL28 alleles. Many people with hep C have absolutely no symptoms, and those that do have symptoms generally have symptoms consistent with liver dysfunction. It doesn't look like "sickness behavior" mediated by cytokines really - it looks like liver dysfunction (which is associated with extreme fatigue in general - see primary biliary cirrhosis, or read about patients awaiting liver transplantation). I don't think this has anything to do with the vagus nerve any more than any other illness, and quite possibly less. We're also talking about fairly well understood pathology in hep c.

Could you give please me some examples of these illnesses where IL-1β is extremely high. If blood levels of IL-1β are high, I would have thought that some manifestation of sickness behavior symptoms will appear in the disease.

IL-1 is high in more or less any acute infectious illness. It's virtually universal in acute infectious illness of any type. It is not by any means unique to a small subset of infections. It is secreted by macrophages/monocytes/dendritic cells as well as endothelial cells early in the immune response, and activates nearly all of the cells in the immune system. It is not a uniquely important modulator of sickness behavior, it is one voice in a choir of immunoregulatory chemicals. It is generally pro-inflammatory and increases monocyte adhesion and capillary permeability, which helps to start the immune response.

IL-10 and IGF-I also reduce sickness behavior:

IL-10 is a key anti-inflammatory cytokine and is responsible for resolution of inflammation. Some cytokines upregulate immune response, and some downregulate it. I think you are overinflating the role of IL-1 in sickness behavior. There are hundreds if not thousands of cytokines - we still don't know them all.

The recent Lipkin and Hornig study found reduced levels of IL-1 family cytokines in long term ME patients, not increased levels, and it was a highly significant result with very low p-value.

Might there be any autoimmune mechanisms that could lead to the chronic activation of the IL-1β receptors on the vagus nerve, by the way?

Theoretically possible that an antibody could both bind to and activate a receptor, but most antibodies that bind to receptors block them. I'm not aware of any known disease process where antibodies activate receptors. Some small molecule drugs definitely activate various receptors, but antibodies do not usually do this to a significant degree - they mostly block other things from doing it.

I think the core aspect of Michael VanElzakker's theory is the idea that ME/CFS is caused by the chronic activation of sickness behavior. So although he postulates an infection of the vagus nerve is the cause of this chronic sickness behavior, it might be good to explore whether some autoimmune processes may lead to the same sickness behavior activation.

I don't believe that he has provided sufficient evidence for any of this. It's a hypothesis - by his own description - and the theory just really does not seem plausible. If I were in a position to award government grants, I'd put it ahead of psychobabble, but I see many avenues of research that are much more plausible and likely to be relevant / productive. I don't think it's all about sickness behavior. Long term ME patients have reduced cytokines, including IL-1, not increased. I think this is a dead end.

The phenomenal similarity between sickness behavior and ME/CFS symptoms is compelling, and thus I think sickness behavior is a fruitful path to explore in trying to understand this disease.

I can't agree - I don't find them that similar.

 

[A.B.]

Can we be sure that sickness behaviour is only the result of infection (increased proinflammatory cytokines)? I would expect the brain to react with sickness behaviour to any health problem where this is appropriate. It is after all a survival strategy.

 

[adreno]

Implicit in the term sickness behavior is the understanding that these metabolic responses and adaptive behaviors are directly caused by an infection.

This is false. Sickness behavior is associated with infection, but also cancer, autoimmunity and depression. It is cytokine-mediated, not infection-mediated.

 

[Eeyore]

The major problem with this whole hypothesis (or one major problem, there are many) is that long term ME patients have lower levels of pro-inflammatory cytokines per Lipkin/Hornig (highly statistically significant results, just published), yet they still exhibit (probably moreso) increased fatigue, lower motivation, decreased exercise tolerance, etc.

You'd expect to see normal to elevated levels of sickness behavior promoting cytokines if this were the cause, but you see the opposite.

 

[duncan]

Hip, that is slightly misleading. Yes, sickness behavior is generally supposed to be associated with infections. In theory, an infection will have "caused" or triggered sickness behavior. That behavior, however, represents a motivational state that defines activities accordingly. The behavior is based on motivations. As such, we fall into a potential quagmire of associated psychogenic crap. This would include psychogenic labels such as anhedonia and depression and even a reduction is grooming habits, according to a quick wiki search.

It is the terms' misuse or misappropriation that I am concerned about.

I am reminded of insurance companies' fondness for the phrase "self-reported symptoms." Technically, the term is accurate for all sorts of symptoms, from pain to fatigue. But inherent in the term "self-reported" is an insinuation or connotation, potentially, of deceit on the part of the claimant. Why not just say "patient reports"? One answer may be an implied accusation just lurking beneath the surface of "self-reported".

I understand the logic for wording that lends itself to objective, even detached, descriptions and explanations. The communication of science, and in particular, medical science, is highly reliant on these.

In my opinion, however, embracing a catch-all phrase like "sickness behavior" lends itself to similar pitfalls to those engendered by terms like "self-reported" - pitfalls that some concerns may try to capitalize on.

ME/CFS diagnoses do not happen in a vacuum. Accordingly, it may be prudent not to indulge in terminology or phrases that invite such problems when possible.

 

[Hip]

Non lytic infections generally are entirely inactive, waiting for an opportunity to reactivate. The cell carries on activities much as normal, and is fully functional. When the virus then triggers lytic infection, the cell is destroyed. In the process though, other cells are infected. This is how EBV works as well - the B-cells it infects are destroyed, but then it invades and lays dormant in other B-cells, eventually reactivating. The low level of infection is not a cellular distinction, but a body-wide distinction. i.e. It's either all or nothing per cell - the infection in a cell is active and will lead to immune response and lysis, or the infection is dormant. The concept of a low level infection is that only a small percentage of cells contain active replicating virus at any given time - so the infection is "low grade." The cells themselves are not experiencing a "low grade" infection in EBV.

Perhaps the terminology non-cytolytic infection is confusing here, because you think this refers to viral latency, such where Herpesviridae for example stay dormant in cells inside episomes or via chromosomal integration.

Perhaps I should be using the term defective viral infection instead, which is a synonym of a non-cytolytic infection. Defective viral infections of cells are not the same as viral latency states. Defective viral infections are low level, but there is viral activity in the cell.

But we have been over this ground before, and I thought this was understood.

I don't think this is accurate. If in fact there is chronic coxsackie B infection in ME patients, that implies an immune deficiency. Coxsackie B is a hit and run phenomenon in general, not a long term chronic infection. In mice, if we deplete CD8 suppressor t cells, we can see infections last longer, as long as 2 months or so. The cellular immune response appears to be more important in coxsackie virus infection than the humoral response.

It's certainly possible that the coxsackievirus B infections found in ME/CFS patients might be due to one or more immune deficiencies; however, that does not negate the view that a not properly controlled CVB infection is causing ME/CFS symptoms.

Although it there were an immune deficiency, it would suggest that, in terms of treatment, we might try to make up for the deficiency if at all possible.

It doesn't look like "sickness behavior" mediated by cytokines really - it looks like liver dysfunction (which is associated with extreme fatigue in general - see primary biliary cirrhosis, or read about patients awaiting liver transplantation). I don't think this has anything to do with the vagus nerve any more than any other illness, and quite possibly less. We're also talking about fairly well understood pathology in hep c.

Chronic hepatitis C often presents with mental symptoms like fatigue, depression, and brain fog, which are sickness behavior symptoms. If these symptom arise, there must be a mechanism that causes them. Nothing happens without a causal mechanism. The sickness behavior mechanism is the most likely one, especially since chronic hep C involves the sickness behavior cytokines.

IL-1 is high in more or less any acute infectious illness.

But you said that there are many diseases with very high levels of IL-1β. I wanted an example of one.

I think you are overinflating the role of IL-1 in sickness behavior.

I mentioned before that IL-1β, TNF-α and IL-6 are the main known promoters of sickness behavior. However, TNF-α and IL-6 promote sickness behavior via the humoral pathways only, whereas IL-1β is the only one that promotes sickness behavior via the neural pathway of the vagus nerve. At least that's my understanding of it. That's why IL-1β is important in the vagus nerve infection hypothesis of ME/CFS.

For a very readable introduction to the mechanisms of sickness behavior, see the first half of this paper: Cytokine, Sickness Behavior, and Depression

If I were in a position to award government grants, I'd put it ahead of psychobabble, but I see many avenues of research that are much more plausible and likely to be relevant / productive.

There seems to me to be a prejudice against infectious etiologies in medical research. I was having an online conversation with an Alzheimer's researcher not so long ago, whose team was working on the theory that a herpes simplex infection of the brain can cause some subsets of Alzheimer's.

She told me that all their grant applications are blocked, and they have to work on a shoestring budget, because the major Alzheimer's experts don't like these infectious etiology theories at all.

I can't agree - I don't find them that similar.

Did you see this table which compares the symptom of ME/CFS with those of sickness behavior?

 

[Hip]

The major problem with this whole hypothesis (or one major problem, there are many) is that long term ME patients have lower levels of pro-inflammatory cytokines per Lipkin/Hornig (highly statistically significant results, just published), yet they still exhibit (probably moreso) increased fatigue, lower motivation, decreased exercise tolerance, etc.

You'd expect to see normal to elevated levels of sickness behavior promoting cytokines if this were the cause, but you see the opposite.

Eeyore, you mentioned this before, and I explained why your point is not valid. Have you forgotten my answer to your point, because you are going over the same ground?

 

[Eeyore]

@Hip - I think we are just going to have to agree to disagree. To me, you seem fixated on an entirely implausible theory without any real evidence. I think this theory is basically nonsense. I've read a LOT of scientific papers in my lifetime, and what I see here is not high quality or interesting work.

I really don't want to spend more time discussing what I consider to be a complete dead end theory. I think Dr. Edwards is right that we should try to explain why we don't think things make sense, but after a point, I think we should just agree to disagree.

I do not believe there is any causal role for chronic enterovirus infections in ME. I don't believe there is any compelling evidence for a causal role of chronic viral infections of any kind in ME. If anything, they may exist as a result of impaired immunity or failure of the immune resolution mechanism.

We have been over all this ground many times and we just aren't getting closer to agreement, so it's probably pointless for both of us to keep arguing it back and forth.

 

[Hip]

Can we be sure that sickness behaviour is only the result of infection (increased proinflammatory cytokines)? I would expect the brain to react with sickness behaviour to any health problem where this is appropriate. It is after all a survival strategy.

Sickness behavior is triggered by conditions other than infection; cancer can trigger sickness behavior, because it can generate the sickness behavior cytokines. However, this would appear to offer no advantages to the animal, because while the sickness behavior of laying low for a while may conserve energy, so helping to overcome the infection (and also would a good strategy to help prevent the spread of infection to other animals in the herd/group), it is not going help for a terminal condition like cancer.


I think it would be interesting to examine whether autoimmune conditions like say rheumatoid arthritis are triggering sickness behavior, since you do get fatigue symptoms with this condition.

 

[Hip]

@Hip - I think we are just going to have to agree to disagree. To me, you seem fixated on an entirely implausible theory without any real evidence. I think this theory is basically nonsense. I've read a LOT of scientific papers in my lifetime, and what I see here is not high quality or interesting work.

I would be happy to accept any evidence or insight that demolished this vagus nerve infection theory. @Jonathan Edwards almost demolished it by observing that the IL-1β receptors are located at a distance of several centimeters from the putatively infected satellite glial cells, and this is too long a distance for a paracrine like IL-1β to travel in significant concentration.

The paraganglia infection does not look likely either, given that there is no evidence that these can ever be infected.

So that leaves us with the speculation that the Schwann cells of the vagus nerve might contain a non-cytolytic enterovirus infection.

So while not dead, the vagus nerve infection theory has taken some flak as a result of these discussions. And I accept that now, this vagus infection theory does look less likely.


However, as mentioned earlier, even if the vagus nerve is not infected, the idea that ME/CFS may be largely due to chronic sickness behavior should not yet be discounted. There may be other mechanisms that can chronically trigger sickness behavior, such as the chronic enterovirus infection Dr Chia has found in the stomach of ME/CFS patients. If a chronic hepatitis C infection of the liver can seemingly trigger sickness behavior symptoms, why not a chronic CVB infection of the stomach?


There are also other very interesting mechanisms to examine. One that is promising is immune system priming, which is where immune responses become oversensitive to triggering. This can happen with microglia, and there are two researchers looking at how microglial priming may be behind ME/CFS symptoms.

Priming is where an initial exposure to inflammatory agents like cytokines sensitizes immune cells, so that any subsequent exposures to inflammatory agents cause exaggerated and much stronger inflammatory responses from these cells.

Immune system priming could in fact explain how chronic sickness behavior might arise.

More info on immune cell priming in ME/CFS is found in this PR article: Part 2: Brain Cells Making us Sick? Messed up microglia could be driving symptoms

 

[Eeyore]

There's a difference between saying a theory is conclusively disproven and that there simply is little or no reason to believe it. In this case I think it's the latter. So many parts of the theory do not hold, and there is no ongoing work being done on it. The fact that one can repair the holes with a complex network of remote possibilities akin to fixing a falling building with duct tape doesn't mean that the theory is worthy of serious consideration.

Rather than a conclusive reason to disbelieve it, I really lack any reason to believe it or consider it a useful or likely model of ME.

It's like the classic example of not being able to disprove the existence of a flying spaghetti monster. I can't disprove it - but I lack any reason to believe it.

 

[leokitten]

There are diseases where the body has an impaired ability to handle intracellular infections, but they are not autoimmune (other than iatrogenic). They are usually genetic in nature - some portion of the cellular immune response is not functioning normally, but can also be acquired. HIV is an acquired immune deficiency (CD4 cells, so not specific to cellular immunity). I've generally read/heard more about diseases with impaired humoral than cellular immunity, but there are certainly both.

Autoimmune disease generally involves the body mounting an immune response against itself. Autoimmunity is not, generally, an immune deficiency, although many autoimmune patients are immunocompromised due to treatments that suppress the immune system.

Some genetic factors may represent more of a predisposition than a pathological state. For exsample, there is a polymoprhism in the IL28 gene (or receptor, can't remember which) which is very important in determining response to Hep C virus. The normal allele is far more common. People who lack the normal IL28 gene have much higher rates of hep C, more complications, and greater difficulty in clearing the disease. It also has effects on other viruses as well - HSV and VZV have been studied as well, and it does affect susceptibility.

So in general, no, I don't believe there is an autoimmune disease that impairs, by itself, the body's ability to suppress intracellular pathogens.

From what I've read autoimmunity can also be the result of immunodeficiency:

http://en.wikipedia.org/wiki/Immunodeficiency#Immunodeficiency_and_autoimmunity
The association between immunodeficiency and the development of autoimmune disease.
Primary immunodeficiency and autoimmunity: lessons from human diseases.
Autoimmunity in Common Variable Immunodeficiency
Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus
Immunodeficiency with autoimmunity: beyond the paradox

There are many more articles. It seems like you can be autoimmune and immunodeficient at the same time and there is a relationship.

 

[Hip]

@Eeyore
Since you don't seem like these chronic viral causes of ME/CFS, would you instead be partial to a discussion on how immune system priming might be responsible for symptoms of ME/CFS?

Priming could fit your idea that viral infection may be an acute trigger, but not an ongoing cause, of ME/CFS.

The acute viral infection that seems to kick off many cases of ME/CFS could provide the initial inflammatory trigger that instigates priming. Then once immune cells are primed, they can be thereafter activated by normally insignificant pro-inflammatory agents. This might then lead to chronic microglial activation and sickness behavior.

So in this case of priming, you don't necessarily need any ongoing viral infection to cause ME/CFS.