Possible chronic viral infection in ME/CFS (& other illnesses inc Long covid). Discussion.

The main reason to believe that ME comes after infection is that people get it during outbreaks.

Syphilis lives in the body forever causes different symptoms at different stages until you get General Paralysis of the Insane after years.

There have been autopsies done where VP1, an enteroviral particle, was found in the brain of people with ME. There have just not been enough specialised autopsies done of people with ME. Who knows what useful information could be found?

I don't think that we can say that if continuing viral infection was involved it would have been found given that very few people with ME are ever tested and even more rarely when in a crash.

There was research reported in the ME world about enteroviral endocarditis, a chronic disease, where it was found that the virus did not burst the cell wall until the cell was stuffed and that the tail of the virus did not replicate true so when it finally reached the blood stream the immune system did not recognise it. More recent research has found that bits of virus genetic material flood into the bloodstream and then form a complete genome when they get together in a cell. No virus will sustain such an effort to evade the immune system unless it wants to persist in the body.

I believe we have barely scratched the surface of viral behaviour in general so no infection in blood means no virus is far too simplistic. Urine was considered sterile until a few years ago but the question should have been why had viruses not colonised the bladder?

Many diseases are believed to be caused by a combination of genetic propensity and then an infection to trigger it. Coeliac Disease and Type 1 diabetes spring to mind.

Then we have to remember that our bodies are full of commensal organisms. It is biological plausible that a virus can have a reservoir which ticks along in some part of the body where it causes very little harm but takes the opportunity to replicate when it gets the chance. E. coli, Streptococcus, Staphylococcus and the viruses that cause meningitis all do that.

The one thing we do know is that ME is a subtle disease.

 

I had all the PCR RNA/DNA testing under the sun done years ago when I felt very 'viral', everything came back 'normal'. I seem to recall the virologist telling me that it was high levels of interferons that were making me feel this way.

I also know what active EBV and HHV6 feels like, it's a completely different experience.

 

The notion of continuous or recurrent infection as foundational and causative (i.e the unique biological event from which all subsequent symptomology proceeds) has arguably provided the greatest misdirection in biological ME research (psych research of course has provided an entire encyclopaedia of misdirection).

As Jo Edwards has already noted if there were continuous and/or recurrent infection at least some sign of this in some patients would be evident and attributable to M.E symptomology. Absence of evidence may not be evidence of absence but at some point one has to acknowledge that the absence is strongly indicative.

This indication of absence might also require questioning of the assumption that a single recognisable infection is foundational and causative in ME. As noted in the first post in this thread, a majority of patients report that they become long term ill after (in their recollection) a virus like infection, however these remembered events may not link actual pathology.

Self reports of a link between onset and permanent decline in health provide a further instance of absence of evidence, there being no being established link between any given virus that is demonstrable in any definable percentage of the patient population. The symptomology of ME resembles many post infection syndromes but correlation isn’t causation, and symptoms are not underlying pathology.

This is not to say that infection, viral or otherwise, has no role in ME/CFS, nor that some patients may accurately identify a pivot point between long term health and long term illness but we should not confuse patient recall of events with underlying pathology that may be hidden and slowly progressing months or years in advance of what otherwise may seem to be a causative infection.

This of course is counter to the history of defining works on ME by Ramsay and subsequently Acheson, where outbreaks of viral illness were identified as causative. It is quite painful for many of us ‘old hands’ to think that Ramsay may have been wrong in his conception of ME as specifically a post acute infection condition, but as the identified patient population has grown in the last 7 decades, so the certainty that ME is foundationally and causatively a result of identifiable infection, has receded.

Prushty in https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1644-y states: In the majority of ME/CFS cases, there is no conclusive evidence for chronic viral infection, but it is plausible that viruses could act via a “hit and run” mechanism; this theory proposes that viruses trigger the disease, cause immune abnormalities and leave a dysfunctional immune system and/or autoimmunity.

A hit and run mechanism does not require an identifiable infection, for example an endemic virus may not cause any noticeable illness, it is also the case that the viruses that Prushty has noted are of interest, many challenge the human immune system in infancy long before the onset of ME/CFS in most patients. Re-activation of dormant virus could cause illness later in life and be a hit and run initiator of ME/CFS at that point, but it may equally be the case that the hit and run is initiated in infancy but that the effect only becomes evident much later in life.

Where does this leave us ? As a patient I don’t have an answer, but I do think that patients and researchers should adopt scepticism about both the idea that persistent infection is a cause of ME/CFS pathology, and about the idea that identifiable infections which seems to occur at the pivot point between long term good health and long term bad health for ME patients, is uniquely an indicator of the commencement of underlying pathology.

 

That "uniquely" provides scope for different interpretations.

 

The persistant viral theory gets recycled every 6-7 years.

 

I had an enterovirus shortly before my first round of EBV.

I don't know if there is a viral reservoir lurking in pwME, or if whatever virus seems to have kicked things off is the tip of the iceberg. I think the theory that everyday environmental toxins may play a role in undermining our systems has merit. And this in combination with one's genetic makeup, and other challenges to one's health.

 

I find it curious though that some long covid patients are reporting improvement or even recovery following one of the vaccines. The hypothesis I've heard for this is that the vaccine promotes a strong enough immune response to clear whatever is left of the (chronic) coronavirus infection and therefore symptoms resolve.

In any case, we should hopefully be getting some answers to the idea of persistent infections from covid research. In this case we have a disease where we know exactly the trigger pathogen, so it follows it should be easier to figure out if long covid patients have a persistent coronavirus infection or not rather than going after all the different candidate pathogens in ME/CFS patients.

 

Is it really that curious? A large majority do not report significant improvement or recovery and there are no controlled studies to suggest it isn't simply spontaneous remission. It is also hypothetically possible that the immune stimulus itself was enough for the body to sort itself out in the minority of reported remissions.

 

I don’t have strong views either way on the persistent or recurrent virus theory, and a total failure to identify any ongoing presence of the trigger virus is a problem for this approach, however not an insurmountable one. If I have not misunderstood, don’t some already propose that the persistent virus is not necessarily the same as the trigger pathogen linked to onset, rather a concurrent infection of one virus creates an opportunity for another virus to establish or reactivate.

My personal experience might be said to support this, though they are also other potential alternative explanations. My initial ME trigger was a bout of glandular fever (mononucleosis) associated with EBV, but after several years I believed I had made a full recovery. Then the millennium bug struck, I had a bad bout of what I believe to have been season flue over the Millennium new year, the specific influenza virus was not formally identified. This triggered a reoccurrence of my ME, very similar in symptom profile to the original presentation, though more severe. With subsequent relapses and partial remissions there has been a change in my symptom profile, with new symptoms emerging on a fairly regular basis. Subsequent relapses were not obviously virus linked, though often it is subjectively difficult to distinguish my PEM or some relapses from mild viral infections.

My experience is that one virus triggered an initial onset, whereas a different virus triggered my second ‘onset’, though I lack independent verification for this. I suspect it will not be uncommon for multiple viruses to be involved in at least some case histories, allowing for the possibility of a persistent or recurrent virus not being the same as an apparent infectious trigger. Similarly in those without an obvious infectious trigger, it would be possible to propose a sub clinical viral infection resulting in the ongoing infection, then opportunistically responding to other non infectious triggers.

 

Yes!

This resonates with my family's experience - we're now up to 6 people with ME among my siblings & my children.

And another key related question is the relationship (or lack of relationship) between post viral fatigue and ME.

Unrelated but early stage of ME present similarly to PVF?

Or PVF develops into ME in some cases?

 

To me, the main feature of MECFS that makes it hard to explain in terms of some chronic infection is that its features are remarkably similar irrespective of what acute infection triggered it (ones we know of are EBV, Ross River virus, Q fever and of course Coronavirus2).

To explain why the outcome is so similar after such a wide variety of different infectious agents, we are left with two options. The first is that the acute infection allows some other latent virus to gain ground, and this other latent virus is the universal infectious agent causing MECFS. The second option is that the very similar symptoms are caused by similarities in way the immune system reacts to a wide variety of different chronic infectious agents.

That second one doesn't seem to hold much water to me, because we know there are lots of chronic viruses that people can carry around for years without being at all sick. So why are we so sick and they are not?

To me all roads lead back to the problem being the immune system itself, that somehow gets sent into a tailspin that is hard to stop.

 

I did not go through all of the posts, but wanted to add a couple of papers from Dr David Patrick in Vancouver (an infectious disease researcher who was awarded grants to research ME.

1) Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

“We were able to identify a 256-peptide signature that separates ME/CFS samples from healthy controls, suggesting that the hit-and-run hypothesis of immune dysfunction merits further investigation”
https://pubmed.ncbi.nlm.nih.gov/30298340/

2) RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease
https://pubmed.ncbi.nlm.nih.gov/28172519/

3) Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing

“Virome composition (P = 0.746 by chi-square test) and number of viral reads (P = 0.098 by paired t-test) were not significantly associated with PEM. These observations do not support transcriptionally-mediated immune cell dysregulation or viral reactivation in ME/CFS patients during symptomatic PEM episodes.”
https://pubmed.ncbi.nlm.nih.gov/30897114/

 

No idea!

But you can do n=1 study on me, if you would like?

2001 PVFS - Yes, I had PEM.

2013 Sepsis > ‘CFS’ > ME/CFS (accepted as UK ME/CFS Biobank participant)

 

Yup that's one inevitable conclusion, that all the "easy"-ish work has been done, what's left is the really hard stuff, except medicine is actually regressing instead of maturing, because it's too used to the first few steps being almost a given. And then you add the ego indoctrination that encourages physicians to pretend to be in control even when they have no clue what to do.

Reminiscent of when various people have called science done and complete at various points in time, or that X is impossible to achieve. Except in all other professions this is in the past, only medicine is still full of hubris like this, probably having to do with the insular nature of the profession. It's... not ideal.

 

I think this makes sense aka the host response theory. The reason ME looks similar but different over a wide range of different types of condition is human nature.

I think the current criteria are so inclusive that only a broad concept about what ME is can fit the criteria. From there we have to work on identifying subtypes.

From my own experiences ME would seem IMHO to involve the innate immune system running amuck for whatever reason. It seems possible the innate immune system has the ability to change mitochondrial activity as an intra cellular defence mechanism and triggering this response systemically might be the essential common element in the wide range of different types of ME CFS cases. At a more abstracted perspective, evolutionary utilitarianism, the innate immune system has a role which means it can presumably prioritise immunity over physical activity and there may be a signalling system which causes this state change (including but not limited to mitochondrial responses) which may be subject to pathology and chronic activation of this state change might be viewed as the nature of ME.

What you term a tailspin is reminiscent of something like asthma or eczema, where the onset of an immune response results in its exacerbation in a feedback loop in cascade signalling processes for those sensitive to this predicament. Also bears comparison to anaphylaxis in that sense of being a runaway feedback spiral but with these allergic examples there is no trap but something has to set the cascade off and there is an overreaction. There is no certanty that this analogy applies lock stock and barrel to ME but is worth considering as a muse.

If ME is essentially an immune state change it might be triggered in more than one way.

1. For some people that could be due to an autoimmune signal accidentally triggered during an infection.
2. For others like myself it may be ongoing virus activity. I think the EBV + another virus scenario is one that crops up a lot and applies in my own case and my own experience is that EBV somehow nobbled my immune system and set it up to fail with future infections resulting in very evident cyclical recurring viral infections as well as the state change which changed my nervous system and physical capabilities significantly and results in PEM just like other forms of ME, because it is our own innate immune system causing it. There may be other subtypes of direct viral signal ME, with ongoing viral replication in refugia or reverse-transcribed viral DNA hanging around creating an immune signal.
3. Hypothetically, others may suffer post viral dysfunction of the recovery phase, viruses having been defeated, where there is hope of recovery albeit protracted and some kind of delay in recovery due to stickyness in the state change reversal but eventually leading to recovery after a couple of years, which I have also seen happen to real people.
4. Others may have missed diagnoses for other conditions which affect their innate immune activity somehow, including biotic infections like Lyme.
5. Others may have conditions which present similarly but are intrinsically different like occult hypothyriodism and many others.

The way criteria are set up today, ME is a broad church. What ME as a diagnosis really reflects today is a huge gap in our understanding of the functioning of the innate immune system. The conflicting perspectives on the nature of ME may be due to multiple different conditions presenting similarly enough to be confounded with each other and the subtypes above would account for most of what I have encountered.

Still have no idea what to make of observations of ME associated with Ehlers-Danlos but it sounds like there may be something we dont understand going on relating to a genetic predisposition to CFS and we need to work out whether it is homologous with ME (types 1-4) via the innate immune system or analagous (type 5) via some other mechanism.

It stands to reason all of these types of condition could be made more or less likely for individuals based on genetic susceptibility but we will get statistical gobbeldygook if we try to compare all 5 subtypes at a genetic level as if they were the same condition.

Longcovid could potentially include subtypes 1,2,3.

 

Not fully read it yet, and everyone else may be familiar with this review article, but if not it may be relevant to this discussion

“Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)” Rasa et al, Journal of Translational Medicine 16 (2018)

link to paper https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1644-y

 

Yes "correlation is not causation" - if we take 100 post covid19 patients who are experiencing continued symptoms, and we accept that a number of such patients will eventually regain good health without any intervention, then it is inevitable that for a percentage of those patients recovery will follow closely on vaccination. How many of the 100 see this correlation depends on the relative timing of infection and vaccination, and the rates of recovery in a time sequence. It's quite possible that (in the UK case) for some age groups the rate of recovery and of receiving a vaccination would be heavily coincident, especially given the preponderance of '2 shot' vaccines.

 

PVF is a convenient label to put on a frequently observed occurrence - that some people following some infections (including bacterial, fungal ?) experience unusual levels of fatigue. Here we have the same correlation/causation problem as with CFS - does the pathology causing the fatigue result from the infection or was it already in progress ?

A reasonable hypothesis is that for some people, and with some infections, the period following resolution of the infection will be accompanied by a level of fatigue not previously experienced and that this fatigue is directly related to the (currently unexplained )impact of the infection but which by definition would not be continuation of the infection.

Is there any reason to consider this post infection feature to be the early stage ME/CFS ? My thought is that do so would be a category error, it seems clear that not all PVF lasts long enough to be classed as ME/CFS, and that PVF doesn't contain all the features of ME/CFS. Of course this doesn't mean someone suffering PVF can't develop ME/CFS but without some definitive pathology to connect the two my view is that conflating them is unhelpful. It's the error that "fatigue researchers" have made and ended up with houses of cards that were untestable. So until we have pathology - ME/CFS is one thing and PVF another.

 

I never had PVF. I had an enteroviral illness then began to experience neurological symptoms including visual problems, speech problems and transient paralysis. Also what I would now call dysautonomia including loss of temperature control, disturbed sleep and neurological bladder problems.

When my husband took a post viral after flu it never crossed our mind it could have anything to do with ME as there was no resemblance to what I had been experiencing for years even though by then I was having crashes where I was confined to bed for days at a time.

There must still be people like me who can carry on with daily life despite strange problems so never suspect they have a disease with chronic fatigue in the name. I wonder if they get worse then have crashes that could be called fatigue and think the ME started then.