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

The possibility of ME/CFS being caused by a chronic viral (or other) infection – for at least some people — has been discussed for a long time. The biggest piece of evidence in favour of t is that infections are very often a trigger for ME/CFS (summary of the evidence here).

A similar case has been made in Long Covid, and in a recent Nature article (thread), Dr Avi Nath made many interesting observations about how hard to detect chronic infection can occur in other illnesses. Elsewhere, he and Walter Korshetz have repeatedly drawn links between one code and ME/CFS, which made me look afresh at the possibility of chronic infection in our illness.

The case against

Two fairly large and well-done studies have failed to find any difference between ME/CFS patients and healthy controls when looking at viruses in the blood plasma. One was done by Dr Ian Lipkin, the other by Dr Ron Davies.

Neither study has been published following peer-review, but the results of both have been made public (anyone got links to these?)

The case for

The criticism of these negative findings in ME/CFS (and other illnesses) has always been that looking in the blood is the easiest thing to do, but it will miss viruses if they were hiding out elsewhere in the body. (This is what Nath explores in the Nature article.)

I'm aware of three specific hypotheses about how specific viruses are responsible for ME/CFS:

1. Dr John Chia's unreplicated study found higher rates of enterovirus in the stomach lining biopsies in people with ME/CFS than in healthy controls.

2. Dr Mark vanElzakker has proposed that Epstein-Barr, EBV (a human herpesvirus) infects the vagus nerve (where it can't be detected) and leads to changes in the brain that are responsible for ME/CFS. I'm not aware of any specific evidence for this.

3. Currently leading the pack is Dr Bhupesh Prusty. His theory, if I have this right, is that ME/CFS is caused by HHV-6 infection of a minority of immune cells. These infected cells then release a factor that affects other cells in the body. The hypothesis focuses on the effect of HHV-6 on mitochondria. Prusty recently landed a €1 million grant to explore this, and ME Research UK has launched £400,000 grant that appears specifically tailored to his work. He has some promising findings.

I'd like to start a general discussion on the case for chronic infection - I assume the details of specific hypotheses are well covered in other threads. But if anyone can fill in/correct correct my descriptions above that would be great.

I'm putting the extracts from the Nature article in the next post.

 

Quotes from/highlights of the Nature piece on Long Covid, focusing on the possibility of chronic viral infection.

...A cohort of patients will be recruited and followed, and their bodies and biopsies will be scrutinized using a broad assortment of technologies...

Is there a viral reservoir?

Even months after an infection, mRNA from SARS-CoV-2, as well as viral protein, have been detected in the intestines of infected individuals. .. Four months after onset of COVID-19, immunofluorescence and PCR analysis of intestinal biopsies showed persistence of viral RNA and protein. There is a vestige protein that the immune system is reacting to, says [Nadia] Rosenthal; an antibody “is picking up something,” she says. That does not automatically mean this is what is making people ill, “but it could.”

Nath says the finding of potential viral reservoirs “to me, is very fascinating.” Some viral infections are known to live in reservoirs in the body, but they tend not to induce an inflammatory response... Nine months after [Ebola] infection, men still had virus in their seminal plasma.

Susan Weiss at the University of Pennsylvania... [said] viral RNA can persist in its central nervous system (CNS) without infectious virus being present. ..The RNA can remain for the mouse’s whole lifetime, and “this is associated with demyelinating disease,” says Weiss. There is “no evidence at all for this in humans so I don’t really want to make an analogy—just an interesting fact.


[Petter] Brodin [of the Karolinska Institue in Sweden] believes that intense study of viral reservoirs, viral persistence and related aspects should be a focus in long COVID and beyond, for example for diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). [Brodin has published a pre-print on treating ME/CFS with nasal (TENS?) stimulation.]

Is it in your head?

“The virus may be gone, but the music lingers on,” says Nath. “What is lingering: is it the immune system that is lingering or is it parts of the virus that are lingering?” ...He recalls one person who was part of the NIH Undiagnosed Diseases Program and was experiencing dementia-like symptoms5. [they suspected Dengue fever but couldn't get a clear signal for virus or antibodies; the man died]. The autopsy revealed that in the man’s brain, “there was dengue virus all over the place,” says Nath. ... the scientists found the virus had persisted in his central nervous system and brain, and it appeared this had led to panencephalitis and progressive dementia.

...Months, even years, after recovering from measles, some children develop a deadly condition called subacute sclerosing panencephalitis (SSPE). Hunting for virus in the sick child’s body yields no findings. At autopsy, “you look at the brain, it’s loaded with the virus,” says Nath. What has taken place is that measles virus remains in the brain and it has mutated to the point at which it no longer forms a complete viral particle. It replicates only in a restricted form: it will form some RNA, some proteins and “it even has the ability to go from cell to cell,” he says. The changes allow the restricted virus in one neuron to fuse itself, along with its RNA and protein, with the cell membrane of a neighboring neuron. It keeps moving, infecting a succession of neurons.
...
As part of his upcoming work on long-haul COVID...[Nath] hopes to check for viral remnants or viral signatures and check for evidence of restricted viral replication in people. That will require immunological profiling of the long-haul COVID cohort now being set up. All the ‘toys’ at the NIH intramural program will be put to work, he says. They will use, for example, the 7-tesla MRI for brain imaging to see if there are remnants of viral pathology in the brain that otherwise can only be seen at autopsy.
...

The NIH has launched a $1.15 billion initiative focusing on long COVID. In samples from people with long COVID, the NINDS lab of Avi Nath is looking for viral remnants or viral signatures.

[Long Covid patients] will be admitted to the NIH’s hospital for many types of tests......PASC also involves an autopsy cohort and detailed analysis of tissue from individuals who suffered from long COVID—including genomic and transcriptomic analysis and various types of imaging, such as electron microscopy.

...

Is it in your genes?

...

Brodin leads the consortium’s long-COVID group. The plan is to share ideas and samples and perform analyses of patients who develop long COVID, says Brodin....The focus is on patients with milder forms of acute COVID-19 who are 12 weeks or more beyond their acute bout but still have long, persistent fevers, dysautonomia or other forms of “clearly abnormal physiological presentations,” he says. “We need to know if there is virus left in the body, but this is very hard to measure in humans,” he says. They plan to perform deep sequencing of genomes, use imaging to hunt for viral particles in tissue specimens and assess autonomic dysregulation....

 

Are there any good examples of chronic illnesses caused by chronic viral infections? I can only think of AIDS where patients eventually become sicker and sicker until they die (in case of no treatment).

Although there are exceptions, for the majority of ME/CFS patients it doesn't seem the case that they become progressively worse over time. Wouldn't that speak against the hypothesis of a chronic viral infection?

 

https://en.m.wikipedia.org/wiki/Hepatitis_C
Another example of a chronic virus that can make people sicker over time.

I do think that MECFS patients get worse over time. I also think that the chronic, sub acute virus concept is a dead end and won’t pan out—mostly an opinion, but also because they haven’t really found anything yet.

Also this concept is being pushed by someone at Polybio and I just think their science base/evidence is suspect/non-existent.

 

What’s the possibility that they find some viral persistence in long haulers, but the virus is not actually what is driving their symptoms?

 

Isn’t the problem finding viruses lurking undetected long term that they are dormant, so could this explain an ongoing symptomatic condition such as ME?

There are active viruses such as Hep C that can be active on an ongoing basis, there are viruses that can remain dormant in difficult to access locations such as the Chicken Pox virus or Ebola, that can re-emerge to re trigger an active symptomatic infection.

A dormant virus is inactive, so of itself is not causing any infection. But are there any known viruses that are both undetectable and simultaneously producing ongoing symptoms of their infection, or is this currently just a theoretical possibility with no evidence base?

 

Michael, actually in the case of our family member, the ME is progressively getting worse over time, very slowly but it is marked. (not due to de-conditioning). I think that you may find many patients who say it is progressive.

 

What do you make of Dr Chia's thesis? Our family member did have a biopsy taken from the GI tract and it was doubly positive for enterovirus. It was of course not treated, as from what I know there is no anti viral that hits enteroviruses, and Dr Chia is using a herbal, which seems for some reason more effective with males rather than females.

 

Isn’t the problem that we need an additional mechanism to explain why some people improve, others remain stable, others experience relapses and remissions and yet others experience on going deterioration.

I am not sure this model easily fits the course of my ME without postulating other factors

• An initial acute EBV infection associated with a sudden ME onset, followed by gradual improvement over a number years to the point where I believed at the time I was recovered
• An initial acute presumed influenza virus infection associated with a rapid major relapse
  
• Then over twenty years of relapses and remissions, with generally each relapse worse than the previous often with new symptoms and each remission involving less recovery.
• The improvement following a relapse is always slow, over a period of years, possibly slower with each subsequent cycle, but the relapses could be sudden, associated with an event such as a subsequent infection or exertion such as a foolish twelve mile walk in winter, or gradual over a period of months or longer.
• After my initial near total remission, subsequent remissions have be less than total, though with an underlying trend of overall deterioration.

[edited to clarify]

 

There's this explanation from Ron Davis:

25:47 Now the other thing that we decided to do in this project is to test some of the ideas that patients have had, are they right or not. So I've heard a lot from patients that "Oh I keep getting viral infections . . .I get them all the time, it's really my real problem . . . I'm very susceptible to viral infections". And I ask them what virus do you think you're getting? "Oh I'm sure it's HHv7 or it's another herpes virus and that's what caused my illness in the first place". So we decided to actually test this and we had to develop a technology to really do it and to do what I thought was correct.

28:24 The results of that is basically there aren't virus infections that are different from healthy controls. A few people do have them but healthy controls have more in this small study, so it makes me suspicious that in fact they don't have viral infections. They have something else going on that feels like a virus infection and a lot of inflammation things things will make you feel like that. Most of these viruses probably, by themselves, don't really do anything by themselves. It's not to their advantage to give a signal to the body that they're there. The body is the one that does the signaling that there's something wrong. And I think if you have that signal like inflammation it may feel like a viral infection. The only reason I'm stressing that point is that if it's most likely you don't have a viral infection you shouldn't be taking antivirals probably, because they're probably not that healthy for you. And the reason they're probably not that healthy is that the antivirals generally target the synthesis of the DNA from the virus and it works because it's a very primitive

 

Sorry to hear that.

I had the impression that those who get progressively worse form a subgroup and not the majority but it is difficult to say because we have little good data on prognosis.

 

I think this idea is worthy of wider consideration. Given that viruses (some, most, all?) have evolved ways to avoid elimination by the immune system, some of which involve reducing the efficiency of the immune system itself, logic would seem to say that if this has happened in someone, so that a virus is holding out against the immune system by reducing its efficiency, then that could lead to secondary problems with, for example, additional infections from other pathogens. Or that a byproduct of the immune dampening efforts causes a chain reaction of some sort, leading to symptoms that seem separate to the initial infection. All speculation of course, I have no proof.

 

Don't know. Would be useful if others could give some examples of illnesses caused by chronic viral infections. I keep thinking of STI's and hepatitis.

Are there chronic illnesses caused by chronic viral infections that look like ME/CFS?

 

There are several genotypes for Hep C, and several medications/combos available depending on the genotype. their treatment time-line is only prescribed for several weeks, unlike ME specialist who put their pts on meds for years with little or no improvements.

 

Thanks very much for all the responses, this is exactly what I was hoping for when I started the thread. I hope it's clear that I'm only considering this as an interesting possibility, I don't have strong views either way.

Medical Microbiology textbook:
Chapter 46Persistent Viral Infections
Diseases caused by persistent virus infections include acquired immune deficiency syndrome (AIDS), AIDS-related complexes, chronic hepatitis, subacute sclerosing panencephalitis (chronic measles encephalitis), chronic papovavirus encephalitis (progressive multifocal leukoencephalopathy), spongioform encephalopathies (caused by prions), several herpesvirus-induced diseases, and some neoplasias. The pathogenic mechanisms by which these viruses cause disease include disorders of biochemical, cellular, immune, and physiologic processes.

not as far as I know, other than ME/CFS looks like a lot of things. I don't really see how this question is relevant.

I don't know. But I don't see any reason why a chronic infection has to aggressively get worse and kill you. A well adapted infection should be able to keep its host alive.

as a couple of the people interviewed in the article I posted above, that is definitely a possibility.

Quite a few of the comments they are bigger question, which I will try to address in the next post.

 

A lot of people are, quite reasonably, saying, "given what we know about chronic viral infections, is it likely they could explain an illness like ME/CFS?".

However, what made the Nature piece so interesting, is that it was looking at chronic viral infections where the virus was undetectable. All current examples of chronic viral infections are, but definition, detectable. I think I should have spelt that out above.

The case in point was Long Covid, where people are PCR negative. Nath and others are playing to look in new ways to discover it if there are lurking, undetectable infections. All the examples people have discussed here are detectable by current approaches. Nath is effectively exploring a new paradigm. He may well find nothing.

however, if, for instance, the virus was in the brain or the vagus nerve, and wasn't actively producing infectious particles and pumping them into the blood, we wouldn't know if it was there or not.

Nath gave a couple of examples where they could not detect a virus — until autopsy. He aims to use a high-resolution 7-Tesla MRI machine to try to detect viruses in living brains.

If

 

For me, a characteristic feature of ME/CFS is that it can keep patients tremendously ill for decades without showing abnormalities in standard medical testing and, in many cases, without making patients progressively worse over time or causing some form of detectable degeneration in the brain. To me, that suggests that the cause is more likely to be internal signaling with feedback loops rather than an infection (which I see as a more chaotic and less stable process). If all of the illnesses caused by chronic viral infections don't look like ME/CFS or share some of its core features, then I would think this is quite relevant to the discussion.

I apologize in advance if I say stupid things! I don't know much about biology and am just thinking out loud.

 

I thought that in the cases of a well-adapted chronic infection the illness is significantly less severe than ME/CFS. And in cases where it gets as severe as ME/CFS it is usually a process that causes visible damage or makes patients progressively worse over time.

EDIT: so the fact that ME/CFS patients are kept in such a severe state for such a long time might not fit well with a chronic viral infection as a cause. That's sort of the idea that I was thinking of.

This is just a guess based on my limited knowledge. Hopefully, somebody could point to an example that doesn't fit this line of thinking.

 

I understand that I'm heading off-topic somewhat here but I think there is value in highlighting something that Karl Morton is interested in, which is L-form bacteria. If I'm remembering correctly, these are cell wall-less pathogens which are hard, or impossible, to detect using standard techniques. A company in the States was looking into the existence of these alongside chronic illnesses, such as FM and ME, and the, admittedly limited, results they have so far suggest that those with chronic illnesses also have higher numbers of L-form bacteria in their system.

Obviously, like any new area of research, there is, for me, a reasonable question as to whether they have discovered something new, or if it's an artefact of the ways of testing that they use, or some other reason for not being the case.

But one hypothesis is that these L-form bacteria might be able to take advantage of a disruption of the immune system, such as a viral attack, which normally keeps them in check, and that they then multiply, causing increased issues.

And obviously if the focus, from the immune system and doctors, is on the viral attack, then no attention is paid to other pathogens. So perhaps Math should be looking for other, opportunistic, pathogens other than just viruses.

I'll try to return and add links to what research is out there on this later, can't do that at the moment.