Do you believe that “viral persistence” is the cause of ongoing MECFS and LC?

[duncan]

I had all the PCR/DNA lymphocyte tests for viruses 11 years into the illness when I felt 'viral' and nothing showed up.

If immune tolerance is at play, odds are nothing would.

 

[forestglip]

If immune tolerance is at play, odds are nothing would.

Sorry, what does this mean?

 

[duncan]

Sorry, what does this mean?

Back in the early 1950's the Nobel Prize went to a couple of guys who demonstrated that a fetus can inherit from its mother an immunological unresponsiveness toward an antigen or group of antigens.

But some veterinarians had been purportedly toying with the concept before that, and well after. In this frame of reference, as I understand it, immune tolerance can be looked at as a state where there is little to no inflammation or antibody response to certain antigens that might typically cause such responses. It happens when elements of the immune system are effectively muted or suppressed.

So - in theory - you could have active infections and not test positive for them.

 

[forestglip]

So - in theory - you could have active infections and not test positive for them.

But doesn't this imply that while you might not be able to test for antibodies, or some other aspect of the body's response, you should be able test for the virus directly with PCR, maybe even more easily, since it's not being suppressed?

 

[duncan]

But doesn't this imply that while you might not be able to test for antibodies, or some other aspect of the body's response, you should be able test for the virus directly with PCR, maybe even more easily, since it's not being suppressed?

You have to know where to look, and what you're looking for.

 

[FMMM1]

pathogens may be sequestered, or not on his list

"not on his list" surely a completely unknow genetic fingerprint/organism would stick out like a sore thumb?
DecodeME will hopefully provide clues in the near future, but I think Jonathan's take (common pathogen but aberrant immune response) is better fit at this point.

 

[SNT Gatchaman]

immune tolerance can be looked at as a state where there is little to no inflammation or antibody response to certain antigens that might typically cause such responses. It happens when elements of the immune system are effectively muted or suppressed.

A few references on immunoparalysis.

The Calm after the Storm: Implications of Sepsis Immunoparalysis on Host Immunity (2023, The Journal of Immunology)

Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis (2016, Nature Immunology)

Monocytes and Macrophages, Targets of Severe Acute Respiratory Syndrome Coronavirus 2: The Clue for Coronavirus Disease 2019 Immunoparalysis (2021, The Journal of Infectious Diseases)

The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity (2018, Cell Metabolism)

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells (2023, Nature Biomedical Engineering)

Sepsis and septic shock (2016, Nature Reviews Disease Primers)

Prolonged Reactive Oxygen Species Production following Septic Insult (2021, ImmunoHorizons)

 

[poetinsf]

Not instant, but this person on Reddit says after testing positive for COVID 1.5 days earlier, they went from a little sleepy to very sick in one hour, though no mention of fatigue as one of the after symptoms.

This person got intense fatigue and fever within an hour, after three days of muscle aches.

Interesting. Don't know how widespread such experiences are; it's something I've never heard of till now. Such rapid fatigue could be secondary rather than directly from infection. In fact, it could be a true PEM rather than a fatigue from the infection. He could have developed post-viral syndrome while he was still in-viral and whatever exertion he did may have triggered PEM. It would be interesting to follow up on him and see if he still has the same fatigue episode after the virus was gone. On the face, however, it opens up the possibility of viral reactivation causing rapid PEM-like fatigue.

 

[FMMM1]

One of the things that occurs to me, e.g. from Jonathan's comments above, is that the underlying cause of ME/CFS and Lyme are likely the same --- thinking of Nath's reference to solve ME/CFS, Lyme or Long COVID - you'll solve the all!

 

[forestglip]

Doesn't viral persistence offer a pretty good explanation for delayed PEM? Exertion and repair from that exertion take energy away from the immune system [Edit: "energy stealing" doesn't have to be the reason, could be some other unknown mechanism where exertion allows a virus to proliferate. Maybe even a mechanism that is specific to ME.], so the virus gets a chance to break out of containment and build up its levels. Replication can take a few days, as can be seen with normal acute infections.

There have been multiple studies showing RNA of SARS-CoV-2 months or years after infection in LC, but as far as I know, no evidence of the actual virus, though. But maybe it's not viral persistence of the COVID virus, but instead the proposed reactivation of other viruses, like EBV. Though it'd be much more satisfyingly simple if it was just COVID persistence that we haven't found yet.

I emailed Nancy Klimas about this "exertion causes viral replication causes PEM symptoms hypothesis", and her response:

"Also in exercise the immune system activates, which could trigger viral expression as well. We all focus on herpes family viruses but not nearly enough on the rest. New technologies ( incredibly expensive technologies) allow a search for all know viruses. You can imagine we are pursuing that. But the tricky part of that is that some viruses are restricted to specific areas - muscle, gut etc So looking in the right place with a pre post exercise sample is the trick.

At this conference Dr Wust showed pre post exercise pictures of muscle after exercise that showed patchy breakdown and inflammation, Now he's digging deeper it's a recent Nature article with the long COVID group"

 

[Mij]

Exercising does appear to activate the immune system and reactivate viruses in my case, but not always.

 

[forestglip]

Doesn't viral persistence offer a pretty good explanation for delayed PEM? Exertion and repair from that exertion take energy away from the immune system [Edit: "energy stealing" doesn't have to be the reason, could be some other unknown mechanism where exertion allows a virus to proliferate. Maybe even a mechanism that is specific to ME.], so the virus gets a chance to break out of containment and build up its levels. Replication can take a few days, as can be seen with normal acute infections.

There have been multiple studies showing RNA of SARS-CoV-2 months or years after infection in LC, but as far as I know, no evidence of the actual virus, though. But maybe it's not viral persistence of the COVID virus, but instead the proposed reactivation of other viruses, like EBV. Though it'd be much more satisfyingly simple if it was just COVID persistence that we haven't found yet.

I found a post from a while ago on Phoenix Rising about a potential model of RNA virus-based PEM. They say that one of the stages that these viruses go through during replication is dsRNA (double stranded RNA), and that cells have a much harder time destroying the virus in this stage, versus other stages. So the "viral persistence" may be accomplished by the virus "laying low" in this dsRNA stage.

The user goes on to describe a model (presumably originally hypothesized by someone else, not the user, though no links to any references that I could see in the thread) which says that if nerve cells infected with these viruses activate, maybe from exertion, the dsRNA immediately splits and resumes replication.

 

[Sasha]

There seems to be pretty good negative evidence for persistence of any initiating microbe in ME/CFS. Also there is no good evidence for reactivation of specific viruses like EBV. I think it is possible that there is reactivation of immune responses to viruses or bacteria that we have raging around all the time.

What kind of thing would reactivate the immune responses?

 

[forestglip]

I don't think you can take energy away from the immune system in any meaningful sense. If anything repair signals would activate cells.

I'm seeing multiple papers suggesting that the heavy energy demand of the immune system is one of the main features of sickness, and the body does what it can to redirect it from unnecessary activities. I don't see why it's implausible to think that forcing the body to use muscles would divert it back away from the immune system, risking proliferation of the pathogen.

The Energy Request of Inflammation, 2006, Peters

In this way, the organism can withdraw considerable amounts of energy used otherwise by the brain and the skeletal muscle. The saved energy can instead be used for heat generation in the febrile state and for the inflammatory response.

Biological Basis of the Behavior of Sick Animals, 1988, Hart

Both anorexia and a possible reduction in drinking water relate to the notion that an animal that does not feel hungry or thirsty has little motivation to move about in search of food and water. If an animal stays in one spot, it engages in much less muscular activity and thus can save on body energy reserves needed for the increased metabolic costs of fever.

 

[Mij]

I had multiple PCR tests done during a period when I felt 'viral'. Nothing was detected. My lymphocytes were well below reference range- CD8 at the lowest. The virologist was only concerned about my very low CD8 count, not reactivating or viral persistence.

 

[forestglip]

I had multiple PCR tests done during a period when I felt 'viral'. Nothing was detected. My lymphocytes were well below reference range- CD8 at the lowest. The virologist was only concerned about my very low CD8 count, not reactivating or viral persistence.

The thinking by me, and organizations like Polybio, is that it'll be a lot harder than a simple blood PCR to find a virus.

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC), 2023, Proal et al

SARS-CoV-2 RNA or protein has been identified in tissue months after initial illness despite negative results via standard nasopharyngeal PCR testing and/or a lack of detection in peripheral blood from the same individual31,33. These observations suggest that SARS-CoV-2 persistence occurs largely in tissues.

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 2018, Rasa et al

Subsequently, the abnormal immune profile post-acute infection may allow for continuous reactivation and incomplete clearance of pathogens, resulting in tissue damage and an overactive yet ineffective immune response leading to inflammation and autoimmune changes. The absence of strong viremia indicates that the viruses that are present are likely quite tissue-specific, and data suggests that the viral activity consists of greater “latency-associated replication”, as was noted for EBV [72].

 

[Mij]

The thinking by me, and organizations like Polybio, is that it'll be a lot harder than a simple blood PCR to find a virus.

Possibly. Wouldn't the length of time after viral onset be a factor? I had all the PCR testing done 10yrs after ME onset.

From one of references above (LINK)
"Treatment with antivirals or combinations of antivirals and immune-modulating agents during acute COVID-19 may also prevent PASC by decreasing or eliminating virus that might otherwise persist in a reservoir. Acute COVID-19 antiviral clinical trials should consequently be designed to capture the impact of treatment on PASC development".

I was prescribed Imunovir based on my PCR and lymphocyte counts results (below normal ref range) and it reactivated EBV and HHV6. I had a full on relapse and couldn't walk for 2.5 months.

 

[forestglip]

Possibly. Wouldn't the length of time after viral onset be a factor? I had all the PCR testing done 10yrs after ME onset.

I assume the longer it's been, the less is found in the blood, as the immune system wipes out all the "easy prey".

Amy Proal discusses this (long COVID) a bit in a podcast (starts at 0:52):

The virus, if it persists, doesn't necessarily just persist obviously in blood. So if you go to the doctor and they draw some blood, even if they look for it with like the tools in the clinic, they're not going to find it. Like it's not going to be there free floating in blood, because that's just it's a dumb thing for viruses to do, like if you're gonna if you're gonna hide out someone being in the blood is where the immune system is most robust and all the immune cells are going to. So instead of free floating often in fluids like blood, the virus will go hide in simple terms in tissue. So for example like the tissue lining the guts or the tissue of the lungs or potentially right like nerve tissue even. So to find it then we have to design studies and this is what we have been doing where we collect tissue samples from patients with long covid via a biopsy procedure...

It may require specialized antivirals. One designed for a virus in the blood won't necessarily ever get to the virus location, if, for example, it is in brain tissue, but the antiviral or monoclonal can't cross the blood brain barrier.

 

[Mij]

Taking tissue samples from lungs from LC patients could produce answers. But I'm not so sure tissue samples(except the brain) is going to produce anything useful for pwME? Dr. Chia took gut samples from pwME for enterovirus but I'm not sure he found anything? My best friend was a patient of his for 11 years but there was no detection of enterovirus in his gut tissue.

 

[Jonathan Edwards]

I'm seeing multiple papers suggesting that the heavy energy demand of the immune system is one of the main features of sickness

Those just look like idle speculation to me. Arguments about adaptive responses are always pretty conjectural. I would need to see some specific evidence for e.g. lymphocytes needing a lot of ATP. Every day we make buckets of red blood cells and repair muscle and gut cells. We also make a billion B lymphocytes and throw most away. I don't see any particularised for more energy for an immune response. Fever requires re-setting the thermostat and using more energy short term but that is nothing to do with mounting an immune response.