Persistence of RNA viruses is deadly real

Pyrrhus

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All this reminds me of a small talk I gave at U.C. Berkeley back in 2013.

I was asked to speak on West Nile Virus, so I talked about how many people infected with West Nile Virus went on to have persistent, fluctuating, exertion-induced neurological symptoms for years after infection.

Just as with other RNA viral infections, the patients were told that their persistent neurological symptoms could not be related to the initial infection, it just had to be something else. They were told that RNA viruses just don't persist in the human body.

The patients also started to develop chronic kidney disease, in addition to the persistent, fluctuating, exertion-induced neurological symptoms. Some patients required dialysis.

Then, in 2010, Kristy Murray of the Texas Health Center published a study that found that even though the West Nile Virus could not be detected in the patient's blood or cerebrospinal fluid (CSF), some virus could be found in the patient's urine roughly 5 years after the infection! [1]

Apparently, the virus persisted in the kidneys, causing the chronic kidney disease, and a bit of that virus was able to leak from the kidneys into the urine.

In case anyone wants to learn more, I have attached my slides from that 2013 presentation.
(For privacy reasons, I have removed my name from the slides.)

Reference
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791189/
 

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livinglighter

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In case anyone wants to learn more, I have attached my slides from that 2013 presentation.
(For privacy reasons, I have removed my name from the slides.)
The slides are really good @Pyrrhus. Easy to read yet still informative. It’s become clearer to me how we can incubate viruses and just how difficult they can be to detect.
 

Inara

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You Probably Have an Asymptomatic Infection Right Now
No, not COVID-19. Many, many viruses can infect humans without making us sick, and how they do that is one of biology’s deepest mysteries.
APRIL 7, 2021
https://www.theatlantic.com/science...-can-infect-us-without-making-us-sick/618530/
From a virus' perspective, isn't that obvious? Ok, my questions might arise only due to missing knowledge...but I always wondered: If a virus kills its host, how can it survive millions of years? The best virus is the one that makes its host mildly sick or not obviously sick so that it lives as long as possible.

Why are scientists surprised to find "dormant virus"? Because they ignored it so long? Ignored patients and what a minority said...

I also never understood how doctors could be so sure that viruses, bacteria, parasites are surely gone...maybe God complex? "My touch, my mere presence heals."

We simply don't have that technology yet!
True. But there were/are hints and traces. I miss humility in science.
 
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I've always wondered if stress of any sort can cause the viral particles in the CSF to get into the brain, through a sudden weakening of one part of the barrier. Temporarily.

I have no idea what the immune system is like in the brain but I guess if it wasn't working too well...that could make things worse than the proposed toxic buildup of lactate etc in ME brains. I say proposed, I am sure a doctor proved this in several ME patient brains.
 
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The problem is that cerebrospinal fluid (CSF) will only tell you what's going on inside the blood-brain barrier, it won't tell you about what's going inside the brain,

There is a common misconception that the brain sits in CSF and therefore debris from the brain washes into the CSF. As long as the blood-brain-barrier is intact, this is not true.

The latest model of fluid flow shows that any debris from the brain will be washed into the lymph nodes at the base of the neck, NOT into the CSF as long as the blood-brain-barrier is intact:

View attachment 42722

These days, it is generally considered unethical to biopsy the brain...
...but, you CAN biopsy any swollen lymph nodes at the base of the neck!
I'm actually a bit gung-ho about the idea of getting some small(-ish?) ports drilled into my skull for research, diagnosis, and opening up (only a little!) some powerful treatment options. The thought of a spinal tap makes me cringe big time. I'd much rather have some reusable ports that can provide access to where we can find some answers (also an alternate where-the-sun-don't-shine place).

Especially for my terribly impaired prefrontal lobe. Even if a slow feed of some mix is used to "brute force" some temporary restoration of my executive functioning so I can get anything done, that'd be worth 100x the price of having ports & feeds sticking out. That doesn't bother me in the slightest.

A special bonus: if my frontal port plugs can accept attachments... y'know, Deely Boppers!! Horns! I'll take requests.


I'm always dissatisfied by the representations of biological barriers & regions... They're too simple like this CSF/BBB one. Thought for a long time the BBB was some brain-surrounding sheath, but eventually read enough to find out that it's the arterioles in the brain, similar to how it works in the rest of the body but more restrictive, if I'm recalling correctly. Kinda fried right now. Maybe this 2nd part of the BBB is some kinda sheath? Or set of various linings? The diagram says it's a vertical black line 😑. Having the full context of the sectioned fluid spaces around the body isn't mind-shattering. Show me where the blood vessels go, which compartments they feed CSF into, where some lymph ducts provide drainage.

Ditto for the interstitial, cytosol, mitochondria, nucleus membranes/regions. Show the arterioles & lymph ducts there too! It's a tad critical to know what substances can reach a space, and what paths they can take, i.e. where they have effect and can be detected. That whole pharmacology deal... that I haven't really studied.

I sincerely hope the spaces-n-flows are being included in the biomodeling efforts along with all the omics. I haven't stumbled across any good descriptions of where the modeling stands, but that's the future of medicine, one that can actually help us folks out. The current statistically-try-to-connect-the-endpoints kinda crap isn't gonna get us what we need anytime soon.
 

Pyrrhus

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If a virus kills its host, how can it survive millions of years? The best virus is the one that makes its host mildly sick or not obviously sick so that it lives as long as possible.
That's an excellent point.
A virus is, by definition, a parasite.
Parasites can only live as long as their host also lives.

Human viruses have evolved to "co-exist" with their human host for many years, occasionally causing disease, but not killing their human host.

Viruses that kill humans, like HIV or the novel coronavirus, are NOT human viruses.
HIV is an ape virus that co-exists with its ape host for many years.
The novel coronavirus is a bat virus that co-exists with its bat host for many years.

The problem is that viruses can occasionally "jump" from one species to another, and that can be fatal.

Why are scientists surprised to find "dormant virus"? Because they ignored it so long?
Well, there's the psychological aspect:
Scientists are human, too. Nobody likes to think that there can be viruses hiding out inside of them. So they simply prefer not to think about it.

But there's a more historical aspect as well:
  1. In the early 1970's the U.S. CDC effectively declared victory over infectious disease, saying that the success of the public vaccination programs begun in the 1950's had effectively wiped out infectious disease. (Yes, they actually said that!)
  2. Any remaining disease, then, the CDC declared to be "chronic diseases" due to "lifestyle choices", such as smoking, diet, and exercise.
  3. As a result, U.S. government funding agencies declared that they were going to be shifting their research funding from infectious disease to "chronic diseases" due to "lifestyle choices".
  4. In just a few years, hundreds of virologists lost their jobs and there began a surge of epidemiologists looking at "lifestyle choices".
  5. Although this happened almost 50 years ago, we are still suffering from the entrenched biases that were created back then. To see this, simply take a brief look at the current CDC webpage for "Chronic Disease": https://www.cdc.gov/chronicdisease/about/index.htm
  6. For more information on this whole history, see the attached paper by the great epidemiologist Arthur Reingold. (Who, coincidentally, is also a PACE trial critic.)

I miss humility in science.
Humility may still exist in science.
But you never hear about it because humility doesn't create headlines.
And if you can't create headlines, you can't raise money for your institution.
And if you can't raise money for your institution, you won't be promoted or receive tenure.
Which means you may decide to leave science, taking your humility with you.
So maybe humility does not exist in science, after all?

I've always wondered if stress of any sort can cause the viral particles in the CSF to get into the brain, through a sudden weakening of one part of the barrier. Temporarily.
That's an excellent point.

Yes, there are certainly conditions where the blood-brain-barrier can become "leaky".
When the blood-brain-barrier becomes "leaky", viruses and other biological particles can leak from the CSF into the brain, and viruses in the brain might leak backwards into the CSF.

One example of this is severe viral encephalitis.
In severe viral brain infections, the neuroinflammation gives way to full-blown classical inflammation, with a leaky blood-brain-barrier and swelling of the brain.
In this case, you might actually be able to detect some virus in the CSF.

Another example of a leaky blood-brain-barrier occurs in menstruation.
Right before, and during menstruation, the lower level of estrogen causes the blood-brain-barrier to become slightly more permeable. Some have speculated that this might contribute to pre-menstrual syndrome.

Hope this helps.
 

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Pyrrhus

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Excerpt:
Nature Methods said:
“The virus may be gone, but the music lingers on,” says [Avi] Nath. “What is lingering: is it the immune system that is lingering or is it parts of the virus that are lingering?” He has encountered many people with symptoms after a viral infection that were assumed to be immune-mediated conditions. He recalls one person who was part of the NIH Undiagnosed Diseases Program and was experiencing dementia-like symptoms. The team performed whole-exome sequencing, immunoprofiling; they studied immune cells in his blood. With a phage-display method, they looked in his cerebrospinal fluid and blood for immune cells that target dengue virus and checked for autoantibodies; they assessed metabolites and tested for infectious diseases; they gave him drugs used in multiple sclerosis. The assays were inconclusive, the symptoms didn’t cease and the man passed away. The autopsy revealed that in the man’s brain, “there was dengue virus all over the place,” says Nath. Using immunohistochemistry, in situ hybridization, quantitative PCR and sequencing, 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.
If anyone is interested in reading more about this patient described by Avi Nath, the case is published here:

Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features (Johnson et al., 2019)
https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25588
 

Pyrrhus

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I was asked to speak on West Nile Virus, so I talked about how many people infected with West Nile Virus went on to have persistent, fluctuating, exertion-induced neurological symptoms for years after infection.

Just as with other RNA viral infections, the patients were told that their persistent neurological symptoms could not be related to the initial infection, it just had to be something else. They were told that RNA viruses just don't persist in the human body.
I just read this:

Evaluation of Prolonged Fatigue Post–West Nile Virus Infection and Association of Fatigue with Elevated Antiviral and Proinflammatory Cytokines (Garcia et al., 2014)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150370/

Excerpt:
Garcia et al 2014 said:
We found that 31% (44/140) of study participants experienced prolonged (more than 6 months) fatigue postinfection, with an average length of fatigue duration of 5 years. Females, those younger than 50 years of age, and those with symptomatic clinical [West Nile Virus] disease were significantly more likely to report fatigue. Pro-inflammatory and antiviral cytokines (granulocyte macrophage colony stimulating factor, interferon-γ, interferon-γ inducing protein 10, interleukin 2, interleukin 6, and interleukin 12p70) were significantly elevated in those reporting fatigue postinfection compared to those not reporting fatigue. Clinicians should consider history of [West Nile Virus] infection as a possible factor when evaluating causes of prolonged fatigue following a febrile viral illness in their patients.
(emphasis added)

I don't know of a single ME specialist that routinely screens their patients for West Nile Virus, despite the fact that more than 10 million people in the U.S. have been infected with West Nile Virus and this virus may even turn out to be one of the common triggers of ME!
 
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Another example of a leaky blood-brain-barrier occurs in menstruation.
Right before, and during menstruation, the lower level of estrogen causes the blood-brain-barrier to become slightly more permeable. Some have speculated that this might contribute to pre-menstrual syndrome.
So this could be one of the reasons the numbers of women with ME/FM are several times those of men? I don't know if use of birth control pills are known to be associated with increased risk for ME/FM, but since they're associated with dysbiosis, Crone's Disease, etc then it's a double whammy for women.

Seems like if taking the pill lessens the BBB permeability symptom, then it might decrease the chance for ME/FM for some who are more vulnerable to a BBB-related pathology, which would make it more difficult to statistically detect the pill as contributing to ME/FM via dysbiosis. Also muddies the statistical picture that might connect BBB permeability to the larger population of women with ME/FM.

If taking the pill can increase ME/FM symptoms for some, but decrease it for some, while not taking it can cause an increase, it'll be kinda hard to figure out if it's related if these aren't factored in the the analysis... in addition to all the other subsets that need to be factored. Maybe we should check out the population of women who have mainly used the implanted contraceptive device in lieu of oral administration to see if their incidence of ME/FM and similar diseases are actually lower?
 

Pyrrhus

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I'm always dissatisfied by the representations of biological barriers & regions... They're too simple like this CSF/BBB one. Thought for a long time the BBB was some brain-surrounding sheath, but eventually read enough to find out that it's the arterioles in the brain, similar to how it works in the rest of the body but more restrictive, if I'm recalling correctly.
Show me where the blood vessels go, which compartments they feed CSF into, where some lymph ducts provide drainage.
Show the arterioles & lymph ducts there too! It's a tad critical to know what substances can reach a space, and what paths they can take, i.e. where they have effect and can be detected.
Great points.

Yes, the exact structure of the blood-brain-barrier (BBB) is very complicated to describe, even in a diagram.
It took me quite a while to understand it myself, and it's an active area of research so we're still learning.

The first thing to explain is that the blood-brain-barrier actually consists of multiple layers or barriers:
  • The outermost layers (dura mater and arachnoid membrane) enclose the brain on the outside, and do not penetrate into the interior of the brain.
  • Below the arachnoid membrane is a space filled with cerebrospinal fluid (CSF). This space is called the sub-arachnoid space.
  • Blood vessels that supply the brain first run through these outer layers and then penetrate into the interior of the brain.
  • The inner layers of the blood-brain-barrier (pia mater and glia limitans) surround and follow the penetrating blood vessels into the interior of the brain. So, the further into the interior of the brain, the fewer layers in the blood-brain-barrier.
  • However, between the penetrating blood vessels and the inner layers there is a space called the perivascular space. Toward the outside of the brain, this space is connected to the sub-arachnoid space and receives some cerebrospinal fluid from there.
  • But as you go further into the interior of the brain, the composition of the fluid in the perivascular space changes. This inner perivascular space may be filled with immune cells and too many immune cells clumped in one spot can result in a "dilated perivascular space".
  • Eventually, the fluid in this perivascular space drains out of the brain along the cranial nerves, emptying into lymph nodes. There, the fluid is processed before returning to the bloodstream.
Here are some rough diagrams that might help:
1621035637318.png 1621036538822.png 1621036608975.png


Another example of a leaky blood-brain-barrier occurs in menstruation.
Right before, and during menstruation, the lower level of estrogen causes the blood-brain-barrier to become slightly more permeable. Some have speculated that this might contribute to pre-menstrual syndrome.
So this could be one of the reasons the numbers of women with ME/FM are several times those of men? I don't know if use of birth control pills are known to be associated with increased risk for ME/FM
Seems like if taking the pill lessens the BBB permeability symptom, then it might decrease the chance for ME/FM for some who are more vulnerable to a BBB-related pathology
More great questions.

So, if a menstruating female's blood-brain-barrier is temporarily more permeable than a male's blood-brain-barrier, does that make them more susceptible to neurological consequences?

If a female takes estrogen pills that strengthen their blood-brain-barrier, will that reduce the chance of developing neurological consequences?

I don't know that we have the research yet to answer such questions.
 
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So this could be one of the reasons the numbers of women with ME/FM are several times those of men?
Seems like if taking the pill lessens the BBB permeability symptom, then it might decrease the chance for ME/FM for some who are more vulnerable to a BBB-related pathology
Re the pill

The pill isn't one thing but a number of different kinds and levels differing with brand, of synthetic compounds that are similar in some way to our hormones. Sometimes only a little similar. As a group, they're associated with many short and long term problems, some being less of a risk than others. And some of the more dangerous ones having already been discontinued.

A drop in estrogen and progesterone before menstruation is normal and what's supposed to happen for the lining to shed. The levels then stay low while menstruating and for some days after. This may affect the blood brain barrier in healthy individuals as part of the natural cycle but it shouldn't be manipulated to be any different, except in the case of health problems. Our hormones adjust throughout the month in an intelligent and synchronized way vital to our health and systemic processes and shouldn't be messed with unless correcting a problem. (Birth control has been a big problem partially for this reason, but also has had undeniable positive public health impacts). When taking birth control the normal way, estrogen and progesterone both should still drop before and during menstruation, otherwise we wouldn't menstruate. I personally don't think a potentially lowered blood brain barrier for some of the month (it rises slowly after menstruation), would be a risk factor for women having more ME, but I could be wrong.

If a female takes estrogen pills that strengthen their blood-brain-barrier, will that reduce the chance of developing neurological consequences?
Estrogen pills the way you probably mean it aren't estrogen, they're synthetic compounds that are not identical to the biological hormone. Another option is synthetic bio identical hormones. Though man made, they are identical to what we make inside and as long as appropriately used, are mostly without risk. They can be helpful for hormone levels if needed and used appropiately. For instance bio identical progesterone is used to attempt to lower estrogen if estrogen is too high or progesterone is too low. This is dosed in a certain way throughout the month and allowed to drop for menstruation. Usually bio identical estrogen is only taken for health reasons during or post menopause if needed, or for some other circumstances.

High estrogen is a significant health problem in women and men now and pms is commonly from too high estrogen. Too high estrogen is a factor in some cancer growth and lots of health problems. Unless there's a need for even the more benign bio identical estrogen for some health reason or documented deficiency at times when it should be higher, neither the bio-different compounds nor the bio-identical compounds are something benign to consider for prevention of ME.

Unfortunately there's a huge lack of education in the US at least, on women's basic biological processes throughout the month, both a lack of education to men and to women and girls, so most people really have no idea what's going on in their own or others' bodies, which is very unfortunate for a number of reasons. And why I felt it was important to step in with some facts about our hormones and the pill. Women in the modern US and I'm sure a number of other places in modern times have little resources for understanding our bodies, birth control, fertility, and our male partners don't either.
 
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Pyrrhus

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When taking birth control the normal way, estrogen and progesterone both should still drop before and during menstruation, otherwise we wouldn't menstruate.
Excellent point.

Usually bio identical estrogen is only taken for health reasons during or post menopause if needed, or for some other circumstances.
Excellenter point.

neither the bio-different compounds nor the bio-identical compounds are something benign to consider for prevention of ME.
Most excellent point!
 

Pyrrhus

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If anyone is interested in reading more about this patient described by Avi Nath, the case is published here:

Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features (Johnson et al., 2019)
https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25588
And here is a case report of a boy who developed ME after a Dengue infection:

Postdengue chronic fatigue syndrome in an adolescent boy
https://pubmed.ncbi.nlm.nih.gov/34099442/

Note that both Dengue virus and West Nile virus are flaviviruses, which are RNA viruses.
 

Marylib

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A good justification for Hormone Replacement Therapy in the many, many women with ME who came down with the whole thing (or FM at first) around an abrupt early-ish menopause? Another sad fact about male domination in science, because who cares, right? Not saying this about all you good people here, but that's the way the world works.
 

Marylib

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I've always wondered if stress of any sort can cause the viral particles in the CSF to get into the brain, through a sudden weakening of one part of the barrier. Temporarily.

I have no idea what the immune system is like in the brain but I guess if it wasn't working too well...that could make things worse than the proposed toxic buildup of lactate etc in ME brains. I say proposed, I am sure a doctor proved this in several ME patient brains.
The glymphatic system changed all the assumptions around blood-brain barrier, as far as I am aware. And before people were talking about the glymphatic system - maybe 6 years ago? - some article came out about how the blood-brain barrier doesn't really exist. Can't remember the article, but it had diagrams and illustrations. Now we have Michael Van Elzzeker talking about it - Poly Bio on youtube (Amy Proal, and all those guys)
 

Pyrrhus

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And just in case the potential implications for Long Covid need to be spelled out...

Here are two papers that hypothesize that some Long Covid cases are actually persistent coronavirus infections:

Persistent SARS-2 infections contribute to long COVID-19 (Jacobs, 2021)
https://www.sciencedirect.com/science/article/abs/pii/S0306987721000566
Jacobs 2021 said:
COVID-19 is a serious disease that has infected more than 40 million people. Beside significant mortality, the SARS-CoV-2 infection causes considerable and sustained morbidity, dubbed long COVID. This paper argues that some of this morbidity may be due to a persistent systemic infection. Persistent infection is indicated by continued virus RNA shedding. The virus’ superantigen could overstimulate anti-virus immune responses, and thereby induce negative feedback loops, that paradoxically allow the virus to persist. The superantigen would induce strong immune response to any residual infection. This hypothesis suggests that clearing the virus infection completely would be an appropriate intervention against long COVID.

Persistence of the SARS-CoV-2 virus as etiological cause of long-term symptoms in persistent COVID-19 patients (Guerrero and Bilbao, 2021)
http://mgyf.org/persistencia-virus-...racion-en-pacientes-con-covid-19-persistente/
Guerrero and Bilbao 2021 said:
At present, there are significant gaps in knowledge regarding COVID-19, the result of infection due to SARS-CoV-2 virus, since a very short period of time has passed since its appearance.

This viral infection has presented with a wide range of clinical manifestations whose severity has varied greatly among the patients: persons who have required hospitalization, very ill patients with fatal consequences, subjects with long-term symptoms and others who are asymptomatic.

From the research group of Long COVID ACTS (patients with persistent symptoms of COVID-19) we have focused on the development of a scientific hypothesis in order to not rule out (and even strengthen) research projects based on the persistence of the SARS-CoV-2 virus as etiological cause of the symptoms in patients who present with Persistent/Long COVID clinical symptoms (CP/LC).
 

Pyrrhus

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Another example of a leaky blood-brain-barrier occurs in menstruation.
Right before, and during menstruation, the lower level of estrogen causes the blood-brain-barrier to become slightly more permeable. Some have speculated that this might contribute to pre-menstrual syndrome.
For what it's worth, here is a paper that briefly discusses pre-menstrual symptoms and ME:

Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Chu et al., 2019)
https://forums.phoenixrising.me/thr...hronic-fatigue-syndrome-chu-et-al-2019.84716/
Although women have discussed amongst themselves premenstrual aggravation of their ME/CFS symptoms for many years, only one other study besides ours has formally surveyed patients. Sixty-seven percent of Clark et al.'s (41) subjects reported worsening of ME/CFS before their periods, close to our figure of 53% (Figure 1).
 
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