Thread at Persistent Autonomic and Immunologic Abnormalities in Neurologic Post-Acute Sequelae of SARS-CoV2 Infection (2024, Neurology)
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Dr Avindra Nath, NIH USA, views on ME/CFS and Long Covid
Dakota15
Senior Member (Voting Rights)
7/11/24: 'NASEM workshop on “Lyme IACI” ft. Avindra Nath, Nancy Klimas and others
Nath: "We think what happens in these individuals, is that they get infected. They don't really get rid of the antigen. So there's antigen persistence. The complete pathogen is not there any longer, they don't have complete viral replication, but you can have still antigen remaining, it never gets cleared completely. I think that's what triggers the process - they have some kind of immune defect that prevents that from happening, that then leads to abnormalities in the neuro-immune axis, and finally affects the brain...and that affects the motor system, which leads to decreased output that ultimately leads to the phenotype of ME/CFS."
Nath: "their cytotoxic T-Cells were also impaired and they had exhaustion...innate immune responses were increased...so, that really suggests that you have presence of some microbial antigen."
Nath: "We thought the best really discriminator after all the omics that we ever did, was really spinal fluid. Most people don't study this in these patients, they never look at their spinal fluid. I think it's absolutely critical to do a spinal tap when studying any neurological disease. What we found...you can just see on the heat map, just eyeballing you can tell there are startling differences between the two populations. What was significantly decreased was glutamate, dopamine metabolites, butyrate...butyrate is fascinating, because it has to come from the microbiome in your gut..so that tells you the brain is being impacted because of something that is happening in the microbiome.."
A question for Nath from the panel, on decreased ability in IgM to IgG - "I was struck by this in ME/CFS...is that simply an association, a byproduct....or do you think it might have some pathogenic role in causing the symptomatology?"
Nath: "I think it plays a really important role in the pathiophsylology of the disease. If you don't get the B cells to switch, you actually don't get T-cell maturation either...you need the switching to occur...so if you don't get good cytotoxic T-cell activity you won't get rid of the antigen, resulting in T-cell exhaustion and antigen persistence.....if your T-cells and B-cells are ineffective, you're left with the innate immune responses that get cranked up...that makes you feel terrible. A lot of these symptoms emerge from from that kind of stuff. I think that B cell defect is actually very critical."
Same MD on the panel: "I think there's a fascinating potential connection with that and Chronic Lyme Disease...Nicole Baumgarth from Johns Hopkins sees this same inability of strong switch IgM to IgG in mouse models of Lyme Disease...and whether or not that's a feature of Chronic Lyme Disease in human patients...this would be fascinating to pursue."
Another question to Nath: "Dr. Nath, is there a blood brain barrier defect associated with the low butyrate?" (also mentions that IgM to IgG switch problem has been reported in malaria)
Nath: "The blood brain barrier is in tact...I don't think there's a blood brain barrier defect. I'm absolutely certain of, at least in these patients, as we measured it in many different ways."
Nath: "We didn't find any evidence of Mast Cell Activation, at least in the ME/CFS cohort. It doesn't mean it doesn't occur, we just didn't find it in our cohort."
"I think T-cell exhaustion is a common feature in Long COVID and ME/CFS..and our data shows that too...I think infection-associated chronic conditions, there is ultimately a host immune defect that leads to T-cell exhaustion for all of these diseases..."
"We didn't do it in our current study, but we have now created a biorepository...for all the data for the community...Ian Lipkin is interested in looking at the Weir scan (not sure if I heard that right?) and we're going to give him all the samples..happy to share them to anyone interested.."
( Link to Nicole Baumgarth, Johns Hopkins:
'Nicole Baumgarth, DVM, PhD, leads efforts of the BSPH to eliminate threats from tickborne diseases, such as Lyme, and studies why some immune responses to infections are successful and others are not.' )
Nath: "We think what happens in these individuals, is that they get infected. They don't really get rid of the antigen. So there's antigen persistence. The complete pathogen is not there any longer, they don't have complete viral replication, but you can have still antigen remaining, it never gets cleared completely. I think that's what triggers the process - they have some kind of immune defect that prevents that from happening, that then leads to abnormalities in the neuro-immune axis, and finally affects the brain...and that affects the motor system, which leads to decreased output that ultimately leads to the phenotype of ME/CFS."
Nath: "their cytotoxic T-Cells were also impaired and they had exhaustion...innate immune responses were increased...so, that really suggests that you have presence of some microbial antigen."
Nath: "We thought the best really discriminator after all the omics that we ever did, was really spinal fluid. Most people don't study this in these patients, they never look at their spinal fluid. I think it's absolutely critical to do a spinal tap when studying any neurological disease. What we found...you can just see on the heat map, just eyeballing you can tell there are startling differences between the two populations. What was significantly decreased was glutamate, dopamine metabolites, butyrate...butyrate is fascinating, because it has to come from the microbiome in your gut..so that tells you the brain is being impacted because of something that is happening in the microbiome.."
A question for Nath from the panel, on decreased ability in IgM to IgG - "I was struck by this in ME/CFS...is that simply an association, a byproduct....or do you think it might have some pathogenic role in causing the symptomatology?"
Nath: "I think it plays a really important role in the pathiophsylology of the disease. If you don't get the B cells to switch, you actually don't get T-cell maturation either...you need the switching to occur...so if you don't get good cytotoxic T-cell activity you won't get rid of the antigen, resulting in T-cell exhaustion and antigen persistence.....if your T-cells and B-cells are ineffective, you're left with the innate immune responses that get cranked up...that makes you feel terrible. A lot of these symptoms emerge from from that kind of stuff. I think that B cell defect is actually very critical."
Same MD on the panel: "I think there's a fascinating potential connection with that and Chronic Lyme Disease...Nicole Baumgarth from Johns Hopkins sees this same inability of strong switch IgM to IgG in mouse models of Lyme Disease...and whether or not that's a feature of Chronic Lyme Disease in human patients...this would be fascinating to pursue."
Another question to Nath: "Dr. Nath, is there a blood brain barrier defect associated with the low butyrate?" (also mentions that IgM to IgG switch problem has been reported in malaria)
Nath: "The blood brain barrier is in tact...I don't think there's a blood brain barrier defect. I'm absolutely certain of, at least in these patients, as we measured it in many different ways."
Nath: "We didn't find any evidence of Mast Cell Activation, at least in the ME/CFS cohort. It doesn't mean it doesn't occur, we just didn't find it in our cohort."
"I think T-cell exhaustion is a common feature in Long COVID and ME/CFS..and our data shows that too...I think infection-associated chronic conditions, there is ultimately a host immune defect that leads to T-cell exhaustion for all of these diseases..."
"We didn't do it in our current study, but we have now created a biorepository...for all the data for the community...Ian Lipkin is interested in looking at the Weir scan (not sure if I heard that right?) and we're going to give him all the samples..happy to share them to anyone interested.."
( Link to Nicole Baumgarth, Johns Hopkins:
'Nicole Baumgarth, DVM, PhD, leads efforts of the BSPH to eliminate threats from tickborne diseases, such as Lyme, and studies why some immune responses to infections are successful and others are not.' )
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Jonathan Edwards
Senior Member (Voting Rights)
I don't see the reasoning behind any of those statements and they don't seem to fit together much. I am not sure about the 'we' think.
Can't help but wonder if antigenic variation might play some role. Also caught my attention that malaria causes this IgM to IgG mishap. I wonder if other parasites might do the same (e.g. Babesiosis), as well as other pathogens.
Great conference, with a curious and good assortment of speakers. Just as interesting as to who wasn't there. Wording matters in these presentations. Interesting Nath made no mention that I saw to effort preference.
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During Q & A, Nath responds to a question about studying more than one disease at a time. I am tired, but it seemed to me he suggested that early on in the ME/CFS study design his group was going to look at ME/CFS and post treatment Lyme at the same time, and that the NIH's Lyme head couldn't supply a single PTLDS patient. I do not recall this. If true, that's extraordinary; it makes no sense to me that she couldn't produce a single chronic Lyme patient (he actually mentions her by name).
Dakota15
Senior Member (Voting Rights)
"Adriana Marques (chief of NIAID's Lyme Disease Studies Unit) was supposed to produce all these patients with post-Lyme. She didn’t produce one patient. Not one”
To my tin ear, Nath sounds a little resentful here. I could be wrong. Still, a simple follow-up question I'd have wanted to hear might have been, "Why didn't she?"
The NIH chronic Lyme/PTLDS ongoing study had been in operation for over 15 years at that point, if memory serves me. They'd recruited from all over the country I believe. Was this a logistical problem, or a political one, or something else?
It may matter because of ties to ME/CFS. It has the feel of an "own goal". I well remember when they announced the PTLDS cohort as part of the ME/CFS study. It felt to me like a set-up: two hotly contested diseases tossed together by an organization with less than a stellar reputation among its respective patients.
I'd love to know what happened.
To my tin ear, Nath sounds a little resentful here. I could be wrong. Still, a simple follow-up question I'd have wanted to hear might have been, "Why didn't she?"
The NIH chronic Lyme/PTLDS ongoing study had been in operation for over 15 years at that point, if memory serves me. They'd recruited from all over the country I believe. Was this a logistical problem, or a political one, or something else?
It may matter because of ties to ME/CFS. It has the feel of an "own goal". I well remember when they announced the PTLDS cohort as part of the ME/CFS study. It felt to me like a set-up: two hotly contested diseases tossed together by an organization with less than a stellar reputation among its respective patients.
I'd love to know what happened.
I'm not sure whether that should be surprising. The ME/CFS cohort required 484 people to end up with 17 PI-ME/CFS study subjects (edit: that is not entirely correct 484 inquires includes those inquires about participating as HV, I currently don't know how many people applied as ME/CFS patients rather than as HVs but I think it's safe to assume that the amount will be larger than that of HVs). With PTLDS patients there is the additional complication that several patients are given pseudoscientific diagnoses based on "chronic lyme tests" that have absolutely no scientific validity and are no different that throwing a dice to diagnose someone. If they'd have to swift through say another 500 people, to end up with a cohort of somewhere under 10 PTLDS patients, I wouldn't be suprised if this study had only been published in the next decade. For me it's rather hard to see how much such small sample sizes would contribute in the first place.
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Sorry, but that is incorrect - at least relative to Marques' chronic Lyme/PTLDS study participants. Each had to satisfy strict IDSA/CDC diagnostic criteria before qualifying to even meet with a Marques underling. This is pedigree Lyme shit we're talking - with the population accruing since 1999 or thereabouts. She should have had a pre-existing reservoir of qualified PTLDS patients.
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I think one reason they found it hard to recruit sufficient ME/CFS patients was their insistence of a diagnosed infectious trigger, and less than 5 years illness duration. Maybe that applied for PTLDS too.
Thanks for pointing that out. However, the problem with the low participant number in the intramural study for ME/CFS patients, is not that there is an insufficient amount of patients that meet the CCC or similar or that there aren't already existing cohorts of ME/CFS patients, but rather the additional things that come with participating in such a study. On the one hand that will be the obstacles posed by even participating in such an arduous study which introduces sufficient hurdles to make participation impossible for many people, on the other hand there will be certain recruitment criteria (illness duration, comorbidities, documented infectious trigger etc) and finally there will those patients that pass through this whole process but that later turn out to have different issues but a priori might not have had sufficient medical examinations (I remember one prospective ME/CFS participant later turning out to have cancer, whilst another turned out to have ME/CFS).
It was my speculation that "scam tests" such as the one offered by Armin Labs or Igenex would only make this process more complicated. Perhaps that may not be the case if the NIH would have adhered to stricter criteria from the get go. I don't know what the recruitment criteria for the Lyme part would have been, but for the ME/CFS part clearly the majority people that applied didn't meet the end criteria of the study.
Maybe. It shouldn't matter. I'd still imagine she'd have been able to pull together a decent cohort. Certainly at least one. Nath sounded bitter to me.
Right. So she had people who crossed all those hurdles. Remember, we're talking over 15 years of recruiting.
a) Igenex sells some good tests. They test for more strains than just B31, and allow 2 proteins/bands, particularly relevant to late stage Lyme, that CDC testing removed due to vaccine interests, etc.
b) The NIH DID adhere to stricter criteria from the get go, as far back as I can remember, at least for their chronic Lyme study recruitment
c) I have no idea what percent of people who applied to the NIH Lyme study were turned away, but its criteria were unimpeachable in terms of CDC Lyme diagnostics standards. Of course, for people like me such standards don't carry much weight.
Dakota15
Senior Member (Voting Rights)
I am not up-to-date with all the different current testing procedures. However, Marques writes in her paper "Persistent Symptoms After Treatment of Lyme Disease"
For the NIH that would seemingly make population recruitment as done for ME/CFS patients in the intramural study, even harder and possibly unattainable for a PTLDS cohort.
Which would be entirely irrelevant had there been criteria similar to those that the ME/CFS part of the study had to fulfill (for example <5 years since onset).
But as you note, Marques should already have such a cohort, in which case the above discussion I started about testing procedures and scam tests would have been entirely obsolete.
From a quick search I've seen 3 possibly routes Marques could have tried recruiting patients from (https://clinicaltrials.gov/study/NCT02446626, https://clinicaltrials.gov/study/NCT00028080, https://clinicaltrials.gov/study/NCT00001539).
I suppose the first meaningful thing to know would be what (additional) criteria for participation in the PTLDS cohort would have existed for patients to be eligible for participation in the intramural study.
Edit: I've only now seen Nath's words. Based on what he is saying there, that would appear to be the case.
As far as I could ever tell, Marques was loyal to the CDC diagnostic formula, including for spinal fluid. Even so, she would have had plenty of qualified recruits. This idea that chronic Lyme cannot fit into the CDC/IDSA diagnostic paradigm is just a myth. Oddly, Marques knows that, I think.
This Lyme debacle is rife with politics. Of course, so too is ME/CFS. It makes me wonder if Nath was forced to confront that as well.
Dakota15
Senior Member (Voting Rights)
'NEAS Grand Round May 2022 COVID 19 Neuropathogenesis by Avi Nath'
Nath: '...this is an antibody mediated phenomenon that's leading to activation of the endothelial cells - I think that's the primary phenomenon that's taking place. The platelets are sticking to it after that and this activation of the endothelial cells is probably what is causing the compromise of the blood brain barrier and leakiness of all the proteins - so we believe that this is the primary pathology that's taking place in the brains…it's quite likely these macrophages are coming in to clean up the mess but once they get in they don't leave that's the problem they're the unwelcome guests and they stay activated so they can cause a lot of harm..'
'...it suggests to you that your adaptive immune responses are impaired and what you have is these activated macrophages that are now taking its place and those are bad actors - because they are not directed against the pathogen, they just produce all kinds of oxidative stress and cytokine production - it's like blanket bombing - they just don't know where the enemy is, they just kill off everything on the way and so once they're in the brain it's bad news...'
"...these activated macrophages are killing the neurons.."
“..our hypothesis here as to what is happening - an immune attack to these blood vessels, there's perforation here - macrophages come in, they release all kinds of cytokines, antibodies over here, the platelets aggregate form these little clots - and these you can get microhemorrhages and then ultimately these microglia get activated and they can cause neuronophagia..”
"If you're going to do clinical trials I would suggest considering immunomodulatory.."
“I’d like to conclude by saying that neurological complications by SARS-CoV-2….this neuroimmune dysfunction is driven by activation of innate immunity, immune exhaustion and antibody-mediated phenomena. Endothelial cell damage by immune complexes is the primary pathophysiological process in neuro-COVID and neuroinflammation may accelerate protein aggregation.."
"...what we found was that there were all these areas of vascular congestion or microhemorrhages, so what we did, wherever we saw it we then went back and made sections from the pawns and then stained it for various kinds of things, so here we stained it for fibrinogen. So, fibrinogen is a large protein it's usually present in the blood vessels it should never get into the brain...so the blood vessels have to be compromised. That's the only way this will happen..."
Nath: '...this is an antibody mediated phenomenon that's leading to activation of the endothelial cells - I think that's the primary phenomenon that's taking place. The platelets are sticking to it after that and this activation of the endothelial cells is probably what is causing the compromise of the blood brain barrier and leakiness of all the proteins - so we believe that this is the primary pathology that's taking place in the brains…it's quite likely these macrophages are coming in to clean up the mess but once they get in they don't leave that's the problem they're the unwelcome guests and they stay activated so they can cause a lot of harm..'
'...it suggests to you that your adaptive immune responses are impaired and what you have is these activated macrophages that are now taking its place and those are bad actors - because they are not directed against the pathogen, they just produce all kinds of oxidative stress and cytokine production - it's like blanket bombing - they just don't know where the enemy is, they just kill off everything on the way and so once they're in the brain it's bad news...'
"...these activated macrophages are killing the neurons.."
“..our hypothesis here as to what is happening - an immune attack to these blood vessels, there's perforation here - macrophages come in, they release all kinds of cytokines, antibodies over here, the platelets aggregate form these little clots - and these you can get microhemorrhages and then ultimately these microglia get activated and they can cause neuronophagia..”
"If you're going to do clinical trials I would suggest considering immunomodulatory.."
“I’d like to conclude by saying that neurological complications by SARS-CoV-2….this neuroimmune dysfunction is driven by activation of innate immunity, immune exhaustion and antibody-mediated phenomena. Endothelial cell damage by immune complexes is the primary pathophysiological process in neuro-COVID and neuroinflammation may accelerate protein aggregation.."
"...what we found was that there were all these areas of vascular congestion or microhemorrhages, so what we did, wherever we saw it we then went back and made sections from the pawns and then stained it for various kinds of things, so here we stained it for fibrinogen. So, fibrinogen is a large protein it's usually present in the blood vessels it should never get into the brain...so the blood vessels have to be compromised. That's the only way this will happen..."
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