Webinar for long haulers by Dr. Patterson and Dr.
Post# of 148170
(Total Views: 861)
Posted On: 02/20/2021 11:17:07 PM
Webinar for long haulers by Dr. Patterson and Dr. Yo
There have been a few posts referencing this video. It is over 2 1/2 hours long and I suspect most have not listened. I only listened to about 40 minutes. A poster here had previously noted that Leronlimab was mentioned early in the webinar. Since the long haulers trial is imminent, I thought it would be interesting to try to get the gist of this webinar. I have been experimenting with a speech-to-text tool (Voice typing) in Google Docs and thought I would use it to transcribe some of this webinar. I am inserting below 3 of the questions Dr. Patterson answered. There are a few references to Leronlimab. I probably won't try this again because I am a slow typist and it took too long for me to edit it into an easy-to-read document.
https://www.youtube.com/watch?v=bSObeeceZos&a...e=youtu.be
Q - (Talking about long hauler index at 16:15) It seems like there's a lot of emphasis on the CCL4 as the denominator. Can you talk about how all of that came about and what the significance of it is.
Dr. BP - At first glance if you look at the difference between active covid and long haulers, it's very clear that some cytokines are very very different between the two. I've always talked about Rantes, but Rantes is elevated in mild to moderate, Rantes is elevated in severe, Rantes is elevated in long haulers. It wasn't a differentiating marker. So one of the big questions I always get is - well you talked about Rantes since February, how come you're not talking about Rantes in the context of long-haulers. I do - I think you have 50% to 2/3 of long haulers have Rantes elevations for instance, but it wasn't the differentiator that said you are a long-hauler or you have active covid. When we did the computer modeling, what really distinguished it was interleukin 2 and interferon gamma levels, I'll talk about that in a moment, and CCL4 which was lower than in the normal population. And again that's a marker produced by immune cells that allows mutant cells to traffic, and similar to CCL3 and CCL5, which of course is Rantes, but it's regulated a little bit differently. So it was really the computer that generated that. What was so intriguing about the long hauler scores, interleukin 2 and interferon gamma are both type 1 cytokines. Type 1 cytokines are very characteristic of a cell mediated immune response against pathogens like viral infections. So in many ways the immune profile of long Haulers is much more appropriate and understandable than say the immune chaos you see in active covid, and that's basically what the computer spit out for us. And you know again, and that’s what led us to looking for viral persistence which we published in November, patients of 90 days with detectable covid, now there’s others out to 100 days and more. Whether that’s replication confident, we don't know, but there's certainly a continuous antigenemia of some type that's causing this elevation into 1 cytokines that make up the long hauler index.
Q - (Starts at 19:15) When you developed the long hauler index, what did you expect to find, what are you finding, and are you seeing any patterns in males versus females, age differences, anything having to do with severity of disease course, any pattern at all.
Dr. BP - I would truly expect there to be the differences in the populations that you suggested, but what we've seen so far is there really aren't many differences. I think there's certainly a suggestion that the higher the score maybe the more severe the symptoms, but what we do know is that when people are treated and they're feeling better, we see a decrease in the long hauler index, and I think that's what we all want to be able to see. And there's two kind of sub-analyses that are taking place that came off of the long hauler score, and that is the relationship between symptoms and a specific cytokine or chemokine, or set of cytokines and chemokines, so-called cytokine specific or symptom specific cytokines, which I mentioned briefly on Twitter SSC, and then the other thing is we're relating different therapies to lowering or normalizing certain cytokines. Those are the major pieces that are necessary cause then we can go from what drugs are best for what symptoms, and we've already worked it out for one cytokine, a lot of computer analysis, but VEGF, which is elevated in 79% of long haulers and causes the burning sensation, the neuropathies, numbness, tingling, weakness, etc., brain fog, is highly correlated with VEGF, and we've taken that in our other modeling one step further. We know that Maraviroc decreases VEGF, and by definition has been improving brain fog. We want to be able to do that. We have a list in our paper of maybe 20-30 long-hauler symptoms. I've seen other papers where maybe it's 200 or more or maybe some variations on a theme, but at the end of the day, what we want to be able to say is: okay you have these symptoms, I think we need to treat you with X Y and Z, and I think we're almost there. I'll say treatment has really revolved around combinations of therapies. Our triad of great therapy so far has been Ivermectin, Maraviroc, that's the CCR5 inhibitor, and low dose steroids for at least two weeks. We’re seeing improvement. The great thing with Ivermectin is it's been proposed as an antiviral, an immune modulator. We do think if there's persistent viral presence somewhere and maybe even low levels of a replication, that that's doing some good work. And of course there's the patients who don't respond, we're expecting that. But I would say 85% and maybe 90% are responding to any of these combinations with Ivermectin, and of course Maraviroc brings Rantes down, it brings interleukin 6 down just like we saw with Leronlimab, and also brings VEGF and TNF-alpha down. We can sort of pick the alterations in the entire 14 plex panel and say okay, how does that steer us toward therapy. So it's been very, very effective, and we're not just flipping a coin or throwing something against the wall and hoping it sticks.
Q - (starts at 23:40) Can you talk about the significance of CD8 and are you seeing those with a low CD8 have a higher long hauler index.
Dr. BP - The CD8 count was something we found, probably in as early as February, that the most severe critical ??? covid patients were supremely immunosuppressed with very low CD8 percentages - in the single digits, 2 or 5 or 7, when normal should be 30% or more, and it was analogous to AIDS, where you know HIV AIDS, you had low CD8, low CD8 percentages, low CD4, low CD4 percentages, but you need both of them - CD4 and CD8 to elicit the strong response against viral infections or a strong response against cancer, and you know these patients, these covid patients, were just as immunosuppressed because of low CD8 percentages. In fact we found a patient early on who had a life threatening Southern Mccalla (?) virus infection because they're essentially imuno-suppressed, immuno-compromised, and then we continue to monitor CD 8. We published a paper with Phil Mudd at Wash U in St Louis in November that shows that an individual with a low CD8% had detectable virus out to 87 days, and that's when we started looking at long haulers, and sure enough, even though the average long-hauler CD8 percent is normal, what we were finding is that 25% of long haulers had low CD8, CD8 percentages, still 8 months, 9 months, 10 months after infection which is incredible. And so we're just now trying to put that together with, like you said the long hauler index or specific cytokine kind of abnormalities to see exactly what the implications are. Hot off the presses today, we've also been doing Delta 32 genotyping for CCR5. As you know, CCR5 - Rantes finds the CCR5 - that's basically what I used to call the quarterback of the immune system and allows cells to traffic to regions of inflammation in response to elevated Rantes, and you know the levels of CCR5 are very important in terms of having a CCR5 antagonist like Maraviroc and Leronlimab, be active against those cells and temper the overwhelming immune response in active covid.
There is also some thought that maybe a Delta 32 deletion, which actually those individuals make up about half the CCR5 receptors, that normal individuals with both CCR5 genes do, and indeed they think that the Delta 32 deletion is protective against severe covid. And in fact today we just finished our first wave of analysis of over a hundred patients across the covid spectrum and the results are in. 20% of mild-to-moderates have the Delta 32 allele, which is common in Northern Europeans and elsewhere around the world, 25% of long haulers have the Delta 32 allele, and 4% of severe to critical covid patients have the Delta 32 allele. Indeed it does seem to have a protective effect against severe disease but may also have ramifications in terms of cellular migration and therapy in both mild-to-moderate group and ultimately in long haulers. Maybe lower doses of Maraviroc or Leronlimab should be considered in long haulers with the Delta 32 because there's less receptors to block. These are some of the key findings we’ve found at the genetic level.
(Note: see posts 78831, 78849, and 78906 for a discussion of the above genotyping.)
There have been a few posts referencing this video. It is over 2 1/2 hours long and I suspect most have not listened. I only listened to about 40 minutes. A poster here had previously noted that Leronlimab was mentioned early in the webinar. Since the long haulers trial is imminent, I thought it would be interesting to try to get the gist of this webinar. I have been experimenting with a speech-to-text tool (Voice typing) in Google Docs and thought I would use it to transcribe some of this webinar. I am inserting below 3 of the questions Dr. Patterson answered. There are a few references to Leronlimab. I probably won't try this again because I am a slow typist and it took too long for me to edit it into an easy-to-read document.
https://www.youtube.com/watch?v=bSObeeceZos&a...e=youtu.be
Q - (Talking about long hauler index at 16:15) It seems like there's a lot of emphasis on the CCL4 as the denominator. Can you talk about how all of that came about and what the significance of it is.
Dr. BP - At first glance if you look at the difference between active covid and long haulers, it's very clear that some cytokines are very very different between the two. I've always talked about Rantes, but Rantes is elevated in mild to moderate, Rantes is elevated in severe, Rantes is elevated in long haulers. It wasn't a differentiating marker. So one of the big questions I always get is - well you talked about Rantes since February, how come you're not talking about Rantes in the context of long-haulers. I do - I think you have 50% to 2/3 of long haulers have Rantes elevations for instance, but it wasn't the differentiator that said you are a long-hauler or you have active covid. When we did the computer modeling, what really distinguished it was interleukin 2 and interferon gamma levels, I'll talk about that in a moment, and CCL4 which was lower than in the normal population. And again that's a marker produced by immune cells that allows mutant cells to traffic, and similar to CCL3 and CCL5, which of course is Rantes, but it's regulated a little bit differently. So it was really the computer that generated that. What was so intriguing about the long hauler scores, interleukin 2 and interferon gamma are both type 1 cytokines. Type 1 cytokines are very characteristic of a cell mediated immune response against pathogens like viral infections. So in many ways the immune profile of long Haulers is much more appropriate and understandable than say the immune chaos you see in active covid, and that's basically what the computer spit out for us. And you know again, and that’s what led us to looking for viral persistence which we published in November, patients of 90 days with detectable covid, now there’s others out to 100 days and more. Whether that’s replication confident, we don't know, but there's certainly a continuous antigenemia of some type that's causing this elevation into 1 cytokines that make up the long hauler index.
Q - (Starts at 19:15) When you developed the long hauler index, what did you expect to find, what are you finding, and are you seeing any patterns in males versus females, age differences, anything having to do with severity of disease course, any pattern at all.
Dr. BP - I would truly expect there to be the differences in the populations that you suggested, but what we've seen so far is there really aren't many differences. I think there's certainly a suggestion that the higher the score maybe the more severe the symptoms, but what we do know is that when people are treated and they're feeling better, we see a decrease in the long hauler index, and I think that's what we all want to be able to see. And there's two kind of sub-analyses that are taking place that came off of the long hauler score, and that is the relationship between symptoms and a specific cytokine or chemokine, or set of cytokines and chemokines, so-called cytokine specific or symptom specific cytokines, which I mentioned briefly on Twitter SSC, and then the other thing is we're relating different therapies to lowering or normalizing certain cytokines. Those are the major pieces that are necessary cause then we can go from what drugs are best for what symptoms, and we've already worked it out for one cytokine, a lot of computer analysis, but VEGF, which is elevated in 79% of long haulers and causes the burning sensation, the neuropathies, numbness, tingling, weakness, etc., brain fog, is highly correlated with VEGF, and we've taken that in our other modeling one step further. We know that Maraviroc decreases VEGF, and by definition has been improving brain fog. We want to be able to do that. We have a list in our paper of maybe 20-30 long-hauler symptoms. I've seen other papers where maybe it's 200 or more or maybe some variations on a theme, but at the end of the day, what we want to be able to say is: okay you have these symptoms, I think we need to treat you with X Y and Z, and I think we're almost there. I'll say treatment has really revolved around combinations of therapies. Our triad of great therapy so far has been Ivermectin, Maraviroc, that's the CCR5 inhibitor, and low dose steroids for at least two weeks. We’re seeing improvement. The great thing with Ivermectin is it's been proposed as an antiviral, an immune modulator. We do think if there's persistent viral presence somewhere and maybe even low levels of a replication, that that's doing some good work. And of course there's the patients who don't respond, we're expecting that. But I would say 85% and maybe 90% are responding to any of these combinations with Ivermectin, and of course Maraviroc brings Rantes down, it brings interleukin 6 down just like we saw with Leronlimab, and also brings VEGF and TNF-alpha down. We can sort of pick the alterations in the entire 14 plex panel and say okay, how does that steer us toward therapy. So it's been very, very effective, and we're not just flipping a coin or throwing something against the wall and hoping it sticks.
Q - (starts at 23:40) Can you talk about the significance of CD8 and are you seeing those with a low CD8 have a higher long hauler index.
Dr. BP - The CD8 count was something we found, probably in as early as February, that the most severe critical ??? covid patients were supremely immunosuppressed with very low CD8 percentages - in the single digits, 2 or 5 or 7, when normal should be 30% or more, and it was analogous to AIDS, where you know HIV AIDS, you had low CD8, low CD8 percentages, low CD4, low CD4 percentages, but you need both of them - CD4 and CD8 to elicit the strong response against viral infections or a strong response against cancer, and you know these patients, these covid patients, were just as immunosuppressed because of low CD8 percentages. In fact we found a patient early on who had a life threatening Southern Mccalla (?) virus infection because they're essentially imuno-suppressed, immuno-compromised, and then we continue to monitor CD 8. We published a paper with Phil Mudd at Wash U in St Louis in November that shows that an individual with a low CD8% had detectable virus out to 87 days, and that's when we started looking at long haulers, and sure enough, even though the average long-hauler CD8 percent is normal, what we were finding is that 25% of long haulers had low CD8, CD8 percentages, still 8 months, 9 months, 10 months after infection which is incredible. And so we're just now trying to put that together with, like you said the long hauler index or specific cytokine kind of abnormalities to see exactly what the implications are. Hot off the presses today, we've also been doing Delta 32 genotyping for CCR5. As you know, CCR5 - Rantes finds the CCR5 - that's basically what I used to call the quarterback of the immune system and allows cells to traffic to regions of inflammation in response to elevated Rantes, and you know the levels of CCR5 are very important in terms of having a CCR5 antagonist like Maraviroc and Leronlimab, be active against those cells and temper the overwhelming immune response in active covid.
There is also some thought that maybe a Delta 32 deletion, which actually those individuals make up about half the CCR5 receptors, that normal individuals with both CCR5 genes do, and indeed they think that the Delta 32 deletion is protective against severe covid. And in fact today we just finished our first wave of analysis of over a hundred patients across the covid spectrum and the results are in. 20% of mild-to-moderates have the Delta 32 allele, which is common in Northern Europeans and elsewhere around the world, 25% of long haulers have the Delta 32 allele, and 4% of severe to critical covid patients have the Delta 32 allele. Indeed it does seem to have a protective effect against severe disease but may also have ramifications in terms of cellular migration and therapy in both mild-to-moderate group and ultimately in long haulers. Maybe lower doses of Maraviroc or Leronlimab should be considered in long haulers with the Delta 32 because there's less receptors to block. These are some of the key findings we’ve found at the genetic level.
(Note: see posts 78831, 78849, and 78906 for a discussion of the above genotyping.)
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