Viral rebound may not be a consequence of antiviral treatment, but rather may be part of a more complex viral/host system paradigm. Some initial thoughts based on a recent LA times article.
When we had suspected covid in December’19 we all thought we were a bit better by 12-14 days but then all felt like we’d got it all over again ( just milder). Of particular note was my 14 year old son who initially missed 4 days of school with high fever and headache ( and cough) and then went back to school, playing tennis etc and then exactly 14 days from the initial onset was off school again with high temperature and headache and cough again. My husband and I just assumed we hadn’t cleared it because we were older!
When covid broke out in March’20, I followed lots of doctors on Twitter to try and find out what the symptoms and disease course was, and I particularly remember noticing a few saying they had it ( tested negative) got better then got it again 2 weeks later ( tested positive). We had omicron in Dec’21 and felt like a mild relapse after 2 weeks again.
Yeah, there were quite a few stories suggesting that people had some return after having their symptoms alleviate. How many people experience that is what is unknown, and my point with this post is to remind people that rebound actually was a thing before PAXLOVID. It's certainly true that PAXLOVID may be looked at for showing higher rebound, but the effects are nuanced and various factors should be accounted for.
Fascinating topic. I am however skeptic on whether rebound is common. For PAXLOVID we have (thanks to Brian) a theoretical mechanism, but for natural infection it seems odd, considering for other illnesses that doesn't work this way. Or at least we assume it doesn't.
My main problem is that we don't seem to define rebound very well. I mean, using symptoms is one step up from just 'testing positive', but apart from countless studies demonstrating how unreliable we humans are in reporting symptoms, covid symptoms are shared with countless other common illnesses each of us get multiple times a year.
(In fact the nasal obstruction/discharge reports suggest they do not have, or not just have, covid, considering pre-omicron that was not a common symptom of covid.)
In fact it seems that even the 'Team Reality' side forgets that covid isn't unique in being widespread. Every one of us gets infected multiple times a year, and also frequently has co-infections. So how do you know a rebound is not just another new illness? It would be great if one could also do some PCR testing with actual rounds reporting, other test confirming a rebound is accompanied with an actual rising presence of covid. And if it is a rebound, was it in part caused/accompanied by another co-infection flaring up?
And if we are really going to be serious, one would need to sequence them to see if we are talking rebound or re-infection/re-exposure. I'm personally even more skeptical on short term re-infection, but let any data prove me wrong.
Currently we seem to have a lot of people on social media bragging that they are testing positive again. Considering they are testing and posting, that already shows they are a subgroup of our population. I have three young kids, and if I was testing every time I got a cough, I'd be racking up more tests than Fauci. None of my friends, coworkers and family bothers to test as well. We just cough like it is 2019 again.
So you've actually outlined a lot of things I should have put into this post.
Viral rebound depends on whether some PCR/antigen test is done, or whether it's based solely on symptoms. I believe for Fauci he tested negative but then tested positive again. For many people who are in a position where they are required to be screened and surveyed daily then they're likely to provide some information on the pos/neg/pos wave that would indicate a viral rebound. Of course, that isn't indicative of an actual infection.
The unreliable reporting of symptoms are a serious issue. The study above notes that some people experienced coughs days after their symptoms were alleviated. What sort of cough was it, or did they just have some random coughing fit that occurred at one time from dust, wrote it down, and now it's counted as a symptom recurrence?
It sort of reminds me of that scene in Scott Pilgrim when he fights against the vegan ex-boyfriend who makes a comment about not knowing chicken parmesan wasn't vegan. You can have someone enrolled in a study told not to eat any processed foods for a month and they may have just randomly forgot to tell researchers about those few nights they had a big slice of cake because they thought it wouldn't be a big issue. 🤦♂️ These things happen far too often that it's really hard to just trust a lot of these self-reporting studies.
The co-infections thing is interesting. We were told at the beginning that this is worse than the flu and any association to other respiratory infections was not allowed. But more and more it appears that the behavior may be closer to the flu albeit more dangerous for specific groups. It was a problem that people were so quick to assume that natural infection would lead to sterilizing immunity, and that's not even something that is now not happening because of Omicron, but something we hsould have known all along. We still see people keep commenting about how their natural immunity is better, and in some regards it is but it's not sterilizing.
However that message is out there and now it's hard to correct for it. The same is happening with PAXLOVID rebound, as I remember that many people originally explained something that seemed like viral rebound before viral rebound was named, but now it appears that this is only a consequence of PAXLOVID or the vaccines.
We have no evidence in the literature because people never bothered to do any studies on this subject. It also explains how there's a lot in science that has yet to have been discovered. We never tested people daily for the cold or flu so how would we know if viral rebound is a thing in those circumstances?
There's an issue in which we assume science has all things figured out, and when there isn't evidence of something we deploy the fallacy that absence of evidence is evidence of absence and that can be very dangerous when one tries to figure things out.
“..this should serve as a reminder that much of the COVID discussion still remains ambiguous, and in fact much of science is still plagued with ambiguity and nuance.”
I certainly would agree with that statement. But, it sure seems like the referenced article could now be teed up for “Fact Checkers” use to dismiss anyone else from attempting to blame Paxlovid in the future...🤔🤷♂️
Well, fears over fact checkers should always look at the intent of the fact checking. If they're trying to argue a more nuanced perspective, sure that's not a big deal as long as we understand that there's no fealty to pharmaceutical manufacturers showing. Between the early treatments and the vaccines, I think the more important battle is the vaccines due to the serious concerns over adverse reactions.
Now, the fact that a lot of these studies are coming at retroactively to show some issues is what's really concerning, because we would hope that some of these things are being looked at before they reach market. The vaccines being recognized for their adverse reactions after billions of doses have been given is alarming. The rebound would infer that other factors should be taken into account, and that PAXLOVID should come with many caveats. The fact that the rebound was not noticed until after release is ridiculous.
A quick glance suggests participants were given antigen tests and the ratio of PAXLOVID to control was 3:1. The rates appeared higher but there's also the real fact that participants who are aware of PAXLOVID rebound may bias their self-reports. The tests shouldn't be influenced by that, but it would be interesting to see how much of an effect that has, almost like a witness reporting on things based on what others have seen creating a difficulty in the witness' own testimony.
So I had a lingering thought, which was about prior immunity influencing the antiviral effects as they may run counter to the intended effects of each other (SARS-COV2 needing to actually infect a cell which has PAXLOVID). I'm wondering if just any prior immunity may influence the effects of PAXLOVID, but unfortunately we have no evidence in the literature since people have never been given widespread antiviral treatment for this sort of respiratory infection before. I was going to add a bit on that but the Pfizer PAXLOVID findings would run counter to that so I shelved that idea for this article. I may return to that idea later on.
I'm actually curious of your thoughts on Eric Topol's coverage of some of these studies. I find that he almost repeats the results verbatim and doesn't add much to the discussion, although this seems to just be how many people report on these studies.
Yeah Topol is basically Mobeen as far as studies, just color-highlights the abstract. But I think he also just gets a lot more info from his personal contacts than Mobeen, who works more solo, and Scripps ran the Pax study so he seems p. familiar with it.
Rebound was in the original trial with no prior immunity. For the vaxxed "immunity" for the first infection can be slower to react to unpaused cells due to IgG4 antibodies as well as lack of post-fusion antibodies (so less ADCC of fusing cells, though that might not matter for the Omicrons). Otherwise immunity should help not hurt at least on paper. The important point is that structural proteins do not get expressed until after nsp5 has already finished being useful so by definition Paxlovid cannot stop replication when there's a lot of immune-recognizable proteins being presented by the cell. That would be after the pause, restart. So that simplifies things. Pax pauses before adaptive immunity is involved, but after the virus is already suppressing innate intracellular immunity, and it may prolong that suppression as I wrote.
My next post may have to be called "Paxlovid Rebound Denialism," ha.
I probably should have realized your post fusion comment meant the spike conformation, and not the antibodies for the nonstructural proteins 🤦♂️ so disregard that comment!
Oh. I was just writing a comment about that, funny.
As for Mon., the N positive might not have been previously infected, just early seroconverters. Either way they are highly protected against severe outcomes in the placebo group and Mon. seems to have negative efficacy. It would be more impressive if Mon. led the treatment N+ to have a similar severe outcome rate as either the treatment or placebo N- but it didn't. So for most of the N+ who took it it didn't make a difference. The extra 3 vs placebo could have been random.
The point about Pax is that putting cells on pause doesn't confer a binary benefit. If the virus resumes replicating in that cell then the task the immune system needs to perform is the same. So in that case Pax didn't do anything to reduce the work required to stop virus, just delayed it. Might be beneficial, might not. Hence why you get rebound. Unfinished business exactly as I said.
I was a bit hesitant with the low numbers; I just thought it was something interesting that might be worth investigating further. Molnupiravir is itself a mess of a drug to really figure out as its mechanism truly is just continuous games of chance.
The PAXLOVID argument would need to account for natural vs vaccinated immunity, and a host of other factors as well. I'm just trying to wrap my head around everything that may be going on and it's a bit much but maybe at some point in the future I'll try and come up with something.
I tried looking back at the study and never saw it, although maybe I glossed over it. Using the term viral rebound or recrudescence won't provide any hits since so many researchers are using different terms.
The lack of post-fusion antibodies is interesting, but I generally wonder what role those antibodies play in the actual infection. My immunology isn't as great as yours, but I tend to assume that many of those proteins won't be made aware until something such as cellular lysis occurs. I don't believe antibodies are able to target the intracellular environment, so I'm generally lost on what factors that plays.
The synergism is what should be expected, as the targeting of the spike may sop up many of the viruses and ones that enter into cells containing PAXLOIVD may be put on pause. I wonder if the pair may alter the body's response to elicit a post-fusion adaptive response then due to the pause delaying the actual ability to create a new immune response?
My thoughts about something else occurring relating to immunity was based on a comment about molnupiravir in the clinical trials, which actually included some people with natural immunity.
Apparently the effects in those who had prior immunity were lower than the other groups:
"Outcomes did not appear to be better with molnupiravir than with placebo in several subgroups (some of relatively small sample size), including patients with evidence of previous SARS-CoV-2 infection, patients with low baseline viral load, and patients with diabetes mellitus; in all cases the 95% confidence intervals of the estimated risk differences included zero."
But this itself is hard to figure out since molnupiravir is such a messy nucleoside analogue. It's not like remdesivir and instead comes with its own huge game of chance. I do, however, wonder if molnupiravir runs the risk of producing mutations that may actually evade the prior immunity from natural infection. It's both inducing and screening at the same time. Strangely, I do wonder if that would also alter the adaptive immune response in those provided molnupiravir.
Well, I hope the Paxlovid rebound denialism isn't pointed towards me! 😉 I'm just trying to put things together and I think there's more nuance to the rebound discussion.
When we had suspected covid in December’19 we all thought we were a bit better by 12-14 days but then all felt like we’d got it all over again ( just milder). Of particular note was my 14 year old son who initially missed 4 days of school with high fever and headache ( and cough) and then went back to school, playing tennis etc and then exactly 14 days from the initial onset was off school again with high temperature and headache and cough again. My husband and I just assumed we hadn’t cleared it because we were older!
When covid broke out in March’20, I followed lots of doctors on Twitter to try and find out what the symptoms and disease course was, and I particularly remember noticing a few saying they had it ( tested negative) got better then got it again 2 weeks later ( tested positive). We had omicron in Dec’21 and felt like a mild relapse after 2 weeks again.
Yeah, there were quite a few stories suggesting that people had some return after having their symptoms alleviate. How many people experience that is what is unknown, and my point with this post is to remind people that rebound actually was a thing before PAXLOVID. It's certainly true that PAXLOVID may be looked at for showing higher rebound, but the effects are nuanced and various factors should be accounted for.
Fascinating topic. I am however skeptic on whether rebound is common. For PAXLOVID we have (thanks to Brian) a theoretical mechanism, but for natural infection it seems odd, considering for other illnesses that doesn't work this way. Or at least we assume it doesn't.
My main problem is that we don't seem to define rebound very well. I mean, using symptoms is one step up from just 'testing positive', but apart from countless studies demonstrating how unreliable we humans are in reporting symptoms, covid symptoms are shared with countless other common illnesses each of us get multiple times a year.
(In fact the nasal obstruction/discharge reports suggest they do not have, or not just have, covid, considering pre-omicron that was not a common symptom of covid.)
In fact it seems that even the 'Team Reality' side forgets that covid isn't unique in being widespread. Every one of us gets infected multiple times a year, and also frequently has co-infections. So how do you know a rebound is not just another new illness? It would be great if one could also do some PCR testing with actual rounds reporting, other test confirming a rebound is accompanied with an actual rising presence of covid. And if it is a rebound, was it in part caused/accompanied by another co-infection flaring up?
And if we are really going to be serious, one would need to sequence them to see if we are talking rebound or re-infection/re-exposure. I'm personally even more skeptical on short term re-infection, but let any data prove me wrong.
Currently we seem to have a lot of people on social media bragging that they are testing positive again. Considering they are testing and posting, that already shows they are a subgroup of our population. I have three young kids, and if I was testing every time I got a cough, I'd be racking up more tests than Fauci. None of my friends, coworkers and family bothers to test as well. We just cough like it is 2019 again.
So you've actually outlined a lot of things I should have put into this post.
Viral rebound depends on whether some PCR/antigen test is done, or whether it's based solely on symptoms. I believe for Fauci he tested negative but then tested positive again. For many people who are in a position where they are required to be screened and surveyed daily then they're likely to provide some information on the pos/neg/pos wave that would indicate a viral rebound. Of course, that isn't indicative of an actual infection.
The unreliable reporting of symptoms are a serious issue. The study above notes that some people experienced coughs days after their symptoms were alleviated. What sort of cough was it, or did they just have some random coughing fit that occurred at one time from dust, wrote it down, and now it's counted as a symptom recurrence?
It sort of reminds me of that scene in Scott Pilgrim when he fights against the vegan ex-boyfriend who makes a comment about not knowing chicken parmesan wasn't vegan. You can have someone enrolled in a study told not to eat any processed foods for a month and they may have just randomly forgot to tell researchers about those few nights they had a big slice of cake because they thought it wouldn't be a big issue. 🤦♂️ These things happen far too often that it's really hard to just trust a lot of these self-reporting studies.
The co-infections thing is interesting. We were told at the beginning that this is worse than the flu and any association to other respiratory infections was not allowed. But more and more it appears that the behavior may be closer to the flu albeit more dangerous for specific groups. It was a problem that people were so quick to assume that natural infection would lead to sterilizing immunity, and that's not even something that is now not happening because of Omicron, but something we hsould have known all along. We still see people keep commenting about how their natural immunity is better, and in some regards it is but it's not sterilizing.
However that message is out there and now it's hard to correct for it. The same is happening with PAXLOVID rebound, as I remember that many people originally explained something that seemed like viral rebound before viral rebound was named, but now it appears that this is only a consequence of PAXLOVID or the vaccines.
We have no evidence in the literature because people never bothered to do any studies on this subject. It also explains how there's a lot in science that has yet to have been discovered. We never tested people daily for the cold or flu so how would we know if viral rebound is a thing in those circumstances?
There's an issue in which we assume science has all things figured out, and when there isn't evidence of something we deploy the fallacy that absence of evidence is evidence of absence and that can be very dangerous when one tries to figure things out.
“..this should serve as a reminder that much of the COVID discussion still remains ambiguous, and in fact much of science is still plagued with ambiguity and nuance.”
I certainly would agree with that statement. But, it sure seems like the referenced article could now be teed up for “Fact Checkers” use to dismiss anyone else from attempting to blame Paxlovid in the future...🤔🤷♂️
Well, fears over fact checkers should always look at the intent of the fact checking. If they're trying to argue a more nuanced perspective, sure that's not a big deal as long as we understand that there's no fealty to pharmaceutical manufacturers showing. Between the early treatments and the vaccines, I think the more important battle is the vaccines due to the serious concerns over adverse reactions.
Now, the fact that a lot of these studies are coming at retroactively to show some issues is what's really concerning, because we would hope that some of these things are being looked at before they reach market. The vaccines being recognized for their adverse reactions after billions of doses have been given is alarming. The rebound would infer that other factors should be taken into account, and that PAXLOVID should come with many caveats. The fact that the rebound was not noticed until after release is ridiculous.
Based on the advice given or not given to the public, their recommended treatments are unlikely to have a beneficial risk to benefit ratio.
There’s a new medrxiv upload in rebound, shows it’s higher with pax. I don’t have link because powers out but it’s on Topols Twitter yesterday
Hopefully our power comes back soon!
A quick glance suggests participants were given antigen tests and the ratio of PAXLOVID to control was 3:1. The rates appeared higher but there's also the real fact that participants who are aware of PAXLOVID rebound may bias their self-reports. The tests shouldn't be influenced by that, but it would be interesting to see how much of an effect that has, almost like a witness reporting on things based on what others have seen creating a difficulty in the witness' own testimony.
So I had a lingering thought, which was about prior immunity influencing the antiviral effects as they may run counter to the intended effects of each other (SARS-COV2 needing to actually infect a cell which has PAXLOVID). I'm wondering if just any prior immunity may influence the effects of PAXLOVID, but unfortunately we have no evidence in the literature since people have never been given widespread antiviral treatment for this sort of respiratory infection before. I was going to add a bit on that but the Pfizer PAXLOVID findings would run counter to that so I shelved that idea for this article. I may return to that idea later on.
I'm actually curious of your thoughts on Eric Topol's coverage of some of these studies. I find that he almost repeats the results verbatim and doesn't add much to the discussion, although this seems to just be how many people report on these studies.
Yeah Topol is basically Mobeen as far as studies, just color-highlights the abstract. But I think he also just gets a lot more info from his personal contacts than Mobeen, who works more solo, and Scripps ran the Pax study so he seems p. familiar with it.
Rebound was in the original trial with no prior immunity. For the vaxxed "immunity" for the first infection can be slower to react to unpaused cells due to IgG4 antibodies as well as lack of post-fusion antibodies (so less ADCC of fusing cells, though that might not matter for the Omicrons). Otherwise immunity should help not hurt at least on paper. The important point is that structural proteins do not get expressed until after nsp5 has already finished being useful so by definition Paxlovid cannot stop replication when there's a lot of immune-recognizable proteins being presented by the cell. That would be after the pause, restart. So that simplifies things. Pax pauses before adaptive immunity is involved, but after the virus is already suppressing innate intracellular immunity, and it may prolong that suppression as I wrote.
My next post may have to be called "Paxlovid Rebound Denialism," ha.
I probably should have realized your post fusion comment meant the spike conformation, and not the antibodies for the nonstructural proteins 🤦♂️ so disregard that comment!
Oh. I was just writing a comment about that, funny.
As for Mon., the N positive might not have been previously infected, just early seroconverters. Either way they are highly protected against severe outcomes in the placebo group and Mon. seems to have negative efficacy. It would be more impressive if Mon. led the treatment N+ to have a similar severe outcome rate as either the treatment or placebo N- but it didn't. So for most of the N+ who took it it didn't make a difference. The extra 3 vs placebo could have been random.
The point about Pax is that putting cells on pause doesn't confer a binary benefit. If the virus resumes replicating in that cell then the task the immune system needs to perform is the same. So in that case Pax didn't do anything to reduce the work required to stop virus, just delayed it. Might be beneficial, might not. Hence why you get rebound. Unfinished business exactly as I said.
I was a bit hesitant with the low numbers; I just thought it was something interesting that might be worth investigating further. Molnupiravir is itself a mess of a drug to really figure out as its mechanism truly is just continuous games of chance.
The PAXLOVID argument would need to account for natural vs vaccinated immunity, and a host of other factors as well. I'm just trying to wrap my head around everything that may be going on and it's a bit much but maybe at some point in the future I'll try and come up with something.
I tried looking back at the study and never saw it, although maybe I glossed over it. Using the term viral rebound or recrudescence won't provide any hits since so many researchers are using different terms.
The lack of post-fusion antibodies is interesting, but I generally wonder what role those antibodies play in the actual infection. My immunology isn't as great as yours, but I tend to assume that many of those proteins won't be made aware until something such as cellular lysis occurs. I don't believe antibodies are able to target the intracellular environment, so I'm generally lost on what factors that plays.
The synergism is what should be expected, as the targeting of the spike may sop up many of the viruses and ones that enter into cells containing PAXLOIVD may be put on pause. I wonder if the pair may alter the body's response to elicit a post-fusion adaptive response then due to the pause delaying the actual ability to create a new immune response?
My thoughts about something else occurring relating to immunity was based on a comment about molnupiravir in the clinical trials, which actually included some people with natural immunity.
Apparently the effects in those who had prior immunity were lower than the other groups:
"Outcomes did not appear to be better with molnupiravir than with placebo in several subgroups (some of relatively small sample size), including patients with evidence of previous SARS-CoV-2 infection, patients with low baseline viral load, and patients with diabetes mellitus; in all cases the 95% confidence intervals of the estimated risk differences included zero."
But this itself is hard to figure out since molnupiravir is such a messy nucleoside analogue. It's not like remdesivir and instead comes with its own huge game of chance. I do, however, wonder if molnupiravir runs the risk of producing mutations that may actually evade the prior immunity from natural infection. It's both inducing and screening at the same time. Strangely, I do wonder if that would also alter the adaptive immune response in those provided molnupiravir.
Well, I hope the Paxlovid rebound denialism isn't pointed towards me! 😉 I'm just trying to put things together and I think there's more nuance to the rebound discussion.