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Posted On: 07/14/2020 10:57:11 AM
Post# of 148903
thanks, kabonk. I'd forgotten about this one. It touches on three of my questions about the viral load load numbers. As with my previous post on the paper, these might be some of the same types of questions reviewers may have for Dr P and gives a hint why peer review does not happen over night.
First, "viral load" in the upper respiratory tract decreased by 85% by day 14 in the remdesivir group. Impressive? Hardly, the placebo was associated with a virtually identical decreasing pattern. Dr P's paper only shows a leronlimab line for viral load. What would it look like if a placebo line was added to the graph? An obvious question that reviewers are bound to ask, but it is not as easy to answer. This almost has to be done with some form of control data to compare untreated vs leronlimab in very critically ill patients. That could either be in the form of data from additional patients or additional data from the tested cohort for days preceding administration of leronlimab. But then a cogent argument would need to be made for how the patient samples are comparable, which may not be simple to do. Expect the final paper to have additional data, which requires a good deal of time to gather and process.
The remdesivir study looked at viral load in (presumably exudates) the upper and lower respiratory tracts. which raises a second question: clearly "viral load" is not a simple issue. In the Chinese remdesivir study , the viral load in the upper respiratory tract was about 1/2 that of the lower respiratory tract, with the levels in the upper respiratory tract dropping by some 85% by day 14 and the levels in the lower respiratory tract dropping only by 1/3. Plasma viral load is a very different thing, observed only in some the most severe cases. If the plasma viral load drops dramatically---maybe even to zero---what clinical repercussions would it be expected to have.for covid-19? For me the obvious question would be, what is happening with the viral load at the main infection sites (most notably, the upper and lower respiratory tracts)? The distinction is similar to the circulating tumor cells vs the solid tumor. You prevent the tumor cells from the moving around via the bloodstream, which should help prevent spread of the cancer, but this doesn't necessarily mean anything for the main tumor (although with leronlimab, it looks like it might, as Dr Kelly's cool animation suggests and the anecdotal data from the mTNBC trials also suggest). Similarly, if SARS-CoV2 is largely cut off from the blood, what kind of effect would we expect in the infected tissues in the nose, throat, and lungs?
Then, if the viral load in the upper respiratory tract decreased by some 85% on average by day 14 in both the remdesivir and placebo groups, then viral load declines markedly on its own in the natural course of recovery (obviously). But what happens with the overwrought immune response that causes most of the damage? It seems analogous to anaphylaxis (albeit different mechanism)...an antigen sets of an absurd and damaging response. The treatment is to tame the immune response, not to gradually eliminate the antigen (something that immune systems are pretty good at on their own, given the chance). With leronlimab in covid-19, blocking CCR5 cuts off recruitment of pro-inflammatories and apparently even decreases IL-6 and CRP. Also, restoration of CD8+ exhaustion should help help the immune system keep up the good fight with renewed effectiveness. I'd like to see discussion of not just the numbers of CD8's in Dr. P's paper but their status w.r.t. functional exhaustion ( Diao et al 2020 ; Weisskopf et al 2020 ; Ganji et al 2020 ). It may be there already, but I can't find it.
The above are just a few questions on one figure by a non-expert. Expect much more challenging issues from the reviewers, who will go through the paper with a fine-tooth comb, asking a bunch of hard questions on every page.
A good review takes a lot of time. Responding to a good review takes even longer. Then, the responses are reviewed and more revisions will be required. In any case, expect at least another month before publication.
[I'm contemplating a couple more posts in this series, but, to paraphrase a line from the Bible, "Mind your margaritas!"]
First, "viral load" in the upper respiratory tract decreased by 85% by day 14 in the remdesivir group. Impressive? Hardly, the placebo was associated with a virtually identical decreasing pattern. Dr P's paper only shows a leronlimab line for viral load. What would it look like if a placebo line was added to the graph? An obvious question that reviewers are bound to ask, but it is not as easy to answer. This almost has to be done with some form of control data to compare untreated vs leronlimab in very critically ill patients. That could either be in the form of data from additional patients or additional data from the tested cohort for days preceding administration of leronlimab. But then a cogent argument would need to be made for how the patient samples are comparable, which may not be simple to do. Expect the final paper to have additional data, which requires a good deal of time to gather and process.
The remdesivir study looked at viral load in (presumably exudates) the upper and lower respiratory tracts. which raises a second question: clearly "viral load" is not a simple issue. In the Chinese remdesivir study , the viral load in the upper respiratory tract was about 1/2 that of the lower respiratory tract, with the levels in the upper respiratory tract dropping by some 85% by day 14 and the levels in the lower respiratory tract dropping only by 1/3. Plasma viral load is a very different thing, observed only in some the most severe cases. If the plasma viral load drops dramatically---maybe even to zero---what clinical repercussions would it be expected to have.for covid-19? For me the obvious question would be, what is happening with the viral load at the main infection sites (most notably, the upper and lower respiratory tracts)? The distinction is similar to the circulating tumor cells vs the solid tumor. You prevent the tumor cells from the moving around via the bloodstream, which should help prevent spread of the cancer, but this doesn't necessarily mean anything for the main tumor (although with leronlimab, it looks like it might, as Dr Kelly's cool animation suggests and the anecdotal data from the mTNBC trials also suggest). Similarly, if SARS-CoV2 is largely cut off from the blood, what kind of effect would we expect in the infected tissues in the nose, throat, and lungs?
Then, if the viral load in the upper respiratory tract decreased by some 85% on average by day 14 in both the remdesivir and placebo groups, then viral load declines markedly on its own in the natural course of recovery (obviously). But what happens with the overwrought immune response that causes most of the damage? It seems analogous to anaphylaxis (albeit different mechanism)...an antigen sets of an absurd and damaging response. The treatment is to tame the immune response, not to gradually eliminate the antigen (something that immune systems are pretty good at on their own, given the chance). With leronlimab in covid-19, blocking CCR5 cuts off recruitment of pro-inflammatories and apparently even decreases IL-6 and CRP. Also, restoration of CD8+ exhaustion should help help the immune system keep up the good fight with renewed effectiveness. I'd like to see discussion of not just the numbers of CD8's in Dr. P's paper but their status w.r.t. functional exhaustion ( Diao et al 2020 ; Weisskopf et al 2020 ; Ganji et al 2020 ). It may be there already, but I can't find it.
The above are just a few questions on one figure by a non-expert. Expect much more challenging issues from the reviewers, who will go through the paper with a fine-tooth comb, asking a bunch of hard questions on every page.
A good review takes a lot of time. Responding to a good review takes even longer. Then, the responses are reviewed and more revisions will be required. In any case, expect at least another month before publication.
[I'm contemplating a couple more posts in this series, but, to paraphrase a line from the Bible, "Mind your margaritas!"]
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