Thanks for the nice, thought provoking analysis. It's good to review this paper some more. A couple of things don't make sense to me.
One thing I missed on first glance was that RANTES/CCL5 no longer appeared to be abnormal in acute or chronic Covid, compared to Patterson's earlier report and claims that Covid is a RANTES disease, with very high RANTES/CCL5.
Table 1 lists normal RANTES level as ~10-12K pg/mL, and Covid showed only modestly elevated RANTES, averaging upper 11K in acute disease (m/m and s/c both), and 12.5K in chronic disease.
Prior paper (Fig. 1d) showed normal as ~400 pg/mL, m/m as ~3K pg/mL, and s/c as ~40K of pg/mL. Maybe I am misreading the numbers, or they are measuring different things or with different assays?
I wonder how he would explain the different numbers in controls, and the apparently less elevated levels of CCL5/RANTES in this acute Covid cohort compared to these (different) controls?
Do the numbers really support his claim that "Interestingly, COVID-19 individuals (including LH, mild, severe) show high levels of CCL5, a chemoattractant that like CCL4 signals through CCR5?" I don't see it stand out from the numbers in the table. I guess would need to see the statistics on that from this paper, which weren't presented.
The second thing is the low CCL4 levels in LH and the purported reduced recruitment of activated T-effector cells via CCR5 activation by reduced CCL4.
Patterson implies that LH have persistent viral infection that can't be cleared because activated T-effector cells don't have the proper migratory signals (CCL4 is low, although CCL5 he says is modestly higher).
How then will blocking CCL4 and CCL5 activation of CCR5 (via leronlimab) help? It should theoretically make this reduced recruitment/migration of T-effector cells worse, right? (Assuming that we want T-effector cells to be able to go where they are supposed to go to fight the infection).
Patterson then has us look at CCR1, saying CCL5 can activate it, CCL4 may be an antagonist of CCR1, that IFN-g upregulates CCR1 expression, and Covid patients have upregulated CCR1. Put that all together, and with slightly higher CCL5 and lower CCL4, LH would have increased recruitment of monocytes and neutrophils expressing CCR1.
Then what? Maybe these increased monocytes and neutrophils just promote the pro-inflammatory state that cause LH symptoms, all without resolution of the underlying (postulated) persistent viral infection or re-setting of the dysregulated immune state.
The rationale for targeting CCR5 in s/c Covid makes a lot more sense than in chronic disease/ LH / PASC.
________________________
Overall, I'd say the immunology of acute and chronic Covid is not well understood, especially by me! I just heard a lecture on the chronic neurological sequelae of Covid this week, and we are still in the early stages of figuring it all out.
It's interesting that Patterson claims 85% success in LH using combination of ivermectin, low dose steroids, and maraviroc. It will be great to see that treatment paper when it comes out, even though it won't be a blinded trial.
It will be good to see if leronlimab helps LHers, and to try to figure out how if it does. The trial should be starting soon.
More importantly, we are almost ready to see the CD12 results! (Hah, we are WAY past ready, but hopefully FDA and CYDY are ready for a big reveal).
One thing I missed on first glance was that RANTES/CCL5 no longer appeared to be abnormal in acute or chronic Covid, compared to Patterson's earlier report and claims that Covid is a RANTES disease, with very high RANTES/CCL5.
Table 1 lists normal RANTES level as ~10-12K pg/mL, and Covid showed only modestly elevated RANTES, averaging upper 11K in acute disease (m/m and s/c both), and 12.5K in chronic disease.
Prior paper (Fig. 1d) showed normal as ~400 pg/mL, m/m as ~3K pg/mL, and s/c as ~40K of pg/mL. Maybe I am misreading the numbers, or they are measuring different things or with different assays?
I wonder how he would explain the different numbers in controls, and the apparently less elevated levels of CCL5/RANTES in this acute Covid cohort compared to these (different) controls?
Do the numbers really support his claim that "Interestingly, COVID-19 individuals (including LH, mild, severe) show high levels of CCL5, a chemoattractant that like CCL4 signals through CCR5?" I don't see it stand out from the numbers in the table. I guess would need to see the statistics on that from this paper, which weren't presented.
The second thing is the low CCL4 levels in LH and the purported reduced recruitment of activated T-effector cells via CCR5 activation by reduced CCL4.
Quote:Therefore, proper T cell activation (high IFN-γ+IL-2) but ineffective T cell recruitment (low CCL4) are characteristic features of the failed antiviral response observed in the LH group supporting virus persistence.
Patterson implies that LH have persistent viral infection that can't be cleared because activated T-effector cells don't have the proper migratory signals (CCL4 is low, although CCL5 he says is modestly higher).
How then will blocking CCL4 and CCL5 activation of CCR5 (via leronlimab) help? It should theoretically make this reduced recruitment/migration of T-effector cells worse, right? (Assuming that we want T-effector cells to be able to go where they are supposed to go to fight the infection).
Patterson then has us look at CCR1, saying CCL5 can activate it, CCL4 may be an antagonist of CCR1, that IFN-g upregulates CCR1 expression, and Covid patients have upregulated CCR1. Put that all together, and with slightly higher CCL5 and lower CCL4, LH would have increased recruitment of monocytes and neutrophils expressing CCR1.
Then what? Maybe these increased monocytes and neutrophils just promote the pro-inflammatory state that cause LH symptoms, all without resolution of the underlying (postulated) persistent viral infection or re-setting of the dysregulated immune state.
The rationale for targeting CCR5 in s/c Covid makes a lot more sense than in chronic disease/ LH / PASC.
________________________
Overall, I'd say the immunology of acute and chronic Covid is not well understood, especially by me! I just heard a lecture on the chronic neurological sequelae of Covid this week, and we are still in the early stages of figuring it all out.
It's interesting that Patterson claims 85% success in LH using combination of ivermectin, low dose steroids, and maraviroc. It will be great to see that treatment paper when it comes out, even though it won't be a blinded trial.
It will be good to see if leronlimab helps LHers, and to try to figure out how if it does. The trial should be starting soon.
More importantly, we are almost ready to see the CD12 results! (Hah, we are WAY past ready, but hopefully FDA and CYDY are ready for a big reveal).
8
