triplehorn

FranceSoir interviews the lead investigator of the new large Italian retrospective study (n=3,451) that shows a 30% mortality reduction in hospitalized patients treated with Plaquenil. google translation of interview with study leader, Licia Iacoviello , Director of the Center for Epidemiology and Preventive Medicine at the University of Insubrie, Varese, and Director of the Department of Epidemiology and Prevention at IRCCS Neuromed. Of note: FS: What do you mean by “they had a high level of C-reactive protein on entry”? LI: C-reactive protein is a marker of inflammation. Having a high level of C-reactive protein when entering the hospital means that the Sars-Covid II infection has caused a significant inflammatory response. We believe that HCQ acts on this very component of the disease rather than inhibiting viral replication. --> After the Yale Med revelations on early immune signatures associated with complicated illness trajectory, last week I suggested it's the anti-inflammatory mechanism of Plaquenil that is most likely reducing mortality and morbidity in Covid, with suspicion that the target is the upstream reduction of inflammasome activation/pyroptosis and associated increased IL-1b and IL-18 secretion which then cascades to late stage complicated immune dysregulation and elevated C-reactive protein among other signs. Same anti-inflammatory effect that is capitalized by rheumatologists to treat Lupus and RA every day. It stands to reason it's why treating as early as possible appears to nip it. Anti-viral replication effects are likely still the same, but would only have a meaningful effect when pre-medicated prophylactically.

This along with other factors would contribute to lowering the threshold for herd immunity. I'm not convinced it's happening everywhere the curves hint at it (other nations in particular), but there is some reason to believe this bug could drop off faster than expected if multiple lines of heterogeneity in our population have an effect, which it certainly should.

Does it have to be new ?

nnm - It might be a little pre-mature yet, but I may owe you a debt of gratitude. After starting the stretching regimen (yoga-for-runners above), right away I could easily appreciate how imbalanced and limited the range is in my right hip. It was pretty obvious both my hip flexors were tight however. I also became aware after some reading that chronically contracted hip flexors probably have been causing my pelvis to slightly tilt forward. It took 2-4 days of the routine but I noticed releases and lengthening starting to happen and my hip posture seemed to be loosening and shifting. To the extent there was pelvic tilt from tight hip flexors, it probably explains general low back fatigue/soreness after long runs and climbs. I also added a couple stretches and strengthening moves for the TFL muscle in isolation. Forever, I have just accepted all this without much complaint until the IT band really flared when I stepped up the trail running last month. Another thing, getting my right hip to release seemed to unmask some aches in my left knee after walking. It's a pain I haven't felt for over a decade. It started in the mid-90's after spraining my left knee at Taos in some crappy rental ski boots. I think I over-compensated with my right hip for years even after that injury faded but I never evened it out. The recent left knee ache lasted about a day and disappeared. I saw a sports orthopedist for the left knee about 15 years ago and got confirmation of no evidence of injury or joint degeneration, so the ache the other day was likely from adjusting muscle/joint use to the shift after days of deep stretching. I got my hip Rolfed around that same time 15 years ago and it worked great then, but I never committed to meaningful routine stretching and it came back. After resting the last two weeks, I started with a climb yesterday without running. Did 5 miles and prolonged steeps ~2500 ft vert up and down. Not only was there not even a trace of familiar IT band pain in my knee, but my knees, hips, and low back felt better than I can ever remember during the exertion and after. Again, I'm also noticing the benefits for everyday standing and walking as well. I'm going to re-introduce running on a flat surface at my neighborhood high school track next. After pushing through the now obvious imbalances all these years, if this benefit holds, it's kind not exaggerating to call it life changing. So Thank You for responding above!

Baylor Cardiologists Support Hydroxychloroquine Emergency Use Authorization by FDA "Dr. Kevin R. Wheelan, chief of cardiology at Baylor Heart and Vascular Hospital in Dallas and Dr. Peter McCullough, a clinical cardiologist and professor at the Texas A&M School of Medicine, issued a letter supporting the emergency use authorization (EUA) of hydroxychloroquine for outpatient treatment and prophylaxis for COVID-19."

India is now all in. In the Spring, they started prophylaxis of health care workers and expanded it to frontline civil workers. Not only are they continuing it, they're aggressively expanding it. India releases 42 millions pills of hydroxychloroquine directed for use as prophylaxis and treatment of Covid-19 patients. Prophylaxis protocols are essentially the same once weekly dosing regimen as is already dosed for malaria prevention. On any given day, our own VA system uses 42,000 doses of hcq across all purposes.

Odds of bad outcome summarized: "This fact is proven by an Oxford University study of more than 320,000 older patients taking both hydroxychloroquine and azithromycin, who had arrhythmia excess death rates of less than 9/100,000 users [0.00009%] as I discuss in my May 27 paper cited above. A new paper in the American Journal of Medicine by established cardiologists around the world fully agrees with this." Also note in this study of 200 hospitalized Covid patients while there is observed QT prolongation (as would be normally expected), there were zero instances of TdP and no deaths. While this is only one study, what's important recognize is that these are really sick Covid patients already hospitalized. Perhaps even more significantly, look at the baseline demographics of the participating subjects: 60% had pre-existing HTN, 42% dislipidemia, 32% diabetes, 7% a.fib., 11% CAD, 15% COPD, CHF 7.5%. Yet no TdP and no deaths with these agents alone or in combination. Given that, keep in mind available evidence points to best use of quinine derivatives in Covid as being targeted for application as soon as possible following exposure/onset of infection, which represents a substantially more medically stable window than hospitalization after crashing from severe illness. So early outpatient initiation would be expected to further reduce a risk that is already orders of magnitude lower under the worst circumstances than rolling the dice with Covid alone.

Thanks. The Maher interview is the best representation. It's a good listen. He uses a lot of public health and epidemiologic nuance in describing and discussing the "Lose/Lose" predicament of Covid, but "lockdowns don't work" and "cure is worse than the disease" does not accurately capture or reflect what he is communicating.

I don't agree with those takes in general, but I'd be interested to hear an argument from someone with his credentials and ability to articulate on these matters. Are you sure it's the same person? What you describe above says nothing about the pragmatic explanation he provides of where we stand on understanding mechanisms and timing for efficacy, and patient selection and safety. There is ample evidence suggesting early therapeutic benefits are significant and real, and safety has not been an issue. Note also the rationale provided around why HCQ/Azithromycin or doxycycline plus Zn as opposed to monotherapy. Taking (H)CQ is not playing Russian roulette. The real roulette is what happens when this virus takes you for a ride.

Former clinical instructor from Yale School of Medicine Dr David Katz. We depend on level headed discourse like this. I'd say this is a must watch I wonder how aware he is of his Yale peers' findings last week on defining Covid disease trajectory clusters and predictive early immune signatures with implications for targeted therapy early on. #Inflammasomes

I completely understand that stance. I wouldn't go so far as to call it roulette, but the national and social conflict over it is like bullets rolling around on a table. Someone may be swept up by the conflict, pick one up, and fire it back at you under adverse conditions. I'd just stay open-minded listening to patients if they bring it up to gauge how well they understand the relative risks of enduring Covid with supportive care only versus off-label use of a drug(s) with a solid safety index (even pregnant women and children take it safely at proper dose). TX permits off-label use, so it's a professional and personal choice as a treating physician. I've found a lot of people understand the relative unknowns of intervention as well as the potential consequences of Covid, and to them it's an easy choice to have on hand. Unfortunately my state currently precludes off-label use for covid but I'm not sure how hard it's being enforced. I know a couple primary docs who are responding to their patients' serious requests for intervention, but it's not being pushed or promoted at all, and no adverse events or bad outcomes have occurred to date.

^^^ I looked at that post above. Those two twitter threads are a beating. Of Note, he completely omits any consideration of viral RNA polymerase inhibition in any time frame. He's talking about effects on pH values related to inhibiting viral invasion of a cell. So the pH/endosomal pathway is a no go? Ok, that's ignoring a lot of other considerations. He doesn't even whiff any anti-inflammatory mechanisms of quinines in this context as a function of mitigating risk of progressing to cytokine storm and death. There are enough studies out now that people can pick and choose in isolation. He's good at that. I did notice he referenced the negative Boulware Minnesota post-exposure prophylaxis study. I saw this critical review of the data and what Boulware failed to recognize about his own data set: Efficacy of Hydroxychloroquine as Prophylaxis for Covid-19: The entire article is in pdf form at the link "Limitations in the design of the experiment of Boulware et al[1] are considered in Cohen[2]. They are not subject to correction but they are reported for readers' consideration. However, they made an analysis for the incidence based on Fisher's hypothesis test for means while they published detailed time dependent data which were not analyzed, disregarding an important information. Here we make the analyses with this time dependent data adopting a simple regression analysis.We conclude their randomized, double-blind, placebo-controlled trial presents statistical evidence, at 99% confidence level, that the treatment of Covid-19 patients with hydroxychloroquine is effective in reducing the appearance of symptoms if used before or right after exposure to the virus. For 0 to 2 days after exposure to virus, the estimated relative reduction in symptomatic outcomes is 72% after 0 days, 48.9% after 1 day and 29.3% after 2 days. For 3 days after exposure, the estimated relative reduction is 15.7% but results are not statistically conclusive and for 4 or more days after exposure there is no statistical evidence that hydroxychloroquine is effective in reducing the appearance of symptoms.Our results show that the time elapsed between infection and the beginning of treatment is crucial for the efficacy of hydroxychloroquine as a treatment to Covid-19." ^^^ Boulware's data suggest you have about 48hrs post-exposure to get a meaningful observable effect. The sooner the better. Or better yet, do pre-exposure prophylaxsis. India is pleasantly surprised with their large scale prophylaxis results: 'Pleasant surprise' with antigen test of BMC staff, 16 of 2,400 +ve Mumbai has been using hydroxychloroquine prophylaxis on its essential civic employees --> expecting to find 360 positive cases in a test campaign, it finds only 16.

Here's a story yesterday on tocilizumab negative findings: Roche bid to retool arthritis drug for COVID-19 fails Tocilizumab (Actemra) targets IL-6 for inhibition. Someone else may be able to offer some detailed clarification, but IL-6 seems to be recognized as a relatively late-appearing cytokine prominent after illness progression to pneumonia Targeting IL-6 may be helpful applied to the timeline of rheumatoid arthritis, but the Covid timeline for progression is far more rapid. By the time you've got pneumonia and you're trying to block IL-6, it's too late. Targeting early mechanisms of inflammation that now appear associated with early Covid immune dysregulation, like IL-1b and IL-18 are likely to offer more help in preventing onset of pneumonia and death. But again, the big difference maker across the board is early recognition and initiation of treatment. Rheumatologists target IL-1b, TNF-a, and IL-6 with quinine derivatives: Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes

Re the study involved in the quote you responded to, pay close attention to the fine print: "The primary outcome was clinical status at 15 days." This is a departure from mortality outcomes and it represents an arbitrary(?) "15 day window" that neglects the potential for outcome measures between groups to diverge after 15 days. Just saying it's a very peculiar design that has built-in outcome omissions where positive findings exist in other studies. Also for all the talk about QT prolongation, in public discourse there's been no accounting for just how many commonly prescribed medications are associated with QT prolongation. Anyone doing a quick search realizes it's a whole lot, many of which are being taken/have been taken by posters right here without having an EKG. The vast, vast majority of the time, for all those meds, the associated QT prolongation does not justify getting an EKG, and in the outpatient setting, typically none are ordered because even with measurable QT prolongation, it doesn't approach clinical relevance. Elevated LFT's? To the extent it even happens for an individual, it would be transient and harmless given that clinical exposure to HCQ in this context amounts to a duration lasting from 5 days to 2 weeks (at the extreme end). Check LFT's after a couple nights of beer and 'rita's and good chance you'll see elevated LFT's in a healthy person that completely subside within 72 hrs of not drinking. This is everyday stuff. With Covid, Quinine derivatives appear to be a two-fer; increased intracellular Zinc (slowing early viral replication rates) and targeted anti-inflammatory effects significantly upstream from associated end-stage cytokine storm with Covid. The unique anti-inflammatory effects (and likely AZ too) wrt covid loom really large right now. Re viral replication, realize that the RATE at which a virus can enter a cell, replicate, and leave the cell is an adaptive trait subject to natural selection. In this case a successful virus can accomplish this cycle faster than innate immunity (ie NK 'killer" T cell / non-antibody mediated) can neutralize infected cells/kill virus. If simply increasing intracellular Zn concentration slows activity of coronavirus RdRp (viral RNA polymerase) - which it does -suddenly the virus is running with its feet in cement blocks and it gets overwhelmed by existing innate T cell immune function from viral inception. If intracellular Zn is optimized prior to or right after infection occurs, it follows you impact disease trajectory. Doesn't mean you prevent detectable infection, but altering the trajectory in this fashion could render it essentially harmless, is is being observed in numerous studies. But again, it's the unique mechanistic anti-inflammatory fit of Quinine derivatives that likely is playing a larger role when taken for about 5 days duration at onset of signs of infection with this coronavirus.

Add Zinc as playing an essential role in adaptive and innate immune response. Quite the refresher, but I don't think I ever learned how integral Zinc is to immume regulation. Having a robust innate T cell capacity is key for rapid response to novel pathogens. This section from the article really jumps out: As an aside and not directly speaking to Zinc, a just published letter to the editor of Intl. J. of Infectious Disease reports a retrospective study from Italy (539 COVID-19 hospitalized patients were included in cohort in Milan) reporting "the use of hydroxycholoroquine + azithromycin was associated with a 66% reduction in risk of death as compared to controls" : Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation? This is not a closed case by any stretch.

Why combine Azithromycin with HCQ, or add AZ at all? This study shows a potentially very significant association that Azithromycin and CQ/HCQ have in common re cell physiology: Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin AZ and HCQ both have uniquely massive Volume of Distribution values and accumulate to massive concentrations inside cellular lysosomes due to the acid/base properties of their poly-amide groups. I point this out as an extension of the post on the previous page as it relates to lysosomal roles in inflammasome activation. Individual susceptibility to immune response dysregulation stemming from activation of the highly inflammatory inflammasome response is a key focus of the Yale collab findings on disease trajectories as a function of newly revealed immune signatures in covid patients. Does AZ share the same specific anti-inflammatory mechanisms as HCQ as described here and is it a function of very high intracellular concentrations in lysosomes?: Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology In short, this association between AZ and HCQ could point to a shared role disrupting the activation pathways of inflammasomes and subsequent cascades contributing to late stage cytokine storm and death. In other words, it points to AZ and HCQ both targeting and inhibiting/disrupting a very specific inflammatory pathway implicated in Covid demise.

I don't think it makes a difference in this case. It's a simple in vitro test of whether a viral polymerase slows down as intracellular Zinc concentration increases. Plaquenil only serves as a non-cell specific, non-receptor mediated, facilitator of passive conduit across the lipid bilayer of a cell resulting in increased intracellular Zinc. That's it. It could be goat-blowing green monkeys and it's the same because of basic fundamentals of cell physiology.

The head scratcher for me is that it appears the US is acting insular in ignoring the preponderance of available international studies that taken together provide pretty compelling evidence of efficacy, and very compelling evidence on safety. But yes, even internationally the HCQ/AZ/Zn cocktail hasn't been studied. fwiw, as of the last two days, my stance on Plaquenil has shifted to its anti-inflammatory effects as being the primary mechanism for reduced morbidity and mortality with Covid infection, not direct viral inhibition. Yale med published breakthrough findings re identifying 4 disease trajectories that involve 3 immune signatures. The people who they identified as likely to progress to complicated illness have various characteristics, but keen attention is being paid to the role of cytosolic inflammasomes. It so happens Plaquenil inhibits inflammasome activation and disrupts lysosomal function which is also involved in inflammasome activation. It's related to the reason why Plaquenil is used to treat RA and Lupus. Palquenil also happens to inhibit Covid viral replication in vitro. But it's not a knockout drug to the virus. That helps explain why it appears to be most effective as a pre-exposure prophylactic when started 4-6 weeks prior to exposure. Think of flattening the curve. In this case, if you flatten the curve of rate of viral replication, you slow it down to let T cell immunity advance to neutralize the infection before it outstrips T cell killing ability with sheer exponential growth numbers. But you can't wait. have to have it early and waiting for the replication slowing/disrupting effect. Not practical for giant populations. The hand in glove anti-inflammatory effect of Plaquenil against what Covid triggers via inflammasomes and IL-1b and IL-18 (ultimately resulting end stage cytokine storm and systemic coagulopathy) appears to be what's happening where it's being used with success. Very bullish on establishing high normal Vit D levels (>35 ng/mL) in everyone middle age and beyond. Masks and distancing - remember an ounce of prevention is worth a pound of cure.

Yeah, I'm here. Still have Anastasis on ignore all this time so I get bits of whatever is said like it's coming from Whoopi Goldberg in Ghost.

There's a rule of thumb that for every 1000 IU of Vit D3 you take, you can expect an increase in blood level by 10 ng/mL. So 5000 IU/d sustained will likely bump you significantly above the general normal level of 30 ng/mL, but not really near the standard toxic level considered to be above 150 ng/mL. If you look at this graph I linked last page, you see that even at a normal level of 30 ng/mL, a pretty siginifcant percentage of folks experienced Covid associated fatal demise (with an average age of 60y/o). So having a blood level in the 40-50 ng/mL range might be preferable to swimming around the 'normal' level of 30 while still not approaching anything considered toxic D3 levels. I'll probably back off to 5000 IU every other day since I've been taking it long enough to sustain the boost (5000 IU daily since March). edit: also re-posting this 2 week old pre-print from Lancet: Vitamin D Sufficiency Reduced Risk for Morbidity and Mortality in COVID-19 Patients

Vit D appears to be essential for healthy and robust T cell function. T cell immunity plays a frontline role in fighting novel infection when we don't have a jump start from antibody protection. As we age, our immune system weakens and we lose our virus-killing fastball. Basement dwelling fast food eating young people still do well on average because of youth. However boosting Vit D in middle age and beyond appears to have a dramatic effect on squashing Covid infection earlier likely through a juiced up initial T cell immune function. This likely applies to fighting multiple respiratory viruses. I'm not much of a vitamin and supplement taker, but I started taking Vit D 5000 IU per day in early March along with Zinc and Vit C. edit: a caveat to Vit D and T cell function is that Vit D appears to help modulate T cell function, so this conceivably could also involve balancing an immune response, ie putting the brakes on an inflammatory response from running amok as we observe in complicated Covid illness.

Following up on the Yale collab above, notice the attention Dr. Iwasaki pays to "inflammasomes" : Inflammasomes are non-membrane bound cytosolic protein complexes that appear to be associated with a variation of programmed cell death called pyroptosis. Pyroptosis is a highly inflammatory form of cell death often associated with intracellular pathogens - like viruses and certain bacteria. Here's a graphic of inflammosomal activation (hook'em UT Southwestern). Note the release of IL-18 and IL-1b. The pinwheel stucture is the inflammasome (originally characterized around 2002). Also note the association with cytosolic lysosomes (membrane bound organelle): So maybe it would be helpful, if not extremely helpful, if we could find a way to attenuate the role of Covid associated inflammasome activation and cell death to reduce the cascade resulting in tissue and multiple organ damage observed with Covid. You had to know where I was going with this lol. Naturally I wondered if there's a possibility that HCQ fits into this somewhere. HCQ is generally thought of as inhibiting replication of Covid virus via a Zinc mechanism that inhibits viral RNA dependent RNA polymerase which has been clearly demonstrated in vitro. But we also know HCQ has anti-inflammatory properties. It's why it's used every day to treat Lupus and Rheumatoid Arthritis. Every freaking day. So where in the vast array of immune function does the anti-inflammatory mechanism of HCQ fit ? Turns out in this study Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Also from this research on rheumatologic mechanisms of action of Chloroquine and Hydoxychloroquine: "These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules." Look again at the picture above. Lysosomal activity works through the cathepsin and NLRP3 pathway to activate inflammosomes resulting in a highly inflammatory response with IL-18 and IL-1b. So it appears the anti-inflammatory mechanism of CQ/HCQ has a direct and intimate tie to inhibiting a key pathway for multi-organ pathogenesis with Covid-19 that has just now been uncovered as crucial by the Yale collaboration I posted above. Would this have potentially beneficial protective effects when applied pre-cytokine storm in Covid-19 infection? Sure appears that way, and is consistent with clinical observations.

This intra-Yale collab just yielded some amazing insights with potential immediate impact on clinical decision making: Longitudinal analyses reveal immunological misfiring in severe COVID-19 this entire twitter thread is an ultra-dense cliffs notes of the above article by one of the PI's an worth close consideration: excerpted tweet: The last tweet stands out ---> one key feature of severe disease formation is low T cell number. Should make you go straight to thinking about the role of Vit D here. Quick reference points to Vit D levels playing a role in T cell numbers and modulating T cell function, and may induce many different anti-inflammatory functions. Read that correctly, anti-inflammatory, or the opposite of having an immune response run amok, ie what we've come to associate with with severe disease formation in covid. See general discussion: The Link. They then progressed to identifying 3 clusters of patients based on 4 immune signatures leading to the ability to form new targets for early diagnostic recognition that could also better inform specific types of early intervention revealed by those immune signatures.