Sequencing Of COVID - 19 Treatment Save

Hi, I'm Jack Cush with RheumNow. I'm here with doctors Lenny Calabrese and Cassie Calabrese coming to us live from the Cleveland Clinic. We asked Len and Cassie to come on and talk about issues surrounding COVID. Good morning folks.

Hey Jack. Good morning.

Good morning. So, tell us what's going on at the Cleveland Clinic. How has the COVID-nineteen changed the rheumatology world there?

It is of course heavily impacted of all of the Cleveland Clinic, but especially the rheumatology department given our patient population, lots of worry on our patients end and then also on our end to keep them safe. We've really moved away from in person patient visits which I know a lot of our peer institutions have done as well really discouraging any face to face visits that are not essential including new patients. We do encourage our patients to keep their scheduled infusions with the thought that if they miss their infusions run the risk of disease flare, which would require higher doses of prednisone, more exposure to the clinic and even hospitalization. Trying to limit face to face contact and also see the right person and patient in face to face visit as we are able.

So we've lived through, you know, other almost epidemics, you know, with MERS, SARS, and then, you know, there's a lot written in last few years about Zika and chikungunya. What have we learned from, those infections that might apply to this story?

That's a

It's a good question, Jack. I think it would be Karnak to answer that right now. I think that this is unprecedented and the speed and gravity of this on balance has made this heretofore a unique situation, Not as gravid as some of these other infections, but the spreadability of this and the global reach of this, think we're gonna be in this situation for a long time. I'm just echoing a lot of what the Epi people are talking about. So we're dug in.

So, Cassie, you want to address why we're being deluged with Plaquenil requests and information and is there a real utility to using it? Maybe you could follow it up and say maybe Plaquenil isn't always cracked up to be by what you know. So Cassie, why don't you start?

Sure, we certainly are being deluged after a couple, know, there's a little bit of data everyone's focusing on this one paper out of Marseille, I think it was that included twenty six COVID positive patients. And so small study, lots of limitations, which we won't get into, but they showed some benefit in decreasing viral load in these COVID positive patients. And this was a study looking at the use of Plaquenil and azithromycin. Again, lots of limitations like six of their patients dropped out, three of them because they died from COVID. So there's been all this buzz about Plaquenil which we do use for other intracellular infections.

So we appreciate the thought that it may be useful in COVID positive patients who have mild or more than mild symptoms, but we just don't know and we need more studies. So it has been included in treatment protocols at a lot of institutions that I've seen and including ours at a dose of eight hundred milligrams on day one after diagnosis followed by four days of four hundred milligrams. This has been misconstrued by a lot of patients that they should be on it prophylactically and just an outpouring of patients requesting Plaquenil. And we just don't know the safety in the setting of this infection, which we can talk about a lot of the mortality and morbidity is from this cytokine storm or pro inflammatory state or immune response from the infection and the timing of when to give something like a steroid sparing agent, we're still just not sure.

I'd like to add to this some granularity about this infection. I think that many people are thinking of this like it's some type of bacterial infection. And in actuality, it's a very complex viral infection and has its own modeling. So early on, this is a new virus for which we have no immunologic memory for. And that as the virus takes hold and people develop their clinical illness, whether it be subclinical or clinical, there is activation of innate immunity and then a very rapid generation of adaptive response.

And by the end of this infection, people have antibodies, and the virus is actually very hard to detect at the end of the clinical illness. So there is an ebb and flow here. Where drugs like Plaquenil, I have no idea about azithromycin, antivirals, anti IL-six, which we'll talk about in a minute, has a lot to do with this timing. So Plaquenil has been used in a lot of other viral infections experimentally. And probably the most alarming model is a non human primate model of chikungunya, where hydroxychloroquine was given to these animals, they were exposed to chikungunya, and out of the box, animals on Plaquenil had higher viral loads than the animals not on Plaquenil.

As they followed over time, and now we blend this in with clinical data from using animal aerials in patients with chikungunya, there was no viral relapse, and there was a tendency when used later on in the course of the infection to have lower acute phase reactants. So the actual question of timing here is critical. Maybe it will be a good thing to use it once infection has taken hold and people have a clinical illness. Maybe it could be dangerous to our patients who are already on Plaquenil. I mean, we don't know that, but it remains, you know, we have to have some equipoise to answer this.

Maybe an antiviral followed by Plaquenil may be the right role. So I'm just, you know, I'm answering, asking questions, and I'm very heartened to see the European COVID consortium are launching a very robust, almost a thousand patient Plaquenil study that should be rolling and have data within a month. So these are the types of questions that we have to ask. Where are you in the infection? What is the intervention?

And what do we do? The final thing I'll mention is when people die of COVID, they're not dying of infection. In fact, the virus is almost non detectable in most of these people it's been looked at. They die of damage. And so we have to structure therapies to treat those most vulnerable people as well.

So you had mentioned earlier about the cytokine storm that might ensue as a result of infection there. At some point, you hit a threshold where there is a sort of massive release of cytokines including IL-six. So you want to explain the role of IL-six and why we're going after that with trials?

I'm very, I'm, you have to be careful what word you use here. I don't want to say enthusiastic. I'm very interested in this area. I think it's very logical. If we think of the model that you have infection, innate triggering, develop of adaptive immunity, eighty percent of people do good, this other twenty percent not so good.

In that group where there's progression to ARDS and intense tissue damage, what we know in the immunopathology is that there are a lot of monocytes, there are a lot of polymorphonuclear leukocytes. The few immunopathologic studies that have looked at detailed peripheral flow over time have shown an increase in population of activated monocytes CD14, CD16 positive and unusual and inflammatory subset that are cranking out, in particular, a lot of IL-six and a lot of GM CSF. And, you know, based upon this type of modeling, you know, this, you know, we don't really have a definition for cytokine storm per se. We know it when we see it, but you know, what the signature is still remains to be seen. But in that population, I think that there's a very, very strong rationale for interdicting IL-six has been the first drug out of the box and some interesting anecdotes.

The question is timing. And I think that my concern is from several of the protocols that I've seen so far at other institutions, they're waiting too late. Mechanical ventilation, macrophage activation, multisystem organ damage, as opposed to patients who have declared themselves hospitalized and now are starting to de sat before mechanical ventilation, I think that's the ideal time to intervene. And I will tell you that from what I understand of both the Genentech and the Regeneron trials, that's exactly the type of patients that will be recruited for these.

So what I'm taking from this discussion is that timing is really crucial to some of these treatment issues. Cassie, let's close with what other treatments are being advocated. What's hard to get? What's easy to get? What should our docs know about?

That's a good question and things are really evolving in real time and the treatment protocol that we have developed here at the Cleveland Clinic has changed probably about 20 times since Thursday. Initially they were giving inpatients Calitra which is a combination protease inhibitor used in HIV which we ran out of and now we think it probably doesn't matter because there was a negative study published on Friday for the use of that antiretroviral protease inhibitor. So that was on our protocol. I don't know if it will be coming off along with Plaquenil. We're still looking for the right place to put IL-six inhibitors on our treatment protocol but something else that has been much talked about is remdesivir which is a kind of broad spectrum antiviral that was looked at during the Ebola outbreak and that has shown possibly some promise in these coronaviruses.

So we are I think we have maybe gave it to one patient last week that we're working on having that in our protocol as well remdesivir.

If I had to think of this in sequence, if we had an effective antiviral and remdesivir is IV, so it's not an oral therapy, you can't just go take it right out of the bat. You're already a hospitalized patient. Antiviral early, perhaps hydroxychloroquine at that same phase because it's not a blistering anti inflammatory drug. And then vigilance for patients who are the one in five who will deteriorate, and then intervention with IL-six. Both the Regeneron and Genentech trials are RCTs with a placebo limb, two to one randomization active drug to placebo.

And hopefully, and unfortunately, because the tempo of this illness is gonna go quickly right now over the next six weeks, we should know something pretty quick.

Okay, folks, thank you very much for your leadership and knowledge. We really appreciate it. We'll stay tuned.

You. Thank you again, Jack.

Be safe.

Alright, guys. Thanks a bunch.