CEimpact Podcast

Convalescent Plasma in COVID

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Respiratory failure from COVID-19 should be treated as soon as possible. Join host, Geoff Wall, as he evaluates the the role of convalescent plasma in treating patients with COVID-19 and on mechanical ventilation.
 
The GameChanger
COVID-19 is still a significant concern acutely and for long-term complications. Convalescent plasma may benefit severely ill COVID-19 patients on mechanical ventilation and with acute respiratory distress syndrome (ARDS).
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Misset B, Piagnerelli M, Hoste E, Dardenne N, Grimaldi D, Michaux I, De Waele E, Dumoulin A, Jorens PG, van der Hauwaert E, Vallot F, Lamote S, Swinnen W, De Schryver N, Fraipont V, de Mey N, Dauby N, Layios N, Mesland JB, Meyfroidt G, Moutschen M, Compernolle V, Gothot A, Desmecht D, Taveira da Silva Pereira MI, Garigliany M, Najdovski T, Bertrand A, Donneau AF, Laterre PF. Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients. N Engl J Med. 2023 Oct 26;389(17):1590-1600. doi: 10.1056/NEJMoa2209502. Epub 2023 Oct 25. PMID: 37889107.

https://www.nejm.org/doi/full/10.1056/NEJMoa2209502?query=featured_home
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss the latest NIH treatment guidelines for COVID-19 patients who are hospitalized
2. Describe the use of convalescent plasma in the context of a COVID-19 treatment algorithm

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-354-H01-P
Initial release date: 11/20/2023
Expiration date: 11/20/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I'm your host, jeff Wall, professor of pharmacy practice at Drake University. Welcome to our podcast. Today we're kind of back to the future whether that's fortunate or unfortunate kind of depending on your point of view but we're going to talk about a paper that was literally just published two or three days ago in the New England Journal of Medicine, looking at convalescent plasma in severe COVID patients.

Speaker 2:

Yes, that's right, I said COVID. Despite what I think all of us are hoping, unfortunately COVID is not gone and in fact, if you take a look at the data in the United States, the primary diagnosis for COVID has actually gotten up in the last six weeks. So we've definitely seen an uptick in numbers in people hospitalized with COVID no, not with COVID as a secondary diagnosis or incident COVID, but people who actually are coming to the hospital because of respiratory problems and COVID. As of this recording, I've actually got three patients with respiratory failure due to COVID in my ICU, so I've definitely seen an uptick and I think most places in the United States have seen an uptick. So, as much as I'd love to say COVID is gone and we're never going to worry about it again, unfortunately that's just not the case. And, yes, I'm aware of the fact that, yes, it will eventually become endemic and it'll become like the flu and we'll see waves of it, but that doesn't help clinicians or patients, I think, who are seeing these patients, who are still dying of this disease, and so it's still a problem, is the bottom line. We now know that, as of March 2023, there's been more than 670 million cases of COVID, including a total of almost 7 million deaths, and let me repeat that In the three years since the pandemic had started, we've had 7 million people die worldwide of COVID. That is a staggering number to me and we can do multiple podcasts about why that is and what we could have done to fix that, but this is not the place for that.

Speaker 2:

We were in the depths of the pandemic, which was just the most craziest time of my professional career. We saw a lot of patients obviously with respiratory failure and about, I'd say, anywhere from 20% of them and that's what other studies have suggested resulted in the workheimer for mechanical ventilation. Not to denigrate Dr Elon Musk, that's a joke I understand that he has recently been purporting the fact that ventilators were killing people during the depths of COVID, proving again that he doesn't know what he's talking about. Because of course, we don't ventilate patients put people on ventilator on a whim. We put people on mechanical ventilators because all other forms of oxygen therapy was not enough to oxygenate the patient. So I mean, there's no physician I know who just blivably goes around and says let's go in and obey people. And so the bottom line is that mechanical ventilation is still a valuable tool in COVID, but we don't use it willy-nilly. We use it when everything else, including high flow and bipap, doesn't work, and that's just literally what's going on Now.

Speaker 2:

Of course, since the beginning of the pandemic, we've been fortunate to come up with some treatments, and again we could do an entire podcast on some of the latest information. As far as treatments, we've been looking at some other biologics, including infliximab for its use, but really the one that has come up in the last six months or so is the drug billabella mab. The billabella mab is an anti-C5A monoclonal antibody and high concentrations of C5A were reported in patients with severe COVID-19. And so basically, this anti-C5A monoclonal antibody basically blocks the immune response and the inflammatory response, including release of histamines, that occurs once someone develops COVID. Now the drug is actually FDA approved recently for the use of COVID in severe patients who are mechanically ventilated.

Speaker 2:

But it is worth noting that National Institutes of Health and their latest guideline update may, of course, have a living guideline that is updated almost, it seems, like, every other week as of right now, as of the recording of this podcast suggests that there is insufficient evidence for the use of a billabella map for the treatment of severe COVID. That's based on the results of something the big study that they looked at. It called the Panama study, and basically the Panama study did not initially find a difference in 28 day mortality in mechanically ventilated patients with COVID compared to those received placebo. However, in a in another analysis that that made some adjustments, they did find a decrease in 28 day mortality and that's basically what the FDA kind of hung on. But that was enough that the NIH has basically said we're not going to make a call whether this is a good drug or not to use.

Speaker 2:

In my hospital we have declined to add it to formulary because of in the Panama study, if you did not get it within 48 hours of hospitalization, it had no benefit and it is quite expensive. And so for all those reasons and it seems to have a fairly minimum effect size. It actually was only about a 2% absolute difference in 28 day mortality. And again, that was only after doing a kind of a reanalysis of the original study, which always kind of makes you a little nervous. So for all those reasons we have not personally added it in my health system.

Speaker 2:

I know some places probably have, but NIH is basically not come down for or against it. So basically when I have a hospitalized patient who is, if they were, primary COVID, if they're on a conventional oxygen, of course we start them on dexamethasone, six milligrams a day, which has really been the treatment almost since the pandemic started, and we have a couple of studies showing that it has a benefit. And then if they are rapidly decreasing in their status they're starting to require high flow nasal oxygen or noninvasive ventilation. Then we often will add mutomodulators. In my hospital it's usually barisitinib. Some places are using tocalizumab and, as I mentioned, the latest update from NIH actually says that that alternative is can be IV abatecept and IV infliximab. Both those are anti inflammatory drugs used for rheumatoid arthritis and Crohn's disease and things along those lines. Again, that's something that I've seen used a lot, also recommending making sure that all these patients are on DVT prophylaxis because of the high risk of thrombosis associated with it. So that's the current state of treatment of hospitalized patients with respiratory failure and covid. But again, these patients who are mechanically ventilated, who have developed acute respiratory distress syndrome, those patients have an incredibly high mortality and treatments of those besides what we've just talked about is fairly minimal.

Speaker 2:

Now, one of the very first treatments for covid in the early months following 2020 was convalescent plasma. Convalescent plasma, of course, is plasma for people who have had covid and survived and theoretically have antibodies against COVID, and in the early phases of the pandemic, we very commonly gave patients convalescent plasma. It kind of was. There was a special protocol that FDA allowed this to happen and while all this was going on, the Mayo Clinic actually was doing a big multi-center study taking a look at convalescent plasma and unfortunately found and we found this out, I think, around the middle of 2021, that convalescent plasma really didn't seem to have a benefit and so it's use was largely abandoned. There was still some evidence of suggesting that immunocompromised patients who have respiratory failure that there may be some benefit from convalescent plasma, but we went from using it quite routinely in patients admitted with COVID to not using it at all in a fairly short space of time.

Speaker 2:

Now the Mayo Clinic study and other studies looked at basically all comers who are hospitalized with COVID. There was no specific study that looked at patients who were mechanically ventilated with acute respiratory distress syndrome, and so the purpose of the study that was just published here just this week in New England Journal of Medicine, which was called the competent study, was actually designed to figure that out. And so the two pieces of the study that makes it a little different than previous studies is that one, again, they really wanted to focus on again quite very ill patients, and the other is they wanted to make sure that the level of neutralizing antibody was quite high. That was the other big study. Things that other studies have found is that they were looking at relatively low antibody titers, you know, one to 64, one to 124, stuff like that. Is it possible that if we gave convalescent plasma to people who had higher titers with that have a benefit? And so that was the competent study and, again, just barely published, it was a randomized two group open-label study that was done in Belgium. It was started actually, you know, in the fairly early phases of the pandemic and has recently, you know, had enough patients that they were able to take a look at the evidence and basically publish their data. They wanted people who were to be given either placebo or convalescent plasma as soon as possible after mechanical ventilation, because of course, that probably plays a role. And so the goal was, if at all possible, to initiate patients in the study if they were intubated for less than 48 hours and then they were assigned a one-to-one ratio to receive a unit of convalescent plasma with, again, that tighter of anti-SARS2, of at least one to 320 or standard of care. They had to have a clinical fragility scale of less than six. So these were patients who weren't you know, who were not fragile, basically patients who weren't likely to have mortality associated with ARDS in the first place or something that's worth looking for. And they used the old World Health Organization clinical progression scale for COVID that was designed in 2020. And again, all these patients had to have, again severe COVID with scores of seven, eight or nine, and again had to be on mechanical ventilation. They also had to have ARDS, which they use, the standard Berlin definition, which takes a look at the PAO2 of a patient and its ratio to the amount of oxygen we're giving patients, as well as some other imaging definitions and things like that. The bottom line was it was the standard definition for ARDS.

Speaker 2:

Donors were recruited by the Belgian Red Cross among adults who'd been infected with COVID-19 and had fully recovered between 28 days and 10 months earlier. Because, as with a lot of other diseases, the neutralizing antibody titers are highest right when you first recover and then decline over time. And it is worth noting that the titers that were looking for it one to 320, were significantly higher than other studies had shown. The primary outcome was, as with most of these other studies that were, in the process, of death at 28 days after randomization. They looked at a variety of secondary outcomes, including adverse effects, inflammatory or anti-COVID-19 antibody responses, sofa scores, which is a way of looking at acuity of patients, and organ failure linked to hospital stay, also days by depth, 90 and one year. The statistics were pretty standard. They anticipated a 28 day mortality of 40%, which was probably even low, in my opinion based on what we saw, and they felt that a relative drop of 30% by 28 day mortality was realistic and relevant and probably certainly as good as the data we have with Barisit, nib and Tocholizumab, which are standard therapies now in severe COVID.

Speaker 2:

Taking a look at the patients themselves, they were pretty much the patients that we saw in the worst parts of the pandemic. Mean age was 64,. About 65% of patients were male. It is worth noting that this was largely an unvaccinated cohort in the study. Only about 11% of patients were vaccinated. So, again, one of the strikes of the study is we really don't know if this data would be generalizable to people who have been either vaccinated or ever seen the latest booster. The other big strike, then, is we of course had different variants of COVID since then, and knowing if you have titers to one variant of COVID and you get infected with another variant of COVID, will that first one work? Early studies have suggested that there's a lot of cross-protection, but that is that it's worth noting.

Speaker 2:

Meantime, since the first reported symptoms, these people had had symptoms for about 12 days before they were hospitalized. They were in the hospital for about five days before they were in the ICU and then in the ICU for about three days. Basically, mean apache score, which is a score of acuity of sickness, was only 13,. But, again, many of these patients were there primarily respiratory failure. They didn't have sepsis. They didn't have acute kidney injury, things along those lines. Almost everybody reached at the definition of ARDS and the cycle threshold for the PCR test was pretty low at 22 and 20. And again, that's something that we've learned a lot about since the pandemic started is that many patients, especially those who are severe to leal, can actually shed virus for weeks after they've been infected and really, even though the acute viral infection phase may be starting to fade, they still have quite a bit of virus that they're trying to fight off. And again, that's kind of the point of convalescent plasma is that remaining virus can be basically inhibited and stopped by the donated plasma.

Speaker 2:

They had a multitude of other disease states, as you might imagine, including hypertension, copd, diabetes, things along those lines. Their mean body index was 30, so I think certainly what we would see here, maybe even a little bit on the low side. And again, only a small percentage of patients had received any sort of antiviral therapy. The majority of the study was done before the development of Paxlavid, so it was really remdesivir and only about 5% of patients had received remdesivir. But almost everybody in both arms did receive dexamethasone. About 95% in both arms did receive dexamethasone. So again fairly similar to what I'd want to see. Unfortunately, because of the length of time we took them to do this study, they did not include a lot of patients who received what some of the standard therapies we have now again, including Paxlavid or Barisitinib or anything along those lines, so it is worth noting that. So what did they find in the study and what can we kind of take from it? What we will talk about that after a work from our sponsor, ce Impact.

Speaker 1:

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Speaker 2:

So we're back yet again talking about COVID and talking about convalescent plasma in the confidence study, looking at severe COVID in ARDS patients. And so what did they find in the study? Again, the primary outcome was 28D immortality, which did occur in 35% of patients in the convalescent plasma group versus 45% of patients in the standard of care group. This was statistically significant and when they looked at a number of other stratification points as opposed to like different disease states that the patients had and things along those lines, it's still largely retained its statistical significance. But it is worth noting that most of that was lost if patients were randomized after, significantly after, ventilation initiation. In fact most of the benefit seemed to occur in patients who did get convalescent plasma within the first 48 hours after mechanical ventilation and that benefit was largely lost after that. But once that, but if you were able to do that, the number needed to treat was only 11. So again, to save one life, to decrease mortality at 28 days, you only have to treat 11 patients with convalescent plasma. So actually that's pretty impressive and certainly at least as good results as we have from the you know modulators that we are commonly using patients with severe COVID. Most patients tolerated the drug quite well. There were a number of adverse effects, but almost nearly all of them were either related to COVID-19 or complications of organ support, and so none of them were directly related to convalescent plasma. And that was certainly our experience in the early part of the pandemic is that we were giving convalescent plasma out left and right and it didn't really seem to have any serious adverse effect on them. The mean neutralizing antibody did increase in both groups, which is really kind of not surprising, and they also probably not all that surprising is that at initiation, if you were sicker you tended to have a better, a bigger benefit, which, again, probably not all that surprising. So they looked at different time frames, they looked at different disease states as compounders and, except and with the, with the exception of the 48 hour break point, it doesn't seem like there was a whole lot of difference in the results compared to the overall results. So I kind of walked away from the study, going okay, if we're going to do this, we need to do it ASAP, as soon as the patient is intubated. So now, of course, this is different than the Mayo Clinic study and it's different than several other studies that looked at convalescent plasma that did not find a benefit and, again, why we kind of abandoned this use in 2021,.

Speaker 2:

The authors note that the that they feel that the big differences occur for three, for three reasons. One, as they noted that use of convalescent plasma had a much higher, tighter than previous studies had, and they were able to measure that when they took a look at anti-IGG antibodies to COVID-19. And so that's worth noting, and they know that that other studies that had not found a benefit had much lower titers on the whole, so that's that that's kind of worth noting as well. The trial did focus on patients they RDS, and so they did not look at all comers and they kind of felt like these were the patients that were most likely to benefit and hadn't been really studied before. They also again noted that even though the acute viral infection phase had probably passed in these patients because they had really low cycle thresholds, they still probably were having some sort of viral effect to their illness and that was kind of propagating the inflammatory response that kind of leads to this kind of wildfire of destruction of lung tissue, and so they felt like you know that this was a good target to take a look at and, of course, because at the time they started this study, there are many of the tools that we are using for RDS, you know, weren't there. So again they, they did not use immunomodulators, paxil, they did not exist, you know, and all those sort of stuff.

Speaker 2:

So it is, again, the study is a moment in time in a disease where its treatments were rapidly changing. And for those of you who were around, for you know, and we're in the depths of COVID, you know how quickly things changed. It seemed like almost week to week something new was coming down. Either they showed a benefit or didn't show a benefit, etc. Etc. So that was the second reason. And and again they wanted to take a look at at speed of administration, because other studies had not either not said when they were going to give a convalescent plasma or, or were, it was beyond the 48 hour window. So for all those reasons, they felt that's why they necessarily may be found a benefit when other studies had not not found a benefit.

Speaker 2:

Now, one of the things that I have is, again, the study was conducted over about a year and a half period and, as we know, we've, you know, cycled through several variants of COVID. We now have had gone through kind of a range of COVID where the variants seem to be as infectious as other variants, in fact maybe more infectious, but with generally lower virulence rate. So again, you know these, these were looking primarily at earlier variants. Would you still find the same, of same results in, for example, vaccinated patients and patients who are affected with a different variant, which may not be as rule? It Then and of course we're never going to be able to answer those questions based on this study. But I think this is something that that, if we see another spike in in severe COVID patients per car in mechanical ventilation, given the fact that convalescent plasma is relatively inexpensive as those things go, and considering how safe it is, I think it's something to really consider in a disease state where, again in this study, 45% of patients died in 28 days and you have an intervention that seems relatively safe that has a number needed to treat only 11. So a pretty large effect size. So we're actually gonna be discussing this and I suspect most healthcare systems are going to take a look at this information and decide whether we're gonna kind of re-put convalescent plasma back on the map for the treatment. It'll be very interesting to see what NIH does with this data and will they alter their treatment algorithms to include it as well?

Speaker 2:

I think that a lot of health systems and the early phases of the pandemic, blood banks were working very hard with health systems to make sure that there was an adequate supply of convalescent plasma as the pandemic kind of, as the acute phase of the pandemic seemed to wane, some that largely dropped off. I know that we've used convalescent plasma a couple of times in immunosuppressed patients and it has been more difficult to get because, again, we blood banks are not routinely saving plasma in patients who have recently had COVID or they're not getting donations specifically of patients who recently had COVID or plasma. So that may be. The other issue that we're dealing with is if we see a significant spike in severe respiratory failure from COVID, will we have the supply to keep up with the demand? But bottom line with the study is that it definitely seems beneficial, it seems safe and even though we're gonna have there is some generalizability issues. I suspect many healthcare systems are gonna consider this as an add-on therapy at least to steroids in patients with severe COVID.

Speaker 2:

So that's it for this week of Game Changers. Thanks for listening. As always, we will see you next week, but until then, remember time flies. I don't know where it's going, but the most important day is today. Take care.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers clinical conversations.