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Corticosteroids for COVID-19: New Evidence of Benefit

Educational Objective
To understand the latest research around using hydrocortisone and dexamethasone for treatment of COVID-19
0.5 Credit CME

A conversation with Jonathan A. C. Sterne, MA, MSc, PhD, of the University of Bristol, Todd W. Rice, MD, MSc, of Vanderbilt University, and Janet V. Diaz, MD, of the World Health Organization (WHO) on the latest research supporting the use of hydrocortisone and dexamethasone for treatment of COVID-19 ARDS. Recorded September 2, 2020.

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Transcript

>> Howard Bauchner: Hello and welcome to "Conversations with Dr. Bauchner. It is Howard Bauchner, Editor in Chief of JAMA. And it's rare that I find myself proud of something that our journal is doing. You know, we have a responsibility each day to present good and high quality research to the world but this is a particularly unique day. Simultaneously we are publishing five papers and the WHO is releasing a document entitled "Corticosteroids for COVID-19, A Living Guidance" 2 September 2020. I'm joined today by a number of individuals who have been part of this remarkable effort. Jonathan Sterne who is the lead author on a meta-analysis which I'll explain in a bit. Jonathan is a Professor of Medical Statistics and Epidemiology at Bristol Medical School. Todd Rice who, along with Hallie Prescott, has summarized the three randomized clinical trials and the meta-analysis that are all being published simultaneously in JAMA as we speak in an editorial. And Janet Diaz. Janet is the head of the Clinical Care Group within WHO Emergencies Program, and Janet and her group has been responsible for this document. But before we start and I ask each of them to make some introductory comments, I wanted to inform our viewers and our listeners what we're actually publishing today. So there are three randomized clinical trials. There's a single meta-analysis and then there is an editorial. So the first clinical trial, The Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19, A Randomized Clinical Trial. First author is Pierre-Francois Dequin for the CAPE COVID Trial Group and the CRICS-TriGGERSep Group. This is a study that intended to enroll 290 patients, was stopped early after the announcement of recovery, ultimately enrolling about 150 patients. This study was done in France. The second study, Bruno Tomazini and Luciano Azevedo are the first and senior authors. This is from Brazil. The Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19, the CoDEX Randomized Clinical Trial. This study included 299 patients. And the third clinical trial, The Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19, the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. The writing group, the REMAP-CAP Writing Committee, corresponding author is Derek Angus. This study, it ultimately enrolled 384 patients, conducted in 121 sites in eight countries. And the meta-analysis, Jonathan led the effort. The writing group, the WHO Rapid Evidence Appraisal for COVID-19 Therapies () REACT) Working Group. The title of the meta-analysis, Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19, a Meta-Analysis. I must thank the peer reviewers. Each peer reviewer saw all four papers. They conducted peer review in two days or three days. These manuscripts were processed at JAMA because the authors, our Senior Editors, our editorial group and the authors worked daily, each day, over three weeks to make sure that we could publish all five articles simultaneously. Jonathan, what do the results say?

>> Jonathan Sterne: Thanks, Howard. And thanks very much for the introduction. And I should probably mention in addition to the groups that you've mentioned the work here was led by Srin Murthy and John Marshall who have been part of the WHO Clinical Characterization Group with Janet and who started convening the trial investigators way back in April. And perhaps mention the investigators of three trials who you haven't mentioned so fa:, Bin Du, Steroid-SARI trial in China; Jesus Villar; and Anders Perner who also led trials and also contributed to the effort. Everybody watching will know that the only drug demonstrated to reduce mortality in COVID-19 is dexamethasone and that we learned that on the sixteenth of June when the RECOVERY trial, a very large UK-based trial, released its results. At that time the investigations of nearly all the world's trials of corticosteroids in critically ill, the sickest with COVID-19, were already talking about a collaboration where they would pool and rapidly disseminate their results. And once the RECOVERY trial had published, it was agreed that that was what would be done. We agreed that the last date for recruitment would be the ninth of June so that patients' care couldn't have been affected by the release of RECOVERY results and that meant that the last day for follow-up, the 28-day mortality, was the sixth of July. And, as you know because you've been part of this process, Howard, subsequent to that the trials rapidly combined their data and we perhaps mention that it's really unprecedented. The trials are taking a big risk when they share their data in advance of publication because then the concern that any trial team will have is that if their data were published by someone, their own, their paper will be less interesting. So in the spirit of trust and because of the urgency of these results for the care of patients worldwide, the trial investigators shared their data and put those together in a meta-analysis, everybody wrote their papers at the same time and we were able to submit the paper within two weeks to JAMA and it has been a real pleasure working with you and your colleagues to get those into finished form and to get us publication, too. In terms of results the bottom line is that these are the sickest patients who are being treated with corticosteroids in these trials and mortality is very high. It's about 40% in the absence of treatment with corticosteroids. The treatment with corticosteroids reduces mortality of 40% to 32%. That's a 20% relative reduction, or, if you like to, and a better way to think about it, an easier way to think about it is that out of every 100 patients treated with corticosteroids eight additional patients do not die. And the final way to think about it is that approximately for every patient, 12 patients that you treat, you save one life and that's really the bottom line from these results.

>> Howard Bauchner: Janet, two questions for you and then I'll go to Todd. The first is how did you pull it off? And then what does the new WHO guidelines recommend? So the first is how did you get everyone to cooperate? It's not something that we often do. We're in the middle of a pandemic and I really have to thank all of the investigators, and I want to echo something that Jonathan said, there's more than these three clinical trials in the meta-analysis but lets, you have to read the paper to see what's in it. But, Janet, how did WHO pull it off and what do the new guidelines say?

>> Janet Diaz: Well, thank you so much, Howard. It's actually a privilege and a pleasure to be here and it's kind of, it's unbelievable almost that we actually made to the end. And so I think to start with we do want to say thank you to all the collaborators up here internally to WHO with my good colleague, John Grove, who leads the Quality Assurance for Norms and Standards, really a key member of our group here, to the Methods Supports Team that worked with us, the External Methods Support Team and that's the MAGIC Ecosystem Foundation so both Francois Lamontagne who is our Methods chair, and Per Olav Vandvik also from MAGIC. And then, of course, to all the trialists as you already described and what Jonathan added on. Really for me it was something that we knew we wanted to bring evidence, you know, science to the bedside. So how quickly can we bring good science to inform patient care? You know, as WHO, we want to write, you know, evidence-based guidelines. We want to bring the best practices to the field, especially to member state, to all our member states, and especially into countries that really rely on our guidance, that don't produce their own national guidance, that don't have their own processes or national societies that will make trustworthy and transparent guidances, as well as the policy makers who are looking to support countries and procurement and distribution of lifesaving medicines. So that was the impetus and we knew from the beginning, even from February, that we wanted to prioritize corticosteroids because we knew people were going to start using corticosteroids, you know, without, because it was around, and we like to do that in intensive care, some people like to do that in intensive care, and that we should just take this opportunity to study it. And so luckily many investigators started to study it and we saw this fantastic opportunity then can we bring the investigators together and try to make, pool analysis, that idea of a prospective meta-analysis, and, you know, is this possible? So we ventured on this experiment. And, of course, I want acknowledge Srin Murthy and John Marshall, you know, our good colleagues who chair the WHO Clinical Research Working Group where our focus was on clinical characterization research and clinical management research. And we together, you know, reached out to the investigators and started to convene on a weekly basis the development of this protocol and then Jonathan joined our team. And I think it was just really with the good nature of everyone, with the transparency, with the trust that we had in each other and in the process. And I think, thinking of the patient at the bedside, I think we were, you know, all of the PIs are, most of them are intensivists working in busy ICUs, understanding that we need to bring good evidence to inform guidance, and I think just were superb in the collaboration effort to help WHO, to work with WHO. And there was quite a bonding experience in the process that we went through. And then I think from the getting the evidence, pooling it together, from the technical side, then rapidly trying to package, you know, convene the GDG which, of course, I wanted to acknowledge. There's 23 of them and they're all in the guideline, then you can see who they were but really them being able to see data, give us good feedback, see more data even though it was unpublished data, we received data early and I think that was also a new, an innovative, an important process. So the manuscripts were not published when we saw them. So we saw the data early. That allowed us to start the process, wait until the manuscripts were peer reviewed and submitted, and refine our guidance. But at least we were able to start early so by the time all these studies were going to become public, we were able to actually then also produce our guidance. And then I have to thank you at JAMA for the collaborative, for the collaboration as well, understanding the need for doing good reviews but doing them quickly and really just the collaborative effort that everyone took part in their part of this puzzle as we were trying to put the puzzle together. So in regards to what does the guidance say, so there are two recommendations in the guidance but it is, it's about eighteen pages long I think with graded evidence, with the summary of findings tables, and so, and all the description of the trials, but the evidence says the recommendations are for, one, a strong recommendation for the use of corticosteroids in patients with severe or critical COVID-19, and that is evidence, and that is a strong recommendation. It is based on a moderate certainty for the reasons of the absolute risk reductions that Jonathan already explained. The second recommendation is for a recommendation against the use of corticosteroids in mild COVID-19. And that recommendation was based on low certainty of evidence but with a concern there could be increased deaths with the use of corticosteroids in patients with mild COVID-19. So the guidance itself, those are the highlights. The guidance itself goes through the entire process of how we convened the meetings, the discussions around things, and a lot of things about practical [inaudible] , practicalities around implementation and also limitations and things that need to be addressed for the future so thank you.

>> Howard Bauchner: Thanks, Janet. So, Todd, you with Hallie Prescott have written the editorial that summarizes the three clinical trials, the meta-analysis. The title of the editorial is Corticosteroids in COVID-19 ARDS, Evidence and Hope During the Pandemic. So, as Jonathan said, 8 per 100 treated lives saved, about nominated to treat 1 in 12. So why did it work, Todd? Why, after 20 years of research of steroids and sepsis, steroids and ARDS, why do think it's worked?

>> Todd Rice: Yeah, well, I get the hard question, Howard. No, I'm kidding. You know, I mean, I think that this is a disease that has phases and the initial phase is damage done by the virus. And then I think it's becoming more and more clear that a later phase of this disease is dominated by an inflammatory component and hyperinflammation. And I think steroids are very good at decreasing that inflammatory component and reducing the damage and the effects of hyperinflammation in the body. And it think that's probably the mechanism although we don't know for sure, that's probably the mechanism as to how the steroids are working.

>> Howard Bauchner: Now one of the questions that's already come in, it's addressed in the meta-analysis and in your editorial, is hydrocortisone or dexamethasone. And, Jonathan, I'll return to you because there's going to be a big issue around the world because every country doesn't have both. Both the WHO recommendation as well as the meta-analysis goes into dose. I think that's a little less critical than actually hydrocortisone or dexamethasone. But, Todd, could you comment about whether or not there's a, do you have a sense if there's a preference for one over the other?

>> Todd Rice: Yeah. My take on these data are that it appears to be a class effect and that it's from the steroids and not from a specific steroid, dexamethasone or hydrocortisone. And [inaudible] to what's the steroid that you have, that you can easily get, and that's what you should use. The effect sizes appear to be very similar between dexamethasone and hydrocortisone. And I don't think, based off these data, that you could say there's a preference for one over the other.

>> Howard Bauchner: Jonathan and Janet, Jonathan, is that your reading of the data, and, Janet, was that the conclusion of the guideline work group for WHO? So, Jonathan, you first.

>> Jonathan Sterne: Yes, absolutely. So the estimated effect of hydrocortisone, as Todd said, was very similar and consistent with the estimated effects of dexamethasone, although, because fewer patients had been randomized in trials of hydrocortisone, the confidence interval was wider, but the effects were very consistent. One trial and then one additional trial that we located late had randomized patients to a third steroid, methylprednisolone, and there there are certainly sufficiently few patients randomized that the effect is imprecisely estimated and the truth is we just don't know. But I think one of the reasons that these results are very good news worldwide is that it really says that there are two options. And, as Todd says, it's hard to choose between dexamethasone and hydrocortisone. They are both routinely used in critical care and therefore if one isn't available, the other should be used.

>> Howard Bauchner: Janet, the WHO guidelines, do they generally agree, either it's a class effect and either of the two drugs that we've been talking about are options?

>> Janet Diaz: Yeah. So when we presented the data to the Guideline Development Panel, yes, they agreed that either dexamethasone or hydrocortisone as well giving the options that those aren't available, then using an equivalent dose of prednisone or methylprednisolone, so a class effect.

>> Howard Bauchner: Now let's move to two really difficult and complicated questions. Todd, I'll start with you. And Janet mentioned it, they're recommending against the use of corticosteroids in mild illness. But if you have a 70 year old whose breathing at 50, may not have met the criteria that would have gotten him or her into any of these studies, but you think is going to deteriorate in the next three or four days, and this actually may be the majority of patients who end up in the hospital. What do you do? >> Todd Rice: Yeah. I think this is hard to clinically implement these data and understand. I think, you know, there's the signal from the RECOVERY group that maybe dexamethasone isn't that helpful in those patients which doesn't bother me that much. What bothers me more is this potential signal that maybe it's [inaudible] .

>> Howard Bauchner: Right.

>> Todd Rice: And then I'm left with the question of in the RECOVERY trial that was based off of whether or not you were on oxygen, which at least in the United States is not a very clear line as to how people get put on oxygen. And so it leads me to the question of there probably is a group that these may not be the best treatment for and how do I identify that group and how do we avoid giving them to patients that potentially could be harmed by them? And what you've proposed, Howard, which I love the idea, the predictive modeling of who's going to get worse, who is at risk from becoming critically ill where we know that they work? And I think there's some work to do to truly understand where that dividing line is and who the population that, you know, it's pretty clear we absolutely should give it and who the population is that it's clear that we absolutely should not give it.

>> Howard Bauchner: Janet, did the WHO guideline committee wrestle with this because, as I said, this is one of the great clinical questions. It's easy if you know the person is, as I said, breathing at 70, has huge O2 demands, and is about to be intubated. They get steroids. But it's this group on the way to that presentation. And as critical care places, hospitals around the country are less busy, they may be able to pay more attention to these patients who are getting worse. Did the guideline committee wrestle with this group?

>> Janet Diaz: We did. And actually if you read the guideline in table one there is a little nuanced statement about that, that it can't be so black and white, right. It could be that someone has a saturation of 93% or 94%, but clinically they look like they're on a downward scale, then the clinical judgment should also be used to consider it. And I think where we struggle is at the beginning because at the beginning we only had the Recovery data and they did the two subgroups, you know, with oxygen or no oxygen and ventilation. And so when we wrote our guidance there was a discussion as do we use the same things we recommended in patients on oxygen? We recommended patients on ventilation? And that seemed difficult for us to do because we didn't want to make it based on the intervention that the patients were receiving already because that could be varied depending on the resources you have. So we chose then to say we make the assumption that most patients that would be put on oxygen is because they have certain indications for oxygen. And in our previous WHO classification system we have a severe classification which is people who usually are on oxygen or have some signs of respiratory distress and with a critical classification so we chose to use those classifications but then with a little bit of a nuanced statement saying that it's not so black and white because we don't know, so clinical judgment in that gray period, in that gray zone where you think someone is on the way crashing but not yet there so.

>> Howard Bauchner: Jonathan, I mean you've lived with this, literally lived this data since we've had a lot of emails back and forth including your quasi-vacation. You've lived with this data for almost three months. Having looked at the seven or eight clinical trials, do you have a sense of how to differentiate patients?

>> Jonathan Sterne: So the area we're talking about has indeed been the hardest bits of text to write and the bit where the authors have argued most about the presentation of the results. And the people who are interested, I would encourage people to look at the supplementary material where we have additional plots that might help. So we do not have definitive results here but we have a couple of hints. And the first is that the trials recruited critically ill patients but the definition of critically ill varied between the trials. In three of the trials we really only included patients who were invasively mechanically ventilated. They had a tube down their throat to help them breathe. But in three of the trials there were a few patients who were not invasively mechanically ventilated -- sorry -- in four of the trials there were a small group of patients who were not invasively mechanically ventilated when they were recruited to the trial. And the signal it's only a signal, was the benefit was if anything greater in the patients who were not invasively mechanically ventilated in a randomization. And that tends to, turns us in the direction that both Todd and Janet have mentioned that it's not that you need the intervention of a tube down to your throat to benefit. It's that benefit is in the sickest patients but not necessarily waiting until there's tube in their throat. The second piece of evidence that pulls in the same direction is that the benefit of corticosteroids appeared greater in patients who didn't see [inaudible] by blood pressure, they're the sickest patients. So it appeared greater in the patients who were not so sick that they needed those additional medications. So Todd may want to comment further but those were two pieces of evidence that really this is about being sufficiently sick that you're getting the problems resulting from the very active immune system rather than waiting until there is a particular intervention given.

>> Howard Bauchner: Todd, can you comment on Jonathan's identification of the clinical information within, in the trials because I do think we're talking about what is likely the majority of patients that come into the hospital and potentially are in a critical care unit.

>> Todd Rice: Yeah. I think he explained it pretty well. I think that, you know, we talk about should we give this when the patient's on the ventilator, should we not give it when the patient's not on the ventilator, and I think the data are pretty, pretty suggestive that the ventilator is not necessarily the trigger for when these should be started. And, you know, giving them to patients that are pre-ventilator before they go on is also beneficial. And we can argue about is it more beneficial, is it less beneficial, I'm not sure the data are that definitive as to more or less but I think they're pretty definitive that they're still beneficial. Let me say this then he can comment. One of the things that Hallie and I struggled with a lot was what to say about the shock group.

>> Howard Bauchner: Ah. Could you explain the shock group? People may not know what you mean by the shock group.

>> Todd Rice: Yeah. The group that had low blood pressure and were critically ill with COVID but also had low blood pressure and/or needed medicines to raise their blood pressure to keep it in the normal range. And we struggled with it because there are, as I think you all know, there are data for patients that have shock from an infection, septic shock, that steroids may help that group. Forget COVID. Steroids may help that group. And so when the signal looked like it was less and maybe not even present in those patients, we looked at that pretty hard and talked about it actually a lot among her and I. And I think it's a hard signal to understand because in many environments patients that were already in shock, had low blood pressure may not be eligible for randomization because their doctor already thinks, "I'm giving this patient steroids because I'm confident that it helps these patients". And then in addition the REMAP paper has a shock arm but less than half the patients in that arm actually get shock, have shock, and get the shock treatment. And so I think that makes it hard to interpret those data, too. Clinically I'll tell you I'm not withholding the steroids in patients that I have with COVID that are critically ill that have low blood pressure. I'm giving it to those patients also.

>> Howard Bauchner: Janet, do you want to comment? I know that and I just want to point out to the people who are watching or who will eventually listen, Janet is a critical care physician who trained in San Francisco. And, Janet, you can depart from whatever the WHO guidelines are and say what you would do but I know you have to probably be pretty careful about that. But can you just follow up on what Todd just said because I know it's a complicated issue besides who should get it, the patients with shock or shock-like syndrome?

>> Janet Diaz: Oh, yeah. I agree with Todd actually. I would give them the corticosteroid. I think we're, you know, based on the guidelines it's also we would give based on the WHO to recommend for patients with severe or critical COVID-19 to use corticosteroids and that's the recommendation. And that would include someone with shock or without shock. So there's no distinction being made at all in the guidance and it wasn't really a topic of conversation. And I do think from the literature, from the non-COVID septic shock literature we helped with the meta-analysis that were done in that, you know, have been done for corticosteroids that there is reasons to believe that it is beneficial and suggestive of benefit in septic shock as well as in potentially sepsis so -- .

>> Howard Bauchner: Jonathan, go ahead.

>> Jonathan Sterne: There is a hopeful piece of evidence that I should quickly mention which is in the RECOVERY trial randomized around 4,000 patients, a really, really large number who were receiving oxygen and many of them in really a variety of ways but were not so sick that they were invasively mechanically ventilated and mortality was reduced in those patients. And we included those data although they're not part of the main perspective meta-analysis. We've included that data in figure three in our paper. And so I think it's really important to bear in mind there are a much wider range of patients in Recovery, and a very large number of patients also provide evidence that if the patient needed oxygen and in the context of UK healthcare mortality was reduced by corticosteroids.

>> Howard Bauchner: Rob Golub who's Director of Scientific Review at JAMA, along with Chris Muth, Rob always says, you know, people need to understand the abstract is just a skeleton of the paper and the paper just only is a small part of entire study so I really, oftentimes when people talk to me about clinical trials I often say, "You know, you actually have to read the entire paper sometimes". And in this case I think it really is worth reading all of the meta-analysis, all the trials and particularly look at the supplement. And I want to go to one additional question. Derek Angus and others have written in JAMA and other journals. We've learned quite a bit but now more complicated questions have come up, the timing of drugs, combination drugs. So now there's a literature around remdesivir. I think it's mixed about its benefit. No definitive data yet about convalescent plasma. But, Todd, how do you see the combination of drugs working now? With steroids is clearly the highest quality evidence with the greatest gain. Remdesivir, some gain. Plasma in the hearts of people, a lot of gain, not a lot of high quality data yet. So, Todd, how do you see the combination of drugs working out?

>> Todd Rice: Yeah, I think you summarized sort of the evidence level really well. I don't think we know because I don't think we have good data of these being used together. Most of these patients in these steroid trials were pre-remdesivir and they didn't get remdesivir so understanding the combination of the two I think is a little bit of a data-free zone. But as I started at the beginning telling you at least what I think is the mechanisms, I think mechanisms that these treatments would work through are different. So remdesivir is an antiviral. Steroids I think decrease the inflammatory reaction. And to me it makes perfect sense that they should be synergistic and work together. And I think that in my practice I would use them together and I do use them together. I think convalescent plasma is a little bit of a fly in the ointment in the fact that its mechanism of action is also antiviral and so it and remdesivir may not necessarily have combined effect when they're used together and they may have similar mechanisms and similar benefit if convalescent plasma's strong beneficial dose. But I think both of those are distinct from steroids. And I think if you're using convalescent plasma, steroids are likely to add benefit to that. And if you're using remdesivir, steroids are likely to add benefit to that also.

>> Howard Bauchner: Janet, before I go to you to comment, one of the things that comes up in the Q and A all the time when this question comes up, Todd, is is there any reason to think that steroids would adversely affect the action of remdesivir or vice versa?

>> Todd Rice: Yeah. I think, like I said, there's not a ton of data but from what I know and from what I think we know from the data, I don't have any reason to believe that the two should have an antagonistic effect and that they couldn't be used together.

>> Howard Bauchner: Janet, does the guideline make any comment about combination therapy?

>> Janet Diaz: No. We do not make any comment about combination therapy. We, in the ongoing uncertainties part of the guideline we do discuss this in the sense of with the strong recommendation for these corticosteroids in severe and critical disease. You know, now let's say you're going to test immunomodulators, right. So in some ways should they now be tested against corticosteroids, right. And so maybe a design of trials may need to be adjusted after this. And then in regards to other antivirals, these are direct antivirals, again, I agree with Todd, I don't think there would be any reason to think that they would not be synergistic and since they're working, you know, not being, what am I trying to say, not being, you know, synergistic I guess in treating COVID. I think the timing of antivirals is the question as well, you know, with those antivirals being perhaps earlier initiation when the viral loads are very high to get the best impact versus corticosteroids, what we're seeing now with corticosteroids is not necessarily the timing but actually the point of the disease where you're having signs of the inflammatory response or severity signs.

>> Howard Bauchner: Jonathan, I know you've really focused on steroids but you've seen the data from all of the trials. Do you have a sense if there's an answer out there or we need more information yet to really, to begin to answer this question?

>> Jonathan Sterne: So I think it would be, I think that the trials from now on, for all that's speaking, are going to be assessing a new therapy with corticosteroid compared with the absence of that new therapy, corticosteroids. So what we're really going to learn about from here on in, at least in the critically ill patients, is about whether adding something else to corticosteroid therapy reduces mortality further than the corticosteroid sort of already reduced it. And probably any of the 4 of us and indeed any of the clinical research community out there would at this point say the same thing. I mean I'm not sure what the total number of patients with COVID-19 to date is worldwide. It might be 25 million. We've seen that we can get definitive results from randomized trials involving a few thousand patients and for most of us whether a treatment or another treatment works is not a matter of opinion. It is just the matter of doing a randomized trial with sufficiently many patients, finding the answer, and then acting on the answer. It's not a political issue whether drug A works or it doesn't work. It is just the matter of doing the randomized trials, finding out, and acting on the result. So we simply need to randomize patients to trials and then, and this is, of course, being done to trials of remdesivir, to trials of convalescent plasma, to trials of the new immune therapies that are coming on, to therapies - a really important area is whether we can find therapies that prevent progression to severe illness and we need, and we're going to need large numbers of patients randomized in trials to do that. And then, you know, I don't have a prior opinion and the investigators of the RECOVERY trial, the senior investigators, to me that before they released their results they had 10,000 tweets telling them that they were evil people for risking corticosteroids in these sick patients because they were going to kill them. And then after the results were released they had 10,000 tweets from people who said they knew all along that corticosteroids were going to work. Truth is if you don't know, do a randomized trial and find out, and please find out quickly because millions of patients need the answers.

>> Howard Bauchner: I'd like to end there because I think it's a call to the scientific community and the clinical community and there is always tension when you're taking care of patients who are doing poorly about how you can think about trying to put patients into a clinical trial. I think clearly steroids are now standard of care so everything must be compared to steroids, but I think real progress will be made by conducting clinical trials and by the clinical trial community cooperating like they've done in this case. It's an extraordinary accomplishment and achievement. So this is Howard Bauchner, Editor and Chief of JAMA. This has been "Conversations with Dr. Bauchner". Once again, I want to highlight the WHO guideline, Living Guidance they call it, 2 September 2020 Corticosteroids for COVID-19. It's being released simultaneously with our publications. The editorial is by Hallie Prescott and Todd Rice who's joined me today, Corticosteroids in COVID-19 ARDS, Evidence and Hope During the Pandemic. Then a summary of the three trials. The effort was led by Jonathan Sterne from the University of Bristol, the WHO Rapid Evidence Appraisal for COVID-19 Therapies, Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19, a Meta-analysis. And then, of course, my ultimate thanks to Janet Diaz who's the head of critical care within the WHO Emergencies Program who has worked tirelessly with many other people, both at WHO and around the world, to get people to cooperate, assimilate data, and be able to really create a database that allows patients to get better. I can't thank the three of you enough, your co-investigators, and the efforts, and thank you for bringing the papers to JAMA. Take care.

>> Jonathan Sterne: Bye, everybody.

>> Howard Bauchner: Bye-bye, everybody. Please stay healthy.

>> Janet Diaz: Bye. Thanks so much. See you.

>> Todd Rice: Thank you.

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