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Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
[00:00:00]
[00:00:07] Erin: Hello, and welcome to "Breakpoints." My name is Erin McCreery, and I'm the senior director of infectious diseases strategy at UPMC and a clinical associate professor at the University of Pittsburgh School of Medicine. Today, we are bringing you the fourth collaboration podcast between Communicable and "Breakpoints," the Society of Infectious Diseases Pharmacists podcast.
[00:00:26] Josh: Hi, and welcome back to Communicable, the podcast brought to you by CMI Communications, ESCMID's open access journal covering infectious diseases and clinical microbiology. My name's Josh Davis, and I'm one of the editors at CMI Communications and an infectious diseases physician at John Hunter Hospital in Newcastle in Australia, and also head of the infection research program at Hunter Medical Research Institute at the Uni of Newcastle in Australia.
and it's great to be doing another one of these collaborations with "Breakpoints." It always really helps our listener numbers for Communicable, which is [00:01:00] an infant compared to "Breakpoints." It's more of a like a teenager.
[00:01:03] Erin: We're so thrilled to do these collaborations, and today's fun because I think the best thing we do is get together and talk about trials.
I've been doing this for almost 10 years, which is insane to me, I was thinking about that the other day. But unpacking the latest and greatest trials will never get old, especially with you gentlemen, which is such a pleasure. So today, we're gonna discuss the results of a trial that is quite a hot topic right now, the oseltamivir for critically ill patients with influenza domain of the REMAP-CAP trial.
The trial was stopped by the DSMB on March 13th, 2026, stating the five-day and 10-day arms had met the trigger for inferiority for adults."
These results were presented at the Critical Care Reviews conference in Belfast in June this year, and it's generated quite a bit of controversy and quite a bit of discussion, so we're excited to talk about it today.
The preprint of the manuscript is available online with The Lancet as is the video of the CCR presentation. So I think this is, in general, just a very wonderful thing the critical care community [00:02:00] does, is you can go online for free public access and watch these presentations in real time. So see not only the presentation by the authors but also the audience dialogue and questions.
[00:02:10] Erin: So we're lucky today to be joined by two guests who can take us behind the scenes and help us understand what these results mean for clinical practice. So first, I'd like to introduce Professor Steve Webb. I think this is Steve's Communicable and "Breakpoints" debut, so we're so excited to have you. Steve is an intensive care specialist in Perth, Australia, and a professor of critical care medicine at Monash University in Melbourne.
Steve led the establishment of the REMAP-CAP trial at the beginning, the whole infrastructure, and he continues to be a member of the International Steering Committee and a member of the design team. Steve, welcome to "Breakpoints" and Communicable.
[00:02:45] Steve Webb: Thanks very much, Erin. Uh, wonderful to be doing the double header
[00:02:48] Josh: And I'm pleased to introduce a friend of the show, or both shows I guess, and a friend and colleague of mine, Professor Stephen Tong.
He goes by Steve though, so it's gonna be a bit confusing to have two Steves here. Do you want us to [00:03:00] call you Stephen Stephen or Steve Steve?
[00:03:04] Steve Tong: Sometimes we do
[00:03:05] Steve Webb: Steve W.
[00:03:05] Steve Tong: and Steve T., don't we?
[00:03:07] Josh: Yeah.
[00:03:08] Steve Webb: Yeah.
[00:03:08] Josh: Okay.
[00:03:08] Steve Webb: Well- Don't, don't call me Stephen, Josh. my mum's the only person who ever did that.
[00:03:12] Josh: Yeah. So that's like me, Joshua. It's only when I'm in trouble with my mum. so Steve T. is an infectious diseases physician at the Royal Melbourne Hospital in Melbourne, Australia, and he's a professor of infectious diseases at the University of Melbourne. And Steve also co-leads the ASCOT trial, which we might hear a little bit about later, but is also about COVID and flu
[00:03:34] Steve Tong: Hi, everyone.
Great to be back.
[00:03:36] Josh: Okay. So as our listeners know, we like to start these episodes with a get-to-know-you icebreaker kind of question for our guests and also for our hosts. because the Football World Cup was happening in North America at the time the results of this trial came out, in honor of that, today our question is: Tell us about one of your most memorable sport watching experiences.
Steve Webb, do you wanna go [00:04:00] first?
[00:04:00] Steve Webb: Josh, I love an underdog coming from behind, and I also love the amazing game of Australian rules football. And if you're watching this in any country other than Australia, just find it on YouTube and watch it for a couple of minutes because it is truly spectacular.
I support the Fremantle Dockers, but I'm actually going to, relay a story about, St. Kilda. they're a side that's had their mixed fortunes over many years and, they were playing a game last season. They were down about 50 points, which is, uh, regarded as an unassailable, lead, and they kicked about eight goals, in a row in the final quarter.
they kicked a goal to take them within striking distance of winning the game with eight seconds left on the clock, and remarkably, they scored another goal inside that eight seconds, which is almost unheard of
[00:04:55] Josh: Yeah, AFL is such an exciting game to watch, so please, those in Europe, [00:05:00] North America, and elsewhere, do as Steve W says and-- just don't mention the Sydney Swans, please, at the moment.
which is my team that's been in, embroiled in a scandal lately. Steve Tong.
[00:05:10] Steve Tong: So I've been to a couple of World Cup cricket games, not soccer or football. So in 1992 at the MCG, England versus Pakistan, and then in 2020, so this was memorable. This was the Women's World Cup final. There were 80,000 people there at the MCG in February, and this was the last large public gathering before the COVID pandemic.
So the following weekend was the Grand Prix, and that got canceled. But this one match, 80,000 people to watch the women play cricket, uh, was fantastic to be there with my daughters. And then picking up on the AFL theme, early this year I went to the Geelong-Hawthorn Easter Monday match, so it's a yearly match.
Geelong's largely had it over Hawthorn over the years, really close game again. Hawthorn won by one point at [00:06:00] the end, and it was just amazing to share that with, again, 80,000 people there with my two kids.
[00:06:05] Josh: Okay. Erin, turning to a sport that the rest of the world might understand that's not AFL or cricket
[00:06:11] Erin: What are
[00:06:11] Josh: yours?
[00:06:12] Erin: You know, guys, I've been to Australia twice, and I've been to zero AFL games, and I think that's
[00:06:17] Josh: your fault. You'll have to remedy that. I think you were here in the wrong season maybe.
[00:06:20] Erin: Probably. Probably. I loved this question. I'm a big sports gal. So my hands down, bar none, most memorable sports moment, is the Kerri Strug vault in the 1996 Olympics.
That was the Atlanta Olympics. She was part of the Magnificent Seven United States gymnastics team, and they were in the, team all around, and she was the last person to vault, and she was the best vaulter. So it was like, United States has got gold. She went, no problem. And she does her first vault, and she broke her ankle or twisted her ankle or sprained her ankle and landed on her butt, and they were like, "It's over.
There goes the gold. No way she can do the second vault." She got up with a broken ankle, foot, [00:07:00] whatever, what have you, and vaulted, stuck it perfectly, and they won gold. And Bella Karoly, like, carried her to the medal stand 'cause she couldn't walk, and she was sobbing. Whenever I think I can't do something or I get sad or I feel overwhelmed, I watch that on YouTube, I've easily seen it seven million times, and, it's just a really powerful moment, and all the subsequent commentary that's gonna come in our comments about US gymnastics and the coaching, we know it was terrible. It was awful. We didn't know it at the time, and it doesn't take away from what Kerri Strug did.
so that is a moment. And then because you guys said two, I'm gonna say two. I went to Auburn University in the United States. It's in Alabama. They're a big American football school, and they have a big rivalry with Alabama. and every year they play in a match called the Iron Bowl, and it's always a wonderful match even if, you know, doesn't matter how good or bad either team is.
And in 2013, that match came down to Alabama was about to kick a field goal to win the game, and it landed in the end zone, and the Auburn player ran it back [00:08:00] 100-plus yards, and it's called the Kick Six. It's, like, one of the greatest moments in American sports history when you watch, like, ESPN reels.
And I was there in the student section, I will never forget that feeling. I will be 90 and have Alzheimer's, and I will never forget the feeling- ... of being in that stadium when they returned that ball and we won the game, and it was absolutely insane wild. And if you're at, next ESMID, I will show you the videos on my phone 'cause It was amazing
[00:08:26] Josh: Look forward to it.
and just to cap this off, mine is not so much about the sport itself, it's about the, people watching the sport. and this was the World Cup soccer final in, 1998, and I was traveling in Ecuador at the time. and, Ecuador obviously weren't in it. It was France versus Brazil. But the whole country really ground to a halt, even though it happened to be on the same day as the Ecuadorian presidential election.
and they had, at the time, really strict laws. they were one of the few countries besides Australia to have compulsory voting. [00:09:00] and they also have a thing called "La Ley Seca," the dry law, the no alcohol allowed on the whole weekend leading up to the presidential election. Despite that, so many people got drunk, partying on the streets, didn't go to the election to vote, were just watching the World Cup soccer final. It was like a massive party atmosphere and even though Ecuador weren't even playing, and that's when I realized, man, Australians think we're sport mad.
Compared to, South Americans, we're not. I think France won. I can't even remember who won the game. But anyway, so that was fun. Now, before we start properly, let's do some conflict of interest declarations so one is that along with, Steve Tong, I co-lead the ASCOT trial, which is a, different trial that , has been looking at COVID treatments.
and I'm also on the antiviral working group of the REMAP-CAP trial, but I had minimal involvement in the part of REMAP-CAP that we're talking about today. Erin, how about you?
[00:09:57] Erin: Yeah. I served as the US pharmacist lead for [00:10:00] REMAP-CAP starting in March of 2020, going through about the end of 2022, so largely all of the COVID related domains.
I can assure you, even with my involvement in the trial, I am still just as confused and intrigued by the conversation of adaptive randomization, the Bayesian modeling, and all the platforms just as much as our listeners. So we're along for this ride together, and I also have not been involved with the trial since about the end of 2022, so did not have any involvement in the oseltamivir domain.
[00:10:27] Josh: Steve Tong
[00:10:28] Steve Tong: Yeah, as mentioned, I co-lead the ASCOT trial, which is for ward-level patients, hospitalized with influenza and other acute respiratory tract infections. And partly because of that, I also sit on the International Trial Steering Committee for REMAP-CAP. So I've been previewed to some of the discussions as the results we're discussing today have been revealed.
[00:10:49] Josh: And finally, Steve Webb.
[00:10:51] Steve Webb: I obviously have, a very substantial conflict of interest with, REMAP-CAP, itself. I wrote the protocol, and, sit on all of [00:11:00] the, domain-specific working groups, as well as the International Trial Steering Committee. I'm quite intellectually invested in adaptive platform trials.
I'm an investigator on about another, eight or nine, platform trials. but also importantly, I'm an executive director of a company called Empiric Health, which is aiming to develop workflow automation technology to permit adaptive platform trials to scale
[00:11:23] Josh: in Australia and probably further afield, we think of Steve Webb as like the godfather of adaptive platform trials.
now put- We think that
[00:11:30] Erin: in America too.
[00:11:31] Josh: There you go. It's probably global. so today we're gonna be talking all about oseltamivir.
I don't know why a lot of people have trouble saying that and they just call it Tamiflu, but A, we're not gonna use brand names, and B, it's not hard to say.
So oseltamivir, Erin, can you remind us what it is and what the current recommendations are?
I sure can, and I'm laughing 'cause Josh is like, "Be better. Pronounce the words right." And I'm about to say some hard words, so bear with me. So oseltamivir is a neuraminidase [00:12:00] inhibitor, and it works by interfering with the release of progeny influenza virus from infected host cells by blocking sialic acid residue cleavage.
[00:12:09] Erin: So that's kind of like a fancy way to say that, virus gets made and packaged, but then it prevents that kind of end release step, which I think that's important 'cause when we talk about effective treatments for other viruses, if you're stopping that late in the game, it's typically a lower barrier to resistance and not as effective as antivirals that work either earlier or have dual mechanism, right, and are attacking the synthesis of viral RNA or DNA at the beginning.
So just food for thought, but that's how it works. It was approved by the FDA for the treatment of influenza in children and adults with uncomplicated acute illness if they're symptomatic for less than 48 hours, so that is at least the American approval. But the guidelines have driven use for quite some time.
So the guidelines, the WHO recommends oseltamivir for suspected or confirmed severe influenza. it says give it and [00:13:00] the duration can be longer for severe disease, which is somewhat nebulous, but that's what they say. not only are they like give it to critically ill patients, but give more if they're really sick.
And then the IDSA says start antivirals as soon as possible for adults and children with documented influenza who are hospitalized. So that's what we're working with going into ReMAP-CAP.
[00:13:20] Josh: Okay. So Steve Tong, can you tell us briefly what evidence already exists or existed before REMAP-CAP from randomized trials of influenza in hospitalized patients, either in the wards or ICU?
Thanks, Josh. I will start by saying that there is quite a lot of randomized controlled trial evidence for out in the community. So for either post-exposure prophylaxis where it's been shown to be effective, or for community-acquired and community-onset, influenza, where, you know, depending on which meta-analysis, it seems to reduce duration of symptoms by sixteen or eighteen hours.
[00:13:56] Steve Tong: So not a large effect, but a measurable [00:14:00] effect. In terms of on hospital wards and in intensive care units, it's very, very limited, to be honest. I think perhaps it's zero patients in intensive care units, and there's been about seventy patients in ward-level patients. There's been a few more patients with other antivirals like peramivir, which is in the same class.
But in terms of oseltamivir itself, it's about seventy patients. So very, very few.
[00:14:24] Josh: So that's seventy, not seventy thousand, right? Seven zero.
[00:14:28] Steve Tong: seven zero. So all our guidelines have recommended this treatment based on such limited evidence is kind of just, remarkable if you ask me, with how broadly these agents are being used.
[00:14:40] Erin: Watching the CCR presentation, I think it was funny the presenter had a slide that said, "RCTs for severe critically ill patients," and it was just blank, and it's like, "This slide is intentionally left blank." I always like when we are brought to that awareness point
[00:14:54] Josh: Okay. So moving on to the REMAP-CAP trial, Steve Webb, many, [00:15:00] probably most of our listeners will be aware of it, but for those who aren't or those who, don't remember the details, can you just tell us a bit about what REMAP-CAP is, where it came from, and so on?
[00:15:10] Steve Webb: Sure. Josh, it's an adaptive platform trial, and that's got certain design features, that I'll cover in a few moments. but I think it's also important to think about the reach, of REMAP-CAP. it's randomized in, about 30 countries, and over the journey, there's been more than 350 sites that have participated, in REMAP-CAP.
So it's global, and it's, quite extraordinary infrastructure that's been, created over time. it's a multi-domain, Bayesian adaptive platform trial, and what that means is that there are many different questions that are being evaluated simultaneously, and indeed, a single patient can be, randomized to, more than one question.
the record is, one patient receiving seven, randomized, treatment assignments. and [00:16:00] so that creates, efficiency, and the logistical side of it means that new domains can be launched, relatively, quickly. a domain being the equivalent of a sort of a standalone trial within this platform structure.
And during the pandemic, REMAP-CAP was able to launch, at times, a new domain, about every, four weeks. So, if you look at all of the pairwise comparisons that have ever existed or still exist within REMAP-CAP, it's the same as 88 standalone two-arm trials. And it uses Bayesian statistics, which, permits validly to undertake frequent, interim analyses.
And at those interim analyses, the results as they exist at that time are compared against, pre-specified statistical triggers for, elements like, superiority or effectiveness or futility, or inferiority. And what that means is that the trial is fairly efficient in its use of [00:17:00] sample size because each question that's being evaluated, terminates as soon as there's sufficient statistical confidence, not with a pre-specified sample size, which may or may not have been enough patients.
[00:17:13] Josh: And it started off focusing on community-acquired pneumonia, right? the CAP part. and then you've pivoted to COVID and now influenza and other acute respiratory infections.
[00:17:24] Steve Webb: correct. It was always set up, it started in about 2017, intended to be able to pivot and adapt in the event of a, a pandemic.
but since then, it's expanded to, all types of, respiratory tract infection, not just, community-acquired pneumonia.
I was just gonna say, I was looking at the REMAP-CAP website today, and as of August twenty-fourth, twenty twenty-six, which is when we're recording this episode, twenty-seven thousand four hundred and ninety-three patient randomizations, sixteen thousand two hundred and nineteen total patients, and two hundred and forty active sites currently, which I know you said at one point there were even more than [00:18:00] that, which is just truly stunning.
[00:18:01] Erin: I mean, that's, that's incredible. That's a lot of patients. And I think the one important point I just wanna highlight for our listeners as we go into talk about the influenza domain is that and Steve Webb keep me honest, that prior to December of twenty twenty-two, patients with suspected or confirmed influenza were enrollment eligible, but then in December of twenty two, the steering committee made the decision to update it to flu confirmed only.
Is that correct?
That's completely correct. the rationale had been that, in large part as a consequence of COVID, rapid molecular testing for, respiratory viruses had become, widely available. And so there was a protocol change at that time to, modify the inclusion/exclusion criteria so that from that time only, it recruited only patients with confirmed influenza.
[00:18:54] Steve Webb: Prior to that, there's a mixture of suspected and confirmed.
[00:18:57] Steve Tong: It's quite interesting when you look back at the [00:19:00] cumulative enrollment curves, most of the enrollment actually comes after 2022, doesn't it? Obviously, during the COVID lockdown periods, there was very little influenza around.
Hmm. Yeah, lots of, infectious diseases kind of disappeared then, right? so yeah, turning to the antiviral influenza domain, apart from the flu testing we talked about, what are the other eligibility criteria and what were the interventions?
[00:19:25] Steve Webb: So in, this particular part of, REMAP-CAP, obviously patients first had to, be platform eligible, which required them to, have, severe community-acquired, pneumonia.
but within the domain, the, predominant, eligibility requirement were that, for patients over the age of 12, who had to be admitted to an ICU with confirmed influenza and they needed to be needing, organ failure support, but couldn't have been, receiving organ failure support, for more than 48 hours.
[00:19:57] Steve Webb: And organ failure support is just invasive or [00:20:00] non-invasive ventilation or high flow oxygen, and/or, vasopressors for shock
[00:20:04] Josh: Mm-hmm. And, what about exclusions?
[00:20:07] Steve Webb: The major exclusion criteria were that death was imminent, or the treating team were not committed to full active treatment.
the patient had received more than one dose of oseltamivir, already. there was a clinical decision to commence an antiviral other than oseltamivir or baloxavir, or, the treating clinician believed that participation in that domain was not in the best interests of the patient.
[00:20:31] Josh: Yeah. So pretty pragmatic, like a small list of exclusion criteria.
[00:20:36] Steve Webb: Correct. and, the E in REMAP stands for embedded, and the intention here is that they're inclusion/exclusion criteria that can be interpreted by, clinical staff 24/7.
[00:20:48] Josh: Mm-hmm.
[00:20:49] Erin: And I just wanted to point out, you do have children less than twelve and moderately ill patients are in the platform at large.
They're in Remap CAP and other domains, but they're not included in these [00:21:00] particular results for this domain.
Correct. So those strata continue to recruit, but they did not hit a statistical trigger, and no conclusion can be drawn about those groups.
[00:21:12] Josh: Mm-hmm. And then still on the flu domain, what were the interventions or the arms that you were testing?
[00:21:18] Steve Webb: so, there's a, quite a number of, interventions. there's, a no antiviral domain, intervention, which is provided on, the basis of, it being open label. there's oseltamivir for either five or ten days, uh, baloxavir or the combination of baloxavir with either five or ten days,
of oseltamivir. sites can choose whichever interventions from that menu that they wanna participate in, but the five-day oseltamivir was mandatory and serves as the, intervention that provides continuity, for, the comparisons that are made, within the domain. [00:22:00] interestingly, a substantial number of sites chose not to participate in the no, antiviral, intervention.
the thinking at the time that this occurred was that it was, going to be difficult to, specify that as, a mandatory control arm. a lot of sites would not have had equipoise to participate in that, and it was felt to be better to just have sites participating, in the domain, even if they weren't participating in the, uh, control arm.
[00:22:29] Josh: Okay. So there were six arms in this part of the trial, but we're only talking about three of them in the publication that you've reported on that we're discussing today, right? The oseltamivir, five or ten days, and no antiviral.
[00:22:42] Steve Webb: Correct.
[00:22:43] Erin: All right, let's get into results then. It's what we're all waiting to hear if you haven't read it already. So, Steve, can you please walk us through what, what you found? How many patients ended up enrolling, and what did you see?
[00:22:54] Steve Webb: Sure. the numbers have bounced around very slightly, over the last, couple of months. The [00:23:00] initial, results that were presented at CCR, have had a couple of patients identified for whom, consent, had been, withdrawn.
the final sort of numbers then I think 572, with suspected or confirmed influenza within these three, interventions, of whom, 442 have been, randomized, with confirmed influenza, which represents 162 patients, receiving the five-day oseltamivir, 156 with the 10-day oseltamivir, and 124 with the, no antiviral.
[00:23:39] Steve Webb: So at least by the measure of many ICU trials, this is a relatively small, sample size.
[00:23:48] Erin: When I was watching the presentation, people, some questions in the audience said, "This is relatively small," and I was laughing to myself because before Steve and Josh started doing their thing with SNAP, I mean, this is 400 patients in an ID trial.
We'd be like [00:24:00] singing praises and so excited. So I was like cracking up. People are like scoffing at 400 patients, but you know, it's 100, 120 to 160 patients in an arm, and nowadays we have the luxury of saying that that's relatively small, which is fascinating to me.
we've come so far.
[00:24:16] Josh: And remembering that there were 70 patients in total randomized hospitalized patients before this.
[00:24:21] Erin: Prior to this. Exactly. That's what I'm saying. -
I think Erin, it's also worth making the comment, that, sample size can only be interpreted, in light of, the size of effect sizes, which are obviously unknown before a trial starts. but I'm fond on ward rounds of, making the comment to, registrars, that we probably wouldn't need a very big trial to demonstrate that penicillin worked for, pneumococcal pneumonia back in, 1945.
[00:24:47] Erin: You're absolutely right in that. So this trial, what was the primary endpoint? What were your key secondary endpoints before we give away the results?
[00:24:55] Steve Webb: Yeah. The, primary endpoint is 90-day all-cause mortality.
and [00:25:00] I think many in, critical care would regard this as the, gold standard, for, trials that enroll, critically ill patients. it's the proportion of patients, alive, uh, after 90 days of follow-up. it's insensitive to the, mechanism, of death. and the reason 90 days is important is if you look at survival curves of patients after critical illness, 90 days is approximately the inflection point between a period where there's a steep decline in, mortality, and it flattens out somewhat.
And of deaths that occur by 90 days, about 10 or 15% will have occurred after the first hospital discharge. So there's still a sizable amount of mortality that's lost if, an endpoint is censored at hospital discharge. The key secondary endpoints, which I think are of very much, reduced importance, once, mortality has been considered, included, days free of respiratory or other, organ [00:26:00] failure support for patients who weren't, intubated at, time of enrollment, progression to need either invasive ventilation, ECMO, or who died.
and then, important endpoints related to, ICU and hospital, length of stay as well as SAEs. in these, results, it's important to understand the direction of the treatment effects. better patient outcomes are reported with an odds ratio of less than one, and odds ratios greater than one, indicate that the direction of travel is towards worse, outcome. There is a pre-specified, trigger, within the, master protocol, to deem a treatment futile
Futility is defined as a greater than 95% probability that there's less than a 20% improvement, in the odds ratio.
So it's important to realize that the futility trigger is not saying that recruitment was futile or the treatment is futile. It's [00:27:00] just evidence that there isn't a large or clinically meaningful, improvement.
[00:27:05] Erin: So before we get into describing what table one ended up looking like after randomization, just very briefly, I'll state for our listeners that in this Bayesian model and in the platform, it does adjust for covariates for patients across the platform, so age, sex at birth, country, site, well, it's site nested within country, eligibility for no antiviral therapy, disease severity including need for mechanical ventilation, time of enrollment, and other randomized treatments.
And then there were pre-specified subgroups of immune compromise, patients with bacterial co-infection, duration of symptoms prior to randomization, and baseline shock. Duration of symptoms prior to randomization, every time we talk about that, it gives me COVID nightmares and PTSD because, you know, for a while, we were allocating remdesivir, which, therapies we thought were maybe life-saving based on these symptom durations.
And I mean, we've all taken care of patients. No one knows when they started their symptoms. You go to the ED, you're like, "I think I've been sick since [00:28:00] Sunday." And it's the most subjective thing in the history of the world, unless you've been sick for exactly five hours, and then you know, right? And so we really struggled with, like, should we go on symptoms, which is very unreliable even amongst reliable patients, or should we go on test positivity date?
Because that's objective, but I mean, it's often you're not getting tested for a few days and so that... It's always challenging with viral trials, so.
[00:28:23] Steve Webb: Erin, I want to make the point the covariate adjustment is, quite a bit more important in Remap-Cap than it is in many trials.
And that's because of a subtlety related to the method of randomization. Many trials are either stratified, by site or, use block randomization, but for reasons related to the application of response adaptive randomization that I won't go into, neither of those, randomization elements are utilized in Remap-Cap, and it will tend to result in greater variance at baseline than, we're used [00:29:00] to in most clinical trials.
So the covariate adjustment then, has, additional importance.
[00:29:05] Erin: I'm so glad you explained that because I do think we saw some differences in that, you know, quintessential table one of baseline variables amongst randomized patients, which we're not used to seeing, right? And when we randomize, we are used to seeing them be pretty darn similar.
But we saw some differences here, so can you walk us through the baseline characteristics and some of the notable differences between groups that listeners should be aware of?
[00:29:27] Steve Webb: Yes. of course, those differences that do exist, have arisen, by chance because, the patients have been randomized.
But they move in, both, directions in terms of, potential impact on, results. the control arm has, lower severity of illness. There's less mechanical ventilation, higher, uh, PF ratios, less, uh, pressor support. but also age, which is an incredibly important, independent, variable associated with outcome, is older in the no oseltamivir, [00:30:00] group.
as I said, I think we acknowledge, the, amount of difference, the variance of difference is greater than we're used to seeing in a, 450-patient, uh, trial. but they go in both directions and, the covariate adjustment, which is pre-specified, serves to, a-adjust appropriately for those differences.
[00:30:20] Erin: For sure. Yeah. They are important, though. I think some other notable ones that were called out were more patients that did not require supplemental oxygen in the control arm, less women in the control arm, less diabetes and renal impairment. But on the flip, your 10-day arm had higher APACHE II scores, more invasive mechanical ventilation, more vasopressor use, as you said, and higher extended SOFA scores.
I think the other important thing, and keep me honest here because you would know best, is that the REMAP-CAP platform did a response adaptive randomization over time, which meant that you would be more likely to be randomized to the arm that was seemingly showing the greater benefit to [00:31:00] patients.
However, in 2024, you reverted to a balanced randomization strategy. Is that correct? And can you kind of explain that?
[00:31:09] Steve Webb: Correct. I'm not sure. I'd need to check if it was at the time of the protocol amendment in 2022 or 2024. it may well be that, we made some adjustments to the application of RAR in 2024, and if it was in association with that, it will be because we had observed some unfavorable, characteristics from the application of RAR, uh, in other domains.
And, where, more than six months was going to occur without a, interim analysis, randomization proportions, reverted, to balance. It may also have occurred because of, a desire to avoid, extreme randomization proportions, which we'd observed in other domains to have, unfavorable, [00:32:00] characteristics, in the platform.
but, there certainly will have been some period of time in which RAR was applied.
[00:32:06] Erin: Awesome. Thanks for explaining that. I think that's important for, listeners to know, especially those of us who enrolled in the trial understood that at the beginning, especially in 2020, but that changed over time.
Okay, the time has come. Ready? Drum roll. What were the 90-day mortality results?
[00:32:22] Steve Webb: I just want to, before we actually give those, Erin, talk about how in the ANZIC CTG, in Australia, when we are normally presenting, the very first results of a completed phase three trial, we always have show of hands in the room as to what people believe the results, are going to be.
And it's a great pity that we didn't get the opportunity to do this, with this, particular trial. a lot of people had priors that oseltamivir might have been ineffective. but I think there were relatively few people who would have, expected the results, to indicate a probability of harm.
But, [00:33:00] the headline results are that, in the five-day oseltamivir group, the 90-day mortality, was, nineteen point eight percent and nineteen point four percent in the 10-day oseltamivir group, but only thirteen point seven percent in the patients who had been randomly assigned to no, antiviral.
so the crude mortality, difference is substantially in favor of, no, antiviral. And then the adjusted odds ratios, for those results are an odds ratio of two point one three for the five days of oseltamivir and two point one seven for the 10 days of oseltamivir, compared to no antiviral.
[00:33:45] Steve Webb: And you'll remember that, odds ratios greater than one are moving in the direction, uh, of harm. The, um, probability that the odds ratio is greater than one,
which is a one-sided, evaluation, is [00:34:00] ninety-eight percent for five-day oseltamivir and ninety-eight point two percent, for 10-day, oseltamivir
Yeah. Wow. I mean, not the results you were expecting when people were allowed to say, "We're not gonna enroll to control.
[00:34:13] Erin: We feel so strongly that we're just gonna enroll to five to 10." So really, really fascinating results. I think the direct conclusion was in critically ill patients with influenza, treatment with oseltamivir was ineffective in reducing 90-day mortality compared to no antiviral and had a high probability of harm.
And I think you guys did run an analysis where the results were restricted to the sites that had the control arm available, and when that was done, the odds ratio actually got higher. So, I think the presenter said this even confirmed the robustness of the results and across all those pre-specified subgroups and other subgroups, these results were consistently shown.
So,
[00:34:51] Steve Webb: I think that's an important, sensitivity analysis. The, um, results that I, ran through, include patients who are [00:35:00] randomized to five or 10 days of oseltamivir at sites that didn't have control. And everyone, knows and understands, that outcome can be different between, different sites.
It's an independent factor associated with outcome. In some ways, the cleanest analysis is the sensitivity analysis that I'll run through now, in which the analysis is restricted only to patients that were, randomized, to, the three interventions at sites that were offering all three of those interventions.
And as you said, the results are very similar. The, odds ratios are slightly higher, but the probability of odds ratios being, over one are slightly lower, around, 96%, and that just relates to the smaller number of patients, that are being analyzed. But I think that it doesn't really matter which of the two analyses, you choose.
they're both consistent, and I think the headline result [00:36:00] is we can be confident that oseltamivir is not an effective treatment for, influenza in critically ill patients. Whether or not it also causes harm, I don't think we've reached what would be regarded as conventional statistical, significance.
But, the clinically important question has been answered. We just shouldn't be using this drug in the critically ill.
[00:36:24] Josh: Yeah. I mean, I, I totally agree that I think this trial has very clearly shown that there's no benefit of oseltamivir, not only on 90-day mortality, but on any of the secondary outcomes in critically ill patients with influenza.
and my feeling is it has shown that there's harm, or at least that there's enough probability of harm that it would make me reluctant to not only use this drug but do another trial in critically ill patients. however, I think it's really important, and we might come back to this later in the podcast, to point out that this doesn't necessarily apply to other patient groups, particularly [00:37:00] those who are sick enough to be in hospital but not sick enough to need critical care support
[00:37:06] Steve Tong: Yeah, I agree with, all that's been said there.
do note that, Steve Webb, you pointed out this before, that we take an asymmetrical view towards proof for benefit as opposed to proof for harm. So we have a lower threshold to stop a trial when there's a pretty reasonable probability of harm occurring. We don't wanna keep putting patients onto that treatment.
[00:37:30] Steve Tong: Whereas to get a drug registered, for example, to say we should positively be using such a drug, we tend to set a higher threshold. So that might be a ninety-nine percent posterior probability as opposed to a ninety percent probability of harm. So to bring a new drug to market, we want to be very sure that this is an effective drug if we could spend, you know, millions or billions of dollars on that.
Whereas if we're showing something's harmful, we don't need to have quite the same level of threshold of [00:38:00] evidence.
[00:38:00] Steve Webb: Especially in the Bayesian paradigm where, an intervention that's got a high probability of harm, whatever high is, has got a very low probability of being benefit, and the magnitude of that, possible benefit, is, extremely small and not, clinically significant.
[00:38:16] Erin: I wanna ask Steve Tong, a question I think Josh was burning through too, in that a lot of the conversation around this trial release was that the sites were allowed to opt out of the no antiviral arm, right? We've alluded to it, but I wanna specifically come to you, Steve Tong, as a fellow trialist, right?
As someone who thinks really long and hard about these decisions, and then, you know, everyone in the world critiques you, right? And you're doing the best you can with what you have at the time. And the investigators when they presented it, they were very honest about this, which I really appreciate it.
They said, "You know, we thought there was equipoise to do this." other people argued there was not equipoise to not do it, and they said, you know, "Should we have mandated the no antiviral arm? Debatable," is how they framed it. What do you think? [00:39:00] Should they have mandated the no antiviral arm?
[00:39:02] Steve Tong: Oh, it's really hard to mandate things, isn't it?
and, you know, if you were to lose sites participating because of that, then that's, a problem as well, and at least those sites are comparing five versus 10 days, and you're still getting information from that. I don't think it's ideal, but it's a pragmatic choice
[00:39:19] Josh: Yeah. I think it's a really nice example of why the world needs randomized trials, right?
There were a lot of people that said, "I, I refuse to randomize my patient to not get oseltamivir because I just think it works," not based on any RCT data. and time and time again, those sort of attitudes are just proven to be stupid. Like, not, just here. There's lots of trial results that go against what we expect to find, and the consistent, implication of that is we need to do randomized trials
if I can make, the comment, critical illness is a non-evolutionary state. It's only since 1950 that, any, member of the human species [00:40:00] has, been, critically ill, supported, on a ventilator. And so all of the physiology and homeostatic mechanisms have not been, developed over eons, to respond to the state of being critically ill.
[00:40:16] Steve Webb: And I think it's wise to then, as a consequence, not be making extrapolation from randomized controlled trials, conducted in non-critically ill patients to the critically ill.
[00:40:28] Josh: And vice versa.
[00:40:30] Erin: That's very wise. I've never heard that framed that way before. I love learning. That was very insightful. I'm laughing too because you guys are saying like, "Sites refuse to not randomize to nothing." I can't get my ED docs to give oseltamivir to people who have four hours of symptoms who I'm like, "They actually might legitimately benefit here."
I-- You know, people always scoff at like, "Oh, 18- 24 hours of disease reduction in, in the moderately ill outpatients," right? But I'm like, "That's like 20% to 30% of the disease course." That's not [00:41:00] insignificant when you feel like horrendous when you have influenza, right? So it's funny, like it's a very polarizing drug, and I can't get people to prescribe it if I wanted to, so I was laughing.
I'm like, at my site, we would've been like, "We're not randomizing to the drug arm. Like just, let's just add patients that didn't get oseltamivir."
[00:41:15] Steve Webb: Erin, I think there is one other, result that I would like to just highlight, which, I think supports the hypothesis, that the drug probably is harmful in the critically ill. For patients who, were in shock at baseline, the magnitude of the treatment effect, in the direction of harm was greater, than for patients who weren't shocked.
And I think it's a not unreasonable hypothesis. I think there's support for there being a substantial heterogeneity of treatment effect for this drug dependent on the severity of illness at time of, commencement. Steve Tong, chatted about how there is good, evidence of biological and clinical activity of the [00:42:00] drug in patients who've got, mild influenza who are in the community.
as patients get sicker and sicker within the critically ill group, we see stronger evidence, of harm. And somewhere in between, there's a break point and the number one question now about this drug is: Where does that break point lie?
[00:42:20] Erin: Yeah, it's a super good point. And I think one of the best things about this discussion too is the fact that you guys in the critical care space do have this live editorial where you have the CCR presentation and lots of discussion. Josh and Steve, myself, Angela Huettner, and a few others are earnestly trying to start this in the ID space with what we're calling the Clarity Initiative.
Shameless plug, we're having a conference in Malta in November. Everyone should come. We want to build this in infectious diseases, right, where we have this thoughtful dialogue because it's like real-time peer review, and it makes us all better and stronger and think about these things that we might not have thought about.
And so to that point, Steve Webb, one of the comments in the audience from the presentation was, we know antivirals [00:43:00] work better earlier on, for the most part. Do we need immunomodulators later? And what we learned with COVID-19, tocilizumab, baricitinib, are you studying that? And it, it seems like you are, that that is in REMAP-CAP, um, for influenza, but there's not results for that yet.
So that's great to know. The other thing that came up that's important is the use of steroids wasn't really articulated in these results, and steroids and pneumonias is very controversial. Lots of RCTs going one way or another, but I think that's an important confounder that wasn't discussed. and then the last thing that the audience brought up that I thought from an editorial perspective was interesting is you guys did not, include flu vaccination status because that was not able to be collected reliably, and that's super fair.
And, you know, based on time of enrollment and seasonality of vaccination, that would get really, really, really messy. So that's not in there either, but, you know, potentially important in terms of disease severity, right?
[00:43:53] Steve Webb: Absolutely in terms of the steroids, there are patients who have been randomized within [00:44:00] REMAP-CAP within these set of results to different steroid regimes, but we're not yet in a position to, evaluate the, the cross tabs between steroid and, oseltamivir, exposure.
that'll be a small number of patients, and obviously there will be some patients in these results, relating to oseltamivir that have, received steroids or not received steroids, uh, based on, um, the preference of the treating clinician.
[00:44:28] Erin: For sure. The last point I'll make, and then Josh, handing it over to you for our next question, is that it-- this was brought up, which again is something I hadn't really thought of but I think could be compelling, is that the sites that chose to not enroll in antiviral-- into no antiviral, so no control, they just did five versus 10 days.
Those sites, those practitioners in those ICUs, they believed so much in Tamiflu having a benefit-- Sorry, oseltamivir,
a- Ha.
I know I did it, oh my gosh. So they believe so much in oseltamivir having [00:45:00] help, right, for their patients that potentially they provided varying supportive care practices and like, you know, dare we say less, right?
And so there's also kind of like that interesting philosophy about like how people choose to manage patients, and you can't ever quantify that or put that on a data sheet, but I think it's something to consider.
Yeah, I think I'd be surprised if, the, amount of support provided to a patient was not determined by anything other than the, level of physiological, derangement.
[00:45:29] Steve Webb: I'd be surprised if it was influenced by, concomitant, adjunctive treatment decisions
But can't be excluded.
[00:45:37] Josh: Hmm. Okay. Well, we've talked a little bit about ICU versus ward level patients with influenza and, and what these results mean. Steve, given that you work primarily with patients admitted to hospital wards, thinking about flu patients, do you think these results apply to ward patients?
And what are you going to do, like, tomorrow when you get [00:46:00] your next severe flu patient on the ward?
So this was a theoretical question for me until a week ago, and I've been on clinical service, and I've had two patients where this question's come up. the first patient was a person in their sixties with diabetes who'd presented with, flu, was flu A positive on the swab, and they were on high flow nasal oxygen.
[00:46:19] Steve Tong: And I got the call, saying, "This patient, we're getting them assessed for intensive care unit. Not sure if they're going there or not. Uh, should we give oseltamivir?" And the patient's, onset of symptoms was probably between forty-eight and seventy-two hours prior to the time of this phone call. and so I was in a bit of a quandary, actually, and kind of ummed and ahed.
And of course, our hospital guidelines haven't changed yet. They're saying give oseltamivir to everyone. and in the end, kind of sat on the fence a little bit. I said, "Look, if she gets assessed and is going to ICU, please don't give oseltamivir. If she's not so sick to go to ICU and stays on the ward, I'm happy for you to follow the hospital guidelines."
[00:47:00] so ended up that she did go to ICU, and she didn't get oseltamivir, based on the results of this trial. Now, I don't know if my answer was right if the patient had stayed on the ward or not, but I just thought at the time, what influenced my decision-making was it was still reasonably early, from the time of symptom onset.
So I think if they had said, "This is five days since symptom onset," I would have said, "Don't give it." But because they were still kind of within that window, I thought that was reasonable, and it's also still within our hospital guidelines. and then we, know, yesterday had a similar patient who was pregnant with flu, was in ICU, and we decided not to give, oseltamivir.
So, for most ward patients, previously, I had said, "Look, if they're , unwell enough to be hospitalized, I think you should give oseltamivir." I think I've changed my tune on that, and I'm taking into account that time from symptom onset a bit more, having greater importance in that decision-making now.
And so if it's early, I'm tending to give probably, and, if it's later, I don't think I would. [00:48:00] But my other answer, I often give talks about staph at least, where one of my first slides is, do you choose treatment A or B as a multi-choice thing? And they're the kind of options I give. But then I provide a third option, which is randomizing a clinical trial.
So if we have the trial up and running, I think that should be the correct answer.
[00:48:19] Josh: Yeah, I think I'm similar to you, Steve. I'm probably a little bit more in favor of using oseltamivir in these patients from discussions we've had before. I've been on general medicine in the last month, and the flu season in Australia, we're seeing a lot less flu this year than we did last year and the year before, but it is just starting to tick up in the last week or two.
I had two or three patients who I had to make that decision on. Two of them, it was easy. They'd been sick for a week, so I didn't give them oseltamivir. The third one was probably within, you know, two to three days, and I did give them oseltamivir. None of them were, you know, critically ill or even heading in that direction.
[00:48:56] Josh: but you know, they were unwell enough to need hospital admission. But yeah, the [00:49:00] bottom line is, personally, I have equipoise. I think it might work and it might not work, and I'd be happy to randomize them. it's good to remind ourselves that when we run a randomized trial, we're not trying to prove something works or doesn't work.
We're just trying to answer the question about whether it works or not.
[00:49:16] Erin: Best thing you can do for the patient in front of you and all subsequent patients, right? So I think, you know, I was very much raised in the school of learning while doing and by you guys, so I very much am a randomize if possible, which is a nice segue into, Steve Tong first, and then Steve Webb, we'll come to you.
Are there any ongoing or planned trials enrolling ICU and/or ward patients with influenza? I know we've alluded to a few perhaps already.
So REMAP-CAP does have an oseltamivir arm in ward-level patients, so that continues. and we, we're seeking funding to try and expand that further to, recruit more patients at more sites.
[00:49:53] Steve Tong: My understanding also is the RECOVERY trial in the UK, is also recruiting patients with [00:50:00] influenza and randomizing to oseltamivir or no oseltamivir. I think that still includes critical care patients as well, but definitely includes ward-level moderate patients.
[00:50:10] Steve Webb: RECOVERY does include critically ill patients, but, the vast majority of its, recruitment is, ward-based.
additionally, if I understand the design of RECOVERY, correctly, for patients who have not received oseltamivir, there is the option of an oseltamivir versus no oseltamivir randomization. and then all patients are eligible for baloxavir. it'll be interesting to see, whether, the number of patients, being randomized to oseltamivir versus no oseltamivir increases now, uh, in RECOVERY.
My understanding had been there'd been relatively few patients who'd been randomized at that level, thus far in RECOVERY.
[00:50:53] Josh: Okay. So thinking about, implications for clinical practice, we've talked about in individual patients. What about [00:51:00] guidelines? So Steve Tong, what do you think our clinical guidelines should say now for ICU and ward patients with influenza?
I think it's pretty clear for ICU based on these results. we shouldn't use oseltamivir, and I think that should be what the guidelines say.
[00:51:17] Steve Tong: for ward-level patients, I find this a lot more difficult. I, actually think our guidelines should have, acknowledgment of the lack of evidence one way or the other here. that's tricky though, when, you know, we usually need guidelines to tell someone who's at their bedside what should you do in this instance.
I am genuinely, unsure of what my answer there should be. if, to reflect my clinical practice, I would take into account the symptom duration and, have that play a role in that guideline. but outside of that, I
[00:51:48] Steve Tong: I would probably err towards saying don't give it more than give it if I were to put it into guidelines. But I would encourage, randomization in a clinical trial.
[00:51:58] Josh: Yeah. The guidelines the [00:52:00] Australian Living Evidence Consortium has updated their flu guidelines recently, and it says, "Do not use in critically ill people," but on ward patients, it's got an only in research recommendation.
So that kind of isn't recommending or not recommending it, it's saying, "Don't use it unless you're enrolling them in a trial." Steve Webb, what do you think guidelines should say?
Well, it's wonderful to hear that the living guidelines have made a, in research, recommendation. I do think, writers of guidelines have missed an opportunity for decades, where evidence is uncertain to make a recommendation that is explicitly, if there's a randomized controlled trial, we recommend enrollment.
[00:52:39] Steve Webb: and if there isn't a randomized controlled trial, this is, our, alternative, recommendation. because I think that would, very much help, equipoise, and enrollment in trials. It would, of course, be a wonderful thing to be able to put in grant applications that international guidelines recommend, that this is a question suitable for [00:53:00] randomization
[00:53:01] Erin: All right. Before we get into our closing segment, I want to end with, I guess a, a provocative question, but not really, because the results are what the results are. But if oseltamivir has a potential to cause harm in critically ill patients with influenza, why? How? What's the mechanism, right? Because I think I can very much believe that oseltamivir has no benefit once the illness has progressed like that, and perhaps even early, I think remains to be seen.
But I have a hard time believing it causes active harm, especially considering the fact, and this is the pharmacist in me, that it's given orally, and a lot of these patients like may or may not even absorb this medication. Like they have such deranged pharmacokinetics, and who knows how we're administering it in these critically ill patients on vasopressors.
Like we would typically not give a plethora of oral meds in that setting. So I just have a hard time getting to harm. So million dollar question, Steve Tong, go first. What do you think could be the possible mechanism?
There are sub-studies that have been, planned. you know, [00:54:00] we can speculate and in the preprint there's a paragraph about the fact that the human host has a neuraminidase as well, and could it be that it impacts upon the host neuraminidase that, has an effect on that sialic acid residue, so a sialidase that then can potentially impact upon platelet function and neutrophil and other immune function.
[00:54:22] Steve Tong: That's very hand-wavy, to be honest, but it's, potentially, has some effect on the immune response and immune system in someone whose immune function has already been so dysregulated because of their acute, infected illness
Erin, I think there's reasonable evidence that oseltamivir can influence the host neuraminidase. There is a randomized controlled trial in patients with idiopathic thrombocytopenic purpura in which administration of oseltamivir, results in a statistically significant increase in platelet count for [00:55:00] patients randomized to oseltamivir.
[00:55:02] Steve Webb: and the, human neuraminidase, uh, has, mechanism that's compatible which is why that, trial was, conducted. So there is at least potential, for action on host pathways, the significance of which in critical illness are, not understood and, absolutely purely speculative.
Erin, what I would say is if you're across the line on believing that there is, a sufficient proof that oseltamivir caused harm, you've now got proof that intra-administered, medicines in the critically ill can be absorbed.
See? Silver linings, people. You heard it here first. Give, give oral meds
[00:55:43] Erin: I have certain IV medications like IV posaconazole, IV isavuconazole, certain things like this are what we call tier one, meaning they cannot be prescribed unless ID is involved. And we don't have twenty-four seven, three sixty-five ID. And so people are like, "What if I need it at night?"
And my answer was, "You don't." [00:56:00] No one needs urgent 2:00 AM IV medications for some of these things, and in fact, they can tolerate PO. So I love it. All right, the time has come, Breakpoints faithful, for I Feel Nerdy. I Feel Nerdy is meant to be a safe place and a closing segment for our panelists to nerd out over their favorite ID topics, quirks, and fun facts.
So for today's I Feel Nerdy, I want you guys to tell me a story of-- It can either be a patient story or just in general a disease you think is very cool. Your most favorite non-bacterial illness because we spend a lot of time on bacteria. I'm talking to like the staph aureus gods of the world. Steve W.,
you've probably seen everything known to man. You've seen it all. So I wanna expand our horizons and go beyond normal bacteria compelling cases. So I will go first and be short and sweet. If you are a Breakpoints listener or have ever interacted with me, you know my favorite infection is CMV. I love it so much.
It's the coolest. It's so intricate, and it's these host complexities that really get me. It's the [00:57:00] fact that we know so little about all of our patients and all of it and how it interacts with the disease. So this antiviral discussion has been really great for me, giving viruses the time they deserve.
Josh, you wanna go next?
Yeah, I think mine's hepatitis B virus. the virus itself and the illness it causes in people and the interaction between those. Steve and I, in fact, first collaborated on hepatitis B virus research up in the Northern Territory in the Aboriginal populations up there in whom it's endemic, and, I'm still working in that area a little bit.
[00:57:33] Josh: But the one thing I love about it so much is the hep B virus is such a simple, organism. It's got 3,200 base pairs, and yet with that tiny bit of DNA, it creates so much havoc. and in fact, one way it does that despite being so small is that it has overlapping open reading frames. which increases its efficiency for the same number of base pairs. it can basically create the equivalent of multiple [00:58:00] genes, kind of like how an adaptive platform trial creates multiple trials for the same infrastructure.
Well, that was the nerdiest, coolest answer I've ever heard on potentially any I Feel Nerdy ever. So Steve Tong, good luck following that. You're next.
[00:58:15] Steve Tong: Well, I'm going to pick something else, but, follow on from Josh, about hepatitis B because one of the really nerdy things that we found out with hepatitis B in the First Nations populations in the Northern Territory was that the circulating virus was unique to this population, to the Australian First Nations population, so hadn't been seen anywhere else in the world.
And within that kind of three thousand base pair thing, we did all this phylogenetic work and demonstrated that this virus had been with the First Nations populations for probably fifty thousand years. So it had entered Australia with the Aboriginal population, and we can show that phylogenetically.
And what was even more fascinating for both Josh and I was to see that as, language groups split off within the Aboriginal [00:59:00] population, the virus also mutated, you know, to follow those language groups. And this partly is because hep-hepatitis B is typically transmitted vertically from mother to child.
and so it follows the lineage of the genetics of the people. So that's kind of super nerdy, super, super interesting. but my pathogen I've chosen is Cryptococcus. again, just really interesting, both CNS, lung disease. There's two main species, Gattii and neoformans. There's differences between immunocompetent hosts and HIV or other immunocompromised hosts.
So really fascinating disease and lots of tricky management decisions, particularly for CNS, disease, where management of both the, the fungus itself with antifungals is important, but also the management of the raised intracranial pressure
[00:59:50] Erin: Only Steve Tong would give the most like beautiful, fascinating history of a virus and then be like, "But that's actually not my answer. I have more knowledge to share with you." Cryptococcus [01:00:00] CNS infections is another we can talk about trials all day. Another thing where we actually have RCT data and we just don't follow it.
So fascinating disease for sure. All right, Steve Webb, last but certainly not least.
Well, how do I compete, against, ID specialists, like this?
[01:00:14] Steve Webb: so I note the question is non-bacterial illness, and I'm just gonna tell a story, a case about pulmonary edema. So, uh, I was,
[01:00:22] Erin: I actually was hoping you'd pick a non-infection
I was like-- I'm like, "I'm gonna leave it vague."
[01:00:27] Steve Webb: Well, there's still an infection twist. So I was caring for a young, a First Nations Australian, who was, only 16 or 17 years old.
And the diagnosis I had made was dreadful, overwhelming bilateral pneumonia. And, he was in severe shock. And this is a good 20-plus, years ago. I used activated protein C, in this patient, which is a now withdrawn, disease-modifying agent, for sepsis. it was only, a [01:01:00] day or two later when he wasn't responding to treatment that an echo showed that he had severe mitral stenosis, and everything that I was managing was, severe pulmonary edema and cardiogenic shock.
So activated protein C, neither good for sepsis, nor good for mitral stenosis.
[01:01:18] Steve Tong: But there is an infectious disease involved, right, Steve? Because the mitral stenosis is due to rheumatic heart disease, which is related to infections with group A Streptococcus.
[01:01:28] Steve Webb: how could have I neglected that?
[01:01:31] Josh: That, that comes down to something I often, tell my trainees, that everything is infection. multiple sclerosis, infection. Cancer, infection. Trauma, that's one organism attacking another organism, infection
[01:01:45] Erin: Shameless plug, but we do have a fellow Australian on a Group A Streptococcus Breakpoints episode that is really fantastic if you wanna learn all about rheumatic heart disease. Also, a fellow, colleagues from the United Kingdom. But gentlemen, this was a pleasure. It was brilliant [01:02:00] as always. So wonderful to talk to you and learn about whether or not oseltamivir is killing our ICU patients.
a huge congratulations to the REMAP-CAP entire global team. It is an unbelievable effort as we continue to talk about with just the community around these clinical trials. Not only to you guys as investigators, everyone who chooses to make-- Every single clinician who says, "Sure, I will randomize my patient," and makes that choice, and then the patients, most importantly, who consent.
[01:02:25] Erin: So thank you so much to all of them and to our guests, Steve Webb and Steve Tong, my co-host, Josh Davis. Thank you for listening to Communicable, the CMI Comms podcast, and Breakpoints, the Society of Infectious Diseases Pharmacists podcast. This episode was edited by Katie Hostettler-Oi. Communicable theme music was composed by Joseph McDade, and Breakpoints theme music was recorded by Dr.
Steve Smoke. You can subscribe to both Communicable and Breakpoints on Apple, Spotify, or wherever you get your podcasts
[01:02:54] Josh: and thanks also from me for listening and helping CMI Communications and ESCMID move the [01:03:00] conversation in ID and clinical microbiology further along, and for helping SIDP achieve the vision of safe and effective antimicrobials now and into the future.