Hello. Can you guys hear me? Welcome, everyone. Thanks so much for attending our talk today. We're going to talk about controversies in the care of patients with severe CAP. And I'm really excited about this topic. I don't know about you guys, but our approach to pneumonia care hasn't really changed in like 50, 60 years. And so there's a lot of newness in our lives and a lot of shifting paradigms, and it's very cool. But there's also a lot of debate. So I'm actually going to start off with our first talk, I think. Oh, and I'm going to introduce you. Sorry, I forgot to introduce you. I didn't really sign up for this job. Marcos Restrepo, professor of pulmonary critical care medicine and board certified in ID from San Antonio, VA. Christina Crothers, professor of pulmonary and critical care medicine at University of Washington and VA Puget Sound. Charles de la Cruz, professor of pulmonary critical care medicine at now Pittsburgh, just moved there from Yale. And are you going to be affiliated with the VA there? Yeah. Yay. Okay. And I'm from Salt Lake City, Utah, and I'm also affiliated with the VA. So I hope I didn't break it. Okay. So I'm excited to talk to you guys about procalcitonin in the care of severe pneumonia patients. And I'm going to give a con argument. And so I'm hoping today that after this talk, we'll be able to describe better what procalcitonin is, the mechanism of the release of procalcitonin and what it means when it's elevated. I want to review procalcitonin's performance in distinguishing particularly bacterial versus viral infection in pneumonia. Because in current care, that seems to be a niche that it seems to be filling. And then we can discuss how we might use procalcitonin more wisely in the future. So first I'd like to start with an analogy though, because I'm from Utah. So it was very exciting to me to be in an ocean place. And so I decided to capitalize on that and try to learn surfing. So every morning I've been waking up at six and pummeling myself in the waves and trying to figure out how to surf. Does anybody know how to surf? Okay. One person. Great. All right. Awesome. So it's hard, right? Like you actually have to know some of the fundamentals about how to read a wave, you know, kind of the how the offshore or onshore wind is impacting it, the stages of the wave. So it's very similar to pneumonia care, I think, in that there is this interaction between theory and practice. And so for pneumonia care, we need to really understand the pathophysiology of the disease. We need to understand the mechanism. And we need to understand kind of immigration, elimination, and the environmental context that pneumonia, you know, the pathogenesis of that, in order to do a good job taking care of our patients. But we can't just know. We have to actually also then have a lot of clinical experience. And that's what makes us experts. Similarly in surfing, you actually have to, I've been kind of taking all these tutorials on the web. There's some great stuff about, you know, stages of the waves, you know, the parts of the wave, in order to really understand the mechanism of the wave in order to catch one. And this is Marge Calhoun. She's like a Honolulu legend. There you go. Okay. And so with pneumonia, we have this pathophysiology of disease. But I like to think of pneumonia as really a pretty indirect view of that phenomenon. So it's not like cancer. We often really don't just open up someone's chest and get a biopsy and say, ah-ha, we have pneumonia. We usually have indirect access. The lung compartment is a very difficult place to sample and study. So we have different views, including bench research, translational research, and kind of traditional disease models that are like the single inoculum in a healthy subject, which isn't exactly clinical care. So in clinical experience, we really have more of a syndrome that we're dealing with. We see signs and symptoms in a chest image, and a patient might feel breathless and fatigued, and that to us is more of a syndrome. But we're trying to tap into the pathophysiology of this disease. Similarly, other kind of perspectives inform our understanding of pneumonia, and together we can kind of build a view. And I'm a health services researcher, so I have kind of different views that we can leverage from the electronic health record. And so in the age of omics sequencing and AI, you know, we really are looking for more precision in pneumonia care. Our treatment has not really advanced since the 20th century, and new tests really seem to be, you know, the answer to pull us out of this shadow. So what is procalcitonin? Procalcitonin was originally, calcitonin was pretty recently discovered in 1960 as a circulating peptide, and that kind of, you know, then we studied calcium homeostasis, and that was all in the thyroid. But a guy named Deflos discovered that procalcitonin as a precursor to calcitonin, also in the thyroid. And then this guy named Lemoullec sequenced the amino acid sequence, and, you know, kind of in patients with medullary carcinoma. But it was a guy named Asakote a few years later, so in 1993, that noticed that there was extra thyroid activity in sepsis. So this is kind of his landmark study, where he studied children with bacterial culture and burn patients. And you can see on the right, I just showed the graph with the children, and so you can see confirmed bacterial infections, very high procalcitonin, and then treated bacterial infection, it goes down, those lines connect the same children. And then you can see, in contrast to local infection, which is lower, and then viral infection, which is basically all over the place. And there were a couple other studies that were observing this correlation. And now it's known that procalcitonin is secreted by neuroendocrine cells in the lung, the liver, pancreas, kidney, intestine, and leukocytes during systemic inflammation. So what's the mechanism of release? What does it mean when our patient has a high procalcitonin? So I'm going to skip the gene expression stuff, but it can be upregulated and downregulated depending on stimulating factors. So one thing, it's directly induced by lipopolysaccharide. So boom, there's your bacterial infection, gram-negative sepsis, right? But it's also upregulated by the cell-mediated host response. And this is a diagram of kind of our complex and poorly understood model of the immune system. But we do know that the host response markers that do upregulate procalcitonin are IL-6, TNF-alpha, and IL-1-beta. It's also suppressed by interferon gamma. And that is potentially one of the mechanisms of when you sometimes don't see a high procalcitonin in viral infection. And it's also nice to know that the half-life is 22 to 35 hours. So if you're treating a patient, this is a very dynamic lab. And so just a snapshot of a procalcitonin is not going to be helpful, but it could give you a pattern perhaps. And the important thing is that it can be elevated in all sorts of other conditions besides infection. So trauma. So this is a great list. And I really liked this review by these folks. And so if you kind of want to geek out on procalcitonin even more. But this is the list that I try to remember in my head. So trauma, burns. So those are pretty easy to disentangle from pneumonia clinically. But then there are a couple like carcinoma, small cell carcinoma of the lung, for example. Immunomodulator therapy. If you have a patient that's on cancer immune therapy, they may actually increase you know pro-inflammatory cytokines. And that makes sense now that we understand the kind of mechanism release. Cardiogenic shock. Interesting. So that's sometimes difficult to disentangle. Peritoneal dialysis, patients with cirrhosis. And I thought this was interesting. The first two days of life. Possibly from a host response to just the new intestinal flora. And then it can be normal even in the presence of bacterial infection. And this is a shorter kind of probably less geeked out list for me. But infections stimulating any interferon release. Abnormal innate immunity. So our growing number of patients with immune compromise with biologics. And any non-classic immune response. So in practice, how does this work? So that was the theory. Now the practice. And so you know in terms of distinguishing bacterial from viral infection, this is a nice meta-analysis of 12 studies that evaluated accuracy against microbial culture as a gold standard. And the pooled AUC was .73. And so that's kind of like a meh AUC, right? But really more importantly, there's really no clear cutoff. So most of these studies used a procalcitonin of .5. And the sensitivity was .55. And the specificity was .76. And this is actually probably exaggerated because these are a population of patients that are typically microbiologically confirmed. And so they either have a positive viral infection or a positive bacterial infection. And you're trying to distinguish. That's not really clinical reality, right? Because most of our patients don't, we don't find anything. And so as a result of that kind of not great practice performance, the guidelines did come down pretty hard on procalcitonin in 2019. And saying that we really, you should not use procalcitonin or a low procalcitonin to withhold antimicrobial therapy. It's just not sensitive enough. And how about patients though with viral pathogens? So that was 2019. Now it's 2023. We have more respect for viruses than we used to. And maybe we don't have to give everyone antibiotics if we identify a viral pathogen. Wouldn't that be amazing? And so this is a work done by Charles's lab actually. And I really liked this graph here. And here's a beautiful AUC in panel B, which was .52. And so this is in severe patients with severe COVID-19 pneumonia. And these patients all had lower respiratory traction samples. They had a decent amount of patients with bacterial infection. Really no, you know, the flip of a coin is about the same performance. And so I was curious. So I work with VA data. So I decided to just kind of throw together a model also with a bunch of pneumonia patients. So these are all patients hospitalized for pneumonia across the VA. And I decided, well, how good would we be if we just used everything that we thought of in the EHR? And this isn't really everything, but this is a lot. So this is 35 factors, including comorbidities, all the risk factors you'd think of, vitals, illness severity labs, and then also procalcitonin when it was available, CRP, and all the cardiac markers too. And this is how good I got a model to work. So in all pneumonia patients, that was 170,000. Culture positivity was about 16%. And the AUC is .63. Influenza, how about for the viral infections? Okay, so AUC's .64. And how about with COVID? We had a decent amount of COVID patients across the VA system. Their culture positivity rate was lower, 6%. But the AUC also, oh, great, a little better, .67. So this is really not a great test to hang your clinical hat on. But how could you maybe use it? And so this is how I think of when I think of these emerging tests. And this applies to a lot of things. We are very actually good at integrating imperfect pieces of information, both quantitative and qualitative, at the bedside to form a pattern of disease, to come up with a hypothesis of what's going on under our patient's skin. And that's how I think we should use procalcitonin. We should integrate it with other pieces of information, know that it's imperfect, recognize uncertainty, and probably to help us characterize the underlying patterns of inflammation in the host response in our patients with shock and respiratory failure, and potentially to monitor the treatment response. And so with that, to summarize, so we hope that there's going to be more precision in severe pneumonia care. And these rapid tests that can characterize the inflammation patterns could really help pull pneumonia out of its syndromic shadows. But it's really poorly understood. And we have to recognize that there's a lot of uncertainty about our understanding of the host response. It's very complex. And procalcitonin alone is a poor predictor of the bacterial infection. And it really prediction using any test, especially in isolation, is not going to be useful for us. But the more we understand the meaning behind each new test that emerges, so how is that released? What's the mechanism? When is it upregulated, downregulated? Then it can help us, I think, become good clinicians. So that's pretty much it. Thank you. So for the initial presentation to the hospital, which patients with suspicion of CAV would you order procalcitonin? Check anything that applies. Yeah, so it's a mix of everything. And a quarter of you said none of the above, which is interesting, right? So how often do you order procalcitonin for your patients? Okay, so whenever you want to deescalate, which is the major one every other day, which is kind of interesting. And again, a quarter of you, a third of you don't use it. So I had a really big problem with the word really helpful. So it was really hard for me to do this part. And I appreciate Dr. Jones to provide her input about the con side of things. And so this is where I'm coming from. You heard about the clinical challenges, the diagnostic uncertainty, potentially atypical presentations, and the reliability or imaging. Is it a pneumonia? Is it a bacterial pneumonia? Potentially other non-infectious causes. And then as providers, we're always concerned about missing a bacterial infection, right? So we do give them empiric antibiotics just in case. And you heard about procalcitonin, where it's produced. And typically, it's from viral origin to sort of induce certain cytokines that would produce procalcitonin. But you know, immunology is not that simple, right? It's complex. And bacterial infection can also induce similar cytokines that can induce procalcitonin. So it's not black and white. And this is sort of the biomarker procalcitonin compared to the other cytokines and CRP in terms of the timeframe, where it peaks usually at 12 hours after exposure to infection. You heard about the half-life and you heard about how it decreases 50% if the bacterial infection is truly treated and controlled. And so other infections, conditions also result in procalcitonin. This slide I borrowed from Dr. Restrepo. You can see the scale of procalcitonin from 0.01 to 100. And as the disease's severity goes worse from a healthy person to septic shock, you can see procalcitonin levels go up. And so we've seen that in our studies that with severe disease, you can track your procalcitonin goes up, which is why some of the viral infection goes increase in with severity of disease. There's some cutoffs people talk about and different cutoffs in different people. So if it's low, bacterial infection is less likely. It's higher, suggestive of systemic bacterial infection and maybe even severe disease. And so what is the goal of procalcitonin if you're going to be using it? And so really it's to reduce antibiotics, exposure without adverse outcomes. You want to think about when to start antibiotics, when to stop antibiotics. You heard about the viral versus bacterial. I'll talk a little bit about that later. Antibiotic course, how to reduce harm, and it's important for antimicrobial stewardship. And then also at the end of the day, it's patient outcomes, which is really important. So the IDSA and the HEF guidelines do not recommend withholding antibiotics only based on the initial procalcitonin. And so they said no, based on the data that's available. But procalcitonin actually has pretty good negative predictive value. If it's low and your pretest probability for a bacterial infection, when you see your patients in front of you based on their clinical features, their imaging, their story, severity of disease. If it's low severity of disease, low likelihood of having bacterial infection, they're stable. It's got a pretty good negative predictive value. It actually has poor predictive value as heard about all the different things that can increase procalcitonin from Dr. Jones earlier. So the IDSA CAP guidelines actually said, do they recommend antibiotics if you have influenza? Actually, they said, you know, yes, initially. But if there's no evidence of bacterial pathogen, including low procalcitonin in the sort of the subheadings and early clinical stability, you can have it used for decontinuation of the antibiotics for stewardship. The CAP guideline also recommended short course, now five days, right? Using serial, potentially serial procalcitonin with clinical stability to reduce duration of antibiotic therapy. And so again, thinking about patients getting better, also being a good steward anti-antibiotics. And so many societies have come up with these consensus and how to use procalcitonin in terms of stewardship. And this is only an example for the mild cases outside the ICU. If you look at the references, they have something similar for moderate and also severe diseases in the ICU. Looking at initial clinical assessment, whether, you know, think about the procalcitonin level, and then also thinking about the recommendation for these patients in terms of do you get another procalcitonin, do you monitor it, do you treat with antibiotics? What's also important is continuous education and feedback, and then also a strong antimicrobial stewardship program. So this is a study that came out almost a decade ago, specifically on critically ill patient. It's called the SEPs, one of the larger ones in the Netherlands, looking at randomizing procalcitonin guidance versus standard of care. And so what they saw that with the standard of care approaches versus the procalcitonin, that with the guidance of procalcitonin algorithm, the mean duration of antibiotic use decreased from 7 to 5, mortality decreased from 27% to 20%, and the one-year mortality from 43% to 36%. It's pretty good, right? So using these approaches to decrease antibiotic usage. And specifically for respiratory infection, and some of these studies are more recent, a meta-analysis showing using 26 randomized control trial overall from 12 different countries, also showed lower 30-day mortality, 2.5 days of days reduction, antibiotic reduction of usage, and also reduction of antibiotic-related side effects. So these studies suggest that it's okay to use procalcitonin to decrease antibiotic usage reduction, but also the patients actually also do better. Some studies actually show no differences in mortality, but still with the reduction in antibiotic usage. This is something very similar, a more complicated slide, suggesting sort of the Cochrane review. I just want to highlight in the bottom the eight days versus five days of reduction with these procalcitonin algorithm. And we all know that the recent, the last guideline with regards to treatment of pre-required pneumonia was really five days. And so previously this was very useful when we were using prolonged antibiotics, but it does show that it's effective, and maybe this needs to be revisited in terms of the role of procalcitonin. So how about procalcitonin as the etiology of CAP? And this study was done through the EPIC study in the United States, where they really look at the causes of pneumonia. And we know from the EPIC study that almost 60% of those patients with CAP, we can't find a reason for CAP. And in this case, you can see only 24% had viruses, 10% have typical bacteria, 4% have atypical bacteria. And here we are talking about antibiotic usage for these patients, right? And so you can see on the graph on the right-hand side, the procalcitonin levels are quite low for viruses, and also interestingly atypical bacteria. But if you have atypical bacteria, which is sort of 10% of these population, you can see higher procalcitonin level. And so what they concluded was a higher PCT correlated with increased probability of bacterial pathogens. But we know that that's not fully cut because there's no perfect threshold to distinguish viruses from other infections. The same study looked at different cutoff points. And in this case, I just want to highlight the cutoff point of 0.01 for procalcitonin cutoff. And if you look at on the far right, the negative predictive value is around 93%. If you include all the unknown cases that is not identified for your CAP patients, and so the negative predictive value actually goes all the way up. So your patient, when you see them, many of them, you won't be able to find the etiology. And so, those patients might have low procalcitonin if your pre-test probability is low for bacterial pneumonia. So it's actually not too bad, 93%. They suggest that maybe you repeat procalcitonin to make sure there's no false negative as a potential. One caveat with the study was like almost 20% of this patient recruited are pretty ill in the ICU. And so there's really no rationale to think about withholding antibiotics for this population. So this is a cleaner population. It might be better data. So this other study called PROACT published in New England Journal, all US hospitals using clinical guidelines. They're actually using real time. This is the real world study. They provided algorithm for them versus usual care. So with the algorithm, 95% actually used procalcitonin. And in the real world setting, 2% only received the procalcitonin results. And what's interesting is that this is the opposite of what you would expect. There's no difference in antibiotic usage, no difference in adverse outcomes. What it does show is that because the physicians and providers taking care of these patients, they're still worried about not covering with antibiotics. And so they still order antibiotics for these patients. And so there's low provider adherence even if you provided these outcomes. This other study, not necessarily pneumonia, but looking at lower track respiratory infection, suspecting with low procalcitonin coming from the clinic or the ED. So instead of sort of having the provider figure out whether they want to follow the algorithm or not, they actually randomized this low risk patient to azithromycin or placebo. Okay, so that patient. And so what they saw was in placebo, there was no major difference, actually didn't make a difference at day five. It's a non-inferior to azithromycin, it's a double negative. And so that didn't work for them. But at day 11 and day 28, actually the placebo, if you leave them alone, don't give them antibiotics, actually they were doing fine. They were doing no different than giving azithromycin. There were no increase in side effects. And their conclusion, which I think is still pretty strong, that low procalcitonin can safely be used to identify non-pneumonia lower respiratory track infection that unlikely would benefit from anti-antibiotics. So last few slides to conclude. So procalcitonin is not a standalone test. You cannot rely on procalcitonin alone. You have to look at the other parameters I mentioned. Its use, which I would probably sort of suggest is probably select application for those who suspect for chlamycardia pneumonia. For example, the stable patients with low pre-test probability, you might have to follow up with a procalcitonin within 24, 12, 24 hours to make sure it's really negative. And it's really not used for those that you think already have pneumonia, right? Because there's no point of sending someone home. They have to infiltrate their sputum production fever with a negative procalcitonin. Maybe you're just not catching it at the right time. You heard earlier about bacterial co-infection. So it's not really good for those at least to identify that there's an additional bacterial infection in terms of viral infection because I think the procalcitonin dose situation actually increases with the disease severity. And so, you know, we have to do this appropriately in terms of context and knowing the limitations. And so we all have different opinions, right? And so it's really about who the patient is and what the context is. So if you think the patient has bacterial pneumonia and with the clinical information, you may not need procalcitonin if you're giving antibiotics anyways. But if you're thinking you might use it later for de-escalation, you'd probably have to do it after the starting point. Okay? And so there are now additional diagnostic tools like POCUS, imaging, molecular pathogen test, and it'll be interesting to find out how this plays with procalcitonin. And lastly, procalcitonin is not the only one that's out there in terms of, you know, determining whether it's virus versus bacteria. This is one example using a BioFire film array, looking at post-transcription signature. This is very early days. And what they did was they looked at whether this assay is able to separate bacteria from virus, and they do a pretty good job, probably a better job, than procalcitonin. So my last question is, just to want to find out the audience, what your practice is. So where do you stand with the use of procalcitonin in your practice of patients with CAT? Do you order it? You don't order it? So I think, Marcos, we have to do this again next year. We have consensus. Yes. Very happy about that. All right, thank you. So I know that my worthy opponent is disappointed that my laryngitis has recovered. He was hoping I'd just forfeit by not giving my talk. So I have the con assignment of corticosteroids are only useful in COVID-19, but nothing else. So I don't have any disclosures, except I am a VA employee. So I'd like to convince you today that there's a lack of adequate data to really support a generic recommendation for use of corticosteroids in severe non-COVID CAP, mainly because I think there's questions about which patient subgroup really benefit, what subset of severe CAP, what corticosteroid regimen and when, and for which bug. So let's look at these questions. So first of all, my first point is our guidelines currently don't recommend routine use of corticosteroids in severe CAP unless shock is present. So the 2019 ATS and IDSA guidelines for CAP here on the left suggest not routinely using corticosteroids in severe CAP with sort of a conditional recommendation. And they recommend not routinely using them in non-severe CAP either, and not using them in severe influenza. But we do endorse the surviving sepsis guidelines for using corticosteroids in refractory shock. And so the ERS and other organizations also put out a guideline in 2023 looking at the addition of corticosteroids to antibiotic therapy in severe CAP, and also provided a similar recommendation that suggests the use of corticosteroids if shock is present. So that's not everybody with severe CAP. So let's look at the data. So this is a meta-analysis and systematic review from a very high-impact, good journal, CHEST. And they showed that corticosteroids are not associated with mortality. So let's look at the study in a little bit more detail. So they included 16 RCTs of corticosteroids in adults hospitalized with CAP. There were seven of those trials that included severe CAP patients. The search notably went only through 2022, and they had almost 4,000 patients with mortality outcomes reported. So I pulled out the studies that included severe CAP in this meta-analysis. And what you'll see here of these seven studies is that many of them initially, except for the last two, were really quite small and of sort of questionable quality. But you'll also note that they had a varied steroid regimen, hydrocortisone or methylprednisolone, but also differing duration and a differing cumulative dose of steroids overall. So really a lot of heterogeneity in these studies. And it's also important to note that the definition of severe CAP varied in these studies. Five of them did use the ATS-IDSA criteria, which are shown here on the right-hand side of the slide, needing one major or three or more of the minor criteria. One study used the British Thoracic Society criteria, and another one made up its own. It's important that the MIDORI trial, which is the escape trial done in the VA, did actually modify the ATS severe criteria. So they added a criteria of having a pH of less than 7.3, based on their analysis of the VA data. And so as I mentioned, their overall sort of summary of the association of corticosteroids with mortality was that there was no significant benefit. They had a risk ratio of 0.85, with a confidence interval that crosses one. And the studies that had severe CAP are highlighted kind of here with the asterisks. And so you can see that they're all mostly kind of on the line or a little bit to the left of the line. But particularly the two sort of larger ones, TORUS and ESCAPE at the bottom, are really kind of close to that line of one. So they did, however, find, I'll concede, that corticosteroids are associated with a decreased likelihood of mechanical ventilation. And six of those eight studies included severe CAP patients in this sub-analysis of the likelihood of mechanical ventilation. But despite this decreased risk of mechanical ventilation, it was interesting they didn't show a difference in mortality, despite that decreased likelihood of mechanical ventilation. So I know Marcus is thinking, Christina, you're like leaving out the most important study. So what about the latest study, hydrocortisone and severe CAP, by Dequin and colleagues from the New England Journal? So this was published after that meta-analysis was done in CHEST. That's why I said the cutoff was 2022 for the studies. So they did show a significant reduction in 28-day and 90-day mortality associated with hydrocortisone in this study. So they randomized nearly 800 patients in this study, and as I said, significant decrease in mortality. They also didn't have an increase in adverse events with hydrocortisone, except for a greater dose of insulin in the patients who were on hydrocortisone. As you might expect, there was more hyperglycemia. So let's take a look at the three larger, more recent trials to kind of try and understand why we're seeing different results. And so I focused on the TORAS study, Dequin, and ESCAPE. And so the ESCAPE is the Midori trial in the middle. They had slightly different inclusion criteria and also included a different subset of severe community-acquired pneumonia. So in the TORAS study, they had severe CAP by ATS and IDSA criteria, but they required an elevated CRP at admission. So that's really important to note. They also excluded H1N1 influenza. In the ESCAPE trial, this was a VA-based study, and they had CAP that was in the ICU or the intermediate ICU, and they met those modified ATS, IDSA criteria for severe CAP. In the Dequin study, they focused on sort of the PSI class 5 or patients who really had significant respiratory failure. So they were on invasive mechanical ventilation or non-invasive mechanical ventilation or high-flow nasal cannula, or they had certain degrees of oxygen with an allowable sort of PF ratio. They didn't, notably, they did not include septic shock at enrollment, unlike the other two studies, and they also excluded influenza. So that's important to note. They also had different corticosteroid regimens and timing. So the TORAS study used methylpetanilone within 36 hours of hospital admission. The ESCAPE trial actually had a tapering regimen over 20 days, and they had the sort of longest duration of time sort of from the onset of pneumonia to when steroids were initiated, so within 72 to 96 hours of hospital admission. The Dequin study had only corticosteroids sort of over an 8- to 14-day period, and they started steroids kind of the earliest, within 24 hours of meeting severe cap criteria. So this may be sort of an important factor in sort of some of these different results. They also had kind of different patient characteristics. The age was similar between the three. The ESCAPE study had predominantly men, since it was conducted in the VA, and that's important because in the Dequin study, when they looked at differences by men versus women, there was a suggestion that the steroids may be more beneficial in women. So maybe that's sort of part of the reason for this heterogeneity in outcomes as well. And as I pointed out, the Dequin study really emphasized more, I think, sort of respiratory failure population, and they had the lowest PF ratio. So and as I mentioned, they had different results. So the TORAS study had fewer late treatment failures, but they didn't have any difference in the secondary outcome of in-hospital mortality, comparing the steroid to placebo. In the ESCAPE trial, they really had no difference in their primary outcome of 60-day mortality of 16 versus 18 percent or any of the other secondary outcomes. And Dequin, as I mentioned, did have a significant decrease in that primary outcome of mortality. And they overall had the lowest mortality of any of the three studies. So I think this raises a question to me of really, is the benefit of corticosteroids in severe CAP because we're treating ARDS or we're treating septic shock? And as I mentioned, you know, we endorse the use of corticosteroids sort of consistent with the surviving sepsis guidelines. And we know that there is some benefit to corticosteroids in decreasing mortality in patients with ARDS. And so this is a meta-analysis showing particularly, I think, sort of the DEXA-ARD study by Villar having a decrease in mortality associated with steroids and maybe particularly dexamethasone. So you know, in that Dequin study, as I've highlighted, sort of with that greater degree of respiratory failure, is it this subpopulation of ARDS that is more likely to benefit rather than sort of everyone with severe CAP should get steroids. So and the other point I'd make is, you know, as you're thinking about this and what my opponent's going to say, is should we change practice based on one study? And so just to remind you, what's happened when we've changed practice based on single RCTs, activated protein C, tight glucose control, do you guys all remember making all those protocols and figuring out, you know, how are we going to do tight glucose control? So I think it's just caution in sort of learning from the past and sort of what we do to change practice and implement different practices. So I think I've shown you kind of that there's these question marks about which subgroups really benefit, which subset of severe CAP, what corticosteroid regimen and when. And so I'll finish with kind of focusing on what bug. Do we really know what pathogen is going to be the kind of get the best response with corticosteroids? And really, it's kind of heterogeneous. I think we don't really know for sure. So we used corticosteroids in COVID-19, and there's a number of studies that have shown a decrease in mortality, particularly the recovery trial with dexamethasone and COVID-19. So in severe COVID-19, that's kind of our standard practice now. And yet, we think that corticosteroids increase mortality and influenza. So why is that so different? And so this is really based mostly on observational studies. I'd say that we don't really know in prospective randomized controlled trials if steroids are going to be harmful in influenza. And it may have to do with differences in pathogenesis and host response that I'm sure Charles could explain more eloquently than I can as sort of potential mechanisms of why, you know, COVID versus influenza are doing different things in the lungs and resulting in a different response to corticosteroids. But I think it just points out that heterogeneity again. So I pointed out the influenza and SARS-CoV-2, and then there's other infections too, right, that are different in terms of our responses to corticosteroids. There's a benefit of giving corticosteroids and pneumocystis pneumonia in people with HIV who have severe hypoxemia, but not in HIV uninfected. And there's sort of limited data with other pathogens. And as you've heard, about 60% of patients with CAP don't have a pathogen identified. So what do we think about those patients, and is steroids going to be beneficial? So I think really it's like, do we know what we're doing with steroids here? And so I think there's multiple reasons for this heterogeneity of treatment effect. And so it remains kind of poorly understood why corticosteroids are beneficial in some patients. That includes host factors, the pathogen and the microbial load, and the immune response. And then also really when corticosteroids are initiated in terms of that sort of cap onset and time of when the patient presents and when you initiate corticosteroids. So in summary, I hope that I have convinced you that there's a lack of adequate data to really support a generic recommendation for use of corticosteroids in severe non-COVID CAP. But I will concede that I would consider using it in select cases, or if it's indicated for other reasons. And I would mostly stick with the criteria as in Dequin et al. Think about maybe looking at CRP inflammatory markers and avoiding for now influenza and making sure the patient doesn't have any contraindications to corticosteroids. And then I think there just also remains a lot of uncertainty in future research to be done on this. So thank you very much. Okay. So I would like to start. The pro in corticosteroids are useful in severe community acquired pneumonia. And I have to recognize that my esteemed colleagues here, we are all part of the guidelines. So whatever I'm going to say today, it is my opinion. It is not nothing that our chairwoman here and our esteemed colleagues will say in the guidelines. So please, please, please make sure that this is not blamed. Second, I'm part of the VA, so this is not what the Department of Veterans Affairs will say about this. This is just my personal opinion. Ladies and gentlemen, by the end of this trial, you will understand and you will be convinced that corticosteroids will be useful in patients with severe community acquired pneumonia with the exception of influenza. So please be ready for this case. This is a 66-year-old woman. Remember what Dr. Crowther said about women? Okay. So 66-year-old woman is transferred from the emergency department to the ICU after presenting with fever, chills, shortness of breath, hypoxemia, and hypotension. At the time of presentation, she has a heart rate of 120 beats per minute. Blood pressure is 88 over 54. Her heart rate is 32 and the oxygenation is 88 on a non-rebreather mask. Her lung exams revealed bilateral crackles on the chest radiograph with diffused mixed infiltrates. She is intubated on arrival. She is fluid resuscitated and placed on norepinephrine at 0.2 microns per kilogram per minute. Influenza test was negative. Blood and sputum cultures are collected. The emergency department starts ceftriaxone and Acetro before transfer. Would you consider the use of corticosteroids in this patient? So please cast your votes and see where are we at the start of this presentation. Okay. So it looks like 79 of you are giving this lecture with me. And then 21, I'm going to try to encourage you to consider this and I'm going to try my best not to discourage the 79 of you. Okay. So why do we have this problem? Look at this. In the world, about 3 million to 2.5 million people die every single year of community acquired pneumonia. You see that the majority of the deaths among the elderly, among those that are older adults, because I'm not included in the 50 years out of the 69. And if you look at in the United States, it has not changed basically like in the world that has been dropping down, but it has not changed. And the majority of these patients are 50 to 70 plus years old. So we still have a lot of people that are dying due to community acquired pneumonia. If you look at only severe community acquired pneumonia patients, we know that one third of them have septic shock. One third of them have mechanical ventilation. Twenty-five percent of these people died with the best appropriate therapy. So one out of four people are not going to make it even if we use the right medications at the right time for community acquired pneumonia. So we're losing these patients no matter what, even doing our best shot. Most of these people died at the beginning of the hospitalization, and these people died, the causes of death is all failures. Failures on the respiratory side, failures on the cardiac side, but they all died of these failures. And the majority of them, except for around 10 percent, then 90 percent of the people have a direct or an indirect cause related to that pneumonic event. Okay, guys, so restart with a mortality that is high, 25 percent. And my esteemed colleague is telling us, stay quiet, do ceftriaxone and Acetro, everything is going to be fine, okay? So we have the pandemic, and we needed a pandemic to teach us that definitely after the infection comes, there is a progression of inflammation that increase all these markers of inflammation. And these people that have these markers of inflammation end up having the failures, end up having the organ dysfunction. And this is why corticosteroids were created, just to help us with the high inflammatory phase that are happening on these patients. Therefore, we go to the guidelines, and the guidelines, as my colleague said, it only is a commutative pneumonia in refractory septic shock. Okay, this is 2019. What data did we have at that time to come up with this recommendation? This is 2015 systematic review. It looked like we have more systematic review than randomized controlled trials. But in this systematic review, you notice that the diamond is towards the left in favor of corticosteroids. But all, the majority of them, they just cross the unit. So they are not a statistically significant difference. But the diamond is. What I want you to take a look of this presentation is that corticosteroids, towards the left of the figure, is always consistently with the little boxes on that side. You will not find almost no boxes on the right. So if you are concerned, okay, will I cause a lot of harm by doing this, or will I end up hopefully making some benefit? Look at the studies, small. So the quality of the evidence was not great in 2015. In 2019, we had more studies. At that time, look at the boxes. There is one in the middle that was not severe, perfectly severe, but everything towards the left. And the diamond towards the left. So these small trials were suggesting that even before 2019, even before the guidelines, and even before COVID-19, even before the Dequin study, there was a trend toward low-quality data suggesting we have a benefit. And then COVID-19 came. We said, okay, what are we going to do with this? We have the recovery. The recovery suggested, yes, we use it. What did we do? We went and started everyone on severe community-acquired pneumonia due to COVID-19 on corticosteroids. Did you need a pro and con session for that? No. You went and did it on your own. So you basically, you changed practice on your own based on the data. And then the guidelines came and say, yes, please, for everyone that requires high-flow oxygen, oxygen therapy, invasive, non-invasive mechanical ventilation of ECMO, you need to use, please, dexamethasone because we might help these patients. But this is a very interesting study. What happened after we incorporated the corticosteroids? Look at this study. These people tried to really see whether the data was concordant according to the CRP, measuring whether there are some patients that are in need, inflamed, that will require corticosteroid therapy. And you notice that the hospital mortality was preventable among those that have the CRP that was elevated. So what I'm trying to tell you here is if you identify the right patients with pneumonia that have a lot of inflammation, the concept of utilizing corticosteroids to drop that inflammatory phase will be great. Now my colleagues show this study on hydrocortisone. It dropped the mortality by half at 28 days. It increased the number of discharges from the ICU. It lowered intubation and vasopressors. It increased insulin requirement, and it has no difference in hospital-acquired infections. And then we have this systematic review that includes the DEQUIN study, the one on top, with the highest box that is towards the left. But you notice that even with the MEDURI study, it's towards the left. It is just that it's not statistically significant because it crosses the unit. But all the other studies are on the left side of the thing. Now I presented this lecture to my daughters, and they said, Dad, I think you got a point. You don't have to keep showing me these slides to really see that everything is towards the left. So when we look at risk of mechanical ventilation, towards the left, in favor of corticosteroids. Then when we look at length of stay in the ICU and in the hospital, less studies looking at this, and there is the left effect again. Okay, so I don't know how many of you will know how to read this meta-analysis. But even if you don't know, if I tell you to the left, and in the left on the bottom it says favor of corticosteroids, you don't have to be a master statistician to understand this. So if we're talking about mortality and other important clinical outcomes, since 2015, since 2019, and the latest with the DEQUIN study, everything suggests that we should be using corticosteroids. Now what is the drawback here? And this is when you go and talk with a lady and tell her, ma'am, we have good news and we have bad news. The good news, the glucose level of your husband was always perfect. We did not require insulin during the whole hospitalization. The bad news is we could not save him. He died. So what is the drawback of corticosteroids? Hyperglycemia. No? Among all the different corticosteroids adverse events, that's the biggest one, the utilization of insulin. But the big event was, oh, mortality is not an adverse event here? Okay. Now, as Dr. Crothers said, and this is important because this is based on observational studies, everything suggests that influenza is not the ideal patient for this, at least not now, based on what we know right now. The interesting part of the story is that we know corticosteroids since 1929, for 94 years. And no one is doing a point-con debate whether we need to use corticosteroids in this other diagnosis. Exacerbation of interstitial lung diseases, acute interstitial pneumonia, diffuse alveolar hemorrhage, acute osinophilic lung diseases, organized pneumonia, pulmonary vasculitis, COP, acute exacerbations of COPD. So now, guys, you all use corticosteroids every single day for these people, and now you're going to tell me, no, I'm going to just use ceftriaxone and acetromycin for this lady that is in shock and respiratory failure. I might save it because we might cause some harm. So in conclusion, severe communicative pneumonia and COVID critically ill high-risk patients died due to this condition. There is a bunch of these patients that will die. Second, corticosteroids have shown, even before the guidance, even before the recommendations, with low-quality data, that it was good. Then we came to Dequin. Yeah, one single study, but it's in the same left side that I show you. And the third is there are uncertainties. We do not have the clear statement what is the best corticosteroid. Dequin study used hydrocortisone, that's good. We don't know the exact doses, but it's consistent with sepsis, about 50q6. And the duration is at least five days, but probably no longer than that, probably five to seven days. But I do not have any evidence to support that. This is my personal opinion. So among those that answer, the 21% of you, if you're still not convinced, if you're still doubting about the use of corticosteroids, if you're still comfortable with a mortality of 20% to 30%, I suggest you to use this approach. Yes for your mom, no for your mother-in-law. Unless it's my mother-in-law, okay, that I love. Okay, thank you so much for your attention. And I have one last question, okay? Where did we end up here? So would you use corticosteroids in a patient with severe community acquired pneumonia that is not influenza? Yes or no? Remember those that answer 79? Keep doing it, okay? Okay! Now, good for you guys. Thank you very much. Mahalo to all of you.

controversies

care

patients

severe community-acquired pneumonia

approach

procalcitonin

corticosteroids

bacterial infection

viral infection