So, I'm Ken Remy. Welcome today. We're going to... I'm going to give the opening remarks for today's session. Really excited about the speakers that we have scheduled for today. I know each of them personally, and truly brilliant people and experts in their topical areas today. And so, I think it's going to be an exciting opportunity for us to hear from them. And so, as mentioned, I'm Ken Remy, and I'm part of the program committee. We decided to come up with this deep dive into precision medicine and sepsis, because we think the timing is right, especially as things start to launch within SSCM discovery and a number of other endeavors that don't have any relevant disclosures. So, not surprising to this group here, but sepsis, obviously, has been a worldwide threat for the last 2,000 plus years. Every year, annually, it kills, sadly, 11 million folks globally, with 270,000 of those individuals coming from the United States. It also accounts for one-fifth of all United States hospital admissions, but factors into actually greater than one-half of all US hospital deaths. Even if the death certificate doesn't say sepsis, there's a contribution of sepsis in more than 50% of those individuals. It is the leading cause of US hospital re-emissions. It's also the leading cause for CMS fines against hospitals for re-emissions within the first 30 days post-actual discharge. And although mortality appears to have at least slightly decreased in the last decade, it still remains about 18% to 25% of all deaths. And not to be too morbid in this conversation, but for every three seconds, one person will die from sepsis in this world. As we know, this is a syndrome, nonspecific, that's kicked off from a pathogen-inducing infection then inducing a host immune response. And this host immune response is complicated, complicated by both an anti-inflammatory and a hyper-inflammatory state. Changes in activation in leukocytes, changes with inflammation at the endothelial level and microvascular oxygen flow redistribution and oxygen delivery, changes in hemostasis and coagulation, and when going unchecked, can lead towards death. This is our problem. We've had a clinical spectrum for sepsis, but it's nonspecific in derivation. It really lends itself to understanding mostly clinical symptoms that are not specific to biology. And it certainly has a number of overlapping conditions. And not included in here for kids, MIS-C, things like HLH. But there's a lot of overlap with a number of other phenomenon syndromes that are very similar in nature. And so it makes, specifically to be more precise, to manage these individuals with this syndrome difficult and complicated. The other thing that's complicated is that there's divergent host immune responses that become maladaptive and muddled. And they become maladaptive and muddled temporal from time infection through duration of the actual syndrome. And individuals will have an exaggerated immune response with certain cell types, but have an underwhelming or immune paralysis state in other immune effector cells. And then as time elapses, multiple hits within an ICU or when people get discharged with additional pathogens certainly cause this to be even further muddled. With high mortality rates and limited treatment options, there's a need for targeted therapeutic approaches. Furthermore, many of our patients that actually do get discharged from the hospital have a high likelihood, as mentioned, for re-admission. And many of them get re-admitted with substantially the same primary pathogen that brought them in in the first place. And so these individuals certainly have very heterogeneous immune responses that certainly can be complicated, at least a study in the clinical laboratory. If we look at what's been going since 2000 with hospitalization rates for sepsis, certainly we've changed some of the definitions, which is why we've seen an increase. But we've also seen an increase by 40% from 2000 to 2008. And we look at deaths from all causes, including respiratory failure, heart attack, cancer, and stroke. These have decreased between 2000 and 2010. And same with cancer. But when we looked at septicemia, it increased. And I'm going to show you data that goes all the way up to 2021, which demonstrates that at least this has plateaued, but certainly has not had a tremendous decrease when you look across all individuals that get admitted with septic shock. And then if you look at trends in septicemia by age group, typically sepsis affects those under one year of age and those that are of advanced age. And when I say advanced age, I mean greater than age 45. And that's when we start to see the increase in risk. Not very exciting for me now that I'm 47 and over the hill. And then if we look at the cases of severe sepsis during that same time period from 2003 to 2007, there was a slight decrease. But that's also made a decrease because of the increase in the denominator for cases that were now labeled sepsis that perhaps had less severity, that previously were not called sepsis. The other thing that's quite interesting is that although we're able to discharge more patients from the hospital, their disposition has changed. They're no longer going home. They're going to skilled nursing facilities. And they're certainly going to short-term or nursing homes. And if you look at their individuals, especially in the adult world, limitations and activities of daily living have certainly worsened at time of discharge over the past 20 years. And this was published about 13 years ago. And then this is the most recent data that looks at trends of mortality for sepsis hospitalization on a nationwide prospective registry. And as you can see here, it is actually somewhat plateaued across the board from 2011 to currently 2017. Not surprising, because although we've gotten better at diagnosing earlier this disease, and then since Kumar's article that was instrumental in 2007 with early antibiotics from time from hypotension, we certainly had an improvement. But we've remained somewhat flat since that time period. As clinicians, we're faced with a big decision a lot of times. Does our patient actually have sepsis or not sepsis? Do they have an acute infection that's not systemic? Do they have a non-infectious illness or another critical illness? Are they really sick? Where do they go? This has been a complicated question for clinicians for many years. And having a test that can tell you yes or no has been challenging to obtain, at least in the clinical arena. And our principles of therapeutic management have really not changed. These are very specific, right? Early recognition, correct antibiotics, rapid fluid resuscitation, judicious use of vasopressors, and prompt removal of source. These have not changed in years. And they're not certainly targeted. They're supportive in nature, although perhaps the antibiotics against pathogen weren't delivered correctly. And so this has certainly lent itself to an opportunity for us to be able to take a deeper dive into understanding the biology of the disease. And so if you look, and this was published in 1998, and there's been subsequent meta-analyses that have looked at a number of targeted anti-inflammatory and also immune-boosting therapies, at least in aggregate in meta-analyses, but one fundamental thing remains. Many of these studies all cross the no effect line, and thus have not made it into patients. Because typically in these clinical trials, we include this one size fits all, that anybody that has sepsis certainly needs to be involved in the same trial. And then we randomize based off just the diet syndrome of sepsis. Well, when I have a headache at home, my spouse and I take two different medicines. I did not cause her headache. But we take two different medicines. I take Tylenol, because it helps when I have a headache. She takes ibuprofen. If somebody were to do a clinical effectiveness study at my house for headache as the predominant diagnosis for the two of us, we would only have a 50% success rate if acetaminophen was the drug of choice for the study. And therefore, I might not have availability of the drug that would help for my headache. The same has been true with using this one size fits all just based off the syndrome of sepsis. And surprisingly, in many of these different therapies, antibodies and IL-1RAs, many of these, if you had 10,000 patients, there actually is a signal that certainly lends itself that there could be a population that this could be beneficial. Without having effective tests actually evaluate this in real time, we lack the ability to be able to put these into patients in a targeted fashion. And so that's one problem that we've noticed in therapies. Today, we're going to talk about a lot of different aspects and take a deeper dive into sepsis. We're going to talk a bit about the pathogen. We're going to talk about some of the changes that occur, certainly in the hemostasis and red blood cell and hemolysis realm, and what may happen at the endothelial level. We'll talk and touch a bit about some of the different immune effects that are noted, at least in sepsis, and why it's complicated to be able to make targeted therapies available to everyone without a better way to define and enrich those populations. We'll talk about how perhaps this can impact our overall outcomes of sepsis and septic shock and mitigate death. Why is this important? We don't have a lot of great antimicrobials coming down the pike. And if you look at what's projected by 2050, we'll have a substantial amount of death from multidrug-resistant infections that are supposed to skyrocket without effective therapies available. And so developing new antimicrobials and having pathogen reduction strategies are paramount to sepsis. But furthermore, finding ways to understand the immune system and to be able to boost or actually downplay those that have either hypo- or hyper-inflammatory immune effector cells that are predominating the actual clinical phenotype you're seeing is also vitally important because we can't rely simply on antimicrobials to get us through what could happen in the next 25 years. And so it's even more important for us to understand development of new vaccines and pathogen reduction strategies that may, in fact, be relevant in patients that are at risk for sepsis. And I would argue today, as we go through some of the deeper dives and some of the different aspects, that sepsis really is a syndrome in need of new biologic disease nomenclature. And so when I think about patients, they have lots of different compartments that have alterations that change in time of their underlying sepsis syndrome. And these compartments each have different factors that need to be understood in each individual patient and across populations for us to define the syndrome, perhaps, into different nomenclatures, sepsis A, sepsis B, sepsis C, sepsis D. And for many of us that have laboratories, taking that basic scientist that's been on the sidelines trying to understand mechanism in both human and animal studies at the translational and basic science approach, they need to be brought also to the table in and around those that are doing artificial intelligence and are able to look at implementation science and conduct clinical research and systems biology and dynamics and multiple omic evaluations so that we can combine, use all disciplines at all points of interaction to better understand this syndrome. So let's take that deep dive today. And so we're fortunate today that we've got three outstanding speakers that I'm looking forward to hearing from, Dr. Jamie Sturgill, Dr. James Ross, and Dr. Julianne Bubek-Wardenberg from the University of Kentucky Case Western and Washington University. Today these individuals are going to talk about three very seemingly different areas. And I'll also give a talk as well. And we're going to talk a little bit about some of the deeper dive aspects of sepsis that will be relevant as we move towards a more personalized and precision approach understanding this syndrome. So the first person to speak is going to be Dr. Sturgill. And thank you very much for coming today.

sepsis

precision medicine

mortality

immune response

antimicrobials