Thanks Mark. So my name is Matthew Taylor. I am coming from New York and I'm going to talk about a little bit about basic and translational research that I think will impact probably not our care tomorrow but our care at some point in the next, you know, five or ten years. So I'm going to start, so I have a few disclosures, none of them affect anything that I'm going to talk about. So I'm going to start with an overview of some studies looking at the microbiome. So the microbiome is the collection of all microbes including bacteria, fungi, and viruses that naturally live on our body, in our gut, in our skin, and in our airway. And there are several studies that really shed some light on the effect of these in the ICU. I'm going to start with one that looked at neonates. So this paper, Gut Pathogen Colonization Precedes Bloodstream Infection in the Neonatal Intensive Care Unit, it was published in Science Translational Medicine. And this was a study in the NICU but I think it has a lot of relevance to pediatrics in general. So what they did, they took a large data set, I think it was about a thousand patients, who had had what's called 16S sequencing, so looking at the microbiome of these neonates, and they looked at exposure to antibiotics. What they ended up finding was that neonates who were exposed to ampicillin or gentamicin, as you can see, anyway, so patients were exposed to either ampicillin or gentamicin had an enhancement of the enterobacter species in their gut. And it turns out that if they were given both ampicillin and gentamicin, they did not have that expansion. If they were exposed to vancomycin and gentamicin, they had a reduction. They actually found the opposite effect when they looked at enterococcus. So what this group wanted to know was, does this precede any bloodstream infection? So they took 19, well they ended up taking about 50 patients, 19 of whom had bloodstream infections during the course of their research, and they did very intensive microbiome sequencing. So they took samples every other day, ending up with about 500 samples. And what they ended up seeing was that there were two separate patterns of gut pathogen abundance before an event of bacteremia. The bloodstream infection species from enterobacter and enterococcus families largely had a high gut abundance of those species before the bacteremia, whereas patients with staph or GBS had low or no gut abundance. And as you can see on your left, the case patients actually had a large expansion of that abundance. When they looked a little bit more closely, what they actually found was that the causative agent of the bloodstream infection within five days before the actual BSI event had an expansion. So that was true of staph, that was true of strep, it was true of enterococcus, E. coli, klebsiella, and serratia. So they could actually predict a bloodstream infection because of expansion of the bacteria in these neonates guts. Now this was preterms. They did not look at anyone beyond that. But if you look at the positive predictive value and negative predictive value of these, the negative predictive value of first staph, if there was an expansion, was 86%. If it was GBS, it was 97%. If it was enterococcus, there was 99% specificity. Serratia, klebsiella, and E. coli were all very high. So they could almost predict bloodstream infection if they looked closely enough at the gut colonization. Now this is another article that came out this year. This is an article entitled Dysbiosis of the Microbiota, an Immune Metasystem in Critical Illness Associated with Nosocomial Infections. This is actually an adult study who looked sort of similar at them. So they looked at the microbiome, but they also did immune system profiling. So you just saw that there was an expansion of the bloodstream infecting bacteria in these neonates. What this group actually found was that in adult patients, the ICU stay, in general, predisposed to an expansion of, or a dysbiosis, or the expansion of a pathobiome. They saw that Enterobacter expanded in a majority of their patients, and that expansion of Enterobacter was associated with a reduction in the diversity of the microbiome, and that's what's shown on the left up here. Along with that expansion of the Enterobacter, there was a significant increase in the risk of a compositive outcome of nosocomial infection or death. You can see the odds ratio there of 6.8 for nosocomial infection if they had, if the ICU patients had this expansion. Now interestingly, the cause of the infection was not necessarily Enterobacter. This was, this occurred no matter, this occurred in all patients, and they hypothesized that it was because of a globally impaired host defense. So they were able to associate the expansion of Enterobacter with an alteration in the neutrophil profile of these patients. So these patients were immunosuppressed in association with an expansion of Enterobacter. Sorry, there's some water under the podium here apparently. Not mine. So they were able to show that an expansion of Enterobacter occurred in ICU patients, and that was associated with an expansion of immature, less functional neutrophils. So one has to wonder what the effect of the microbiome on our pediatric ICU patients are. There have been studies showing the pediatric, the pediatric microbiome is changing over age, so perhaps this is a predisposing factor to infection. There are other studies that have come out recently. This is another one that came out in JCI looking at the integrated host and microbe metagenomics and in lower respiratory tract infections. What they were able to show is that there was a pattern of the host genomics that associated with a lower respiratory tract infection, that they could use tracheal aspirates to predict whether a patient had a true lower respiratory tract infection, or if it was just a respiratory failure that was not associated with an infection. And if they added in the microbiome, the microbiome data to this, they were able to have an AUC that was upward of 0.98. So they could predict whether a lower respiratory tract infection was associated with a specific microbiome with very high specificity and sensitivity. And you'll hear later on other genomic assays that are being used clinically to help predict responsiveness to steroids and other things. And I think that this is something that is coming in the future. There was another large study looking at the microbiome, and this also came out this year, that used 1,000 microbiome samples from patients with ARDS. What they were able to show is that, as you can see on the left, if patients had specific bacteria in their microbiome, then they were prone to developing ARDS. If they had Staphylococcus, then they were prone to developing ARDS. If there was no Staphylococcus, but if there's Ralstonia, then they were prone to ARDS. And the same for Enterococcus. And you can see below that the probability of needing invasive mechanical ventilation associated with this ARDS signature. They were able to show a similar signature for hospital- acquired pneumonias, though those were associated with different types of bacteria. They were also able to show that prolonged mechanical ventilation associated with specific bacteria. So I think this is showing that the importance of the microbiota in infection and in the immune response to infection in our ICU patients is very important, and something that we don't currently understand in our pediatric ICUs, but is likely to come into play in the next 5 or 10 years, or even sooner. This is not only important in infection. This also came out this year. It was a large study out of, I believe, Denmark, demonstrating that the gut viromes, so viruses in the gut, actually associate with predisposition to asthma development. So if you looked at the microbiome and the virome, if you had a high, if you had a specific signature from both of those, you had a very high chance of developing asthma. So they could predict, based on these things, whether a patient would develop asthma in retrospect. So they have not applied this to prospectively yet. Similarly, another study out of In Nature Communications showed that delayed gut microbiome maturation actually led to pediatric allergic disease. You can see the significant values here. They were able to show that dysbiosis led to different metabolic changes in the microbiome and in the gut, and that that associated with allergic disease at 5 years. So one has to wonder, in patients who have ICU stays, what kind of dysbiosis they develop, what kind of pathobiome they may develop, and what that does to them, you know, 5, 10 years down the road. I'm going to switch topics. I'm going to go over two other papers briefly, and then I'll go through one more a little bit more in depth. So okay, I'm going to do it a little more quickly than that. So the first paper, recently there was actually this outbreak of idiopathic hepatitis that a group was able to show is associated with adenovirus, adeno- associated virus 2, through methods that I'm not going to go through. But they concluded that because of delayed exposure with COVID, that perhaps the immune response was different, and that that was causing hepatitis. And this is a hepatitis outbreak that has been regionally identified. One of the other exciting papers that came out is chimeric autoantibody receptor T cells. So this is CAR T cells that are able to deplete NMDA receptor-specific B cells and can treat NMDA receptor encephalopathy, and this is in mice still. But it's exciting in that it's one of the first autoimmune diseases that can be targeted by CAR T cells, and it will likely be coming to our units in the near future. And then this is the last study that I'm going to go through. So there was a paper in BMC Medicine that was able to show that exogenous mitochondrial transplantation improved survival and neurological outcomes after cardiac arrest. Now this was in rats, not in humans yet. But they were able to show that cells in culture and rats, when they were given them, would take up exogenous mitochondria. They were able to show that when they were given to rats immediately after a cardiac arrest, fresh mitochondria improved survival. They decreased lactate levels, they improved pH levels, and they were able to show that neurological outcomes were better. And this only occurred with fresh mitochondria, not with frozen mitochondria, which explains some differences that have been previously seen. And then they were able to show that the cells in the brain, the kidney, and the spleen all took up those mitochondria through staining techniques. Finally, they were able to show that cerebral blood flow improved whenever fresh mitochondria was given to these rats. So I think that this is a promising potential treatment for the near future for our cardiac arrest patients. So in summary, I've gone through the emerging impact of the microbiome on critical illness and development. Perhaps early antibiotic treatment could be impacting child health, and we don't know the prolonged effects of early antibiotic treatment on our patients. Perhaps early empiric antibiotics could be affecting outcomes, and then could microbiome sequencing in the near future predict risk for disease states? I briefly touched on a new viral hepatitis and the impact of delayed exposure on host responses from COVID, and it's interesting to think how that may continue to affect our patients. Then there's a new treatment for NMDA encephalopathy and a possible new treatment for cardiac arrest. Thank you for listening, and I'll pass it on, I think, to Carrie.

microbiome

critical illness

healthcare advances

neonates infections

pediatric asthma