Good afternoon, everybody. Thanks so much for joining us for today's webcast. We're going to be talking about RSV in critically ill children. I will be the moderator today. My name is Bria Coates. I'm an assistant professor of pediatrics at Northwestern University and at Ann and Robert H. Lurie Children's Hospital of Chicago. I'm an attending physician in the pediatric ICU. A recording of this webcast will be available within five to seven business days, and you'll be able to access it by logging into your mysccm.org. We have a few housekeeping things to go over before we get started. There will be a question and answer session at the end of today's presentation, so if you want to submit a question throughout the presentation, please go into your question box located in the control panel, type the question there, and I will be looking out for those. The other thing just to note that this disclaimer that the content to follow is for educational purposes only. So I would love, I'm really excited to present our speakers for today. First up, we will have Andrew Prigge. Andrew is an instructor of pediatrics at Northwestern University and Lurie Children's Hospital of Chicago, where he also works in the pediatric ICU. Andrew has a particular research interest in why children get so sick from viral respiratory infections, and I'm excited to hear him share his research in that area today. And after that, we will have Briseida Morales. Briseida is a nurse practitioner in the pediatric ICU who will be helping us better understand the state of the field for therapy and management of critical RSV infections. So I'm really excited to hear what they have to share with us today. So here is the outline of what's going to be talked about today, and I will just actually let Andrew and Briseida take over so they can walk us through all this. Thank you, Dr. Coates, for that kind introduction, and thank you, everyone, for attending our webcast today. This is a brief outline of all the things that we're going to talk about today. We're going to talk about the risk factors for severe RSV infections. We're going to talk about pathophysiology on the cellular level of RSV infections, and then I'm going to tell you a little bit about a study that we did here at Northwestern University and Lurie Children's that looked at gene expression in the nose of children admitted to the ICU with RSV infections. We'll then touch on the long-term consequences of these infections in young children, and then we'll tell you about the current treatments that we're using in the ICU and the evidence behind them, and then we'll wrap things up with what's new and upcoming in therapeutics and vaccines in RSV. So this is a list of risk factors that are well-established for severe infections in RSV. They come from a multitude of observational studies that look to associate clinical factors with severe disease, and in those studies, the definition of severe disease varied a little bit, but for the most part, it was defined as admission to a pediatric intensive care unit. And so these risk factors that are associated with severe RSV are young age, less than 6 months, a history of prematurity, specifically less than 35 weeks' gestation, the presence of a medical core morbidity. Down syndrome is an independent risk factor for severe RSV as is smoke exposure in the home. And while we know these factors that are listed here predispose children to more severe infection when they get RSV, actually, the majority of children who are hospitalized for RSV infections, in fact, are previously healthy, and they don't have any of these risk factors. And so to better understand why that may be and really to hypothesize a question why that may be, we need to understand the pathophysiology on the cellular level of RSV infection. Our airways, our human airways, are lined with a diverse group of cells, and these cells can broadly be split into three groups, and those three groups are ciliated cells, which are the columnar cells that have cilia on them. Those cilia have rhythmic beating that facilitates normal mucociliary clearance of the airways and allows individuals to clear particles and mucus from the airways so they can cough it up or swallow it. The next group of cells are basal cells, so these are the cells that are the small yellow triangles in our diagram, and you can really think about these cells as the stem cells of the airways. So these cells are able to proliferate and differentiate to replace dead or dying cells or normally regenerate cells and also regenerate the epithelium in situations where it's damaged. And then the final group listed here are goblet cells. So these are cells that make the secretions, so you can think of these as secretory cells, but these cells create normal airway secretions, and then they also increase secretion production in the setting of an insult. One other thing that's really important about the epithelial barrier in human airways is that it's a very tight, intact barrier that doesn't allow things to cross it. And then the last thing that's not pictured here are surveillance immune cells. So there are tissue resident immune cells that are present in the airway that are able to survey what's going on in the airway and what's present in the airway. And so here are some pictures of what a normal airway epithelium looks like in humans. This first picture is actually cell culture. So you can take human airway epithelial cells and you can put them in culture and culture them in a plate and create an epithelial barrier, which can be used to study disease processes. And so what you see here is a light microscope picture. So we're looking under the microscope, and what's outlined here is a columnar epithelial cell that has normal cilia on it. And what you'll notice is that, again, there's a very tight barrier with tight junctions and the presence of those healthy cilia on the barrier. To the right is actually a nasal biopsy from a child who was recovered from RSV. And this picture is an electron micrograph, and so it's very high magnitude and very high resolution. And again, it's here just to illustrate that nice, tight barrier intact epithelial cells and the presence of those cilia across the epithelium that facilitate mucociliary clearance in a healthy individual. And so when a child is infected with RSV, much like many other viruses, RSV enters the cell by binding surface receptors on the cell. And the primary cell type that is infected by RSV are ciliated epithelial cells. And what happens is there's a progression of disease once those cells are infected. And you can see that picture here on the right. So here's that same picture of a healthy ciliated epithelium. And what happens over time during the infection is these cells begin to become dysmorphic and they become dysfunctional. They actually start to have non-functional cilia, and the cilia can become damaged and be completely removed. And then those cells start to protrude and lift off the epithelial layer, and you can see that progression here. Here, they're protruding into the luminal space. And then at the extreme, they ultimately flop off. And you can see here in this picture, and again, this is from airway epithelial culture that's been infected with the RSV virus, is there's complete denuding of that top layer of the epithelium. And all those cells are slopping off into what would be the luminal space. And what happens is that you get loss of ciliary clearance. You're no longer able to clear the airway with the rhythmic beating of cilia. And as I said, you get protrusion and ultimate sloughing of these cells. There's hypersecretion of mucus. And then when the barrier integrity is lost, you get leakage of fluid. And then of course, you have inflammatory infiltrate as well. And actually, this bottom picture, which we're going to look at a little bit more closely in the next slide, is a cross-section of an area of an airway from an autopsy sample. And this is from a child that unfortunately died from an RSV infection. And this is a cross-section through one of the small airways. And it's a little bit hard to make sense of this, the light micrograph, because there's so much debris. And so I put this illustration next to it to kind of help you visualize. But what happened is this was initially the airway epithelium. And you can see all of these dysmorphic cells that have been sloughed off. And you can actually see these very large, giant, multinucleated cells. And these are infected cells that fuse together. And those are called syncytial cells. And that's actually where the respiratory syncytial virus gets its name. And so these syncytial cells and these dead cells and all of this mucus and other protonaceous fluid is sloughed into the airway. And in preclinical models in animals, it's actually been demonstrated that these sloughed off cells contribute to increased airway resistance. They contribute to the obstruction that we see at the bedside. And that's primarily the pathophysiology that we see with RSV, right? We see an obstructive physiology. So there's all of this mucus and other debris in the airway, which increases airway resistance. That results in air trapping, forced expiration by our patients, which we see at the bedside as tachypnea and increased work of breathing. And so as I said, the majority of children that we see with RSV bronchiolitis, infection of those small airways, will have obstructive physiology. However, there is a subset that will have either progression of the disease or sort of a mixed phenotype where they have hypoxemic respiratory failure. And these patients develop pediatric acute respiratory stress syndrome. It's approximately, depending on the study that you look at, about 20% of patients who are admitted to a pediatric ICU with an RSV infection develop pediatric ARDS. The hallmark pathophysiology in a picture that may be familiar to you is pictures here on the left. And that hallmark pathophysiology is the loss of the alveolar epithelial endothelial barrier. And RSV is known to infect the type two alveolar epithelial cells that are in the alveoli, in addition to those ciliated epithelial cells. The nuances and the details of this pathophysiology is much beyond the scope of this talk and really is a talk or two in itself. So I won't go into detail, but really just understand that there's a very broad spectrum of disease with RSV that ranges from infants who are at home with a runny nose and upper respiratory infection to those infants that are admitted to the floor with some mild obstructive physiology who are observed to those infants that are much, much more critically ill and severely ill in our ICU who have obstructive physiology or go on to develop pediatric ARDS. And again, this spectrum of illness doesn't exist in just those children with risk factors. This spectrum of illness exists in previously healthy children without risk factors for severe disease. And so it's the spectrum of disease that led us here at Northwestern and Lurie Children's to begin to wonder, well, can we look in the nose and can we look at gene expression in the nose of infants who, when they arrive to the emergency room and then ultimately arrive to our ICU and clinically look identical or indistinguishable, is the gene expression in the nose correlated with their clinical outcome? And the way that we started to try to answer this question and investigate it is we designed a study that's relatively simple. We recruited infants who were less than two years of age, are previously healthy, so they have none of those risk factors that we talked about at the beginning of the talk for severe disease, and we took a nasal scrape biopsy of their nose. Now nasal scrape biopsy sounds a lot more invasive than it actually is. The word biopsy I think is a little extreme here. But what we do is we take a plastic curette that has a silicone cup at the end and we gently drag it across the inferior nasal turbinate inside the nose. And what we're able to do is we're able to lift some of that tissue off of the nose. And within that tissue, what we have are the epithelial subgroups that I talked about, those different cell types, as well as virus and immune cells. And so we take all of those cells and we put them in a test tube. And within that test tube is a solution that lysis the cells and releases their RNA. And then we're able to freeze those samples and store that. And then once we're ready and we have all of those samples, we extract the RNA from those samples and we perform next generation sequencing to sequence the RNA. So what we're doing is called RNA sequencing. And so we're not sequencing the genome of these patients. What we're sequencing is the mRNA transcripts that they are upregulating. So what we're really looking at is we're looking at the genes that are expressed in the tissue. And from that gene expression, we can get information about how the host or the child is responding to the virus. And we can actually also detect the viral RNA in those samples as well. This slide gives you a summary of what our patient cohort looks like. So ultimately, we included 33 patients. We had to exclude a handful because they had inadequate or degraded RNA samples that we weren't able to perform sequencing on. But these are the 33 patients that were included in the study. And again, they didn't have any of those risk factors for severe disease. They were all previously healthy. Ten of those patients received mechanical ventilation. And 23 of those patients received non-invasive support. And so this includes both high flow nasal cannula as well as non-invasive positive pressure ventilation. But in the case of this cohort, all of these patients received high flow nasal cannula. And so I'll refer to them as non-invasive support through the rest of the talk, NIS for short. And the abbreviation for invasive mechanical ventilation is IMV. Importantly, when we looked at these patients and we compared the day of illness that we collected our sample, it was at a similar day of illness. This day of illness, of course, is subject to recall bias from the parent to the guardian. But it's important that they were at a similar day of illness because that's an approximation of where they are on the disease course. And of course, we want to compare patients when they're at a similar point in their illness. Now a couple of these patients have their sample collected pretty far out. And we were really interested in what does nasal gene expression look like really early in their hospitalization when parents are deciding to bring their child to care and to the attention of medical professionals. And so we set a cutoff of three days. And so moving forward, our analysis looks at 28 total patients. And what we found when we did our analysis is that among our patients, affiliated cell gene signature correlated with the length of hospitalization of these patients and the length of their RCU stay. And the way that we did that is through some computational techniques. And so this first technique is called weighted gene correlation network analysis. And you really don't need to understand sort of the fine details of how it works. And really the sort of simplest way to think about it is that what we do is we identify clinical characteristics, which I've listed here at the bottom of the slide, and we correlate those and we use this computational technique to correlate those with the expression of genes. And so we get the output of these different groups of genes, which are labeled modules. And what we found is that, as I stated at the top, that PICU and hospital length of stay correlated with a group of genes. And so when we looked at those genes and we looked at what processes, you know, biologic and cellular processes do those genes enrich for, they enrich for things related to cilia and ciliary function and ciliary cells, which was really interesting to us. And so when we further looked into these genes and we plotted them, just some example genes that are listed here on the right, and we plotted them against hospital length of stay, we saw a positive correlation between the expression of those genes and the length of stay of the patient. And so we further looked at this a little bit, or in another way rather, by looking at sort of the estimated amount of cells. So as I mentioned, when we collect our samples, we're taking a gross specimen of the node. So we're getting all of that tissue and all those different cell types. And we're not actually, part of our process is not to measure the number of different types that are there, but using computational techniques, specifically digital deconvolution, what we're able to do is we're able to use the relative expression of different genes to estimate the relative abundance of cell types. And you can see pictures here in this sort of middle panel at the bottom that the relative abundance of ciliated cells also correlated with hospital length of stay, which I apologize, it looks like the axis got cut off there, but this is hospital length of stay that it correlated with. And so altogether, what this tells us is among our entire cohort, so the patients that received non-invasive support, as well as the patients that received mechanical ventilation, that ciliated cell gene signature correlated with a clinical outcome. And in this case, it was both hospital and PICU length of stay. And so the next question we asked is actually that initial question that I posed is, if we retrospectively look at the gene expression in children who are otherwise clinically indistinguishable when they present to our ICU, can we learn something about their gene expression and their clinical outcome? And so what we did is we did a subgroup analysis of only those patients who received non-invasive support. And we split those patients into two groups. One was a shortened group, and we set the cutoff at three days. We picked the number three days empirically based on the median value of all of the durations of non-invasive respiratory support. And so the shortened group are children that received non-invasive respiratory support for less than three days. And this prolonged group is patients that received non-invasive respiratory support for more than three days. And we retrospectively compared those groups and looked at the gene expression in the nose. And what we found was actually consistent with what I talked about in the last slide. And that is that the patients that had prolonged respiratory support upregulated genes that are associated with ciliary cell function and the differentiation of ciliated cells. Conversely, the children that had a shortened duration of non-invasive respiratory support upregulated genes that are associated with those basal cells that we talked about, stem cells of the airway. And this was very, very interesting to us. And we thought a really interesting finding because we have these two groups of children that have very different clinical outcomes. Children who come in the ICU and leave within 70 or, you know, are off the respiratory, their advanced respiratory support within 72 hours. And these patients that have a more prolonged course of their illness and they have different gene expression in their nose. And so when we thought about this biologically, sort of what could this represent? What does this mean? We thought about the fact that these basal cells are the, like I said, the stem cells of the airway and differentiate to regenerate the airway epithelium. And so what we did is a secondary analysis where we looked at genes related to specific processes. And so we used a technique called gene set enrichment analysis or GSEA for short. And what GSEA does is it looks at a set of genes that are known to be involved in a biologic process. In this case, epithelial differentiation. And it compares between two groups of patients how that gene expression looks between the two. Is one group expressing more and higher level of those genes relative to the other? And sure enough, what we saw is in these children that had prolonged need for noninvasive respiratory support, we saw enrichment of those epithelial differentiation genes. And so this led us to a working hypothesis that in this moment that we were capturing gene expression, because we did only look at one moment and that is within three days of admission, that the children with prolonged need for noninvasive respiratory support had damaged mucosal epithelium and that epithelium needed to be regenerated by basal cell differentiation into ciliated cells. So that's our working hypothesis of the data that we saw. And we think, like I said, that's really interesting and I think tells us a little bit about sort of the biology of what's going on in the pathophysiology. And so the big conclusion from this study was that increased ciliated cell damage may be associated with prolonged critical illness in infants with RSV. And that ciliated cell gene signature is associated with clinical outcomes. And now our study was not designed nor was it powered to really look at predictions. So we weren't able to derive and validate a predictive model where we could actually predict what the clinical outcome of these patients would be. But this is certainly a proof of principle that that may be possible. And so there may be a day, and it may not be gene expression, it could potentially be protein or some other measurement in the nose of patients that is able to tell us a little bit about what their prognosis is and what their disease phenotype is going to be like. And that could be a very powerful tool in the future. Of course, our study, like all studies, had some degree of limitations. As I stated, this was bulk tissue. So we took all of these cells and we looked at gene expression representative of the tissue. So we can't attribute the expression of any of these individual diseases or any of these individual genes to any individual cells. And then also we only recruited for this study patients in our pediatric ICU. So we don't know that these findings will hold in patients who are admitted to the floor for some observation and suctioning and ultimately go home or even patients, you know, infants who are at home with a mild upper respiratory illness. And sort of the last thing that I'll say is you may be wondering, well, why the nose? Why did you guys choose to look at the nose when we talked about at the beginning that this is a disease of the lower airways? And that's because a group at Boston University actually showed that gene expression in the nose correlates really well with the lower airways. And so we are able to use the nose as a window to get an idea of what's happening in the lower airways in terms of gene expression. You also may be wondering sort of, you know, why is this important? Why do we want the prognostic, this prognostic information? And on the surface, parents are always asking us, how long are we going to be here, right? They're trying to plan their lives, think about work, trying to think about childcare if they have other children. But also I think, you know, not just in RSV, but across the board in medicine, we're moving towards precision medicine. And more and more, we're going to tailor our therapies to the exact phenotype that a patient has. And while we don't have any specific disease-modifying therapies that can, you know, sort of prevent some of the long-term consequences of RSV, we may, through techniques like this, be able to identify targets that we could intervene upon, and then we would need to be able to identify those patients that would benefit from those targets. And so that's important because there are long-term effects, and there are long-term consequences of RSV infections in young children. I know it's really easy for us to say like, ah, it's another respiratory virus. Oh, that kid's got another respiratory virus. But what we're finding more and more is there are long-term consequences. Thankfully, the mortality rate is low. The overall mortality rate of RSV is less than 0.1%. So we're all doing an excellent job in critical care of supporting these children through their illness. But we do know that there's long-term effects. Up to 30% of children who are previously healthy and have an RSV infection in infancy will have recurrent wheezing throughout infancy and into early childhood. The frequency of that recurrent wheezing does decrease with age, but it is persistent in these children. And then further, there's been some studies that have looked at cohorts of children who had lower respiratory tract infections, specifically RSV, under three years of age, and followed them over time. There's actually the Tucson Respiratory Study, which has been following kids since the late 80s, early 90s, and is now starting to follow these children into early adulthood, and has looked at their pulmonary function over time. And what we've seen is with children who've had RSV at less than three years of age, their pulmonary function, which was measured by forced expiratory volume, into early childhood was reduced relative to their peers. Now, they're not necessarily clinically symptomatic from it, and it can be a very modest reduction in their pulmonary function. But when we think about pulmonary function over time, and we think about sort of the health span and lung health over time, it's sort of these repeated infilts that can lead to chronic pulmonary disease in adulthood. And I think that's really nicely summarized in this figure that's here on the right, which comes from Robbie Calhoun's group at Northwestern Medicine, a nice review paper that they wrote about exposures and the risk of chronic pulmonary disease in adulthood, is we all have a trajectory of health that we're on, and specifically in this graph, we're looking at lung health. And sort of as we follow that trajectory, there can be exposures prenatally in early life, like an RSV infection, that can alter that trajectory. And then we enter adulthood on a different trajectory than we may have started on based on those exposures. And then exposures in later life, like work hazards, like environmental exposures, or illnesses in an adult, or genetic differences, can further alter that trajectory and can lead to chronic lung disease. And so it's important that we continue to investigate and understand why some children who are previously healthy have these severe RSV infections, so we can learn more about them, so we can identify them earlier, identify those therapeutic targets, and we can intervene earlier to prevent this alteration of lung functions, which alters their entire course of cardiovascular and pulmonary health. And with that, I'm actually going to hand it over to my wonderful colleague, Brie, who's going to talk to you a little bit more in detail about how we're currently managing RSV in the ICU. Thank you, Andrew, and thank you, Brie. Let's talk about the supportive care that is currently in use in the ICUs. Specifically right now, let's talk about high-flow nasal cannula. High-flow nasal cannula has the physiologic benefit of facilitating carbon dioxide washout from the dead space, thus decreasing work of breathing. And with that washout, we're then able to meet the peak inspiratory flow rate that we can deliver the prescribed oxygen that we are attempting to deliver with the flow rate. If you just do a quick math in your head, I usually do four times your minute ventilation, so tidal volume times rate, so that I don't have to remember ranges. But thinking about your peak inspiratory flow rate and wanting to then meet this requirement for patients, when we start high-flow nasal cannulas, we typically try to do it a max of two liters per kilo. Anything above that, and I have seen us try to do that in our setting. I'm sure that others have done the same. Anything above two liters really does lead to increased agitation with patients, and then the work of breathing that you're trying to actually ameliorate is actually worsened. My practice has been that when I go into the room and I hear the air I'm breathing blowing out of the nose from the doorway, it's likely a little too much for the patient. And so my practice has been to decrease it, get them settled, and then see how that goes. And the literature actually supports that anything above two, there's no significant value to that. Looking at high-flow nasal cannula in comparison to other modalities, such as low-flow nasal cannula and CPAP, it was noticed that in a randomized study with almost 1,500 patients, that there is no actual decrease in hospital length of stay in comparison to high-flow nasal cannula. However, there is a decreased need of escalation of respiratory support when compared to low-flow nasocannula. So while the patients did not necessarily stay less time in the ICU, there was a perceived worsening, specifically on 60% of those started on low-flow nasocannula, requiring the escalation to high-flow nasocannula. So from this, it gives me the, we should probably start patients on high-flow nasocannula and wean down rather than try to give them the lowest possible and then titrate up. When compared to high-flow, sorry, to CPAP, a randomized study done by Ramnoryan et al, they actually noticed that there was no need for intubation for those who were started on high-flow nasocannula. And as you can imagine, the need for sedation was decreased in those with high-flow nasocannula. CPAP tends to need patients, especially those who are prone to RSV bronchiolitis, who tend to be less than two years old, need sedation in order to keep a positive pressure mask in their face. So a decreased exposure to sedation was seen with those started on high-flow, and ironically, a decreased length of stay both in the PICU and in the hospital overall. For those that were termed non-responders to high-flow nasocannula, they tended to be those that when they presented, they were already hypercarbic, severely hypercarbic, and then had already a lower respiratory rate. So that meeting of the peak inspiratory flurry that we would have achieved with starting them on a two-per-kilo nasocannula would have been of no benefit to them. So yes, there are those who are non-responders, but if they're already in that too ill to even try category, they just are automatically excluded from that subset of people. And then bronchodilators, as Dr. Andrew Prigge was talking about, there's this clinical manifestation of obstructive respiratory distress or even the forced expiratory phase that you sometimes see on these RSV broncholytic children. And so it's not surprising that albuterol is one of those therapies that typically we tend to try. There was a study done by Drs. Gadomski et al. that looked at 30 trials that included more than 1,900 infants, and they looked at both inpatient and outpatient settings. Shockingly, there was no improvement in oxygen saturation with this magic albuterol that we all tend to try. And while there was no decrease in length of stay, in the outpatient setting, there was a 20% decrease in hospitalization. So those who were already outpatient and not too sick to need hospitalization, they actually responded to albuterol much better. So in the outpatient setting, perhaps there is an adequate use for albuterol for all when compared to those inpatient. However, there is an unclear subset of critically ill infants that actually may be responsive to albuterol. We have all seen it. But there is a theoretical benefit that perhaps these patients who do respond to albuterol are actually those who have asthma, and this RSV was the trigger that brought that asthma to light to the family or the caregivers. Many guidelines actually recommend a trial of albuterol for critically ill infants. So there is obviously, unless there's some history of bronchomalacia or trichobronchomalacia, there's no harm in trying albuterol and seeing how they respond, especially when we have this forced expiratory or obstructive pattern presenting. However, and this is the big asterisk, the ability to accurately assess the responsive to the trial of albuterol is pretty poor. I found a study that was done by Shrum et al. in 2017, where they looked at a single children's hospital, looking at before and 20 minutes after following a RAC epitherapy, where a nurse, an RT, and a physician, all three performed simultaneous examinations and assessed the response to albuterol in the population of intubated infants with bronchiolitis. And then they also at the same time took measurements of ventilator-derived pulmonary mechanics. And surprisingly, the provider clinical assessment was not a reliable method for determining responsiveness to albuterol in children with bronchiolitis. So when we, I know that in our setting, we talk about this patient is albuterol responsive or not. It is definitely a very subjective assessment and not one that currently we have a objective one. And this study clearly shows how poor we are as clinicians at assessing that responsiveness. And then there's the hypertonic saline that in our institution, I know that we use it a lot. And given the data out there, it seems like other institutions use it as well. Hypertonic saline, well, let's discuss more of this. There's different studies that show how effective it is. So when compared to normal saline and standard care, there was a shorter length of stay noted by half a day in this particular study that involved over 3,000 patients in 24 different trials. There was decreased hospitalization rate from outpatient to inpatient by 20% as well. And there was a lower post-treatment clinical score when you assess their responsiveness in the first three days of hospitalization. And the incremental analysis of RCTs involving over 4,000 children saw that there was also a significant improvement in the severity of the respiratory distress, shorter length of stay, and increased children's nighttime sleep quality with hypertonic NEVs when compared to normal saline NEVs. So clearly this feels like, yes, this works. But of course, then we see that there are other studies that are very specific to RSV. So the other ones, and this is something that we can talk about later on, but the other ones were not specific to RSV. These studies were very specific to RSV, and they were smaller as a result, did not show any significant difference in length of stay when looking at hypertonic solution and normal saline. And the same happened when, again, another small study in Switzerland looked at just standard of care, so fluid valence and oxygen therapy as needed compared to hypertonic nebulization. Again, there was no significant difference in length of stay. And then there's suctioning. Suctioning, as a bedside nurse, will tell you that whenever I heard anything that was not clear, I felt the need to go and looking for it with a deep suction, a good NP suction. And this finding did not shock me at all. The fact, deep suctioning actually is associated with increased length of stay. And this is where perfect is the enemy of good. Wanting to make someone sound clear might actually keep you in the ICU. We are suctioning more frequently because you're trying to get clear. So not shockingly, in a retrospective cohort study where 740 infants were looked at age 2 to 12 months with bronchiolitis, deep suctioning was associated with increased length of stay. And any suctioning that wasn't invasive, so just like the oral and just not deep, but simple external nasal suctioning with frequencies that exceeded four hours also led to increased length of stay. So it sounds like the magic bullet, based on these studies, is non-invasive external nasal suctioning that is no more than four hours and not trying to go for a clear whistle. And with that, I pass it on to my colleague, Dr. Coates. Thank you. So I'm just going to talk briefly about, you know, what can we get excited about, what is coming next in therapy and prevention for RSV. So recently, there's been an increase in the use of percussive ventilation in multiple ICUs across the country. So percussive ventilation, if you're not familiar with it, is oscillatory ventilation on top of normal convective rate with the rationale that this might help with secretion clearance to clear it out of the airway to improve CO2 clearance as well. And recently, Ben White published, in Respiratory Care, a prospective trial of 41 patients. And what this sort of proof of concept study showed was that if you look at before starting percussive ventilation versus after, you could demonstrate that there was improved ventilation in those children and improved oxygenation, in addition to a decreased peak inspiratory pressure after 24 hours of initiation. So I think more to come on how percussive ventilation might fit into the management of bronchiolitis. Next we have azithromycin. So azithromycin has had some attention in RSV over the last couple of years. There's a couple of reasons for that. One is that in vitro, it's been shown to have some direct antiviral effects on RSV. And there are also some known anti-inflammatory effects of azithromycin in the lungs. And so those two reasons have drawn attention to it as a potential therapy for RSV. Michelle Kong in Alabama did a small RCT a few years ago that included 48 patients. And what she found was she had three groups. One received low dose azithro, one high dose azithro, and the other placebo. And these were critically ill patients on high flow or intubated. And she found that the 16 patients who received the high dose azithromycin had a decrease in their PICU length of stay. So to follow that up, she has a randomized controlled trial currently enrolling in, I think, six PICUs across the country to see if that holds true with a larger number of patients. This has been looked at in non-ICU patients. And originally, there was some excitement that azithromycin might decrease the recurrence of wheezing after a RSV infection. And unfortunately, in larger studies, that has not held true. So right now, there's no data to confirm that azithromycin during an RSV infection can prevent future wheezing. And then the exciting things on the frontier for prevention of RSV infection, clearly both Andrew and Bri have talked about the negative consequences of an RSV infection, not just in the short term, potentially landing a child into the ICU, but also in the long term with recurrent wheezing. So nearing approval are long-acting monoclonal antibodies. So unlike our current monoclonal antibody, which has to be, you know, a brand name known synergist has to be given every month throughout the RSV season. These longer acting monoclonal antibodies are designed to only be given once per season. And there was a recent publication in the New England Journal of Medicine demonstrating that when they treated, they randomized almost 1,500 infants to receive this antibody. They decreased the need for medical intention during an RSV infection by approximately 75%, so 12 versus 25, and then decreased the need for hospitalization, but that was not significant. So these will be interesting to see how, once these get approved, if they are adopted and how they impact the children coming into our hospitals with RSV. And then in addition, there've been multiple RSV vaccines in the work. So the history of vaccination for RSV is complicated because the original study in treating infants with an inactivated virus actually caused antibody-enhanced disease. And those infants who were treated with the vaccine back in the 70s had an increased risk of hospitalization and death. So that slowed down the research into RSV vaccination for quite some time. But with new advancements in understanding what part of the vaccine the body best responds to to make antibodies, we have a better understanding of this pre-fusion F-protein such that it's been manipulated in a way that can optimize the antibody response. And this has been reported recently, but not yet published. So we're waiting to see the actual publication from Pfizer, who has made this vaccine, which is designed to be given prenatally, so to people while they're pregnant, to passively deliver antibodies to the infant and protect them for hopefully up to six months. So in their report, they have said that they had a randomized trial of 7,400 mother-infant dyads and were able to show that they decreased the incidence of severe illness in infants less than 90 days by about 92%—sorry, 82%—and infants less than six months by almost 70%. Hopefully this would, if this holds true, would dramatically impact the number of infants developing severe illness with RSV. But of course, we have to see if this, how this data plays out in real life, and also how many families choose to get these vaccinations or these antibodies to see whether or not it really impacts our rates of hospitalization. So, there's lots of people that I think the folks here today had wanted to thank and some funding. We also have listed references here for people to go back to if you pull up the webinar later, so that you can go through the papers that were described. So there's two pages of these in here that I'm pausing on so that you can pull up later. And I'm really excited to actually spend the rest of our time discussing the things that were presented today and hear what people are interested in. I have, there's a couple of questions that have popped up in the chat that I will start with. One is for Andrew, in regards to your research for the nasal transcriptome. There's a question about how this might be relevant to other pathogens, like rhinovirus flu or paraflu, et cetera. Yeah, that's a really great question, and thank you for that question. So, you know, our group actually thinks about a lot of different viruses, not just RSV, but also SARS-CoV-2 during the height of the pandemic, we're interested in influenza virus. And while all viruses are different in sort of the ways that they enter cells and the proteins that they express, there are some things with regard to the host response that do appear like they're conserved across viruses. And so certainly there could be utility in scraping the noses or swabbing the noses for whatever, ultimately, it ends up being, whether that's gene expression or some protein analyte to help prognosticate and understand sort of what phenotype these patients are going to be in with their disease. But there are certain things that are conserved across viruses in terms of the immune responses, and there are certain things that are different. And I think we would have to study each virus independently and compare them, but I certainly think it could be applicable to many different types of viruses. Awesome. Thank you. There's a couple of questions coming in about seeing older children with RSV, particularly recently this season, and then in general, not like adults with RSV. So let's start with if, I have a couple thoughts, but I'm curious to hear yours about why we might be seeing some older kids with RSV more recently. Yeah. So I think we are still in an ongoing pandemic with SARS-CoV-2, but there were a lot of different sort of public health policies that were put into place to try and curb the sort of peak of the pandemic. And obviously those, you know, for the most part were shelter in place and to wear masks. So, you know, there's a cohort of children who would have otherwise seen RSV from an older sibling, from a parent, from daycare, from school, who didn't see it because they were sheltering in place and they were appropriately masking and they were being very conscientious about their hand washing. And so I think some of those kids who would have previously seen RSV haven't seen it before. And so we're starting to see those children present to our ICUs. And there's another question about adult patients, like when do we expect an adult vaccine, which actually that is coming on the heels of the maternal vaccine. So probably in the next couple of years, we've certainly, we do know epidemiologically that patients over 65 can have severe RSV infections similar to younger children. And there are a couple of questions about ventilating both children and adults with RSV. So one question about, you know, suggestions for a question about how best to address the secretions that we see with RSV in a ventilated patient. And I think we could maybe, Brie, you could talk a little bit about that and what tricks we have in children that may or may not be relevant to managing an adult. Yeah. Interestingly enough, this is something that actually came up last night. I was on call last night with several of our patients and one of the things that we actually tried successfully for ventilation was IPV, also ventilation and secretion management. So yeah, while I fully support that perhaps deep suctioning in a non-ventilated patient does not seem like the right thing to do once the tube is in and secretion burden is a problem, then definitely suctioning with, sorry, doing IPV suctioning with hypertonic solution has actually been successful from what I'm seeing clinically. And there is a question about the use of percussive ventilation versus conventional and if we see a difference in ventilator days. My understanding is we don't know that yet. I haven't seen a study at comparing the two directly. I think, Brie, do you want to speak about your experience with percussive ventilation and when it's most useful? Yeah. I think that when I think about percussive ventilation, I think about the VDR specifically. And most of that I see that it's useful when the secretion burden is high. So it feels like on its just hyper, sorry, it's just hypercarbia on its own doesn't seem to be sufficient enough for the VDR to be significantly useful, at least not different from IPV. I don't know if you both would disagree with that, but that has been my experience that when I think about the secretion burden being the issue with hypercarbia, I think about percussive ventilation. Excellent. And Andrew, there's a few questions about co-infections. So what do we know about multiple viral infections? Does that make a child more sick, less sick? And does that change your management strategy? So in terms of whether or not it makes a child more sick or less sick, the data is actually mixed. It depends on the study you looked at in terms of whether one, two, three, sometimes we can have four positive viruses on these multiplex panels, whether or not that makes a difference in the severity of illness. And some of that sort of mixed data may play into whether that these infections are active because we know for viruses like rhino enteroviruses, you can continue to shed genetic material and that will be picked up on the PCR assay for long periods of time after the infection. And the combination of viruses, depending on the study that you look at, may make a difference. It seems that perhaps RSV plus something else, there may be some signal to suggest that those kids do a little bit worse clinically and specifically RSV plus adenine. But in general, the clinical data out there, the observational studies that have looked at kids that have one versus one or more viruses is pretty mixed in terms of the clinical outcomes. In terms of the management, when I'm taking care of these patients in the ICU, you know, the only time that it would change something is if one of those viruses has a treatment that we could use. So, you know, if the patient is positive for SARS-CoV-2 and RSV, I would, you know, implement the strategies that we use for SARS-CoV-2, you know, including remdesivir and decadron. And if the patient was positive for influenza virus, I would employ Tamifluzine if they're critically ill and in the ICU. But otherwise, in terms of my management, in terms of supportive care and how to support them through their illness, the number of viruses doesn't really change how I manage this patient. And since we only have five more minutes, I was wondering if you guys could give me like your wish list of what do we need to know, like what do we need to know about RSV? And how might your research, Andrew, help us with that? And Brie, how is that going to help us better manage these kids in the future? Yeah, so I'll start. So I think, you know, what we need to know is sort of what I alluded to in the talk is sort of why is it that there's a spectrum of disease? Why are previously healthy children having this severe infection? And the literature that exists out there, we didn't really talk a lot about this in detail, suggests that it's related to the host response, but it's something about the child's immune response to the virus that is contributing to their severity infection. And so we really need to sort of boil down to what specifically is that response? What is it about their immune response that's contributing to the severity of disease? And then we need to identify therapeutic targets. Are there proteins or different receptors? And can we target those with small molecules or biologic agents to interrupt or modify the disease course? And if we're able to do that, we can prevent hopefully the worsening disease, all of the comorbidities that go along with critical illness in the acute setting, and then some of these long-term effects that we see. In parallel to that, we need ways to understand or ways to identify which children are at risk for that more severe disease. And so things like, you know, like we've done and are continuing to do, looking at the nasal genome or the nasal transcriptome, rather, and finding ways that we can potentially identify patients early in their disease course, so that when we identify these pathways, we can intervene in an appropriate time when it's not too late to have a modifying effect on their disease course. I think for me, it would be lovely to actually have more studies that were done in the PICU setting. When I was doing, just looking at literature for this talk, I actually did not find enough that was just centered around PICU patients. There was just extrapolation of how to prevent admission to the ICU, but there was very little information about ICU patients, especially in this age group. And then there is an understanding that bronchiolitis is most likely RSV, but there is actually not a specific, there were very few that were specific for just RSV. So it would be nice to see, truly, let's quantify what RSV is actually, what virus is actually causing this bronchiolitis, while I agree with Andrew that the management would not necessarily be significantly different, just to understand the phenotype or the presentation and therefore the interventions that are, do we need to tailor it? Do we eventually change that? And then, percussive ventilation, I think is an interesting thought, especially when secretion management isn't there. Is there actually a benefit to just percussive ventilation for the sake of hypercarbia and not just for secretion burden? I think that there's still a lot that could be learned. Fantastic. Thank you guys both for sharing your wisdom with us today. I know there are a couple of questions that I didn't get to in the chat, so I apologize for that. I'll try and see whether or not there's a way to answer them separately, since we're running out of time, but thank you all for your attention today, and I certainly learned some things. I hope the rest of y'all did too. Thank you so much for having us, Dr. Cook.

RSV

respiratory syncytial virus

critically ill children

gene expression

treatments

ICU

therapeutics

vaccines

severe infections