Good afternoon, and welcome to the first of CHESS's RSV webinar series. My name is Dr. Ryan Maves. I'm a professor of medicine and anesthesiology at the Wake Forest University School of Medicine in Winston-Salem, North Carolina. I have the pleasure of being your moderator today. I have the pleasure also of working with two fantastic speakers who are going to discuss today the impact of respiratory syncytial virus infections in adults, measuring the impact. I'd like to first introduce my colleagues and our speakers for the day, Dr. Megan Conroy, who is an assistant professor of medicine and the associate program director for pulmonary and critical care at The Ohio State University in Columbus, Ohio, and Dr. Kelly Pennington, also an assistant professor of medicine and the associate program director for the ALD and Lung Transplant Fellowship at the Mayo Clinic in Rochester, Minnesota. We're going to get started right away with Dr. Conroy, but before we get totally on the road, if I could ask any attendees to please feel free to put any questions in the Q&A on your Zoom links, and then we will address those to the best of our ability at the end of our talks. So, Dr. Conroy, take it away. Thanks, Dr. Maves. So I, as I mentioned, I'm at Ohio State University in Columbus, Ohio, and my practice spans both pulmonary medicine as well as critical care medicine, within that sort of a focus on obstructive lung disease. Next slide, please. So today, I am tasked and hope to give you a good general overview of RSV, reminding you of the pathophysiology involved with this virus, and also give you an idea of the key components of the epidemiology of RSV in adults. Next slide. So starting with our pathophysiology, RSV is a single-stranded RNA virus that causes seasonal epidemics of respiratory infections. I think even the lay public know this is a significant cause of death and disease in children, but it really is very significant in the elderly as well as the immunocompromised patients among adults. And as viral testing expands, we're really learning more and more about just how often RSV is affecting hospitalized populations. Next slide. RSV attaches to the ciliated apical respiratory epithelium cells and causes fusion of infected cells to neighboring uninfected cells, creating a syncytia of cells. This is where the name respiratory syncytial virus derives. Shedding virus from those cells further travel through that respiratory tract by the beat of the cilia along that respiratory epithelium. And RSV can infect the surface of really any conducting airway, extending from the nasal passages down to the smallest of bronchioles. And it leads to a damage on the superficial, the airway lining there. And it's really that damage to the airway lumen that causes many hallmarks of the disease. So causing further obstruction among the really smallest airways, which can lead to a really severe bronchiolitis in the smallest of patients. But also this luminal epithelial damage can drive some of the susceptibility that comes for secondary bacterial infection. Next slide, please. RSV in adults really can create a broad spectrum of disease. It is very rarely asymptomatic in adults and often is going to give you upper respiratory infectious symptoms. For those with underlying obstructive lung disease or cardiac disease, this may also cause an exacerbation of those underlying conditions. And in others, RSV can progress to a significant lower respiratory tract infection, viral pneumonia, usually up to the severity of the acute respiratory distress syndrome. RSV virus itself is classified into subgroups A and B based upon antigenic variation. Usually one of these subgroups will predominate in a season with a little bit of geographic variation therein. The molecular structure of the virus seen here on the left is comprised of an envelope that encases the viral genome. This genome encodes a total of 11 proteins, two are non-structural and nine are structural. One particular protein for you to be aware of as we learn about more of the emerging pharmacologics and treatment of RSV is the F-protein or the fusion protein. This protein brings about the fusion of the host and viral cell membranes, but it also further potentiates infection by causing downstream fusion of the infected and non-infected adjacent respiratory epithelial cells leading to that notable syncytia, that hallmark of the RSV disease. This protein becomes rather important as a target for a variety of treatments targeted at preventing RSV infection, and we'll learn more about those pharmacologics in next week's webinar on July 18th from Dr. Maves. RSV is spread predominantly by droplet transmission, but like most respiratory viruses, also has the ability to travel slightly in aerosols, and it's thought that RSV aerosols can travel a few feet. It is notably able to stay stable on hard surfaces or pans for several hours, and fomite transmission can be a significant modality of transmission within these droplets. So compared to many other respiratory viruses that we're used to, what this means is that hospital precautions should both be droplet as well as contact, so not only wearing that mask and that eye protection, but also the gown and gloves to reduce fomite transmission from contact. Incubation of the period of the virus from exposure to disease manifestation can range from two to eight days, and people are often contagious a day before symptoms start. They may remain contagious for three to seven days after the start of symptoms. And unfortunately, a single infection does not confer long-term immunity. Neutralizing antibodies show a significant four-fold decline just one year out from infection in about 75% of adults. So you absolutely can have repeated infections from RSV. In addition to that humoral immunity, though, cell-mediated immunity plays a pretty important role in viral clearance and recovery. This becomes important with those who have altered CD4 or CD8 T cell function, they become at higher risk for prolonged viral clearance and time to recovery, especially in our patients who have immunosuppression such as stem cell or solid organ transplants. But it also may be a part of the component of why those with more advanced age show more prolonged shedding and longer recovery with the feature of aging, including altered cellular immunity. How common is RSV? This is actually a surprisingly difficult question to answer. We don't have a great idea of the total incidence of RSV in the country because unlike influenza, we don't actually have really robust tracking systems for the prevalence of RSV. It is estimated that it is prevalent enough though that almost all are infected with RSV by age two. But our lack of long-term immunity from a single infection means that we can get repeated infections thereafter. It's estimated that it probably counts for over a million health care visits in a year and up to 100,000 hospitalizations per year. You'll see on the slide these variations from 60,000 to 100,000 hospitalizations are pretty wide range to quote you, but it really gets to the lack of really robust tracking systems. It's estimated that it may account for up to 10,000 deaths a year among patients over the age of 65. But again, these numbers aren't perfect. With expansion of viral testing becoming more readily available, we are probably more likely in these years compared to a decade ago to be recognizing the role of RSV in our patients and their respiratory infections and really becoming more and more evident over time. Next slide. So overall, I can tell you though that RSV really makes up a meaningful proportion of respiratory infections. Some estimates suggest that it may be 5% to 7% of all upper respiratory infections in a given season and adults are due to RSV. And there is a significant seasonal variability to this virus. It's up to a nine-fold increase in its incidence at its peak compared to its trough. Next slide. And there in the before times, before COVID, before the pandemic was a very kind of predictable cadence to that seasonal peak of the virus. Shown here in varying shades of blue, progressing from the mid-20-teens up to 2020 in darker blue, there was a significant peak really going from about November to about March here, shown from morbidity and mortality weekly data. 2020 broke it, as with everything else, and really kind of decreased that curve. But by the next season, we did start to see a resurgence in RSV, and in fact, earlier in the season than typical, but really starting to inch up more towards that peak. And I think kind of moving more and more towards the prior typical seasonality of this virus, we're seeing that peak in winter months of RSV, as much of viral transmission behaviors kind of return to pre-pandemic baseline. Next slide. This data is about 10 years old now, but it looks at a subset of hospitalists from 2010 to 2012 with an active population-based surveillance program, looking at people who are hospitalized for community-acquired pneumonia. So just among adults hospitalized for community-acquired pneumonia, this is five hospitals in Chicago and Nashville. And it doesn't exclude those who are immunocompromised or have recent populations, so are really just a snapshot of community-acquired pneumonia. What's the most common pathogens seen there? And in this population, RSV is the fifth most common isolate. Here behind rhinovirus, influenza, strep pneumo, and human metanemovirus, in this patient population, 3% of adults who were hospitalized with pneumonia tested positive for RSV. So while it certainly is not the most common cause of pneumonia, it is an important cause of pneumonia, including among those who require hospitalization. Next slide. And we know that an important risk factor for hospitalization and severe disease due to RSV is advancing age. This data again from the CDC, looking at the mid-20 teens to 2020, you'll see that with advancing age comes increasing prevalence of hospitalization, really seeming to increase significantly after the age of 65, picking up that risk of hospitalization due to RSV. Next slide. So what, in addition to age, is a risk factor for requiring hospitalization? I think any of the pulmonologists on this call will be unsurprised to hear that certainly underlying lung disease, and specifically obstructive lung disease, is a significant risk factor to require hospitalization with RSV. But also importantly is immune compromise, and specifically those who have stem cell or solid organ transplants at higher risk to require hospitalization. We'll hear more about that patient population from Dr. Pennington later. An additional comorbidity that is really very frequent, however, and increasingly recognizes the importance of CHF. We do know that COPD and asthma may flare or exacerbate from RSV. As for kind of what proportion of flares of obstructive lung disease that may not even require hospitalization, or even those that do, is due to RSV is really hard to quantify. Sometimes these things are under-tested, but we know that viruses are a very common cause of flares of obstructive lung disease, and RSV is likely a reasonable proportion among those. Next slide. CHF, in particular, is a very significant risk factor for hospitalization for RSV. This also from CDC data, an analysis that looks over a three-year period of time among patients who are hospitalized with RSV, those with CHF, or those without CHF, those with RSV. Hospitalization rates are actually a lot higher in those with CHF. In all adults, those with CHF are eight times more likely to require hospitalization than those without during RSV infection, and that holds to three times higher still in our more elderly population that's more likely to be admitted. CHF is a really common comorbidity to see here, and RSV alone may be a cause of CHF exacerbations as well. Next slide. So as we're thinking about the impact of various viruses, I think some of us may have a tendency to kind of compare viruses to the flu. I think we all kind of have this mental snapshot of the badness that seasonal influenza can cause, and it can be easy for us to kind of conceptualize things in relation to influenza. So taking one comparison here among hospitalized patients with RSV versus hospitalized patients with influenza, this is from a data set of a four-year-long study at a Kaiser Permanente facility in Southern California. And they found that in comparison to influenza, RSV infection was associated with a greater odds of a length of stay over a week, greater odds of ICU admission and pneumonia, more likely for COPD exacerbation, and even greater mortality within one year of admission. Next slide. So there's a mortality trend shown here, really, that RSV does seem to have importantly worse outcomes compared to influenza. Next slide. From this same study, looking at a variety of outcomes, you'll see the point estimates here in Forest Plot comparing influenza on the left and RSV to the right, looking at a number of outcomes. Shown here in the Forest Plot are estimates for length of stay, the presence of pneumonia, and the higher number of recurrent hospital admissions up to six months out. There are also trends for higher severity in RSV infection compared to pneumonia for risk of ICU admission, mortality, and more subsequent hospitalizations. Next slide. So this meta-analysis combined data from 103 studies to provide pooled point estimates, and I think provides some really striking estimates of outcomes among higher-risk individuals. So for those who are of more advanced age, greater than 70, and those who are high-risk patients who are both of advanced age and with underlying cardiopulmonary disease or immunocompromised, some of these outcomes of having lower respiratory tract infection with pneumonia requiring hospitalization, a quarter of patients here, or among ICU admission and are high-risk patients, those with immunocompromised, up to 25% of patients really requiring ICU admission for this RSV infection. This same study also provided case fatality rate in a variety of populations, approaching 8% here for hospitalized older adults, and really going up further for those who are immunodeficient or with underlying cardiopulmonary disease. So there really is an appreciable mortality among this disease, and a pretty significant proportion of these patients that are not just showing up in our pulmonary clinics, but are really ending up in our ICUs. Similar data from the CDC, looking kind of across all ages and all adults, shows really pretty high frequency of ICU admission, here estimating up to 20% of patients admitted to the hospital with RSV may land in our ICUs, and with appreciable death rates as well. Next slide. So overall, what I think this data can show us is that RSV is of public health importance in the adult population. Though we hear a lot about the system strain in our youngest patients, it really does have a significant impact, not just in the prevalence of upper respiratory tract infection, but really in significant hospital admissions, morbidity, mortality, critical care stays for a lot of these patients. This is most significant among the RSV patients, and it's really a pretty significant number significant among those greater than 65, those with underlying cardiopulmonary disease, and very significant in our transplanted populations. You may see it in your pulmonary clinics, flaring obstructive lung disease, but also really seeing it in the ICU. And up until now, really entering a new era, we haven't had much in the way of prevention of this disease. We've had hygiene and masking, kind of behavioral measures that we all know can help to contain infection in a community and contain for risk of nosocomial infection, and until recently, really no targeted treatment options, but really just supportive care for this virus. And so hopefully entering a bit of a new era when it comes to RSV, and we'll hear more about some of these targeted prevention treatment options from Dr. Maves in next week's webinar. But for now, I will hand it over to Dr. Pennington to explore a little bit further the impact of RSV in immunocompromised patients. Thank you so much, Dr. Conroy, for that excellent overview of RSV in our adult population. For those of you who are just joining, just a reminder to put any questions that you may have in the Q&A form in the chat box so that we can answer those at the end of this presentation. As announced at the beginning, I'm Kelly Pennington. I'm an assistant professor of medicine at Mayo Clinic in Rochester. My clinical area of practice really focuses on lung transplant patients, as well as pulmonary complications and other transplant populations. Next slide. Today, I have the privilege of talking to you guys about RSV in immunocompromised patients, specifically RSV in transplant populations. Respiratory syncytial virus, or RSV, is a common respiratory virus that can cause infections in people of all ages. While RSV infections are usually mild and self-limiting in healthy individuals or adults, they can be more severe in certain populations, and specifically in our immunocompromised patients. We likely don't know the true impact of RSV on immunocompromised patients, as alluded to by Dr. Conroy. A lot of this could be secondary to the fact that we just don't test for RSV, and every patient who develops respiratory symptoms are a respiratory illness. Lung transplant patients and bone marrow transplant patients right now are the best studied populations that we have in terms of our immune-compromised hosts, and that's probably because they have the highest morbidity and mortality, or what we assume to be the highest morbidity and mortality, from RSV in comparison to other immunocompromised patients. More recent reviews using contemporary diagnostics measure our incidence of RSV to be somewhere between 4 and 10 percent, although it has been reported up to about 12 percent in allogenic bone marrow transplant populations. Next slide. Just like in healthy adults, RSV in our immunocompromised patients spreads by respiratory droplets. The incubation period is anywhere from two to eight days, and most patients are contagious for about 10 days, although, as we'll see, that can last for quite a bit longer in our immunocompromised patients. Generally, this remains a community-acquired transmission with seasonal variation. In addition to the seasonal epidemiology of RSV, however, the time that it takes to RSV, however, the time from transplantation really plays an important role as the clinical course of RSV tends to be more aggressive in the early post-transplant period when our patients are under the most intense immunosuppressive regimens. It is also very important to mention in our immunocompromised populations that nosocomial transmission really also plays an important role. In wars where there are specifically isolated transplant patients, such as bone marrow transplant or lung transplant patients, nosocomial transmission has been responsible for maybe up to 50 percent of all cases of RSV. Next slide. So, RSV makes up a significant portion of respiratory viruses in transplant patients. In a retrospective study performed of 1,300 immunocompromised patients published in the New England Journal in 2015, routine assessment of BAL fluid and multiplex PCR of 20 viruses, about 35 percent of those were found to have viral infection. And of these, RSV was the fourth most common respiratory virus identified, comprising about 10 percent of cases. If we look at this table that was compiled by Paulson and colleagues and published in the Clinics of Chest Medicine in 2017, we can see that RSV is not the most common respiratory virus in our transplant patients, both solid organ and bone marrow transplant patients. But it is identified in up to 20 or 30 percent of cases, depending on the exact population. And there's significant morbidity and mortality associated with RSV in our immunocompromised population. Next slide. As I alluded to earlier, bone marrow transplant and solid organ transplant recipients have a prolonged relation of illness that's also driven by longer periods of viral shedding that can last for weeks or even months after the initial infection. Immunocompromised hosts do have a higher risk of progressing to more severe disease with lower respiratory tract infections or pneumonia, which is associated with higher morbidity and mortality when you compare it to other respiratory viral infections. Up to half of bone marrow transplant patients or about 40 percent of lung transplant recipients with RSV progress to lower respiratory tract infections and experience a high rate of RSV associated mortality. In a 10-year retrospective cohort study of 239 patients with RSV, approximately 15 percent of those patients developed a bacterial co-infection of whom 80 percent had bacteremia and about 20 percent had bacterial pneumonia documented on a BAL. Bacterial co-infections are likely common in the result of RSV-induced injuries to the respiratory epithelium, thereby increasing bacterial adherence, but also increasing the morbidity and mortality associated with this disease. Next slide. Looking specifically at bone marrow transplant populations, there are several risk factors that may increase the risk of contracting RSV. Many of these have to do with the severity of immunocompromised state. For example, the pre-engraftment phase, allogenic transplant recipients, and patients with graft versus host disease have a higher risk of contracting RSV. It's also important to note that those who are hospitalized likely also have an increased risk of developing RSV from nosocomial spread. Currently, the estimated incidence in RSV in bone marrow transplant patients is as high as 12 percent. Next slide. Progression to lower respiratory tract infections or pneumonia is estimated to occur in about 40 percent to 50 percent of RSV cases in bone marrow transplant patients. There are several factors that are significantly associated with disease progression, including a history of smoking, conditioning prior to bone marrow transplant with high-dose total body irradiation, or an absolute lymphocyte count of less than 100 at the time of upper respiratory infection onset. Other factors include allogenic transplant recipients, neutropenia, and graft versus host disease, particularly those who have pulmonary graft versus host disease. Extremes of age also increase the risk of patients being more likely to develop lower respiratory tract infections. Specifically, those less than two years of age are greater than 60 years of age. Next slide. Data is really limited on RSV in solid organ transplant groups. Our most robust data comes from lung transplant recipients. They tend to be the best studied and appear to have the highest risk of RSV-related morbidity and mortality compared to other solid organ transplant recipients. Other solid organ transplant groups likely have an increased risk of developing RSV compared to healthy adults and likely have a slightly increased risk of morbidity and mortality, but the overall mortality for this group is believed to be relatively low. RSV has an incidence of roughly 6 to 15% in adult lung transplant patients and accounts for about 10% of respiratory viral infections. It's noted to progress to lower respiratory tract infections and about 40% of lung transplant recipients. Lung transplant patients may initially only present with shortness of breath or subtle changes in pulmonary function testing without the typical symptoms of severe disease, but then may subsequently progress. Risk factors for morbidity and mortality in this population include young age, being early in the post-transplant period, or recent rejection. Those are areas of more intense immunosuppression that may make them more susceptible hosts. Next slide. Determining the exact attributable mortality of respiratory syncytial virus in specific patient populations is actually pretty challenging. The mortality rates due to RSV and BMT patients have been reported to range anywhere from 4% to 30% in different studies, but most often is reported to be around 10%. The same is true for lung transplant recipients. RSV attributable mortality has been estimated to be around 5% to 20%, and other solid organ transplant recipients, as mentioned, likely have a much lower attributable mortality. The best estimation for this population as a whole is likely to be somewhere around 10%. Risk factors for mortality in bone marrow transplant and solid organ transplant populations overlap and are primarily due to the degree of T cell immunosuppression as well as older age, specifically greater than 60 years of age. More than just mortality, though, RSV infection can have a long-term sequela in both our bone marrow transplant and lung transplant populations. Specifically, the infection can have long-lasting effects on lung function. Bone marrow transplant patients who have contracted RSV are estimated to have a long-lasting decline in FEV1 of around 5% to 10%, and some studies even report a lasting reduction in diffusing capacity. In terms of long-term sequela, lower respiratory tract infections caused by RSV have been associated with pulmonary graft versus host disease in bone marrow transplant patients, as well as chronic lung allograft dysfunction in lung transplant recipients. Next slide. In summary, most data on RSV in immunocompromised patients comes from retrospective studies in bone marrow transplant and lung transplant recipients. We know that there's significant risk for progression to viral pneumonia and possibly secondary bacterial infections. The degree of immunosuppression appears to be the biggest risk factors for contracting RSV, developing lower respiratory tract infection, and for morbidity and mortality. At this point in time, we'd like to open it up for questions from the audience. Well, thank you very much, Dr. Conroy and Dr. Pennington, both of you. That was fantastic. Just a quick reminder that next week we'll have a follow-on session with the three of us where we will talk about vaccines in detail, but this actually gives us a nice lead-in that we can maybe, not everyone can go to both sessions, maybe chat for a moment about it. When can we expect the RSV vaccine? My understanding from GSK and from Pfizer is that their vaccines should be available sometime this autumn. We haven't seen a date yet, and there is still some discussion about who would be ideal to receive it and so forth. ACIP has issued some recommendations. Largely, this would be incorporated into the influenza and presumably COVID booster season. How we tie those together going forward is still an open question, though, but we'll talk about that more in greater detail. Let's just start with diagnostics. In terms of diagnostic testing, and I'll start off with Dr. Conroy for this one, what in your practice is the most common mechanism for diagnosis that you use? Usually, these are pharyngeal PCR-based swabs and diagnosis of RSV. In my facility, we often swab for RSV co-swabbing with flu and may also get it in some of these extended viral respiratory panels that might be more indicated, particularly in the immunocompromised patients. In patients who are presenting with upper respiratory, lower respiratory viral symptoms, even admitted to the hospital, it's very important from an infection control standpoint to consider RSV in addition to considering influenza, particularly with that seasonal variability. But I think, as we discussed our numbers of under-recognition, probably less likely to be swabbing in the clinic. Patients coming in, we can do our flu swabs. They've got their COVID home testing because it doesn't, at this point, impact our treatment to things. It's going to be symptomatic treatment regardless. Really largely seeing that testing from nasopharyngeal PCR-based swabbing among patients getting admitted to the hospital. I think, in a lot of places, still opportunity to increase the diagnosis of RSV among patients presenting with respiratory complaints to the hospital. Excellent. Dr. Pennington, how does this differ in your practice, if at all? I think we have a very similar practice. Just speaking a little bit more onto our immunocompromised host patients because those are the patients that I see and interact with most often. I think we have a little bit more of a tendency to do broad-spectrum PCR from nasal swab or even lower respiratory tract collections, such as with a BAL, especially if patients are demonstrating signs of lower respiratory infections. In our general ICU population, that's not necessarily immunocompromised. We do often do the co-swab with just influenza and RSV. I can say in my own practice that what I do in the ICU and what I do in the office are a little different. In the unit, at least at Wake Forest, we do tend to get the broader-spectrum PCR, in part because of how it affects infection control, that we do have slightly different infection control practices for RSV compared with, say, influenza or obviously COVID. When I'm doing transplant ID clinic, though, very much like Dr. Pennington, we tend to cast a very wide net. In a more general population, RSV, we kind of jokingly say we treat it by admiring it with primarily symptomatic management. One could argue that there's not a lot of benefit in diagnosing a disease we can't do anything about right now. All right. Another question. Dr. Conroy, this is for you. You mentioned CHF exacerbations in RSV. Certainly, we've seen in other populations and in other settings an associational link between viral respiratory infections and cardiovascular disease. I think one of the more classic ones is influenza, where with influenza, we know that influenza is associated with an increased risk of myocardial infarction, increased risk of stroke. We've seen that influenza vaccination reduces the incidence of those things. When you look at this RSV heart failure relationship, does this seem to you like it is something like that, that's just sort of an epiphenomenon of severe viral infections? Or is this something unique to the virus, do you think? It's probably a little bit of a combination of both. Similarly, in RSV to what we've seen in influenza, the presence of this acute viral infection really increases systemic inflammation. It's probably that link of increase in systemic inflammation that's leading to plaque instability, more likelihood of MIs among those with coronary artery disease. In CHF, even separate from those who require admission to the hospital, RSV seems like RSV may be an underlying cause of CHF exacerbation that's under-recognized in similar ways that we're under-recognizing or under-diagnosing due to lack of proliferating and testing of RSV. CHF certainly seems to be a significant risk factor for being admitted to the hospital, but we certainly do see a similar risk of increasing acute coronary events. I'm not certain on the data for CVAs, but there is very similar pathophysiology in terms of the increased systemic inflammatory response that you're seeing in the site of these viral infections. Thank you very much. Dr. Pennington, have you noticed anything syndromically distinctive about RSV in transplant recipients, or is it kind of clinically at the bedside difficult to assess any particular pattern for you? Yeah, I think I would say that it's a little bit difficult to differentiate between other respiratory viruses that may cause viral pneumonia for our patients. I mean, I think our patients are going to get very sick from viruses that may not cause significant morbidity in other patient populations. I think syndromically for me, it's a little bit hard to differentiate just at bedside. Yeah, yeah. I guess one thing I found really striking that Dr. Conroy shared with us was the very, very low rate of asymptomatic infection. I mean, that's very interesting. I think we all learned during the last few years how often people can walk around shedding viruses asymptomatically. And I guess from the part of me that used to be in an infection control chair is reassured that asymptomatic disease or asymptomatic infection anyways is very rare. And it's certainly helpful in outbreaks to have some idea about that. But that does seem sort of distinctive to me, I suppose. So here's a question from Dr. Patel, which is, given that RSV can infect across the airway epithelium, is a tracheal aspirate acceptable in lieu of a BAL? And I assume this is probably in reference to patients who are intubated. Although I imagine you could get a nasotracheal aspirate in non-intubated patients. Any thoughts? Yeah, I think certainly BAL is not necessary for diagnosis and RSV certainly can even just get it from a nasopharyngeal swab. But respiratory tract assessment kind of along anywhere is probably acceptable for testing. I don't know off the top of my head sort of sensitivity specificity differences between a tracheal aspirate compared to a nasopharyngeal swab compared to a BAL and comparing across those. But given sort of its presence along the respiratory tract, generally can diagnose along any of them. Dr. Pennington, any thoughts about that in transplant recipients? No, I agree with that. I think if your primary concern is RSV, then probably a tracheal aspirate would be acceptable. I would say oftentimes, as mentioned before, I don't know what I'm dealing with. So we end up getting BALs. But I think this was RSV that there would probably be no difference in doing a tracheal aspirate versus BAL. Yeah, we've had a problem at my facility lately with some false positive viral panels on the lower respiratory tract multiplexes. And it seems to be more of an issue with tracheal aspirates than it is with BALs. And so I'm starting to wonder in our group whether or not I'd kind of put nasotracheal, nasopharyngeal swab and BAL kind of like here, and then tracheal aspirates somewhat lower down. We've actually had a couple of pseudo outbreaks, not specifically with RSV, but with other respiratory viruses. And so I would say that yeah, I mean, BALs, if you're getting a BAL anyways, it's a perfectly acceptable specimen to run it on. But I don't think I would BAL someone specifically for RSV. All right. All right. Excellent. So for Dr. Pennington, you know, you noted the very heavy burden of nosocomial transmission in certain high-risk units, particularly immunocompromised hosts. The example you used was hematopoietic stem cell transplant recipients. So in terms of sorts of like added precautions we need to take, is there anything beyond standard infection prevention precautions that we should be doing when we go in to see these patients, especially during RSV season, which is just sort of respiratory virus season generally? Any thoughts? I think this is a good question. I mean, I think Megan or Dr. Conroy really highlighted the multi-faceted interventions when we have patients who know that we know are RSV positive, that we do droplets as well as contact precautions for these patients. But I think it's also important to universally screen visitors and healthcare workers for any sort of respiratory virus to direct visitors into these units that could have any potential respiratory symptoms. I think since the COVID pandemic, we've really learned that, and especially at our institution, we're still masking in these units universally. And I think that while there may not be direct evidence to show how that may be preventative for these patients necessarily right now, but I think that is a low-risk intervention that may be actually helpful. There has been some research or discussions about using preemptive or empiric therapy and settings of nosocomial outbreaks for patients who may not necessarily be positive yet, such as RSV-directed immunoglobulins. And in some small studies, that has been shown promising results. However, I think right now, there's no evidence to suggest or to say that we can uniformly recommend. Excellent. Excellent. Thank you very much. And this is sort of for everybody. During these high periods, obviously during COVID, and I'll be delighted when during COVID is no longer the preamble to a third of my sentences, but during COVID, obviously we did active surveillance in many hospitals for COVID-19 and patients being admitted to the hospital. Do we think there might be populations where that kind of active surveillance could be useful for RSV? I guess one, well, what do you think? I was going to say, I think, you know, prior to transplantation or prior to like, so someone's coming in for a lung transplant or for a bone marrow transplant, but active surveillance in those settings is promising, has promising results that they have better outcomes if you delay transplantation or delay a known immunosuppressing event. I'm not sure that there's data to support that practice necessarily at other time periods, although it is certainly intriguing, especially in high-risk units like a bone marrow transplant or lung transplant unit. Dr. Conroy, any thoughts? I think thinking about the seasonal variation of the virus becomes important in the concept of active surveillance too is, you know, is there a certain time of year, patient population, you know, for my institution, anyone who's presenting into the ICU in a certain season with any respiratory complaint whatsoever gets a flu swab, right? And with that co-testing with RSV. And so there's opportunity, I think, for surveillance among those patient populations that we maybe even are just generally under testing and thinking about, you know, is it everyone admitted to the ICU who needs to get swabs on that? I don't think you're going to see policies at many institutions that do that very broadly, but thinking about really those targeted populations. Yeah. I suppose in a non-immunocompromised population, the rate of asymptomatic disease is so low that that would perhaps preclude the utility of that in a kind of a general all comers kind of picture too. That's super interesting. Thank you. Thank you both. Dr. Conroy, back to you for a second. You know, you had some very interesting mortality curves on the risk of in-hospital mortality for patients admitted with influenza compared with RSV, and the mortality is in fact higher with RSV, which is a little surprising, right? I mean, you think of it as in many cases, you know, I think until we started having the widespread availability of these multiplex PCR panels, I mean, I was a relatively junior attending when those came out. I remember being startled by how much adult RSV we were finding. You know, this was a thing we thought of fundamentally as a pediatric disease. And so when we see that worst mortality, it is also on some level a little surprising. How much of this do you think is a virus factor? And how much of this do you think is a host factor? That is, is it that the people who get admitted with RSV are perhaps sicker at baseline or have a heavier burden of comorbidities than people who get admitted with flu? I'm genuinely not sure. I'm curious what your thoughts are. Yeah, I think it's hard to parse out from the data, again, without sort of great surveillance programs for RSV. Those mortality numbers that I was looking at were really, you know, of hospitalized patients. So those hospitalized with the flu versus those hospitalized with influenza. We all know there's, with RSV, there's a large number of patients that get influenza and do not require hospitalization. And so what is the threshold for either of these viruses? You know, is it really only, you know, in comparison, you know, more advanced age, slightly worse underlying disease that's likely to land a person in the hospital with RSV in comparison to influenza? And I don't think that we have large scale epidemiologic data showing sort of in large populations over many seasons to be able to kind of give competent comparisons to those. I do think that a component of it is inherently this virus's ability to, you know, to cause really significant lower respiratory tract infections, that leading pneumonia, respiratory failure, intubations, and sort of the critical illness that can come along with that, and potentially more severely. So just from a hallmark of the virus in comparison to influenza. But I think any and every critical care doctor has a healthy respect for the badness that influenza can cause. And so I hesitate to ever downplay that. Yeah, no, absolutely. I was also really struck by the high rate of bacterial superinfection in hospitalized patients. I have to admit that there was a little part of me that thought that was going to be lower, that you'd see more pure viral pneumonias. And the fact that it was, what, 15%, I think was the number you quoted? Yeah, I was from Dr. Pennington among the immunocompromised patients, but risk in the larger populations, too, even just from the level of airway epithelial damage that is, you know, inherent to this disease. Yeah, yeah. And certainly would affect empiric antibiotic use, too. I think you'd be pretty hard pressed if you find RSV in someone with an airspace opacity who's in the ICU, you'd be fairly hard pressed to not start empiric antibacterials, although you'd likely need to find a way to dig yourself out of that hole if it is, in fact, purely viral. All right, wonderful. Thank you very much. Dr. Pennington, so we mentioned that there aren't really a lot of therapies out there, right? But there are some. And how we treat people who are significantly immunocompromised differ considerably from how you would treat a more general hospitalized critical care population. What are some of the therapies we do have available? Let's say if you have a recent lung transplant recipient who comes in with respiratory failure and you identify RSV, what are some of the treatments you do have? That's a really great question. So when I think of treating respiratory infections and my immunocompromised, I think about sort of twofold. One, do I have room to lessen immunosuppression or modulate their immune system? And then the second part of that is, are there antibiotic medications or antiviral medications that can target the organism directly? And I think for RSV, there's not a lot of great data out there for more than supportive care, but there is some options that we can have and certainly lessening immune suppression as we're able to. Immune modulation really for RSV infection has been with IVIG. There used to be RSV-specific monoclonal antibodies that unfortunately is no longer available except for in the form of a palovisumab for pediatric patients. Broadly, IVIG sort of alone hasn't shown a benefit in our immunocompromised patients with RSV, probably because there's not enough concentrated RSV antibody to help fight off the virus. There has been some data that using IVIG in small retrospective populations in conjunction with ribavirin that there may be some benefit, which leads me to the next part, that really the only antiviral agent that we have at this time is ribavirin, which is a broad spectrum antiviral agent against RNA viruses that comes either aerosolized or oral. To be honest, in my practice, I've only ever used the oral formulation. I think the aerosolized formulation sort of went out of favor about five years ago. Most studies on efficacy are retrospective, not really very high quality data, and cumulative data does suggest though that there are better outcomes when used early in the course for these immunocompromised patients or those with upper respiratory tract infections, but really you have to watch out for hepatotoxicity with this. I will say in my practice here, when we have a lung transplant patient that's diagnosed with RSV, we do use oral ribavirin on them. Maybe it makes a difference. Yeah, we do the same. We don't do lung transplants awake, but we do do hearts and kidneys and bone marrow. When we find ourselves in the situation, oral ribavirin and IVIG is our usual practice. I think as kind of joked earlier, no viral infection is truly untreatable until you've thrown ribavirin at it. So finding out, parsing out how useful it is, is tricky. Yeah, I don't think I've seen anyone use inhaled ribavirin for quite some time. The aerosolized formulation is both logistically difficult, has some staff safety issues, and when that went away in favor of oral or occasionally intravenous, I think I was pretty happy about that. Excellent. Well, gosh, yeah, I think we've addressed the majority of the questions from the audience that we've received before. I will say one, there was a question about when we'll be able to access copies of the slides. Those should be available in a couple weeks. Those will be recorded on this talk and this discussion, and the slides will be available on the website, so people will be able to review them later on. That is essentially all we have. If anyone has any last comments, then we can perhaps wrap it up a few minutes early. Dr. Conroy, any last thoughts? I think just a reminder to the group, we've got another webinar next week to discuss further some of the emerging vaccines to think about ways that we can prevent the prevalence of disease that we've discussed, the impacts of critical illness in adults and in compromised patients, and remembering to, as the summer comes around here, remembering to co-test and think about presence of RSV in our patients. Thank you very much, Dr. Pennington. Thank you, everyone, for attending. I think this was a great informative session, and thanks to Dr. Conroy for presenting and providing their expertise as well. We'll look forward to seeing everyone next week. My only final comments is I'm just very grateful to be here learning from Dr. Conroy and Dr. Pennington. I want to thank our friends at CHESS for giving us the opportunity to put all this together. We look forward to talking to you next week, and have a great rest of your day. Take care.

respiratory syncytial virus

RSV infections

adults

immunocompromised patients

respiratory symptoms

lower respiratory tract infections

hospitalization

prevention strategies