So welcome, everybody, for this session on viruses. This is a topic put in by the Chest Network of Infection. The title is Are Viruses Taking Over Lower Respiratory Tract Infections? So we have four speakers. The first speaker will be Dr. Jamie Felcher, coming from Mayo Clinic. She'll be presenting a case, followed by Dr. Marcos Restrepo from University of San Antonio, who will discuss about the current epidemiology and impact of respiratory infection to the many patients that we see in our lung clinic with pulmonary diseases and the critical care patients. Dr. Christina Crothers, coming from University of Washington, Seattle, she'll be discussing some updates on the viral diagnostics that will be challenging and how to incorporate that into our practice. And then lastly, Charles De La Cruz, currently at University of Pittsburgh, will be updating some of the antiviral therapies and also the new vaccines for specifically respiratory infections. So to start, Dr. Felcher. Good morning, everyone. I'm Jamie Felcher. I'm a new faculty at Emory University in Atlanta. And I'll get things started off with the case presentation. So we will have some audience response as part of this. So get your phones ready. So the case presentation is a 70-year-old male. He has a history of 60 pack years of smoking. He is a current smoker. He has severe COPD. He's currently on inhaler therapy with ICS Lava Llama therapy. He also has a history of small cell lung cancer. He's on chemotherapy with cisplatin and etoposide, which he did receive seven days prior to this presentation. And he also received radiation therapy. He also has rheumatoid arthritis on Humira. And he has some coronary artery disease. He was recently admitted to the hospital. And he, at that point, was told that he had a COPD exacerbation. He was prescribed steroids, nebulizers, and discharged from the hospital with oral prednisone and levofloxacin. So today, he presents to the emergency department. And he's complaining of increased shortness of breath, some wheezing. He also has a productive cough, sore throat, a headache, and he's feeling a little achy. His vital signs, you can see he's afebrile, 97.5. His blood pressure is 106 over 72, heart rate at 98. And he's saturating 85% on room air. He's sitting comfortably in bed. But with any movement, he becomes quite dyspneic. He has some labored breathing. And he's coughing with any sort of talking or movement. He also complains of some rhinorrhea. He has wheezes bilaterally in a prolonged expiratory phase. And notably, cardiovascular sounds are normal. He has no pitting edema. So on laboratories, you can see he's slightly leukopenic with a white count of 0.74. He's slightly hyponatremic. And he has a bit of an AKI, baseline creatinine, and is around 1. He has a little bit of a transaminitis. Otherwise, as you can see, his laboratory values are mostly within normal limits. So this is his chest x-ray. As you can see, he kind of has an interstitial pattern, worse in the right base than the left. And he has a bit of a pleural effusion on the left base. So I guess when we see a case presentation like this, we try to ask ourselves some questions. What is going on with this gentleman? And so some of the questions I think we all pose are, is there a viral prodrome? So he complained of some rhinorrhea. So that sometimes we think of as part of a viral prodrome. Does he have injected conjunctiva? Is he complaining of muscle aches? Does he have a fever? And often, with a viral prodrome, we'll see that they may have bilateral multifocal patterns. They may have bilateral multifocal patchy or ground glass opacities if we obtain a CT scan. Their procalcitonin, if this was obtained, would normally be a little bit low rather than elevated. And they could have normal or mildly elevated inflammatory markers. In comparison, when we think of a bacterial pneumonia, we think of a dense consolidation on x-ray. We'll see fever, cough. And we may see some air bronchograms. And if a procalcitonin was obtained, it could have been high. And then we think about, OK, if we're thinking bacterial pneumonia, is this severe? And severe pneumonia, we think of an elevated respiratory rate greater than 30. We think of a P to F ratio of less than 250 multilobular infiltrates if the patient is confused or disoriented. If they have evidence of uremia, leukopenia, thrombocytopenia, hypothermia, hypotension. These are signs that we would think of as severe pneumonia. And then for this gentleman, we know that he has a history of cancer. And he was receiving chemotherapy. He also has rheumatoid arthritis on a biologic. And so he does have some indicators that he could be immunocompromised and have an atypical infection. So these are all things that I know everyone in the audience is thinking about when we see a patient and we're trying to figure out what is going on. So if you want to pull out your phones while it's loading. So at this point, what would your next step be? All right. So we'll see what everyone thinks. Still got a few coming in. All right. Excellent. So I think everyone, or the majority of the audience, thought that we'd want to go with the respiratory viral panel. I think the majority of us also agreed with that because he is at risk since he's immunocompromised. So with this, I will turn it over to Dr. Carothers. Thank you very much. And thank you for the organizing committee to allow me to share with you today this presentation. So I do not have any conflict of interest related to this. I will be covering the epidemiology and the impact of viral respiratory and chronic lung diseases in critically ill patients. So I do not have any disclosures, and this is part of the, like with my colleagues here, part of the panel. I will have one question, I think, very coming soon. So I hope that by the end of this lecture, you will have a much better understanding on the changes that are occurring epidemiologically in regards to respiratory viruses in high-risk patients and the impact of outcomes. To do this, I have divided the session in three parts. The first part is the public health problem, the viral epidemiology, and the impact in clinical outcomes. So let's start with the first question. Which of the following viral respiratory pathogens was recognized as the most prevalent in a landmark community-acquired pneumonia epidemiological study? Answer A, influenza virus, B, metanemovirus, C, respiratory syncytial virus, and D, human rhinovirus. Please cast your votes. 12, 13, 15. Okay. So it looks like we have consensus. So the majority of you answered human rhinovirus, and the second group was metanemovirus followed by influenza and RSV. So this is a key study that I wanted to show you because it really challenged what we have been seeing in the past, and as a matter of fact, many people still criticize this study, thinking that the human rhinovirus may not be the largest one, and it was just laying in their lungs. However, it was recognized as the most common one. What I want you to remember here is that if you see the asterisks, there are seven common pathogens that were included in the list, and the reason why this happened was we have all these platforms that are identifying more viruses compared to what we did before. What we did before was influenza. That was it. Then we have COVID-19, and then we started to include RSV. Therefore, you really see the news. Right now in Australia, they have a big problem with human metanemovirus. So the ones of you that answer human metanemovirus, I hope you don't come from Australia because you're having a big problem over there, but this is definitely one ongoing public health issue. This is what we wanted to really see, what were the common pathogens before COVID-19. This is out of the GLIMP platform, and when we look at all the 3,700 patients that were included in the GLIMP, we identified that only 15% were tested for a virus, and among those that were tested, only 28% of those tested had a viral community acquired pneumonia, and among those, the majority, 81%, was influenza virus. You see the three different groups in gray. You see the number of patients that were enrolled in all the different participating countries. Viral in blue and in red is influenza virus cap. So what we do have is a big heterogeneity problem. What happened in one place is not relevant to what might be happening in other places. So we do have to recognize this heterogeneity. This is what's going on with RSV. The darker number is RSV activity. So what I want you to see is what happens in January to February, February to March, March to April, and you see what's going on in the southern hemisphere compared to the upper hemisphere. So every time we have winter in the south part of the world, they have more RSV. When we have winter in the upper part of the north, we have more RSV, and everything starts to mimic, by the time it hits October to November, it starts to mimic exactly what happened with RSV and influenza infections. These are the number of deaths of COVID-19, so those that we believe that COVID-19 is gone, but unfortunately it's not. These are still people that are dying due to COVID-19, and probably SARS-CoV-2 is here to stay. So we need to make sure that we prepare for this change on the epidemiological studies because most of the epidemiology that happens in community-acquired pneumonia have changed in the past three years. These are the number of admissions, and you see that there is a spike that was reported at least in September 16 from the different areas comparing to those that happened in 2020 and 2021. And this is what's going on with the virus that has changed the different strains and the different... What's the name? Different thing, okay. Then we have these different age groups in which you can notice that there is a variation depending on age on the SARS-CoV-2, influenza, and RSV in the United States, respiratory virus, respiratory network follow-up. You notice what is going on over the past few months and weeks is that there is a starting spike that this is why we're having this session in preparation for the winter. And this is probably the reasons why we're seeing more viruses because we can detect them. Before, we did not. In this rapid thing, this is what the topic of Dr. Crothers will be talking about soon. Regarding the viral epidemiology, we recognize that there are certain group of people like with virus infection due to influenza, and this one is H1N1, that identify several risk groups in the multivariate analysis like pregnant women, people ages between 24 and 65, and obese patients. Very similar things, it happens on complications can occur without any of these comorbidities. And when we look at this seasonality between influenza and H1N1, you notice that there are differences exactly what we saw on COVID-19. The GI manifestations happen more in the pandemic H1N1. The pneumonia rate was higher on the PH1N1, but the extra-pulmonary complications were higher and the ICU admissions and death was much higher with H1N1. And also the bacterial superinfections, something that we did not see as much, especially the co-infections at the beginning with COVID-19, but the rate of superinfections occur in many places. In particular, in this study of influenza pneumonia, this is the most common pathogen, was prevalent on 4 to 29% of the patients and pneumococcus was number one, and it was associated, especially when it was staphylococcus aureus, with higher mortality. This is the story with RSV. It's a U-shape. The younger you are, you may have some bronchiolitis, pneumonia, tracheobronchitis. The older you are, more pneumonia, acute exacerbations of COPD, heart failure, asthma, and bronchitis and myocardial infarction. The thing is, everything looks like a flu, like a cold, but these patients may present without fever, particularly when they are in the elderly, but all the symptoms are the respiratory symptoms. This is the impact of RSV that by the age of two, almost everyone is infected with RSV, and by the age of this time, the RSV risk is twice, spreading all over to the adults, particularly in those that have young kids at their homes. If we recognize the risk groups, elderly and other conditions, particularly cardiovascular and respiratory conditions. So the last part of the lecture is impact on clinical outcomes. This is data pre-COVID-19 showing you that in gray, it was a lot of people in the millions that were getting sick. The rate of hospitalizations due to influenza was in the quarter million to half a million cases, and the number of deaths was happening in about 20 to 60,000, and this was already happening before COVID-19. This is the story with RSV that has been looked at in many different studies, and RSV is also attributed to the exposure and the heavy burden in certain older people, leading to 14,000 deaths, hospitalizations, and a 5.5% attack rate in 2.6 million cases a year. This is a particular association that I want you to remember that is RSV in cardiac disease, because among those patients that develop RSV and develop cardiac disease, the mortality is much higher in the healthcare utilization. So what I tried to show you is, yes, COVID-19 came up, but all these things were happening even before COVID-19. With several of the similar viruses, influenza, RSV, they all had the same affection to other organs, leading to higher morbidity and mortality. So when we look at all these patterns, there are these interconnected factors that occur among all these patients that are high risk and interconnected outcomes that leads that these patients will do worse. So with this, I would like to conclude that, yes, viral pathogens are more identifiable now than they were before, that all these are developing this public health problem with high morbidity and mortality, and that this etiology was happening even before COVID-19, but now with SARS-CoV-2, we may have a new phase of what epidemiological problems will lead to some uncertainties on what's going to happen, what will be the distribution among these different pathogens and the impact of care. So I would like to finish with this quote by Charles Darwin that says, it's not the strongest of the species that survives, nor the most intelligent that survives is the one that is most adaptable to change. And this is exactly the story on nature on what we're dealing with with viral pathogens. Thank you very much for your attention. So we're going to continue our case a little bit and then we'll cut over to some other things. So the case, the patient was found to be positive for RSV on the respiratory viral panel. No other viruses were identified and the MRSA swab was negative. The patient was initiated on steroids, duonebs and ceftriaxone. So then I'll just get into the case a little bit more and turn it over to my colleagues. So a couple of days into the admission, the patient was initially admitted to the floor. Unfortunately, their disease progressed and they had worsening hypoxic respiratory failure. They were initiated on high flow nasal cannula, but that was unfortunately not sufficient and they required intubation with mechanical ventilation. They were then discovered to have worsening pulmonary infiltrate. So as you can see, compared to the prior chest X-ray on admission, there were denser consolidations, bilateral lower lobes, worse in the right than the left. And so we have a couple cuts of the CT scan. So you can see there's some emphysematous changes. There's a dense consolidation, most significant in the right, greater than the left. And yeah, there's a bit of a pleural effusion as well. So we have a little bit of a poll and then I will turn it over. So if you guys want to get your phones out again, we have another question for you. So at this point with the worsening chest X-ray, worsening CT scan, dense bilateral consolidations, worse on the right, greater than the left, more independent areas, patient's now intubated. What would you do? All right. So at this point, the patient's already intubated. It sounds like most of you would go to a BAL with ICH protocol. So with that, I will turn it over. Good job. Thank you, everyone. I'm Christina Crothers and apologies for my voice. I had laryngitis last week. And I guess my talking over the weekend has made it come back. So hopefully you can hear me okay. So I do also have some... Why isn't it advancing here? Okay. So I do also have some ARS questions in here. And I'm going to be speaking on implications of diagnostic testing, thinking about non-influenza and non-SARS-CoV-2 viruses, mostly in adults with CAP. We've heard a little bit about already what viruses should I test for, thinking about which patients should I test for viruses, and then the second part kind of thinking about does detection of the respiratory virus change management of CAP. I'm going to skip this. So I think the questions really are, we know, as Marcus showed us, that most of the viruses are the common cause of being acquired pneumonia, but in two-thirds of patients, no etiology is identified. So the question is really why pursue a microbiologic diagnosis. One, there's certainly implications epidemiologically and for infection control, also to identify drug-resistant or unusual pathogens, and then also to de-escalate broad-spectrum antibiotics. And I think if a virus is detected, we should ask the question, can I now stop antibiotics? And we know that even or potentially shorten the duration of antibiotics because even each day of additional antibiotics increases the odds of antibiotic adverse effects by 5%. So the prior guidelines really didn't say anything about viruses other than influenza and suggested getting that if influenza is circulating in the community. So what are really our options? Clearly, testing for influenza and COVID-19 is something that we do routinely now, and there's direct implications for infection control and there's antiviral treatments available. But what about other respiratory viruses? Really, other than the sort of infection control implications, there are sort of limited treatments, and we'll be hearing about those next. And so I have an audience poll question here for you. Which of the patients do you routinely send an extended respiratory virus panel beyond flu and COVID? So all outpatients, all adults hospitalized with CAP, adults hospitalized with severe CAP, or all of the above? Okay. So most of you chose adults with severe CAP, and another quarter sort of kind of said all adults. So let's look at what the guidelines say. So the ATS asked the question, in adults with suspected CAP, should routine diagnostics include nucleic acid amplification of respiratory samples for viral pathogens other than influenza? And the literature review was all done before SARS-CoV-2, so this wasn't included in our question. And after reviewing the evidence, we decided that in outpatients with CAP, we suggested to not routinely obtain an extended respiratory virus panel. In hospitalized patients with CAP, we also concluded to not routinely obtain a respiratory virus panel, but suggested to obtain it if the patient had severe CAP, as most of you had chosen, or if they were immunocompromised, as indicated here on the right. Both of these were conditional recommendations and were based on very low-quality evidence. So some of you may have seen IDSA has a slightly different wording of this recommendation based on antibiotic stewardship program guidelines. And they actually suggest the use of rapid viral testing for respiratory pathogens to reduce the use of inappropriate antibiotics in patients who are hospitalized. And it's important, though, to notice that in their literature review, they included pediatric studies, which the ATS guideline was focused on adults, and they included influenza, which we excluded. So that may explain some varying practices at your hospitals and antibiotic stewardship programs for those who answered sort of all hospitalized patients with pneumonia. So I'm going to just touch briefly on sort of the different platforms. And really I think it's just important to understand that there's a lot of different lab methodologies for the nucleic acid amplification tests, which are proprietary, and the sequences that are amplified are also proprietary to the particular commercial platforms. There's also a number of different test options. So you may have a panel that is viruses only, or you may have viruses and bacteria. Some of you, if you don't have commercial assays in use, your local lab may have developed their own PCR tests, and that often takes like a couple days to get back. That's not usually the point-of-care test. And then it's important to note that most of the commercial assays do have kind of all of the seasonal respiratory viruses, or the most common of them, so including influenza, sort of not coronaviruses, RSV, parainfluenza, metanemovirus, rhinovirus, adenovirus, and others. Another important point about the diagnostic test considerations is the sample type. And the key point here I want to think about is just the upper versus the lower respiratory tract sample, and they don't always correlate. So in somebody who has progressive disease and requires intubation, I would resend a respiratory virus panel. And with the PCR tests, we also have a very increased diagnostic yield, and sometimes we don't know what that means. So we'll detect the organism. It's much more sensitive, but we are also able to detect dead organisms as well as live, and patients, particularly immunocompromised or COPD patients, can have prolonged shedding. So just detecting it doesn't necessarily mean that it's the pathogen, that it's the cause of the pneumonia. So that's something also to consider in interpreting the test results. So I have two questions now, which really don't have a right answer. I'm just interested in your practice. And so take a look at the X-ray, and I'll advance to the next slide, which has the poll, but it doesn't have the X-ray. So a 7-year-old with CAP admitted to the acute care ward. He has RSV. His blood cultures and sputum cultures are negative at 48 hours. This is his urinary antigen testing. So he had the chest X-ray, which was actually the initial one that Jamie showed, and he's gotten ceftriaxone and thromycin for 48 hours. So I want to know, what would you do? Would you continue his antibiotics for at least 5 days, give him at least 3 days of antibiotics, stop his antibiotics now after 2 days, or I don't know, just consult ID? We're getting a plateau in our votes cast. Let's see. Okay. So interesting. So 50% of you would stop antibiotics now after 2 days and then otherwise split mostly between 5 days of antibiotics or at least 3 days of antibiotics. So this is the same sort of scenario, but now let's say he has severe CAP, and here's his chest X-ray, so now showing worse infiltrates. And let me take you to this one. So, again, his cultures and everything are negative. He's gotten 48 hours of ceftriaxone and Zithro. His procalcitonin is 0.2. So now I want to know, what would you take? They're the same choices. Okay. So, okay. So most of you now would continue antibiotics for 5 days, and that's interesting. That's what this that I think one of the studies I'll show you that presence of radiographic infiltrates, I think it sways people, plus knowing that he has severe CAP, despite having a low procalcitonin. Most of you would continue his antibiotics. So now I want to just turn to that question of, so what's the impact of rapid molecular testing for respiratory viruses and CAP? And kind of the bottom line from these studies is that it does improve the diagnostic yield to identify a potential pathogen. However, poor quality data from retrospective studies and quasi-experimental studies suggests that antibiotic duration may be shortened. But really, that's poor quality data. And the data from prospective randomized controlled trials in patients who really have confirmed pneumonia is limited. And it often includes a mixed group of patients with lower respiratory tract infection and has an inconsistent reduction in antibiotic duration. And so that's why in the guidelines, we concluded that we wouldn't routinely send a respiratory virus panel because it doesn't seem to be correlated with change in management or patient outcomes, at least from the literature currently. And so prior chart review studies do at least suggest that there could be a theoretic possibility in changing antibiotic based on knowing what the respiratory viruses show. But most studies really didn't show that providers were changing their behavior based on the results. And so I'll just highlight a few studies. One was this prospective observational study that had a 12 virus respiratory virus panel. And they had acute respiratory and tract infection mixed group of patients. Again, only 40% had radiographic suspicion of pneumonia. And of these, most, 50% had influenza. They did find that influenza positivity was associated with shorter duration of hospitalization and appropriate antiviral management. But radiographic suspicion of pneumonia was really the most significantly correlated with antibiotic management and really a positive respiratory virus panel for something other than influenza was not. And so again, this sort of, this clinician's suspicion of pneumonia kind of drove their practice. This was another study that was a prospective open label RCT called the RESPOC trial. They had 720 patients. They did have about a quarter of the patients had pneumonia, but then again, a mixed group of lower respiratory tract infection patients. They compared the film array respiratory panel with results in two hours to their lab PCR where patients got results in a couple of days. And they did not find that the point of care test was associated with a change in the receipt of antibiotics or the duration of antibiotics. In their secondary outcomes, they did have more patients who got only one dose or less than 48 hours of antibiotics. And they did have a slightly shorter length of stay. And that was more significant if they restricted the analysis to patients who had COPD. So another study combined procalcitonin in an algorithm with the multiplex PCR. It was an RCT, but they included non-pneumonic lower respiratory tract infection patients. And they overall found a similar antibiotic use in the two groups but that orange arrow kind of shows that in the group that had low procalcitonin virus detected and the providers were adherent to the algorithm, they had a lower duration of antibiotic use. So the last study I'll highlight is one that included a best practices alert in the electronic health record combined for patients who had a positive virus and a procalcitonin that was less than .25 within 48 hours of each other and who were on one systemic antibiotic for respiratory indication. So the alert triggered for providers to encourage them or to prompt them to think about stopping antibiotics in those patients. They had a mixed group of infections. They did have sort of about a third of the patients who had influenza, but they had a representation of other viruses too. And they did find that the best practices alert was associated with sort of more lower antibiotic days, more patients had antibiotics stopped within 24 hours of initiation and fewer of them were prescribed antibiotics on discharge. They didn't have a statistically significant difference in the antibiotic reinitiation after discontinuation, although it's numerically a little bit higher. So I think some of these studies really highlight that combining the multiplex PCR with antimicrobial stewardship as well as maybe biomarkers may be sort of the most promising avenue for this. So kind of to sum up, I think there's improved, viral diagnostics definitely increase our diagnostic yield, but the data is really limited from prospective RCTs and we don't have any data on severe cap or mortality outcomes and so there's kind of an inconsistent reduction in antibiotic duration if only a viral pathogen is identified. And there's kind of multiple factors that influence decision making and use of antibiotics that I think need to be looked at in subsequent studies, including sort of this suspicion of bacterial pneumonia, how can we sort of just, you know, make sure that we're not missing a bacteria that should be treated with antibiotics and then how really to implement this with appropriate fast turnaround time and with antibiotic stewardship practices to help guide clinicians on how to interpret and use the results. So thank you and I will turn this over to Charles. Thank you. Thank you, Dr. Carruthers. Let's see. So I'm going to be providing some updates on the antiviral therapeutics that we currently use and some novel vaccines in the pipeline. I have no disclosure for this specific talk. So the learning objective is to review some of the antiviral therapeutics for respiratory infection, followed by some of the current vaccine recommendations against the respiratory viruses that you just heard about and then some understanding of the novel vaccine approaches and currently in the pipeline. I have a case similar to what you heard from Dr. Felser. The 6 to 7-year-old gentleman, former smoker, moderate COPD, frequent exacerbation presented with these symptoms, comes in with sort of low-grade temperature, oxygen requirement, chest x-ray and interstitial infiltrates that you saw earlier. Respiratory viral panel shows positivity for influenza RSV, negative for SARS-CoV-2. Procalcitonin is 0.3 and CRP is also low. So what are the treatment options that we currently have with regards to viral infections? So I don't think they allow us to check all that applies, but if you can, just pick the ones that you would do first. Antibiotics, Fibrovarin, Seltamivir, protease inhibitor with valoxavir, Synergis. Okay, so this really highlights what's available currently in terms of our antiviral approaches for our patients. We've learned a lot from COVID-19, but our antivirals would be desivir, which I won't talk about today. But currently, really, I'll talk about some of the antivirals that are currently being used in practice and the ones that have been coming. So most of you pick also Tamivir, which is a neuraminidase inhibitor. A quarter of you, a third of you would want to use antibiotics, and some would use Fibrovarin. So this is sort of the current updates on the MNWR. With regards to COVID-19, you see this is the end of May. You can see the spike last fall of both RSV and influenza, usually coming in October, November, which is coming up. And so to understand antiviral drugs, you need to learn about the life cycle of the virus. Here you see the importance of the different viruses in terms of viral attachment, entry, penetration into the host cell, and there's a process of uncoating, early protein synthesis, and nucleic acid synthesis, because the cells itself is a factory for the new viruses. Later, in terms of the processing of all the proteins that are being made, and then packaging of the virus and assembled into a new virus for release. You can see at this different areas of the life cycle of the virus are potential drugs that could be targeted with regards to fusion inhibitors for entry, inhibiting viral encoding. There are nucleoside analogs, reverse transcriptase inhibitors, protease inhibitors, and then also drugs that target inhibition of the viral release. You've seen this slide many times already in this symposium, but I can highlight on the left side a similar sort of CDC EPIC study with regards to children and the pediatric population. And you can see a majority of these kids at the different age groups also have primarily viral infections as a cause of their community-acquired pneumonia. And obviously, since 2020, we learned that COVID-19 is now part of our concern for our patients who present with respiratory infections. And this is the current pattern leading up to this week, and this is looking at mostly the spike of COVID-19 infections circling in the U.S. You can see that the blue and the red are still pretty flat, but likely going to come up in the next month or so. On the right-hand side, the CDC described the potential scenarios for like this triple peak, triple threat of these viruses coming up with regards to potential hospitalization of the patient leading up to this coming respiratory season. And so we all know about also Tamivir, which is a neuraminase inhibitors. There's many other types, Zanamivir, Paramivir. And some of these, Zanamivir, are oral drugs. Some are inhalational. Based on sort of decades of studies, there's strong recommendation using these antiviral treatment, both as an inpatient for an outpatient. The hazard ratios for these and odds ratios are improvement in terms of mortality by a third for these patients who receive these neuraminase inhibitor. We also know that the benefit is strongest within 48 hours of symptoms. However, many other studies suggest that possibility of some benefit independent of the duration. And specifically for hospitalized patient, earlier initiation is also very important for reduction of ICU admission, 30-day readmissions, and also mortality. Beloxavir, which some of you have used in the past, sort of works in a different way. It affects the viral replication, acts on the endonuclease, and in several capstone studies, specifically on uncomplicated influenza, single dose, well-tolerated, reduced complications of the symptoms. It's actually going to have some better effects than ulcetamivir for influenza B, and then also superior to ulcetamivir in shortening the viral life cycle in terms of shedding. There are, however, variants that can be arising from the decreasing susceptibility of this drug, and also not recommended for pregnancy and breastfeeding for these patients, if you think about your patients currently. There are some studies, such as the Flagstone study, for example, that shows the use of combination antivirals, Beloxavir and the neuraminidase inhibitors. However, these studies do not show any significant benefit, additional benefit to using two antivirals. These are some of the newer drugs, FFAPirivir, working at polymerase inhibitor against influenza, some open-label study. This drug, however, didn't do so well because of poor absorption, and there's a later phase three studies that shows the reduction in time to illness improvement compared to placebo. Both were reduced viral titers and detections. However, this is still a work in progress in terms of what's available for the public. There's other approaches, for example. Some of the challenges of influenza virus, as we all know from medical school, is that influenza goes through many antigenic drifts, antigenic shifts. Frequent updates are needed for these vaccines, and we also need to know about pandemic preparedness. And so some of the strategies is really looking at the stock of the hemagglutinase, which is a well-conserved, if you look at the green sort of schematics, targeting this that it can cover many of the different influenza strains. People are starting to use this as an approach to target using monoclonal antibodies, as well as vaccine designs. One of the study here that's shown here has shown that targeting these with monoclonal antibodies are able to show resolution of some of the symptoms, reduction of viral load. However, some common side effects include diarrhea. Other approaches, another monoclonal antibody at the bottom here, also targeting these HA stocks in a similar symptom profile improvement. But there's no specific benefit over oseltamivir. These antibodies actually might be useful with regards to what our experience with COVID-19 using convalescent blood products. There are some studies sort of before COVID-19 that use a flu IVIG. This is a study which is an international randomized trial using high titer IVIG against flu. And what they found was there no specific benefit when given with these oseltamivir-like drugs. And there's a question whether the specific influenza would be a benefit. NIH study did something very similar, focusing on high titers of these plasma. It was terminated because of low conditional power and they weren't able to achieve what they wanted to do. And so what we learned from COVID-19 is actually these convalescent plasma might be quite useful for immunocompromised patients and actually for many of our immunocompromised patients these convalescent plasma or high titer antiviral specific antibodies might be useful for future use. RSV you've heard is sort of has gotten some resurgence of interest in many fronts. The FDA approved drugs include what we know as a reverberans, one of the older drugs. It's a glutathione analog that inhibits viral replication. It's a nonspecific RSV activity, potentially toxic and costly. Because of this it's very similar to human metanemovirus. Some of these approaches are also applicable to human metanemovirus, but not as many studies are focused on that virus. We also know and heard about Pellevisma, which is Synergis. Most of this is actually humanized neutralizing antibody against the fusion protein for the virus. It specifically has been used quite a lot for infants and young children and it's limited to high risk kids and it prevents RSV related hospitalization and also specifically the development of BPD in children. So these are just the two drugs that are available for RSV and you can see we really don't use this unless we have severe cases of RSV in our ICU. And so there are more interest in studying antivirals for this patient population. And so many centers now are looking at actual human challenge studies with respiratory viruses. And this is one example, it came out last year in the New England Journal, which is using a new drug which is an RSV inhibitor. It's a non-fusion replication that targets the viral nucleoprotein. This is an early phase study, challenge trials, volunteers, humans, these RSV8 Memphis strain and then use several drugs, dosages. What they found was actually both doses in terms of frequency daily or twice a day for 10 days was able to decrease the viral load based on the AUC curve versus placebo, was able to come down with the symptom score. They also were able to measure the mucus production of these patients or subjects decreasing the mucus production by 70%. On the right-hand side, it's actually just a pictorial graph of what I just told you in terms of how effective this approach has been for actual challenge study for this. And so it looks promising. Other new pipelines, I won't go into the details, just to say that there is many efforts with regards to small molecule inhibitors, really looking at the RSV fusion pathway. Some are using nucleoside analog, some studies are using coming up with RSV human challenges already, and others are in clinical stages. Similar approaches using monoclonal antibodies, using pooled plasma or monoclonal antibodies specific to RSV fusion proteins, some have shown, as you can see here, questionable efficacy. And others, for example, the nanobody trivalent approaches, which is inhaled, was able to inhibit viral load, but they were only improved after, not able to improve after the infection has been established. It's mostly for prophylaxis. And so they're working on some of the timing with regards to early intervention. This really has implications to how we treat our patients and when our patients present. So this is going to be a challenge for the drug developers. There's also recombinant antibodies against the F protein that some of these are healthy infants currently in phase three. So this is actually one of the phase three trials on infants born gestational age 35 and above. Nercevumab, which is a monoclonal antibody against RSVF versus placebo on late term and term babies. You can see that this antibody actually is quite effective with quite impressive vaccine efficacy, at least at this first stage, decreasing hospitalization and also decreasing respiratory tract infection as a preventative for these newborns. There's a concern currently with this drug whether or not they make antibodies against the drug, which has implications for repeated use. And so rhinovirus you heard, we don't think about rhinovirus potentially in terms of a drug as part of our treatment plan, we can detect it nowadays more and more as you heard earlier, because it's often self-limiting. However, many of our patients because of rhinovirus have their exacerbation of their underlying disease, gets hospitalization and exacerbation of their pulmonary symptoms. And so I think it's important to have targets of drugs against this respiratory virus that we think is benign but not so benign maybe for our patients. And so some of the interests have been focused on viral capsid attachments and the viral RNA uncoating that I heard from the life cycle. Some of these drugs are early phases, some have multiple randomized control trials and some are experimental challenges actually showing symptom reduction in some cases. And some of the challenges with the second drug here, you can see is actually in post-inoculation, whether this drug is able to decrease viral load and also symptom, which may highlight the importance of maybe enough drug reaching in terms of stopping the rhinovirus in the lungs. Ribavirin has been described to be important at least in four immunocompromised patients. This is in addition to interferon-alpha and there's other trials, for example, looking at soluble ICAM to block viral entry. So this is the current ACIP vaccine recommendations against respiratory viruses. This is what most of your patients should be having and all of us for some of them. And so a lot has been learned about influenza vaccines from the southern hemisphere and the influenza vaccine interim analysis has shown that it actually has 50% efficacy in reduction of hospitalization, which is actually really good for our patients. All vaccines are going to be quadrivalent. You can see two influenza A and two influenza B strains there. This is all for six months and above. CDC has the Fluzo, high dose for our elderly patients. Flu block recombinant protein and then the Fluad, which is adjuvanted vaccines. Depending on your institution, many of these are available. What's exciting actually is RSV. There's a lot of new advances and also FDA approval for RSV vaccines, specifically for children less than eight months and also eight to 19 months for those who are high risk for RSV disease. There are RSV vaccines that are available for adults above 60 and people who are, women who are pregnant, 32 and 36 gestation. There are also RSV vaccines available. These are single doses. There are different types of RSV vaccines. One's for the infants that I mentioned already, which is multiple antibody. And then the other one is actually a recombinant protein from, called a Brisa for 60 and above. For COVID, I think people are starting to get these COVID shots now for age 12 and above. There are multiple types of these booster shots, specifically for current variants. I listed here and then more recently Novavax, especially for those who are the uninitiated, as two dosing for that patient. And then with regards to immunocompromised, there's some recommendation for additional dosage boosting. So RSV protein, this is a phase three that came out this year, adjuvanted RSV protein, specifically looking at a large proportion of subjects. Many of them have cardiopulmonary diseases and metabolic endocrine diseases. Vaccine efficacy is up to 82% for confirmed cases and similar for RSV A and B type, transient adverse events. And for severe cases and very small numbers, there's question about possible immune-mediated effects of this drug vaccine. And you can see on the right-hand side the effectiveness of the RSV vaccine in preventing cases. There's a bivalent prefusion F vaccine, again, called Matisse in the New England Journal this year. This is specifically targeting pregnant women, 24 to 36 weeks. So it's an interesting study. So they follow the mothers who are vaccinated and also follow their infants, half randomized to placebo and half to vaccine. Ninety days, 180 days later, they look at severe respiratory tract infection. And you can see vaccine efficacy in the 80% range, and then just sort of dwindles down at the 180 days range. It also decreased RSV-related lower tract respiratory infection. There's no significant safety effects. And then the AEs are listed here. So there are multiple new vaccine developments. And so this year we heard about the Nobel Prize given to the inventor of the mRNA vaccine, the modification that we all learned from COVID. So a lot of the approaches are looking at conserved regions, for example, of the flu. Some uses peptide conjugate vaccines. And then more recently because of the successes with COVID, there's a lot of interest in mRNA vaccines. There is currently a trial going on at the NIH using a sort of a mRNA lipid nanoparticle specifically for influenza in the Vaccine Research Center. There's some interest already going on with combination mRNA vaccines. Moderna is working on that. And then also plan mRNA vaccine for RSV. So interim analysis for the Conquer study showed actually vaccine efficacy of the mRNA vaccine for RSV is actually quite high. And so all of these are intramuscular vaccines. There are a lot of work and interest with regards to intranasal inhalational therapies. I listed here the ones in red didn't work. The ones in black are either old or still in the works. And so there's a lot of challenges of intranasal inhalational therapies as listed here, including anatomy, the mucosal reclarence, potential toxicity locally, and effectiveness of absorption and effectiveness of the drug. And so I think this would be, this would work well if I think of it as if we could target directly to the lungs to protect our patients. And so looking forward to more of these advances, but I think there are some challenges. So going back to the case, you know, so really, also Tamivir is really what we have currently. There's no specific RSV treatment unless patient's severe. So we, you know, maybe because of the patient doing okay, the antibiotic would stop and negative culture. And one of the things to highlight is not maybe for this admission, but maybe for future is prevention with vaccines, and then also management of COPD with regards to frequent exacerbations. So this is sort of what we learned from COVID and something similar can happen in influenza, RSV. I'll mostly talk about the vaccine on the front and then also monoclonal antibodies, but they are an antiviral treatment, but there are post-modulating drugs that could be used for some of our patients. And those studies are still active and still in the works. And so I won't have time to talk about that. So in summary, I think there's increased recognition, importance of RSV infection to human disease. It's actually, you know, really probably spurred upon by COVID-19, unfortunately, but it is important for our patient with chronic lung disease. I think we need more antiviral therapeutics. As you can see, there's quite limited. It's encouraging that we have more vaccines now for our patients, and we're looking forward to some of these newer and combination platforms. And thank you for your time. I think. I think we have time, a few minutes for questions. And so feel free to come forward and address any of us here. Hi. Thank you very much. That was super interesting. So infectious disease with a focus in immunosuppressed patients and also critical care. My question is about RSV. With reviving one of the points of content where we always have to talk to a pharmacy and have a lot of meetings about that, is it's only recommended for lung transplants and hematopoietic stem cell transplants. So I'm wondering your experience with heart transplant, liver transplant patients, or other types of immunocompromised patients. Is it worth the fight to try to get this medication to them? Would it have any improving outcomes in your experience? Yeah. I think if they show up in our ICU and they may not necessarily be immunocompromised, you know, I think, and you find RSV, we usually try to fight to get the drugs for the patients. I know there's some challenges, whether it's inhalational, you know, Ribavirin, because you have to make sure that there's no exposure to caretakers and stuff like that. So because we know what the virus can do and always forget the potential impact on ARDS and, you know, hypoxemia of these patients, we always try to do that. Although there are barriers, as you can see, with pharmacy and also even, you know, implementing some of these. I think the use of monoclonal antibodies that are available are now more available. We're looking forward to more advances and approvals. And I think, you know, you heard about human metanumobirus. Many of our patients are also susceptible to human metanumobirus, especially our transplant patient, and so similar drugs. Which is why I think, you know, we need to work in partnership with more drug development, getting some of these antivirals that are effective. The other thing is with diagnostics, we know the RSV can, you know, can pick up RSV longer, right, for many of these patients. And so the question, usually the challenges would be when you have this positive for like the third week or the fourth week, how do you treat these patients? Do you keep on treating with, you know, antivirals, right? We just don't know. And those studies are quite limited. Thank you. Any other questions? Feel free to, we have a whole panel. Thanks a lot. Those are great talks. I had a question, I was kind of thinking about when clinicians are seeing all these new technologies, so new diagnostic tests. It's kind of like the cone of light phenomenon is perhaps getting a little crisper, but we're still sort of stuck in the cone of light where we're looking under the street lamp for our keys. And we, you know, have a few, you know, the cone of light is maybe a little bit larger, but we're not seeing what's outside the cone of light. And it seems like there's a race between the, you know, viral tests, the rapid multiplex arrays for bacteria, and then, you know, markers of the host response. And so as we kind of are seeing this race play out in the development of our new technologies, it's very disorienting because if we start to develop algorithms based on what we see under the cone of light today, in two, maybe three years, they may be obsolete. And so how does a clinician kind of integrate that when all of these tests are imperfect? And, you know, the kind of question to you is, in terms of the trials that we're seeing, what should they be optimized for? I see a lot of trials that are optimized for, you know, the target outcome is antibiotic use. And there's less trials that are, the target outcome is actually, you know, clinical outcomes. And so when a clinician is seeing, you know, some of these studies, what are the sort of pitfalls that they should be looking for? And how does a clinician integrate all of this kind of fuzzy information at the bedside? Thank you.

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