Aloha, everybody. Welcome to the update in pleural disease session. I hope you guys are enjoying the conference and Hawaii. This is a picture across from where they filmed Jurassic Park, which, as the mother of a 10-year-old, we had to go to. So, if you haven't been to Kalua Ranch, you should check it out. I'm joined with an esteemed panel to give you an update on pleural disease over the past year. My name is Satya Fez. I work at MD Anderson Cancer Center in Houston, Texas. I have no financial disclosures. I'm going to have you guys just click the QR code. We've tried to make this as interactive as possible, and I've left time for questions at the end. I'll give you just a minute here. Okay. And I have the honor, the esteemed privilege, to work with a pleural ohana of sorts. We're going to cover our objectives. I'm going to talk about the landscape of pleural disease. We have Gary Lee from Australia, who will talk about pleural physiology and procedures. We have Labib Debian, who will talk about perineumonic infection. And I have George Chang from San Diego, who will talk about malignant pleural fusion and all the updates so far. So pleural disease itself has somewhat exploded. When you look on PubMed and you search just pleural disease, you'll see the amount of literature that has developed in this space has tremendously increased. Following that, we also have a lot of landmark studies and professional society guidelines to help us direct care in how to practice evidence-based medicine with our patients. Just in the past year, we have some exciting consensus statements, trials that have come out. For example, the IRS Management of Pleural Infections and Adults Act came out in 2022. The British Thoracic Society guidelines, which were much awaited by many of us, came out this summer with guidelines for pleural disease, as well as a statement on pleural procedures. So now we will go to our question. So estimated cost in 2016 to the United States health care system was over $10 billion. Which type of pleural disease contributed the most to the cost? And I'll wait until I get to several votes. It looked like it was split, let's see, there you go. So, the number one answer is non-malignant pleural disease, oh, no, actually the number one answer is malignant pleural fusion. And actually, the right answer, surprisingly, is non-malignant pleural disease, and I'm gonna show you the data why. We all kind of think that it is malignant pleural disease, but when we look at what's described, at least in the United States, based on this Mamondi study that came out in CHEST, it's from the Cleveland Group, they looked at retrospective cohort study databases from 2007 to 2016, and when they looked just at 2016, they found that the cost of pleural disease based on emergency room visits, hospitalization readmissions, was $10 billion. In that, and you look at the bottom table, non-malignant in millions was the highest, okay? And when you look at the waterfall diagram below, you can see that 65% of the patients that were actually admitted or came to the ER had non-malignant pleural fusion, and only 16% had malignant pleural fusion, although there are a lot of studies, there's a lot of data on malignant pleural fusion. The other thing I'd like to highlight is both empyema and non-malignant pleural fusion had increased hospitalization rates when you look from 2007 to 2016. Most of these are related to cardiac dysfunction, liver dysfunction, and renal dysfunction, and they present as transidates. Cardiac disease, I work at a cancer center, cardiac disease is still the number one killer, right? The morbidity and mortality in humans. It's a second leading cause of disability-adjusted life years worldwide. Most patients with heart failure will have small pleural fusions, and data on association with pleural fusion and poor outcome is conflicting. There was a recent study in 2020, which was a propensity-matched analysis looking at inpatient databases, and they looked at actually two million patients, 70,000 or 72,000 of those had thoracentesis, and what they found is in those with acute heart failure that had thoracentesis, they had an increased rates of cardiac arrest, pneumothorax, hemothorax, and sepsis, and their odds ratio adjusted for death was high, 1.5. Liver disease is the 11th leading cause of death and 15th leading cause of morbidity worldwide. With hepatic hydrothorax, five to 15% will have liver cirrhosis and have recurrent effusions, and in general, there's a higher rate of complications. The studies that are out there, there's a retrospective, a multi-center, and a single center, they all report a high rate of complications, so in general, we don't recommend it. Renal disease, chronic kidney disease is responsible for 41.5 million disability-adjusted life years. 20% of these patients have pleural effusions. You can also see uremic pleuritis in 25%, but remembering these patients is important because they are immunocompromised to exclude infection and malignancy. In general, with these non-malignant pleural effusions, we recommend treating the underlying disease. However, recently, there was a study, the REDUCE trial by Steve Walker and the England group, and there was a prospective multi-center randomized control trial where they looked at indwelling pleural catheter versus repeat therapeutic thoracentesis. The cohort was 68 patients. Most were heart failure, and the primary outcome was actually visual analog scale of breathlessness over 12 weeks, and what they found is there was no significant difference between the two. In terms of secondary outcomes, justifiably so, there was increased drainage in the IPC group. There are fewer invasive procedure in the IPC group, but the IPC group had more adverse events than the therapeutic thoracentesis group. I think the bottom line for the study is you really kind of have to go, we need more data. You have to determine based on the patient, but to me, if symptomatically it doesn't necessarily help the patient, then you need to think twice about what needs to be done. So in general, try to treat the underlying organ dysfunction, but of course, case-by-case basis. I'm sure we've all had patients with nonmalignant where we've committed to a catheter. Pleural effusions in general are probably gonna increase. We know, and Dr., sorry, Labib will talk about this later, about how there's an increase in pleural space infections. There's an increase throughout the world. This is from the ERS statement, and even with cancer, now this is actually old. I think this is from 2017, but it shows the five-year survival rates in the United States from cancer has significantly improved. Part of this is because of immune checkpoint inhibitor and target therapies, and especially in those with lung and breast cancer where we see the most pleural effusions with increased cancer survival, we'll probably see more malignant pleural effusions as well. And finally, just to touch base on this mortality study, I'm not gonna go too much into the detail, but these are older studies from the Yale group and from the England group, and they both show that, for the first one, shows that malignant pleural effusion we know has increased mortality when it presents, but so does non-malignant pleural effusions or effusions of benign hetiology. In the England study, they showed that those that had effusions with heart dysfunction had a one-year mortality of 50%. So I hope I've given you a nice overview that research and our knowledge of pleural disease continues to evolve, healthcare dollar expenditures are significant, and as treatment for other diseases improve, pleural disease also increases, and there's increased morbidity and mortality associated with pleural disease. And so now I'm gonna welcome to the stage Gary Lee, who needs no introduction. Good morning, and thank you for the opportunity to come and contribute to this section. I'm going to shortchange you by escaping from the procedure part, and I'm going to concentrate my 12 minutes on physiology of breathlessness in pleural effusion, which is something that we found was quite interesting in the last couple of years. This is my disclosure slide. So my objective today is to talk about why people with pleural effusions become breathless, what are the potential mechanisms, what are the new data to support those mechanisms, and how it affects your everyday clinical practice. Breathlessness, as you all know, is the most common symptom for pleural effusions. It can be distressing, impairs quality of life, and drainage is often required to provide symptom relief. This is Eleanor Misha's study of five randomized trial pooled together, two of us, two of that from our group, of malignant pleural effusions amounting to 550 patients. All of these patients has a visual analog scale measured for breathlessness at the beginning of the study. So this is a 100 millimeter line where the patient makes a mark of how breathless they are, is anchored at one end as no breathlessness at all, and at the other end as the worst breathlessness imaginable. And what should be found is that those patients who are more breathless at baseline, and those who are more breathless at the seven days post-drainage are having poorer survival. So breathlessness has a prognostic value, and if we divide those 550 patients into four quadrants based on their level of breathlessness, on this Kleppenmaier survival curve, you see that those quadrants, those 25% of people who have the worst breathlessness also has the worst survival. Back in 2015, we wrote a review article of why patients are breathless with pleural effusion, and it was literally an untapped area. So most of the studies were small, they're heterogeneous, they focus only on limited outcome measures. I don't have the interactive things, but I will just check with a raise of hands, how many of you have told your, what do you tell your patients when they come in breathless and you try to explain to them why they're short of breath? So how many of you have told your patients that the fluid compress on the lung, and therefore the lung cannot expand, and therefore they're short of breath? And I do too. Although now I know that that may not be as simple. How many of you tell them that a reduced cardiac output reduces venous return because we increase intrapleural pressure? No one, okay. Altered diaphragmatic mechanics, quite a few, that's excellent. And intrapulmonary shunt? A few. I bet no one mentioned about neuromechanical uncoupling, which has reduced ventilatory output relative to neurodrive of the hemidiaphragm, but that is being studied quite a lot at the moment. And the truth is that it's probably a combination of all the above. But let us step back and ask ourselves, have you ever thought about how does hemiforax expand to accommodate the many liters of purine effusion suddenly from these patients? I bet many of you haven't thought about that. So this is a very good CT scan, is a patient on the chest X-ray, you can imagine a complete whiteout. But the chest X-ray doesn't tell you all the information that the CT scan provides you, right? Because to expand the hemiforax to accommodate that extra fluid, the first thing you do is that you evert the diaphragm, and then you push the hemidiaphragm down, and in this case, down to the kidney level. This is what you cannot see on the chest X-ray. And then the hemiforax also hyperexpand, a bit like COPD, you can see the rib spaces are much more spaced out on this side than the opposite side. So it's like a unilateral hyperexpansion. The lung is collapsed and the mediastinum is pushed to the other side. All these components serve to alter the respiratory mechanics and makes breathing harder. So when we put in an indwelling pericardial catheter, you can get the sensation that we decompressed the hemiforax, the hemidiaphragm moves up, the hyperexpansion settles, the lung expands, and the mediastinum settles back to the normal position. But don't just think about the volume, think about the weight as well. One liter of... I'm sorry, Sirius doesn't understand, but I might have to explain a bit later. All right, so one liter of pure water is one kilogram. And malignant perifusion, for example, have a specific gravity up to 10% higher than pure water. So in this particular patient who has three liters of malignant perifusion, it is about three to 3.3 kilograms sitting on the hemidiaphragm that you have to lift up 12 breaths per minute, 24 hours a day, even at nighttime. And when they feel better after you drain the effusion, it is a lot to do with lifting that 3.3 kilograms of the hemidiaphragm. So to understand this better, my group has embarked on a journey called the PLEASE studies. So there's a series of study on perifusion and symptom evaluation. The PLEASE one was the most comprehensive study of patients with symptomatic perifusion by looking at the mechanical and physiological response after perifluid drainage. So we had 150 patients, 145 devaluable, two-third of them malignant effusions. We did measurements before and after drainage. The median among drain is 1.7 liters. So these are not small effusions, they are moderate to large perifusions. As a group, the visual analog scale that I showed you before improved from 40 to 75. That's quite significant. As a group, the six-minute walk test, the functional level also improved by almost 50 meters after the drainage. But if you look at individual level, only three out of four patients actually have symptomatic improvement. And I think that is probably everybody's experience. Not every patient get benefit, even if you are there to drain a large for an improved effusion. So on the multivariant analysis, those who are more breathless at the baseline, not surprisingly, are more likely to improve. And those who have abnormal hemidiaphragmatic movement on ultrasound before drainage were more likely to improve. We look at all the vital signs and not surprising, the respiratory rate actually didn't improve that much. The heart rate didn't improve that much and the oxygen level only improved by about 1%. And this is important because it confirms that breathlessness from peripheral effusion is the result of that increased work of breathing that we showed you before because of the auto-respiratory mechanics is not about hypoxemia. Sorry. And then like many other studies which has looked at lung volumes before and after drainage of peripheral effusion, we find that the spirometric volumes only improved by about 20%, 25% of the volume of the fluid you actually drained. So it helps to confirm that lung compression is not the key way of how the effusion is accommodated. So if you have all done ultrasound and this is a ultrasound of a small peripheral effusion, the hemidiaphragm remains dome-shaped and moves normally. This is when you have a large peripheral effusion, the hemidiaphragm is averted and does not move or even move paradoxically. So in our study, we find that 50% of the patient has got abnormal diaphragm shape or 50% has normal and the others were either flattened or even averted. But once we drained them, the vast majority returns to have a normal hemidiaphragm shape. But the diaphragmatic movement was normal only in about a third of the patients and in two third of them, they either do not move or even had the paradoxical movement but 75% of them had returned to normal hemidiaphragmatic movement after drainage. So what does it mean to your daily practice? So the weight of the fluid on the hemidiaphragm clearly plays an important role. So in patient like this where the lung doesn't expand or the patient has a lobectomy or pneumoniactomy, even if the underlying lung is not expandable, drainage can still potentially improve symptoms and we should not exclude these patients at least for a trial of fluid removal for their symptoms. Importantly, if the patient has significant hypoxemia, always, always, always looks for an alternative cause. This happens to me almost every week and I have to convince people that the prural effusion, no matter how large is unlikely to be the driving force of significant hypoxemia. This is one example in my hospital, but I see these kinds of situations almost every week. So this patient has lung cancer, primary malignant prural effusion known to have pulmonary emboli, had an IVC filter in place, anticoagulated. And he come one day on ambulance, very sick, hypoxic distress in a para arrest state with this large prural effusion with contralateral mediastinal shift. So I think in many places, the emergency department would put a large ball tubes in him immediately. But in my place, they asked me first and I said, no, the effusion is unlikely the cause, go and look for some other reason. So the patient was immediately intubated and we did an urgent CTPA and you can see the subtle pulmonary emboli. And because he was fully anticoagulated, he wasn't thrombolyzed and the very clever interventional radiologists went in there and do clot retrieval. And this is the clots from his pulmonary artery. And he's got immediate physiological improvement and it was extubated the next day. We then went on to publish PLEASE-2, which is the hard work of two of my fellows, Deirdre Fitzgerald and Sanjeevan Muruganadan. So the rationale of the study was that the diaphragm is only one piece of muscle. We don't have two diaphragms. We got one piece of diaphragm. So if the purifusion is affecting the ipsilateral hemidiaphragm, so the logical question next is what happens to the contralateral hemidiaphragm? And this slide just summarize the whole study. If you have a ipsilateral hemidiaphragm, a ipsilateral purifusion, the hemidiaphragm is affected and move a lot less, but on ultrasound grounds, that contralateral hemidiaphragm works over time to compensate and moves a lot more. And once you drain the effusion, the ipsilateral returns to normal and that hypermobility of the contralateral hemidiaphragm also settles. So this is important because this for the first time, take us out of the mindset that if you've got a ipsilateral purifusion on this side, it only affects your breathing on this side. It actually affects the breathing mechanics on both sides. So what does it mean to your daily practice? Think not just the impact on the ipsilateral side, but also the contralateral side. If the patient has a very bad contralateral lung, they're going to be affected a lot more by the ipsilateral purifusion because you don't have a good backup generator. In the bilateral effusion situation, the compensatory ability of the contralateral side is lost. So the effect of the breathlessness will be a lot more profound than just the sum of two ipsilateral purifusion. So one plus one maybe equals to four. So in those kinds of patients, I do a lot more to try to keep at least one side dry like an indwelling catheter. We are on to please three. I don't have any results, but just to tell you what are fun things that we are doing. How many of you have a show of hands that you have had patients who told you when they have purifusions, they can't bend down or they get short of breath when they put their shoes on and put their shoelaces on? You've all seen that, but what have you done about it? So I haven't done anything about it. We're just going to look into it. We've done a pilot study and confirmed that the literature actually has a name for it called bandopnea, like band and then opnea. I did not invent it. It's already in PubMed. So bandopnea on our pilot study was extremely common in patients with purifusions. So we now want to confirm it in a large study. And I think we have more than 100 patients now to look at the incidence, the severity, look at the ultrasound and the diaphragmatic movement, et cetera. We think it is something to do with the diaphragm and we want to see whether that can be a simple test to see whether patients will benefit from the drainage. So I want to spend the last couple of minutes just to talk about is breathlessness the right thing we want to measure? Is it the only thing? Is that what the patients really want, especially in the setting of malignant purifusion? We are all into patient-centric or patient-relevant outcome measures, but a lot of the things we're using are subjective measures like the VAT scores that we talked about. These things can be compounded or confounded by pain, by breathlessness, sorry, by depression, by fatigue. If the oncologist gave you bad news today, you're going to feel more short of breath on the VAT score. So I think we need something more objective and oscillometry, which is like the sophisticated version of Fitbit or Apple Watch is a wearable device that can capture the physical activities like the step count and how intense you actually do it over a time. It is non-invasive and it is an end point that the patient can actually understand and relate to rather than quality of life scores. And it encompasses a broad palliative goals. If the patient can move more, then usually it means that their breathlessness, their pain, their psychopenia, et cetera, are better controlled. So when we use oscillometry on our patient with malignant purifusion in our cohort, we find that these patients in their awake time spend about 75% of their day sitting or lying down, sedentary, and only about 25% time in light activities, which is walking around the house, and very, very minimal time, two or 3% of the day in moderate to vigorous activities, which is like walking up here or walking upstairs. I think this is a very important point that we often underestimate. Why is objective measure important? Well, when we pull together all our studies before that use oscillometry, 160-odd patients, we look at what the clinicians grade them on the clinic record of ECOP status versus the actual physical activities that we measure on actigraphy. So remember, ECOP2 is the cutoff line to say that the patients need to be up and about more than 50% of their awake hours. So if someone is ECOP0, 1, or 2, they should fulfill that criteria. Have a guess, how many of the patients on actual actigraphy measurement spend 50% of their awake hours up and about? It was less than 5%. So we are grossly overestimating what the patients told us. So this is hot off the press from my group. So if we then divide the patients by the number of steps they walk into two halves, the higher half and the lower steps counts half, even after adjusting for known risk factors like the ECOP status or the histology, gender, age, et cetera, we find that those who walk more steps have significantly better survival in the Klepp and Meyer curve than the lower half. All right, at this point, I'd just like to thank my research group that has generated a lot of the data that you have just seen. Thanks for the invitation to speak here. And if you're interested in Peru research, we always like to talk. Thank you. Thank you. Thank you, everyone, for joining today's session. My name is Labib Dabian. I'm an interventional pulmonologist at Henry Ford. And it gives me great pleasure today to talk to you about updates in perineumonic effusions. This is the QR code that you will need to answer the first question. Learning objectives today, I hope from today's presentation to be able to outline a little bit the microbiology of community-acquired and hospital-acquired pulmonary effusions, discuss a little bit the optimal antibiotic strategy, compare small and large-bore chest tube drainage, and finally, discuss intrapleural enzyme therapy as well as surgery. First question, a middle-aged patient presented with fever, productive cough, dyspnea, and right pleural chest pain, was diagnosed in the emergency room with inoculated right perineumonic effusion, and a pigtail chest tube was placed. Which of the statement below is correct? Number one, large-bore chest tube is superior to small chest tube drainage. Two, Staphylococcus organism would be the most likely cause of infection. Three, intrapleural enzyme therapy would reduce the rate of referral to surgery. And last, the optimal first choice of antibiotic therapy is piperacillin-tazobactam. All right, it sounds like we don't have the answers up, but the correct answer is intraplural enzyme therapy would reduce referral to surgery. So we're going to go over that data today. It's very important to understand the current burden of paranormonic effusion. There's about 2.5 million people who would die of paranormonic effusions worldwide. And about 30% of them would present with a plural effusion at the time of diagnosis of a paranormonic effusion. And this has been associated with increasing mortality. And as you can see on this graph, from the past two to three decades, in most institutions, whether it's in the US, in Europe, Taiwan, Asia, there has been an increase in the number of hospital admissions because of paranormonic effusions. So when we look at updates in that field, there hasn't been that many randomized controlled trial coming out lately to try to address paranormonic effusions. But in 2023, we have three important papers that came out. One is an ERS statement on the management of paranormonic effusions. The second one is coming from the British Thoracic Society, who in 2023 have published their guidelines on the management of plural effusion in general, touching base on infection. And third one is a meta-analysis comparing small and large chest tube, bore chest tube, which I'm going to be talking about today. So when you think of plural effusion and pneumonia, does the microbiology match? Does this mean the same organisms you would find in the community acquired pneumonia would match that of the plural effusion? And the thought process initially was that it does. But now there is more thought into this because the medium, the plural effusion medium may not necessarily be exactly like the microenvironment within the lung. The pH is not the same. The amount of oxygen in the alveolus compared to the plural effusion may not be the same. So there's this emerging thought that maybe the plural effusion should be approached in a different manner. Maybe this is a different microenvironment with different microbiology. And so based on review of many studies in that ERS statement, it was found that the community acquired plural effusions predominantly in Streptococcus viridans, followed thereafter by Staph aureus, and then followed by the gram negatives. And this is about 85% of paramnemonic effusions presenting to your practice. The other 15% tend to be hospital-acquired infections. And those actually predominantly are going to be Staph aureus, including MRSA infections, then gram negatives, and further lower enterococci. And what is the yield of plural effusion culture in the first place? It's not as high as we like it to be. Some have published as low as 40, could be as high maybe at 60. But at best, it's in the range of the 50th percentile or 50%. And one thing that has shown to maybe improve that culture is the use of blood culture bottles to try to improve the yield on top of regular standard culture bottles. But the question is, why is that? We're getting a good sample of fluid. Why are we not getting a culture? And the idea is that sometimes the organism are fastidious. Maybe they need a little bit more nutrition to be able to grow. Number two, it could be that you're studying your empiric antibiotic therapy way ahead of time before you even do the plural effusion tap. And at that point in time, maybe your yield is a little bit lower. Not to mention that in a very low pH, organisms may not all grow as well. So unfortunately, culture is not as reliable as you would like it to be. So what is the optimal antibiotic coverage? We're going to think of community-acquired versus hospital-acquired. For community-acquired, your most common are gram positives. And so you want to cover with a penicillin with beta-lectamase. And if there is a suspicion of an aerobe, that would be a metronidazole or clindamycin. Now in those patients who cannot tolerate that kind of antibiotics, or they have allergies, your alternatives would be quinolones or maybe second-generation cephalosporins, which unfortunately would require an intravenous treatment. As for the hospital-acquired, if you remember, the microbiology is different. And gram negatives, including pseudomonas, become a little bit higher. So we need to have good coverage for that. And as such, an anti-pseudomonas penicillin would be actually a drug of choice, like, for example, papiracil and tezobactam. And depending on whether the patient is MRSA-positive on the nasal swab, or they're coming from a community-acquired MRSA where the prevalence is high, then coverage with lenazolid as a first choice has been recommended. Now obviously, if you don't have tolerance to that kind of medication, your alternative is going to be an anti-pseudomonas cephalosporin, such as cefepime, and maybe the use of vancomycin in that case. Mind you, those are guidelines. You should always think about your own local community, the epidemiology within your own local area, as well as your local hospital, and try to tailor your antibiotic therapy accordingly. So now that we know that our patient has a paranemonic effusion, the next thing is, is there anything that could predict mortality when those patients come through the emergency room? And the answer is yes. The rapid score is a score that was actually developed from MIST-1, MIST-2 trial data. And it's been developed and validated as well. And it really relies on renal function, age of the patient. Whether you see or not pus or purulent drainage on your initial thoracentesis, what is the infection source? Is this community-acquired versus hospital-acquired? The dietary status as well. And when you create a score and you find a combined score, you can put that patient into a low, medium, or high-risk category, which one matters the most. And this recent publication looking at association with mortality found that when you belong or when that patient belongs to the high-risk score, rapid score, their mortality is actually significantly increased. Now how do you use this in day-to-day practice? When you calculate this on arrival after a thoracentesis or fluid drainage, it can help you decide how aggressive you want to be, maybe how soon you're going to send those patients for surgical drainage, and how much more attention that patient might need compared to the other patient population. So now that we know that, the big question is, do I place a small bore chest tube or a large bore chest tube? Several studies have been published discussing that topic. And finally, a meta-analysis in 2023 came out with me and colleagues looking at this. And the three important outcomes we're interested in are, how many times do we need to send our patient for surgery by choosing one versus the other chest tube? What is the mortality difference? And finally, one of the most important clinical outcomes is length of hospital stay. As you notice, those patients get admitted, and sometimes they stay in the hospital for quite a bit of time. So looking at surgical referral and comparing a small bore on the top and large bore on the bottom, there actually was no statistically significant difference between small bore and large bore. So 0.16 was the risk with the small bore, and 0.20 for the large. How about mortality? The meta-analysis found the same thing. Actually, no mortality difference if you choose a small bore chest tube as opposed to a large bore chest tube. And finally, length of hospital stay did also not differ 23 days to 24 days median. So basically, what we've learned, quote unquote, from that meta-analysis that was published this year is that maybe no difference in small and large bore chest tube, probably favoring more the use of a small chest tube because it's more tolerable to the patient, less chest pain, less symptoms, even easier to manage. So how about use of intrapleural enzyme therapy? MIS-TU trial remains the gold standard trial here when it comes to comparing TPA and DNAs versus placebo came out in 2011. And what it worked on is two major outcomes, improved radiographic clearance and the rate of referral to surgery. However, there has been multiple other studies that came out throughout time, either comparing a lower dose of the TPA or comparing different frequency. Instead of having the two dose for three days, a total of six. Some have done a little bit less than that or went into a once-daily regimen. And so the paper that just published in 2023 has actually reviewed all those studies. And as you see, there is a bit of heterogeneity and diversity in terms of these medications being used concurrently, sequentially, a total of six dose or less, and a different variation in the dosages. And at this point in time, we don't have a final kind of like evidence-based practice in terms of what would be best. But I think for the most part, as you're going to see in the algorithm that I'm going to discuss a little later, is that after the first 48 hours, you can always assess how much drainage you have achieved with the intrapleural enzyme therapy and tailor your decision-making accordingly. You're not necessarily, there's enough evidence to say you're not necessarily bound to complete all six doses together. So what is the role of surgery? Surgery remains the ultimate objective, quote-unquote, for best control and best outcomes for paranormonic effusions. Ideally, you would want to be referring those patients within 10 days, some even say seven days. So you can work in parallel. As the patient gets that chest tube drainage and you started the process of maybe the intrapleural enzyme therapy to start thinking about involving your surgical colleagues. And definitely, if there's ongoing sepsis, poor source control, multiloculated effusion, the chest tube is not able to drain all of the loculations, maybe even despite placement of different other chest tubes at this point in time, it becomes more and more necessary to involve surgery. Is there a role of medical thoracoscopy? And the answer is it's an option. Medical thoracoscopy is actually, it depends also on the comfort level of the person doing it and how much equipment and support do they have. But if you feel like you're well-trained to be able to break down loculations, achieve good response equivalent to, quote-unquote, a surgical thoracoscopy, that could be an option. I do know that there is a lot of learning experience in this and not many institutions necessarily would be able to achieve the same outcomes as surgeons. So finishing off with an algorithm, algorithm of a patient presenting with a paranormonic effusion. First thing is to measure the pH. I personally don't measure it as much. The reason is because it's not easy to measure a pH that would end up being an accurate pH that you can rely on. Most of the time, patients have already had their pleural effusion tapped in the emergency room and the pleural fluid was sent in an improper manner. The ideal way of sending a pH would be in a ABG syringe or a special tubing. That tubing has to be sent to a proper machine, which is usually the ABG machine, and it has to be processed within 15 minutes. And if you don't have that kind of reliability within your institution, you may be acting on wrong data that may affect your management. But provided you have all of this available, well-calibrated, and you rely on it, pH is a good way to start. And based on that algorithm, you want to put your pH at 7.2, 7.4, and the in-between. Those at less or equal to 7.2, those are high risk for complicated paranormonic effusions. You want to be aggressive, chest tube drainage placement, and you proceed with that. And then those who have a pH larger than 7.4, those are probably a very low risk for a complicated paranormonic effusion infection. So maybe there's no immediate urge in trying to drain it. Maybe just a large volume thoracentesis at the beginning. And then continue to monitor for improvement. And then you'll have the in-between, which is the intermediate risk. And here, the suggestion is to look at your pleural LDH. Is it more or less than 900? If it's less than 900, basically indicating maybe less inflammatory activity. And then maybe you can just continue to watch. So no indication for an immediate chest tube. And if it's higher, proceed with chest tube and basically take it from there. So these algorithms, I apologize, the screenshot was a little small here, but I'm going to walk you through it. So a patient comes in, and you decide this patient needs a chest tube placement. So you go ahead and place it. And this is the right timing to look for the rapid score. You want to have that data early on as soon as you start the treatment. And then next, you're going to ask yourself, OK, I'm going to place a chest tube. What kind of size chest tube? Recommendation is small bore chest tube. Question is, what is the definition of a small bore chest tube? Sometimes in the literature, they would say less than 20 French is small bore. Others would say less than 14. I think for most practices, 14 is around the number that people would use. So bottom line is that large chest tube is not necessary. And once you place it, you're going to wait for 48 hours and reassess clinically how this patient is doing. If this patient has a very good clinical response, you look at the radiograph, there is decent re-expansion of that lung. They're not in sepsis. You could continue to manage that way, continue the drainage. When it decreases, maybe pull the chest tube, switch from IV to oral antibiotic, and start preparing for recovery at that point in time. If the patient is unstable, then at that point in time, surgical referral becomes something to think about. You could have a maculocutative effusion. You haven't achieved good source control. This is the time to involve surgery. Now if there is poor clinical progress, then sometimes it's due because of pleural thickening in the effusion. So proceed with a chest CT scan if this has not been done yet, obviously. And then based on this, decide again surgical candidate or not. And if they're not surgical candidate, this is where we'd consider the intrapleural enzyme therapy. And you'll complete that intrapleural enzyme therapy and then reassess again. If those patients are still surgical candidates and have not achieved good resolution, reconsider surgery one more time. If they're not excellent surgical candidates, now you have a very sick patient with not a very good response to all the treatments you've provided for that perineumotic effusion. At this point in time, you want to consider either switching antibiotics, prolonging the duration of the antibiotics, or other possible interventions. So take home points from today. There continues to be an increase in the incidence of pleural infections. This is an important problem. It requires ongoing research and a better understanding of how to manage it. Overall, the clinical outcomes and complications do not substantially differ between small and large bore. So until now, there's no evidence for any difference between the two. Deoptimal intrapleural enzyme therapy dosing has not been necessarily confirmed with strong evidence. Probably ongoing studies could lead to that. But MIS-2 remains really the strongest clinical control trial that we have. And remember that proper timing of surgical referral is important. I know we always say proper timing. No one really knows how to define it. It's always a challenge. And sometimes we can get intimidated approaching our thoracic surgery on and off, but we shouldn't. This is the best thing for the patient, and pretty much probably what's going to be the best treatment overall. Thank you. So for most of us, this is going to I'm the guy who's standing between you and lunch break, so I know how hard that is. So we are going to talk about, for the next 15 minutes, we are going to talk about updates on malignant pleurifusion. And these are my disclosures. So pleural risk research, we all know is a very, very active field of research. And on top of here, it's not a complete collection of all the studies that have been published or are ongoing. We're going to pay attention to the malignant pleurifusion component, and a little later we're going to break it down into which questions each one of those studies are attempting to address. But that's not the focus. The focus is this, the burden of disease, which you have already heard a little bit earlier. About 125,000 hospital admissions per year in the United States, costing about $5 billion per year in terms of both diagnosis, management, and lost manpower in terms of productivity lost. Of note, lung and breast makes up a majority of the cases and is associated with often poor survival, poor prognosis. Median survival is around three to 12 month, but you have heard that that target is shifting as better treatment options for our patients are arriving. So this is probably the key message to take home today. Two month ago, a month ago, this two updates have been put out by the BTS group. The British Thoracic Society Guideline for the pleural disease covers both pneumothorax infection and malignant pleurifusion. It's a great document to review, but don't just review the actual document itself, do review the 21 accompanied supplemental documents that's with this. There's also a statement on pleural procedures. It's a great document to review. It kind of reviews about tips, tricks, recommended ways of performing certain procedures. Now, what is the contemporary approach about first diagnosis of a malignant pleurifusion? This diagram is very complex. I'm going to distill it down to much easier one to remember on the next slide. Keep note, not all cancer cells behave the same. The ones that like to shed, the ones that do not have tight cell junctions tend to shed into the pleural fluid, and they often can be diagnosed versus the ones that have tighter cell-cell junctions. They don't like to shed into the pleural fluid, so you won't be able to get it in the pleurocytology. So when you look at the different cell type, lung endocarcinoma, ovarian cancers tend to produce more yield than in excess of 70%, but only about 25% of long squamous cell cases are diagnosed by pleurifusion cytology. Of note, the pleurifusion cytology sensitivity is around 60%, so there are other ways that we need to consider when it comes to diagnosis of McGlynn pleurifusion, and those involve different forms of biopsy, ultrasound-guided, CT-guided versus metothoracoscopy-related pleural biopsies. This is the distilled version. You need to differentiate between whether the patient has suspected cancer versus a patient with known cancer. If you have a patient with suspected cancer, the recommendation in that particular diagram shows the pleurofluid cytology should be attempted for the first try, but please do go on to a biopsy procedure next. And for a patient with known cancer, and you have recurrence of pleurifusion, you want to diagnose in the least invasive manner. If the primary tumor is an exfoliative cell type, then do try to do two thoracentesis to see if your pleurifusion have pleuropsychology or not, but you do have the option to also go forward with a biopsy. Consider, especially in patients with nonspecific lymphocytic, exudative pleurifusions are recurrent, and if there are pleural thickening, do consider using ultrasound-guided biopsies or CT-guided biopsies if you do not have medical thoracoscopy as part of the portfolio. So, this is the management guidelines that come from ATS, published a couple years ago, but much of it remains the same. What's important to note that we do want to use ultrasound to guide pleural interventions because it's safe, it produces a safer procedure, and do not perform pleural interventions in asymptomatic patients, or you can either use IPC or chemical pleurodesis for symptomatic patients with expandable lung, and performing large volume thoracentesis to assess symptom response is very important in the algorithm, and think about using PUDRAJ or SLURRI as a way of performing chemical pleurodesis, and using an IPC should be considered for non-expandable lung or trapped lung, and finally, treating the IPC infection with antibiotics, do not try to remove the catheter, try to treat through the infection, and as one of the colleagues here, Dr. Li mentioned in an earlier talk, infection is actually a very powerful pleurodesis agent, so if you did have infection, perhaps that's the silver lining. So, and if you think about the other, this is a diagram that's accompanying that particular paper, do take a moment to kind of think about how we're thinking about approaching to this problem of ligament pleural effusion, this is looking at how, I would argue that this is looking at the problem through the lens of effusion, not necessarily the patient, is this lung, is a patient's lung expandable, is there symptomatic improvement, it's probably something that we want to keep in mind how we should manage malignant pleural effusion, and this is actually something that British Thoracic Society as a guideline for pleural disease do stress. Number one, if you look at this simplified, very much more simplified diagram, you want to confirm that indeed that there is a malignant pleural effusion, and you want to ask whether the patient will benefit from intervention, and if the fluid that's in the patient is amenable, and if the lung is expandable, but then if you look at the two bottom green blocks, they're considering the intervention through a lens of ambulatory versus inpatient, which is a different way of thinking about the problem, in terms of developing an ambulatory pleural service program versus an inpatient driven pleural service program. So what is the ambulatory strategy? It has to do with extended pleurodesis strategy with IPC plus or minus a pleurodesis agent, like TAUC, versus inpatient or an early pleurodesis strategy like chest tube and slurry, or thoracoscopy with prodroge. So I highlight these three topics here, where there are actually consensus statement from the BTS guidelines, where the management of malignant pleural effusion, when treated with indwelling catheter, you can choose either symptom driven drainage strategies versus daily drainage strategies. If the goal is to get the IPC out and to achieve autopleurodesis, then daily drainage will be recommended. But if you're treating a patient with a malignant pleural effusion that has unexpandable lung, trapped lung, then you probably don't want to drain on a daily basis because it kind of defeats the purpose. So you may wanna do a symptom driven. And that particular recommendation got the strong recommendation by consensus from the group. Systemic therapy, often when we are approached with malignant pleural effusion, our oncology colleagues come to us and say, why don't you guys wait a minute? We can give the chemo to the patient, we can give the treatment to the patient, and then let's see what happens to the pleural effusion. Well, there's no data to actually support what they're claiming is that the systemic treatment for the underlying cancer can defer or can decrease the need for definitive pleural interventions. So in this particular case, the consensus is that definitive pleural intervention should not be deferred, should not be deferred until after systemic anti-cancer therapy being applied. So finally, talc or other pleurodesis agent, the consensus is that the installation of talc via IPC should be offered to the patient with expandable lung and if the pleurodesis and IPC removal is a go. Let's take a step back and let's think about the problem through the lens of inpatient pathway versus outpatient pathway. So if we do an inpatient pathway, they often involve with a patient stay, this usually requires a medical thoracoscopy with a prodroge or catheter-mediated pleurodesis. It treats the lasting symptom in terms of providing symptom control. The evaluated pleurodesis success rate is around 75%, not 80, not 90, 75%, 70 to 75%. Patients often go home without any foreign objects on their chest cavity. There's no long-term infection risk with this patient, but however, it does require additional training. And that pleurodesis success rate is taken from studies like TAPS where we compared tau prodroge versus slurry. So the outpatient pathway requires no inpatient stay, similar symptom control, but the pleurodesis success rate at best is around 45%. And this involves the indwelling pleural catheter that's being placed and it can be used for trapped lung, but there is an infection risk when you have a chronic placed catheter and that risk increases with time, with time, right? The longer the placed catheter there is, the longer the foreign body is in the body, the more likely you're gonna have infection. And of course, there is increased home care needs because now we're no longer having that patient come to us, but they're draining their own pleural effusion at home. These are the breakdown of the evidence-based studies that were mentioned earlier in terms of grouping each study addressing specific questions that I actually outlined. Now, I'm gonna move on to the notable studies that happened in the past 365 days. So there is one study that came out that I'm quite disappointed about the result, but it is a silver nitrate coated indwelling catheter. So think about it. If we have an IPC and we have a pleurodesis agent that is already manufactured onto that catheter, perhaps like silver nitrate, perhaps we can augment pleurodesis event and it just involves placing a catheter like what we're used to. However, in this particular study, over 17 sites in United States, three sites in the UK, the primary outcome is again, to measure pleurodesis efficiency or efficacy at 30 days and all patients were followed to about 90 days. We see that only about 22% of the patient in the silver nitrate coated IPC group got pleurodesis versus 32% in the control group. Note, so this is a negative study. So silver nitrate somehow didn't cause earlier pleurodesis or rather more effective pleurodesis, but the medium time to pleurodesis, you can see it took four days to pleurodesis in the silver nitrate catheter versus the control catheter that didn't have silver nitrate. So what gives? What's the difference? The reason why we don't get a better pleurodesis in terms of overall patient population, but had a shorter timeline in terms of pleurodesis. So when you actually look down, look into the details of the study, 31% of the patient actually passed away before 90 days. So it's a very, very sick population. Number two, it did not adjust for baseline performance status inpatient versus outpatient status or cancer type. So perhaps there are more, and it's not perhaps, for sure, there are more patient in the silver nitrate group that were inpatient as compared to the control group. So they're not balanced. So perhaps what we need to do is actually do something what Dr. Lee was saying. Well, maybe you should actually see how much your patient is ambulating, see how they're performing before you're offering a IPC to the patient. And perhaps there's ways for strategies that we can use to prognosticate and then to recruit the patient. Okay, there's also a large number of protocol deviation. So this study is fraught with issues, and I think we should take it with a grain of salt in terms of whether silver nitrate guided or IPC augmented pleurodesis is truly on the horizon or not. What we do know right now though, is with IPC plus study and MPL-2 is that we can perform IPC with talc in the, to augment pleurodesis. Now, there's a separate study looking at using ultrasound to predict whether talc pleurodesis was successful or not. And can it help us to reduce the number of days of hospitalization for these patients? Well, suffice to say in this particular study, 11 sites were, sorry, 10 sites were noted were in the UK, one site in the Netherlands, and it's a one-to-one design. The primary outcome is again, length of hospital stay. We do notice a difference about one day, one day. So yes, you can use ultrasound by looking at systematically through nine different quadrants and quantitate in terms of a score of lung sliding, whether you observe lung sliding or not. Now, one of the things is that as we move into the era of molecular pathology and being able to get enough samples to actually undergo NGS or molecular testing is very, very important for our patients, treatment and therapeutic options, and also for downstream, for down the line evaluation of various different clinical studies. So in this particular paper that was published this past year, the authors looked at 183 patients, of course, four sites in three different countries. The primary outcome is to ask the question of the adequacy of molecular marker status. And the secondary outcome is to look at clinical factors that predict molecular diagnosis. The authors noted that in comparing medical thoracoscopy versus CT-guided biopsies versus ultrasound-guided biopsy, the highest molecular diagnostic yield came from medical thoracoscopy-guided biopsies as compared to CT-guided and ultrasound-guided. So earlier in the talk, when we talked about diagnosing malignant plurifusion, we did mention about using a biopsy technique. This suggests that we should think about doing medical thoracoscopy and biopsy as the preferred method for getting both the cytologic and hisopathologic diagnosis and the molecular diagnosis. Now, very, very recently, this paper came out that looked at, well, what about if we just look at the fluid? You remember the cohort of the cells that the type of cancer cells actually shed into the plurifluid? What if we look at those patients and just ask, do we get enough DNA from plurifusion in the particular patient that we can actually get diagnosis from plurifusion samples? And in this particular study, that's exactly what the authors did. Note the cell type that they were looking at, lung adenocarcinoma, malignant plurifusion. In that particular case, when we look at the plural cell-free DNA versus cytology, isolated DNA versus pleural biopsy, isolated DNA versus cell-free DNA that is obtained from the plasma, the author note that the pleural effusion-related cell-free DNA gave the highest number of detectable oncogenic mutations. So suggesting the medium, and also more importantly, the medium amount that is needed was only five cc's. So that is a diagnostic thoracosynthesis that you can actually use to give a lot more, to provide a lot more information. So these are the final take-home points. It's a rapidly emerging field with lots of data-driven clinical practice. Do tailor your treatment to the patient. Robust plural service forms a basis for any outpatient management. So please think about generating a plural service at your own institution. And also consider a patient-oriented outcome for designing clinical studies and choosing approach. Thank you.

pleural disease

pleural physiology

perinominumonic infection

malignant pleural fusion

literature

guidelines

evidence-based care

US healthcare system

cost