Today, first of all, thank you to our presenters and all of you who have come here. Today, we are looking forward to a good talk on plural effusions and we'll get started. I think it's 10.30, we can get started now. So, we'll get started with Dr. Twaddle from Australia. He'll be talking about plural effusion and nets and we're all looking forward to it. Dr. Twaddle. Morning. My name's Scott Twaddle, I'm from Newcastle in Australia. It's about 75 miles north of Sydney. That's a gratuitous photograph of my hometown. You can see the surf, very similar to Hawaii in a lot of ways. I have no disclosures. And today, I wanted to talk briefly about some of the early results we have in regards to our basic science investigation of plural effusion and in particular, paramnemonic effusion. So, let's start off with the basics. What are nets? Nets are essentially neutrophils in distress. And we all know that neutrophils are the superheroes of our immune system universe. They can move through walls. They can cross tissue barriers. They do extraordinary things for us, the community. They can phagocytose. They can blow themselves up in order to protect us by degranulating. And they can undergo a process of netosis, where they organise their internal DNA structure, decorate it with antimicrobial proteins and exude it from inside of the cell. As you can see here, this is a net, a neutrophil extruding nets and catching some Shigella in this modified electron micrograph. And like all superheroes in any immune system universe, that's our preferred one. We love them because they do great things for us. But they are flawed. And in the case of nets, it's been suggested that not only are they beneficial for us at times in terms of acute inflammation and infection, but they can be bad for us as well. And it's been suggested that they're involved in chronicity of pulmonary conditions such as asthma and bronchiectasis and cystic fibrosis, and also in systemic diseases like rheumatoid arthritis and systemic lupus. It's also possible that they're involved in metastasis of malignancy. It seems that netosis can travel down two pathways. One pathway that seems related to lipopolysaccharide exposure and the presence of NADPH oxidase, which causes a movement down a suicidal or terminal pathway where the neutrophil exudes DNA from its nucleus and ultimately sacrifices itself in the fight against the microbes. There seems to be an alternative pathway, and there's some argument over exactly how this happens, but that neutrophil can move down a vital or viable netosis pathway and ultimately survive the exudation of its DNA material, which comes from its mitochondria, and ultimately leaves us with a zombie neutrophil that still floats around our circulation and does what it's meant to do, but largely like other zombies, a little bit directionless. Some time ago, we asked ourselves, is it possible that nets could be present in pleural fluid? And we looked at this briefly and basically with the presumption that paranumonic effusions are a highly inflammatory environment. We know that we treat empyema with DNAs, and that suggests that there definitely has to be DNA present in empyema. We collected some samples of pleural effusions and categorized them into four groups based on clinical and biochemical categorizations into paranumonic, malignant, transudative, and a fourth group of unclassifiable effusions. And we looked at markers of inflammation. We looked for extracellular DNA, alpha defensins, which are a marker of neutrophil activation, and so very highly inflammatory environments, and citrullinated histone, which is a marker of nets production or net presence. And as you can see by these graphs, our results showed some really interesting things. And just to point out that the vertical axis shows logarithmic scales, and so we showed in the paranumonic groups that these were a log power greater in terms of extracellular DNA, activated neutrophils, inflammatory environment, and in fact, nets. And the really interesting thing is when you compare this to some of the basic stuff that we do in terms of biochemical analysis for every empyeme or paranumonic effusion that we see, and all the others as well, these correlate fairly closely with lactate dehydrogenase as just an example of one of the basic markers that we use. And if you look specifically at those specimens from paranumonic effusions, that correlation becomes even stronger. So now armed with that information, we said, okay, so there are nets there. Citrullinated H3 is a marker of nets. What kind of nets are these? And so we went back and collected 112 pleural effusion samples, and again, four separate groups based on biochemistry and clinical findings. We looked at markers of inflammation and soluble urokinase plasminogen activator receptor and plasminogen activator inhibitor one, which had been previously suggested to be involved in the persistence of effusions and fibrosis of the pleura. And we did ELISA analyses on those. And we did polymerase chain reaction and reported mean cycle thresholds for mitochondrial and nuclear DNA in these specimens. What's really interesting is that the interleukin 6 concentrations were, again, a log power greater in the paranumonic effusion group compared to all the other groups, as well as the SUPAR being a log power greater. And that's just a graphical representation of that. Interestingly, mitochondrial DNA was significantly higher in the paranumonic group, and that's evidenced by a lower cycle threshold for PCR. So just for those who are a bit unfamiliar with this, a lower cycle threshold indicates a higher concentration when you're doing PCR concentrations. And so you see in the other groups, 40 is the upper limit of negative. If we get to a PCR cycle threshold of 40, we say whatever we're looking for is not present. And a cycle threshold, which is, if you imagine PCR is doubling, basically, a cycle threshold of 20 suggests that you've developed a positive response at a power or several powers of logarithm lower. And interestingly, citrullinated H3 was strongly correlated with mitochondrial DNA in this group, as well with a Spearman's correlation of .74. And that's just a graphical representation of that as well. So some really interesting findings from our perspective that in these paranumonic effusions, it seems that a lot of them are mitochondrial in their origin. And this indicates that they're very, very, very inflammatory. And it also indicates that there's a lot of zombie Spider-Man running around in there. Interestingly, the nuclear DNA was not significant between any of the groups in terms of difference. And the PAI1 and TGF1 beta was not significantly different either. So what can we conclude from this? And very basically, we can say paranumonic effusions are clearly highly inflammatory. The concentrations of NETs are very high in those paranumonic effusions. And it seems that they're predominantly related to mitochondrial sources. From our point of view, we see this as a way to move on from a basic science into a translational way of thinking about how we can better treat pleural effusions, and in particular, paranumonics and empyema. And so we're interested in looking at those things. The take-home message for you today is next time you drain a paranumonic effusion, think of all of those zombie Spider-Men who have given up their lives for that patient. Just to summarize or conclude, I'd like to thank the team who are involved in this research. And if anybody's interested in doing collaborative research in terms of, as my children say, lung pus, which is apparently how they explain it to their friends when they're asked what I do. I know a guy, and there's his email address. Thank you. Next, we have Dr. Grover, who will be talking about features of iatrogenic urinothorax. Thank you, everyone. Hi. My name is Dheera Grover. I'm one of the gastroenterology fellow at Allegheny General Health. Welcome to the topic, welcome to the pleural effusion session. Today, we'll be talking about clinical etiological features of iatrogenic urinothorax, a systematic review. And I don't have any disclosures. So, the main objective of this session is to understand the clinical etiological features of iatrogenic cases of urinothorax. Importance of early diagnosis and treatment. What is the diagnostic workup and treatment modalities for urinothorax? So, what is urinothorax? It's a rare cause of pleural effusion. It's due to the accumulation of urine within the pleural cavity. Now, the first ever reported case was by Cody et al in 1968. Majority of the cases are due to the obstruction in the genitourinary tract or due to the iatrogenic etiologies. We're going to talk about the iatrogenic etiologies a little bit more in detail later. Majority of the effusions are transudative in nature, but it can be exudative. Some of the cases have reported that. The major hallmark and the reliable marker for diagnosing urinothorax is the serum to pleural fluid creatinine ratio, which should be greater than one. There are other markers like LDH and urea levels and things like that that have been reported. But this is the most reliable marker for diagnosing urinothorax. I just want to give you a little brief, like how we came up with the idea. So during my training in residency during my intern year, we had a patient who had urinothorax due to stent migration. So they were pulling out this urethral stent, and that's how the patient ended up having the urinothorax. So when I was digging literature a little bit, we could not find any review or any literature specifically on the hydrogenic etiologies. And majority of the cases that were reported of urinothorax, they were either cases or case series, or it was just a review, nothing, no like trials and no systematic review. So we analyzed the clinical etiological profile of all the reported cases of urinothorax specifically secondary to the hydrogenic etiologies. We just did a literature review from 1974 to 2021. We found 99 studies, which documented around 117 patients. Out of these 99 studies, only 65 of them, which included 71 patients, were due to hydrogenic pathologies. We did the descriptive analysis on the demographics, symptoms, biochemical features, and the treatment modalities. This is just a Prisma chart. So what we found out, the mean age of the patients was around 44 years. And the distribution amongst male and female was approximately equal. 53% of the cases that were reported were females. And when it comes to symptoms, it was quite variable. Though majority of the patients, you will see around 69.1% presented with respiratory distress. However, there were some patients that had either constitutional symptoms or symptoms related to the genitourinary tract, including oligouria, dysuria, or abdominal distension. Actually, two patients out of the patients reported, they were asymptomatic. So though respiratory distress would be the main symptom, but the patients can present with other symptoms as well. Now, when it comes to the etiologies, more than 50% of the patients either had nephrolithotomy or nephrostomy prior to having the puerile effusion. But the other common causes included renal transplant or total abdominal hysterectomy or cryoablation, even the kidney biopsy or radiofrequency ablation of renal pole. So this just kind of highlights that urinothorax can be because of multiple prior procedures or surgeries or pathologies. We just found only one case due to stent migration. Due to stent migration, the case that we saw was not reported yet, and that's why it's not included in the study. But that would be the second case due to stent migration. Now, when it comes to the puerile effusion, majority of the cases were right-sided, 56.4%. Not sure why, but there were some cases left-sided or bilateral in nature. We could not find a reason why there was a right-sided predominance of puerile effusion. Similarly, 56.3% were ipsilateral to the side of pathology, but 8.5% of the cases were contralateral, something to keep in mind that it can be on the other side to the primary pathology as well. So for the diagnostic purposes, majority of the patients underwent thoracentesis. For one patient, they collected the fluid analysis from intercostal drain insertion. Again, majority of the patients, like around 42.3%, had transudative effusion, but 26.8% did have exudative as well. Amongst 18 patients with exudative effusion, there were four patients that had protein-accordant studies, and there were six that had protein discordant. This is what I wanted to highlight. You will see that 76.4% patients had the puerile-futocreatin ratio greater than 1, but there were other patients that didn't have that ratio greater than 1. It was less than 1, but two patients had urea levels which were elevated, and that's how they were diagnosed with urinothorax. There were a lot of patients that I couldn't really find how they were diagnosed with urinothorax, but it might be just suspicion or it was not documented properly. There has been some studies that elevated LDH levels. They do correlate with urinothorax. In our review, we found that the levels were available only for 26 patients, and the mean range that we found was around 39 to 3,400 approximately, but the mean was around 43. So if we do have elevated LDH, we should be thinking about urinothorax as a potential cause. For the treatment modalities, a majority of the patients underwent thoracentesis for the symptomatic treatment, and 43.7% underwent intercostal brain insertion after the thoracentesis. Some ultimately required nephrectomy, and actually four patients ultimately died because the diagnosis was little delayed and the suspicion was low in those patients. But the main treatment modality would be treating the symptomatic treatment plus treating the underlying etiology. This is just indicating the various treatment modalities including thoracentesis, intercostal brain insertion, removal of the obstruction, or the surgical repair of the injury itself. Only six patients underwent spontaneous resolution and around 4% actually passed away. So just indicating how it's really important to have a high index of suspicion for the early diagnosis and treatment. Couple of take-home points. Urinothorax, though it's rare, but it is well-documented and it's under-diagnosed. It's essential to have it, to have like an early diagnosis because if it's missed, it can, it's pretty reversible at the early stages, but it can, it can have complications when diagnosed at the later stage and patients might ultimately pass away. And when we are collecting the puerile fluid analysis, the puerile fluid for the studies, if patient has had procedures before, we should be sending the puerile fluid creatinine ratio and calculating the ratio if our suspicion is high. So again, condition is managed by treating the underlying cause and supportive management, including therapeutic thoracentesis mainly. I would like to thank my co-authors and thank you everyone for listening. Okay, yes, next is Dr. Brehm, talking about pleuroscopy in chronic pleural effusions. Good morning, everyone. Thank you for joining. So as was mentioned, today I'll be speaking with you all about pleuroscopy in chronic pleural effusions, specifically at a VA medical center. This was an eight-year retrospective review. I'm Victoria Brehm. I am a second-year resident at Baylor College of Medicine, so I definitely have no financial disclosures to share with you all today. Really today, our goal is to discuss the causes of chronic pleural effusions, specifically within our unique population at the Houston VA Medical Center, as well as to highlight some important diagnostic and therapeutic practice implications that we noticed when we were going through this data. Now, this was really born out of a desire to better understand our specific unique population within the VA, why they end up getting pleuroscopies, how those pleuroscopies go, and what they can tell us moving forward. This was a retrospective review, and it took place over eight years, from 2014 to 2021. The inclusion and exclusion criteria were pretty broad. We didn't want to exclude, essentially, anyone at our Houston VA that underwent a pleuroscopy with one of our pulmonologists over those eight years. We didn't have any exclusion criteria, and we really just wanted to get a better handle on who has undergone pleuroscopies and what they look like. We looked at a very broad set of outcomes, their demographics, their diagnostic and therapeutic timeline, of course, the pleural fluid analysis results, and then their final diagnosis is something we focused on quite a bit, as well as the procedural interventions that they underwent, both during the pleuroscopies and afterwards. We ended up with a cohort of 60 patients. Again, this was a VA, so all of our patients were male, and they were, on average, 71 years old. We had an average of about 2.6 medical comorbidities that included things like heart failure, CKD or ESRD, liver disease, COPD. And our patients really presented with kind of typical symptoms of these pleural effusions. 90% of the patients in our cohort presented with dyspnea, 20% with cough, and 13% with chest pain. Interestingly, we actually had 5% of our patients who were completely asymptomatic. They had generally gone to their PCP for something else, and the PCP had picked up on decreased breath sounds or had just gotten a chest X-ray and noticed a pleural effusion, and they made their way to us. Now, of these patients, the vast majority of them, 93% underwent at least one invasive procedure prior to their pleuroscopy. Most of these were thoracenteses plus minus a chest tube. And we had a very large range of time between that initial intervention and the ultimate pleuroscopy. Some of these patients had their initial intervention, and then the next day underwent a pleuroscopy, and one of our patients made it almost three years before undergoing a pleuroscopy. But on average, our patients had about 68 days between their initial intervention and the pleuroscopy. Now, most of these patients, 56 of them, had had prior thoracenteses, and we had pleural fluid studies for those. The vast majority, 95%, were exudated based on Leid's criteria. 40% were bloody. And then something I want to really highlight here on this slide was the cytology from these thoracenteses, from the pleural fluid study. As you can see, 30% of the patients had cytology that was positive for malignancy prior to their pleuroscopy. But 70% were negative. Now, this was kind of the meat of what we were looking at. What was the final diagnosis after these pleuroscopies? What did these pleuroscopies tell us, and how did they guide our further management? As you can see, we had quite the proportion of patients who had a final diagnosis of some sort of malignancy, 52%. Now, I'll remind you again, only 30% had positive cytology with their pleural fluid studies. 13% of our patients had a final diagnosis of chronic pleuritis. These were the patients that had documented inflammation in the pathology and really going through chart review and based on the diagnosis that was determined at that point in time, no other etiology of the pleural effusion was found. 5% of our patients had infection. We had a couple of tuberculosis cases, one histoplasma case actually for a pleural effusion. And then this large other category encompassed pretty much everything else you could think of, ESRD, heart failure, hepatic hydrothorax. This malignancy is what I really want to hone in on because we found it very interesting. Of that 52% of our patients who had a final diagnosis of some sort of malignancy, 48% of those had mesothelioma. 29% had metastases from the lung from other sites. And then as you can see, we had a kind of smattering of other types of malignancy as well. But this mesothelioma, 48%, it's a pretty high number. It's something that really piqued our interest. I told you I'd tell you about the interventions that our patients underwent. Only 23 of these patients, 23% of these patients that had a pleuroscopy underwent the pleuroscopy alone. Most of them had a pleuroscopy and an indwelling catheter placement. And 20% of the patients actually had a talclerodesis at the time of pleuroscopy. In terms of our procedural outcomes, we had 19% of patients or so that had some type of pneumothorax. The vast majority of these just required a little bit of extra monitoring or a tube in place. We had one bleeding event and one infection that was possibly related to the procedure. Then of those 46 patients, the majority of whom with our pleuroscopies that had the indwelling catheter placed, we had 6% or so that had dislodgement and then about 10% who had some sort of catheter clogging or clotting that required intervention. So really to sum up our data, the majority of our patients did present with those typical symptoms that we would expect to see in patients with pleural effusions. They had dyspnea, they had cough, they had chest pain, and most of them had exudative effusions. Really this key point was, over half of them had an underlying malignancy and half of those had mesothelioma. And most patients that had prior procedures. Of course, with the catheter placement, we did have some catheter clogging, some pneumothorax, given that we were doing pleuroscopies. But again, I really want to highlight this underlying malignancy and mesothelioma point here, which was not unexpected that our rates of malignancy as a final diagnosis were higher based on biopsy than based on the pleural effusions, but definitely something that interested us. So overall, at least in our population in our Houston VA, it's really told us that we do need to keep maintaining that high suspicion for malignancy in these patients who have chronic pleural effusions. We have a pretty high rate of mesothelioma in this patient population out of the malignant pleural effusions. There have been studies at other VA sites looking at malignant pleural effusions and what the specific etiologies of those are. And it tends to range between 14 and 18% of mesothelioma. Of course, our patient population is different. We specifically selected for patients who are undergoing pleuroscopies. Perhaps they had imaging findings that made us more likely to pursue a pleuroscopy, but it was kind of a discordance from some of the literature that's been done. Of course, our veterans have quite a variety of toxic exposures. Most of them are smokers. And it really highlighted, again, the fact that the pleuroscopy for us really provides an opportunity to expedite diagnosis and to actually therapeutically intervene. As you saw, very few of our patients only underwent a pleuroscopy. Most of them had some sort of therapeutic intervention done at the same time. And it ultimately kind of brings us back to our original question of how can we improve this process for our veterans? So we're continuing to expand the patients that we're including in this study, changing the years and including more patients, and starting to dig even deeper into how we can associate some of these findings with the underlying demographics and exposures of the patients who are involved. And I truly appreciate your time. Thank you so much. Thank you. Thank you. Next, we have Dr. Duval talking about hepatic hydrothorax. Hello, everybody. For our session today on pleural effusions, we're gonna be talking about characterization of X-rays in patients with hepatic hydrothorax, comparisons of likes criteria with alternative parameters. I'm Axel Duval from Roberts in Jersey, and I have no disclosures. Basically, the idea today is walk us through what else can we be doing for these patients that have hepatic hydrothorax instead of the likes criteria with this specific population to try to figure out a better way of characterizing these X-rays. Just as a little bit of background, around 40 to 12% of the patients with cirrhosis present with hepatic hydrothorax as one of their complications. And we, up to these days, we keep using the likes criteria to differentiate between X-rays and transcurate, even though it's been up there for 50 years already. We consider it being critically in this population given the high morbidity and mortality that it carries on, given how sick our acirrhotic patients are. We try to point it out to, we need better and more accurate testing for these patients, and we're just trying to narrow down the things that we are missing with this population. So, to kind of explain the methods of our research, we went with the basic definition of hepatic hydrothorax, it's the scleral diffusion in which has been ruled out already any cardiorespiratory, infectious, or malignant process. We took all of our adult patients who had a suspected hydrothorax, and that underwent thoracic thesis for a period of five years, respectively being looked at a center since we focus on this population since we're a major liver transplants and referral center, so we have a high incidence of these patients. We evaluated protein LDH albumin levels, both in the pleural fluid and in the serum, and we evaluated with some statistical analysis. We screened a population of 221 patients initially, but we were able only to work with a sample of 151 based on sampling and data. We had a mean age of 62 years old, the predominant gender was a male with 55%. As we can see here, the median values for the serum parameters, the LDH was 252, proteins is six, and albumin is 2.9 to our normal ranges. Six is the bottom line of what is considered to be with the normal limits, and albumin is considerably less. Our lower limit is 3.5, and we have the numbers for our pleural fluids as well. Moving on with this, we are able to see that again, LIKE's criteria is doing what it is supposed to, right? It has a 96% sensitivity ruling in our exudates, but when it comes to specificity and accuracy, which is what we're looking for in this specific set of patients, the serum to effusion albumin gradient, what we determine a cutoff of less than 1.2 will perform way better with 98% for both values. When we were trying to evaluate each distinct parameter of the LIKE's criteria, the effusion to serum LDH, the proteins and the two-thirds of LDH, neither perform better nor on sensitivity or specificity, and the wider range of variability was definitely not ideal when it comes to evaluation. It was particular to us that the LDH values were very far off on behalf of the patients that were deemed to have an exudate by LIKE's criteria, but not by the serum effusion albumin gradient, especially with an 81% margin of error, which is critical for our patients. So what we're trying to propose is that we need to take a better and deeper look when it comes to making a decision in this specific subset of patients with hepatic head and thorax, given the fact that if it's deemed to be an exudate, there's many more things that we need to do, right? If it happens to be a transudate, therapeutic is deemed, but if it happens to be an exudate, it can carry on higher morbidity and mortality that needs for us to pay closer attention, both in more diagnostic methods for their imaging and therapeutics, right? One key remark that I wanted to mention is when we go back and look at the literature is the fact that this value, this parameter, the use of the albumin gradient, it's only valuable in this subset of patients with hepatic head or thorax, and it has been used before as well in patients with heart failure-related effusions. So it's critical to be limited to this specific population to achieve the numbers that we have seen before. If we have to give a couple thoughts on why these patients perform better with this specific parameter, it seems like the subset of population, of course, is being exposed to diuretics as part of their treatment, which has incredible variability in what the results are gonna be. And one of the things that we're gonna look back into is the number of RBCs in the fluids, given the fact that higher RBCs in the fluids, higher LDH levels that are gonna give us a different range of value. I wanted to take a moment to thank our mentor, Dr. Andrew Berman, and thank you all for being here. Thank you. Thank you, Dr. Duval, thank you. Well, thank you, thank you once again. Thank you to all the presenters, and thank you for coming, supporting CHEST and our presenters. Thank you so much. Thank you.

pleural effusions

neutrophils

inflammatory conditions

paramnomic effusions

iatrogenic urothorax

pleuroscopy

hepatic hydrothorax