Good morning, I don't know if you guys are having the incredible difficulty. I am sort of acclimating to this time change. For me it's six hours. We have some West Coasters here who it's not as bad, but I know for me it's been absolute torture. So today I feel a little better. Yesterday I felt like I was drunk when I didn't even drink, so it wasn't even fun. Today I feel a little better. So let me just give some housekeeping points. All sessions, including all of our six puzzler sessions, can be evaluated through the mobile app, so please make sure that you use the app and give your honest opinion of what you think of the sessions. I'm proud to say this is actually our 16th year of doing clinical case puzzlers. So let me give you a little bit about the background and how puzzlers came to be with the ACCP. So many people, many of you have busy practices or work as fellows or residents and manage patients beautifully. But you don't sort of get to run it by faculty like we have up here, who are literally the world renowned experts in their field. So it's very nice, and that's sort of the spirit of how the puzzle is formed, was to have your cases presented and sort of dissected by these people who may have more resources than you and certainly have vast wealth and a plethora of knowledge and experience. And that's really beneficial, and so we've been doing it for 15 years. This is the 16th year, and hopefully we'll do it another 16 at least. So let me introduce our faculty, and this is certainly the best part of the puzzlers for me. My name is Anthony Sala, I'm from Brooklyn, as you could tell by my vast Brooklyn accent, so please don't hold that against me. Both of my daughters really make terrible fun of me and say, when are you going to lose your Brooklyn accent? And I say, probably never. So I am from Brooklyn. We are so blessed to have Dr. Kevin K Brown, who if you know anything about interstitial lung disease and diffuse lung disease, you know just about every article you read, Dr. Brown is either the lead author or one of the authors. And as nice, as brilliant as he is as a clinician, I've gotten to know Dr. Brown well over the past 16 years, and can tell you he's even a better person, if that's at all possible. So, Dr. Brown, we're thrilled to have you. You bailed on us last year, but to have you back is great. Making her initial, her debut, and I am so proud and honored to welcome Dr. Lauren Groner. Dr. Groner comes to us from New York Presbyterian Weill Cornell Medical Center. I'm in Presbyterian across the river in low life Brooklyn. But yet she is so generous with her vast knowledge and time. And many years, almost every year, I say when I come up here, I wish I had a radiologist like this at my hospital. I wish I had a radiologist like this. Well now I do. So it's so great to have you. Welcome, Dr. Groner. And finally, the MVP, and that does not mean most valuable player, although I am an avid sports fan, our most valuable pathologist, and really the one who connects all of the docs in our sessions is Dr. Kirk Jones. Dr. Jones comes to us from San Francisco. And I still will say, I wish we had a pathologist like you. Dr. Jones has been lecturing for the ACCP for years. For those of you who are either fellows or graduated, I'm sure you saw him lecture at the fellows course. His sessions are really legendary with the fellows. And Kirk, this year, has been gracious enough. He's doing every single session. So Kirk, thank you. It's so good to have you back. It's so good. Doesn't pay so good, but a lot of things don't. No, it's out of love. That's for sure. So I have no financial disclosures. I don't think I've ever been paid a penny for anything I've ever said, which is probably reasonable. You know, after COVID, I'm sure many of you were in the trenches as we were, just humbled by the bravery and courage. And while I am happy to be in such a nice location, I still have jet lag. And I don't know if it's ever going to go away. Next year in Boston may be a little easier. I'd also like to thank ACCP leadership, and in particular, Lisa Alvarez. All of us have been sending her slides and revisions and re-re-re-revisions. And she's been so gracious and helpful in putting these sessions together. My additional disclosures, I am a very, very depressed New York Yankee fan. The Yankees had their worst year in many years. I like the University of Wisconsin primarily because my daughter went there. I like Coach Fickle. I think he's doing a good job. And I am a Michael Jordan fan. So, this is how you can evaluate us, take a picture. So, the way the sessions work, we will give, we'll have Dr. Brown, we're gonna pepper him with questions for about ten minutes. And he's gonna give us just such great insight as to how he manages cases. Then Dr. Grona is gonna give a ten minute overview as to the radiology of diffuse lung disease and how she approaches it. Finally, Dr. Jones will give us a ten minute overview as to diffuse lung disease pathology and what he looks for. So, you'll have that sort of as a segue. And then we have two really, really interesting cases. So, if you have any questions, feel free to chime in during this informal session. And then when the cases are presented, we have interactive questions. So, please feel free to answer them. And again, you do it on your mobile app. So, Dr. Brown, we'll start with you. I'm gonna give you some questions that I know the audience and many busy, active practitioners would wanna know. We read a lot of nowadays about cryobiopsy. And many places are using it, many places aren't using it. We don't use it in our institution. So, a couple of questions. One, is it indeed ready for prime time? Two, when would you do it instead of a conventional transbronchial biopsy, if ever, and three, when would you do it instead of a surgical biopsy, if ever? So, tell us state of the art cryobiopsy, what are your thoughts? So, we don't use cryobiopsy at our place right now. I'll give you my blunt assessment of it. One is, in theory, it's actually in that space between the one to two millimeter transbronchial lung biopsy and the sonometer plus surgical lung biopsy. And in diseases that are patchy, right, that are not homogenous, it's at least in theory, you're more likely to get the diagnosis. All right, so what are the drawbacks? Number one, I think it's still more an art than a science, meaning that the performer is critical. So if you have somebody who does it all the time and is really good at it, the likelihood of finding diagnostic tissue is much higher than those folks who are doing it sort of randomly. Second, the adverse event profile, the complication rates can be considerably higher, dramatically higher than transbronchial lung biopsy in some centers. And if you're substituting this for somebody in whom you are afraid to do a surgical lung biopsy, I am not convinced that the risks are worth the benefits right now. And thirdly, with all props to my colleague to the right here, the interpretation of a cryobiopsy is not exactly the same as looking at a surgical lung biopsy or looking at a transbronchial lung biopsy, at least in our experience. And that the pathologists need to become comfortable with it as well. So in centers who do it all the time, do it every day, I'm okay. In places that do it quite intermittently, I'm uncomfortable or not confident that we're getting the benefit for the risk, and we don't do it at our place. And now I've completely forgotten the other two questions. The other two questions, I think you embedded them in all, so I think you answered all of them. So let me take it further. I grew up in an era where PCP, now PJP, was extremely common. And I literally, as a fellow, did hundreds of transbronchial biopsies, became very comfortable with it. Is there, so we typically will do transbronchial for sarcoid, for PJP. There's a few diseases, lymphangitic carcinomatosis, where the yield of transbronchial is pretty high. Now for the idiopathic and estitial pneumonias, we would, at least in our institution, we don't do a transbronchial other than maybe to rule out infection. So is there any time where you would do a cryobiopsy instead of a transbronchial, or you feel again like you said, it's just operator dependent and institution dependent? Well, there are two things. One is, right, you're combining a clinical context with a chest imaging pattern on a high resolution CT scan. And our radiology colleagues these days have gotten so good that the pattern that they describe on high resolution CT scan, even in non-expert centers, is with high confidence directly related to the underlying pathologic pattern. So if a radiologist, particularly a thoracic radiologist, says this is a UIP pattern, I have 85 to 95% confidence that's what we would see on pathology, even by surgical lung biopsy, and it really obviates the need for additional tissue. The trouble is, that's only about half the cases, right? So you use UIP, you look at NSIP, I mean, you can go through all the patterns and the likelihood or the confidence level drops off a little bit, but not dramatically. But the issue is, that only accounts for about half the cases. So the other half the cases are a nonspecific or a non-diagnostic pattern, and so what do you do in those cases? And that's the question. You can break them into fibrotic and non-fibrotic patterns. I think that we find that to be particularly useful because longitudinal behavior helps, particularly in the fibrotic patterns. It's a little less beneficial in the non-fibrotic patterns. But I don't want to get too far afield here. So it's in that half of cases where you don't have a non-diagnostic pattern, a high resolution CT scan. You have a clinical context that does not provide enough information to obviate the need for additional information. The question is, what do you do in that setting? And I think there are circumstances where the combination of BAL and transbronchial lung biopsy are useful in those cases. Not because they give a positive diagnosis, but they exclude some of the other things, right, in the differential. So you're really trying to peel away other considerations, recognizing that from a prevalence standpoint, if you have a idiopathic interstitial pneumonia with a UIP-like, or NSIP, fibrotic NSIP-like pattern in a longitudinal behavior, that's one of progression, particularly in the face of some therapy, that you know what's going to happen with those patients with high confidence. Great, final question, and then we'll get to Dr. Groener. What about COVID-induced fibrosis? We actually, Dr. Groener and I, wrote a algorithm as to maybe how to approach these patients. How do you feel about OFEV in these patients? It seems to me that we're seeing it less and less. We saw a lot after the first wave, the catastrophic wave back in March, April of 2020, and in our experience, the newer strains are much less pneumopathic, so to speak. They're not really, so what do you do when those patients, we have some patients who we do have on OFEV. How do you feel about the post-COVID population? I don't know what to do with those patients, but I'll give you my very limited and uninformed opinion. One, I think particularly early in the pandemic, and Denver actually was hit early because it turns out a lot of Northern Italians come to the mountains to ski. So right after Seattle and New York, we actually had an outbreak, and I think, first of all, nobody really understood how to take care of them. Number two, when your hospital's overwhelmed and the fourth-year medical students are managing the ventilators, you're probably not getting the kind of expertise around management that you would like. And I do think that the lung injury that occurred for a lot of those patients, number one, they were really sick. Number two, the management was probably less than what we would like just because of the overwhelming nature of the patient population. There was probably more lung injury than we anticipated. Second, I personally think that this is mainly ARDS and independent of the cause, right? So antiviral, there are a hundred reasons, right? You get ARDS. And we know actually a lot about the longitudinal behavior of ARDS in those folks that have recovered, right? If you've been ventilated, it's worse. If you were on the ventilator longer, it was worse. But those patients we know for actually at least two years, probably more, can gradually improve, spontaneously improve. So the natural history of those patients is radiographic abnormalities and physical limitation and respiratory symptoms that gradually improve over time. So what I worry about is that there are clearly patients who, in terms of the total population, are likely to improve spontaneously over time that we're intervening in. So no matter what you do, they're probably going to get better unless you give them something that actually harms them. Having said that, there are clearly patients who have a progressive fibrotic phenotype that occurs after lung injury. And whether those are folks that were predisposed to the development of it because of their underlying genetics and or environment or actually had an underlying fibrotic injury to begin with and the COVID on top of that actually accelerated that, there are clearly that population of patients. But I think we can find those, right? We can see them by paying attention. The one thing that I say right now is I've seen a lot of patients who got sent to me because of persistent radiographic abnormalities after COVID. I say, let's not do anything. I'll see you back in three or four months, right? We'll see how it goes. If you're getting better, we'll just hold tight. So I do a lot of sitting on my hands. Thank you. Thank you, Dr. Brown, for those great comments. So now we're going to get to Dr. Groner, who is going to go over imaging of diffuse lung disease. Thank you, Dr. Groner. Thank you. Hi, everyone. Thanks for having me and thanks to Dr. Sela. I am the least experienced person on this panel, but I feel like the experience is rubbing off. So I am an assistant professor of clinical radiology at Weill Cornell. I'm also a health services researcher. I'm thrilled to talk to you about diffuse lung disease and the role of imaging. So I also have no financial disclosures. And whoops. So today, I'll briefly go over just sort of the definition of. And by the way, I'm not known for my brevity, so I'm really going to try to hurry through these slides because I've never been told that I'm a succinct, concise person. So I mean, I'm twin B. Like, I was born second. It's like I've always been just a little slower. So anyway, so definition. And then we'll talk about the appearance. So what am I looking for? What distribution or pattern isn't following? The role of temporality and chronicity in terms of narrowing my differential. And of course, the role of clinical history. So definition and indications for imaging. So diffuse lung disease is kind of an umbrella term for a heterogeneous group of diseases with multiple different etiologies. Some of the imaging features can overlap. And some of the etiologies can overlap. But typically, we're talking about either parenchymal, interstitial, or diseases that are a combination of the two that are either widespread or patchy or kind of scattered throughout the lungs. And of course, they can be acute or chronic. So imaging, I think, is important and definitely plays a role in diffuse lung disease in terms of either detecting lung disease in a patient who is symptomatic or, of course, potentially detecting lung disease in a person who is asymptomatic but maybe has a systemic disease that is known to be associated with diffuse lung disease, like a patient with connective tissue disease or rheumatoid arthritis and UIP or scleroderma and NSAP. And then, of course, so it can help us characterize the diffuse lung disease. We can formulate a differential diagnosis. And that will help us guide further workup and treatment. I appreciate the compliment that you think radiologists are getting so good. We try. And I think, again, this was mentioned, but in terms of just assessing or evaluating kind of the longitudinal progression of the disease or response to treatment, exacerbation, et cetera. So what am I looking for? So when I open a CT, the first thing I do is decide, like, is it normal or is it abnormal? And hopefully, I can do that. So if I've decided that it is abnormal, that there is something there that shouldn't be there, then I say, like, OK, well, what does this look like? Is the lung abnormally increased in density? Or is there something that's there that shouldn't be? Are there too many lines? Are there holes in the lung, maybe, where they shouldn't be? Or is the lung abnormally lucent? So what do I mean by that? So increase in density, I'm typically talking about consolidation, so filling of the alveolar spaces or air spaces. Atelectasis, which can often mimic consolidation, but is really helpful if you have a contrast-enhanced scan, because atelectasis will enhance, because it's lung that's just compressed, whereas consolidation will not. So atelectasis really is just incomplete expansion of the air spaces or lung, or partial or complete collapse. And then ground glass opacity is nonspecific. It can typically be either partial alveolar filling, or cellular infiltration of the interstitium, or thickening of the interstitium, like in the case of fibrosis. And then, of course, nodules and masses. Nodules being round opacities that are less than 3 centimeters, and masses being the same that are greater than or equal to 3 centimeters. And so here's an example of consolidation in a patient with cryptogenic organizing pneumonia. We'll talk about distribution and pattern, but typically it's peripheral. You can see reverse halo signs or perilobular opacities. And then nodules and masses. This is actually a patient with peripheral T-cell lymphoma. So whenever I'm deciding between whether something is a consolidation or a mass, it's always the diagnosis ends up being one of two things, either fungus or lymphoma. And, of course, if you have a patient who has had a consolidation, and then you image that person 10 years later, and they're alive, and they have a consolidation in the same place that's bigger, that is lymphoma, because nothing else, it just couldn't be anything else. And then, of course, so this is a patient with acute lupus pneumonitis, which is a combination of diffuse alveolar hemorrhage and DAD. And whenever I formulate a report, I'm always trying to narrate kind of a story where if somebody's reading it, they can picture the abnormality in their head. And so whenever I see something and it looks fluffy, I think that's hemorrhage. And I use the word fluffy even though I don't think technically that is like a real medically approved term. I just want to let you know, but I use it. So consolidation in ground glass opacity. So commonly, that will be things like pulmonary edema, alveolar hemorrhage, acute lung injury, infectious pneumonia, of course, inflammatory diseases like OP, eosinophilic pneumonia, hypersensitivity, pneumonitis. Oftentimes, you rarely see one without the other, although you certainly can. But I think just because, you know, ground glass opacity can at least be partial alveolar filling and consolidation is alveolar filling, they often go hand in hand. And, you know, of course, neoplasms, lymphoma, lymphoproliferative disorders, primary lung cancer, metastases, iatrogenic causes like diffuse lung disease, or sorry, drug-induced, pardon me, drug-induced lung disease, or of course, radiation fibrosis can cause consolidation as well as atelectasis and then aspiration. Whenever I am going through a study, I always try to give things a chance to not be cancer because I think if we say can't exclude infection neoplasm or inflammatory processes, we're not really helping anybody. And I think, you know, more often than not, we raise alarm bells when they don't need to be raised. And so I always try to give at least narrow it down to my top two differentials and give those two, and sometimes I'm wrong. But I think that you are more helpful if you say what you think something is than either not giving a differential at all or giving too many differentials. OK. So nodules and masses, so these can be things that are cancer. We talked about lymphoproliferative disorders, primary lung cancer, metastases, smoking-related lung disease which tend to be more airway-centered and upper lobe predominant like respiratory bronchiolitis, pulmonary lingual hand cell histiocytosis, inflammatory diseases, again, like hypersensitivity pneumonitis, things like rheumatoid nodules, which tend to be more peripheral, whereas hypersensitivity and pneumonitis, rheumatoid nodules are usually consolidation. They're solid nodules. They can cavitate. Hypersensitivity and pneumonitis is often ground glass, upper low predominant central lobular. Of course, occupational lung diseases, sarcoidosis, and then infection. You know, 90 plus percent of the time when you see tree and bud, it's going to be infection. This is a patient who has tree and bud nodules with consolidation, and this is tuberculosis. Viral pneumonias oftentimes cause a central lobular nodules, or even like a bronchopneumonia type of pattern. And of course, we talked about respiratory bronchiolitis, upper lobe predominant. You know, inhalational lung diseases typically affect the upper lobes because they're cleared better by the lymphatics in the lower lungs. Okay, and so then when I see too many lines, this can be either interlobular septal thickening, and or interlobular septal thickening, so which is basically thickening of the alveolar walls, and then of course, reticulation in the setting of fibrosis. So this is a patient actually who has rheumatoid arthritis associated UIP, and that's why you see this, the anterior upper lobe predominant fibrosis. I'm not showing you actually that the lower lobes are, the bases are more affected than the anterior upper lobes, but when you see upper lobe involvement, it's typically the anterior upper lobes with like a connective tissue disease associated UIP pattern. This is a patient with lymphatic carcinomatosis. Whenever I see an asymmetric pattern of septal thickening, certainly in a patient who has a history of cancer, but even if someone didn't, and maybe they're at an age where, or of a certain sex that they would have a cancer that has a predilection for lymphogenic spread, it's certainly something that you have to think about, and then of course, this crazy paving pattern, which I've only ever seen in real life, like a couple cases of PAP, but it's the classic kind of crazy paving pattern. that we describe. Okay, so holes in the lungs. So this would be things like cysts. So this is a patient with lymphangiomyomatosis, and they have pneumothorax from a rupture of one of these cysts into the pleural space, and then other things, other cystic lung diseases, like LIP, birdhog to be very, very rare. I've seen one case of it in my real life, and then things like cavities, so septic emboli, vasculitides, fungal pneumonias that can cavitate, of course, if you have a thick-walled cavity, like in the case of a primary cancer or even metastasis sometimes, emphysema and bulla, so severe bulla emphysema and upper lobe predominant in this patient who is a lung, who's smoked for many, many years, and then, of course, honeycombing in the setting of UIP. So abnormal nuisance, I wanna be, gonna have my end time, couple minutes, I'm gonna wrap it up soon. Okay, so distribution and pattern. So I, I mean, really, you can just kind of divide the chest coronally into thirds. Some people talk about, you know, at the tip of the anterior second rib and above is the upper lung field, and then between the anterior second and fourth ribs is middle, and then below the fourth is the lower, but I think, you know, reasonably, you can just divide it into thirds, and then I made this very kind of, I'm not an artist, if you couldn't tell. So the peribronchovascular central or axial distribution is really most of the axial plane of the lung, and so, and then beyond that is kind of the subplural or peripheral distribution. And so I think distribution is really helpful to kind of steer you in terms, cranial, caudal, and axial distribution, so whenever I see diffuse lung disease, I ask myself, where is it sitting in the cranial, caudal, and axial planes? And so upper lobe predominant processes tend to be your smoking-related lung diseases, a lot of the inhalational lung diseases, and, or airway-centered diseases like HP. Sarcoidosis, of course, just given the, the lymphatic involvement, or the perilymphatic distribution, and then post-ARDS fibrosis, because the lower lobe atelexis is thought to be protective. And then lower lung predominant, so these are a lot of your progressive fibrosing interstitial lung diseases, UIP, NSAP, hypersensitivity pneumonitis, which, of course, is a fibrotic lung disease, but is airway-centered and upper lobe predominant, tends to, tends to be more upper lobe predominant, and then, this is a little controversial, but that's been, that's what most people say, and then lymphoproliferative disorders, LIP, aspiration, DIP, all of those are lower lung predominant. So, OP and chronic eosinophilic pneumonia can be a little bit variable, but I find that OP actually is more lower lung predominant, and CAP is more upper lung predominant. Pulmonary edema is usually upper lung predominant, because it's cleared better by the lymphatic than the lower lungs, and then miliary infections can kind of run amok anywhere. And then axial distribution, so things that are really more so related to the heart and mediastinal structures, and then involving the bronchovascular bundles, lymphatics, so pulmonary edema, hemorrhage, pneumonia, sarcoidosis, and then peripheral processes, or tend to be more like LID, or ILD, excuse me, UIP, NSAP, chronic eosinophilic pneumonia, organizing pneumonia. So, the, I just want to be mindful of time, I'm almost done, I'm so sorry. So the last thing I look at is, you know, what pattern is it following? So, central lobular, perilymphatic, and random can actually be very difficult to distinguish between, but the first thing I do is I look at the fissure. If the fissure is involved, it's not central lobular. And so, then it's either random or perilymphatic, and if it's following the bronchovascular bundles, if it's along the interlobular septa, actually, if it goes into the center of the secondary pulmonary lobule, and is along the subplural interstitium, those are things that are telling me that this is a perilymphatic pattern, rather than random. And so, central lobular, again, is going to be more of your airway-centered stuff, perilymphatic are things that involve, of course, the lymphatics, and then random pattern, things like that involve hematogenous spread, so miliary infections and hematogenous spread of metastasis. Okay, so temporality. So, a radiologist's best friend, sometimes their only friend, is prior scans. Well, hopefully not their only friend. I have one friend in the audience who I see. If I don't have a prior scan and I'm not totally sure whether this is acute or chronic, there are certainly clues. If you have any degree of architectural distortion, organization, those are things that are at least suggesting that this has been there for a few weeks, right? Or at least a week, I guess, or so. But it can be hard to distinguish, so I think, so things that are acute, really, again, like I said, I try to give everything a chance to be not cancer before I call it cancer, especially because if you have acute fungal pneumonia that's an invasive fungal pneumonia, that will kill somebody before a cancer does, so I think that it's important to distinguish between things that need to be treated right away and things that have distinct treatments. So, for the sake of time, I won't go through all of this, but consolidation, GGO, pulmonary edema, acute lung injury, alveolar hemorrhage, pneumonia, of course, aspiration, lines, interstitial edema in the acute setting, and hopefully it would be reversible, infection. So, whenever I see a nodule, especially in a young patient, and they have signs of infection, fungal pneumonia is kind of the first thing on the top of my list, and, of course, inflammatory disorders as well. Holes, so cystic lung disease, PJP can cause pneumatoceles, septic emboli, and, you know, vasculitides all can cause acute abnormalities, and then abnormal lucency, so air trapping or decreased perfusion from like a pulmonary embolism. So, chronically, so kind of either things that are acute but recur, like aspiration or edema, can all lead to things like pulmonary fibrosis, but usually, you know, if something's kind of been there and it's waxing and waning, or it's persistent in the case of lymphoma, or if it waxes and wanes in the case of OP, you know, those are the kinds of things I think about. Nodules, of course, fungus can be chronic, and then sarcoidosis, inflammatory cavities, rheumatoid nodules, vasculitides, et cetera. And then, lastly, clinical history. So, hopefully we get a really good clinical history from whoever is ordering this study. If not, I tend to just go ahead and look in the medical records, but, you know, what are the signs and symptoms that patients are presenting with? What is their medical history, their social history? Are they on any treatment or medications? Did they travel recently? So, in summary, my approach is just, what is the abnormality, or is it abnormal? What is the abnormality, what is the distribution, the pattern, temporality, and medical history? And that is it. How did I do? Okay. Thank you, Dr. Grone, and now you can see why we're so happy to have her in our institution. Thank you. So, you got the clinical, you got the radiological, but many times the definitive answer is in the pathology. Dr. Jones, thank you and welcome. Thanks again, you guys, for having me for the last several years. I always appreciate coming here, because it's obvious, because I fly out on my own dime and pay the exorbitant registration fee on my own dime. I'm like, I'm a pathologist, I'm really not gonna go to the other sessions, but I do. So, it turns out okay. Anyway, so today I'm gonna talk about fibrosis, a specific part of interstitial lung disease and how we can treat it. And I'm gonna talk about the pathology of fibrosis, interstitial lung disease, and how we can build our differential based on the fibrotic pattern. And actually, Dr. Brown was with me in China and I watched these clinicians be so good at patterns in radiology that I thought maybe I can apply this to pathology and teach clinicians how to do pathology as well. So, if we look at the normal lung, it's divided up into secondary lobules, similar to what you're used to seeing radiologically. So, usually about a half a centimeter, between a half centimeter to a centimeter and a half across with a bronchovascular bundle in the middle with arteries running with airways. And this makes sense, right? Because the airways have what the arteries want, which is oxygen. So, they follow along closely until they get to the alveolar spaces where gas exchange occurs. And then the veins are present in the interlobular septus. So, here we can see the bronchovascular bundle in the middle, the veins at the periphery, and all these alveoli in the center with the pleura binding it. If we look at the, hmm? You moving that around doesn't show on the... It doesn't show on their big screen? Oh. That's the point, yeah. You got it. It's like the weakest laser ever, but it does work. This is the normal alveolar septal cellularity. And so, we can see when we go from one intersection to another intersection, there's usually about seven nuclei there. Those are usually alveolar capillary nuclei because the type one pneumocyte is so flat and spread out that it isn't seen very commonly. This is a normal bronchial going into the alveolar duct, and we can see the little budding alveoli off to the side, and of course, the accompanying pulmonary artery next to it. So, this is normal cellularity and normal amount of interstitial tissue. So, if we think about fibrosis, it's usually in patients who have chronic or insidious disease, and it's often observed on the CAT scan as reticulation, possibly with traction bronchiectasis or honeycombing, or as nodules sometimes when it's bronchiocentric. And our pattern of fibrosis, our distribution of fibrosis, can help us kind of build our differential because it's often going to correlate with the nature of the injury. So, a bronchiocentric fibrosis tends to occur in diseases with inhalation injury. So, it can be from something like fume inhalation injury, like in the case of popcorn worker's lung, for example. It can be in hypersensitive pneumonia where it's an antigen that's being breathed in, like bird dander or mold. Or it can be from smoking, like in respiratory bronchiolitis, that's the RB there. Or it can be from bronchiolar inflammation, like you might see in a patient with an autoimmune connective tissue disease, such as Sjogren's syndrome. NSIP tends to occur in diseases with diffuse alveolar inflammation and thus diffuse alveolar fibrosis. So, we're thinking autoimmune connective tissue disease where there's a circulating antibody, a drug reaction where there's either an antibody or a toxin. And then, strangely, in hypersensitivity pneumonia, because that antigen-antibody reaction is then kind of distributed throughout the lung with lymphocytic inflammation, HP can be diffuse as well. And then UIP, what you guys see in IPF, is kind of this odd peripheral basilar distribution. And this is likely related to accelerated aberrant senescence. These patients tend to have telomereopathies or just short telomeres, which just is a telomereopathy. And we can look at that and see that this is stretch injury, it's from a cough, things that you would think are relatively mundane that are driving the disease forward. So, our first pattern is gonna be bronchiocentric fibrosis. Here we can see a bronchiole in the center with kind of this lacy bronchiolar epithelium coursing out into the alveolar spaces. And we can see in the upper, there's one, two, another one down here, and they're bursting out throughout the lung, much like you would see fireworks bursting in the sky, or if you're a geology nerd, snowflake obsidian looks a lot like this. So, when we zoom in and look at this, you can see the artery with its red cells in there. And normally just next to it would be the bronchiole kind of round and round with no other epithelium, but instead it's all throughout here. And if we zoom in, you can see all the epithelium tagged onto the central bronchiole, comparing it to a normal bronchiole. And here, this is bronchiolecentric fibrosis. And again, we're gonna look for either effacement of the central area with scarring, or this lace-like central regions like fireworks. So, we're gonna think about inhaled diseases as are driving our differential. NSIP is characterized by diffuse alveolar septal thickening, either by inflammation, cellular NSIP, or fibrosis, NSIP fibrosis. And it can be variable, it doesn't have to be perfectly uniform, but it should show fibrous thickening of alveolar septa around bronchioles in the subpleural regions as well as in the midzones. So, here's a nice example of that in a patient with a connective tissue disease. And we can, I've likened this to dusty cobwebs. And we can superimpose it on there, dusty cobweb fibrosis. I wrote a term by Kevin Leslie, it turns out that he actually said thick cobwebs, which is correct grammatically. Dusty cobwebs is repetitive. So, but dusty cobweb I like. So, NSIP pattern, we're gonna look for variable but diffuse alveolar septal thickening, dusty cobweb fibrosis, or inflammation. And then we're gonna look for additional clues to help us figure out what's causing this. Dr. Talmadge King used to tell me, if my pathologist says that the biopsy shows NSIP, then my job has only just begun. And that's because at that point, he's gonna give the patient an HP checklist. He's gonna do an extended serologic panel to look for autoimmune connective tissue disease. Here's an example where we have diffuse alveolar septal thickening by chronic inflammation, but then we also have these large lymphoid aggregates with germinal centers. This is almost always connective tissue disease, although in this case, it's nitrofurantoin toxicity. So, we're looking for, is there lymphoplasmicytic inflammation? Is there an overlapping NSIP pattern with a superimposed acute lung injury like organized pneumonia? This is actually something that I learned from my radiology colleagues. Is there pleuritis? Is there vascular thickening? These are clues we can use for autoimmune connective tissue disease. Another example where we have a little bit of accentuation centrally, again, with that bronchiocentric fibrosis here, as well as some diffuse thickening, but then some granulomas. This is hypersensitivity pneumonia where we have bronchiocentric accentuation with an NSIP pattern with poorly formed granulomas. So, we use all the clues available to try and narrow our differential. The UIP pattern is fibrosis that begins at the periphery of the lobule and moves centrally with the buzzwords of temporal and spatial heterogeneity. Temporal heterogeneity means that there's injuries at different time points. Honeycombing, old fibrosis, fibroblast foci with recent injury in normal, and then the spatial heterogeneity where we see it worse subplurally and at the bases in patients. So, here's a nice example of that. We can see the subplural scarring. Because I used analogies for different cases with the dusty cobweb and the fireworks, for here, it looks a little bit like a baseball diamond. Not like the Yankees are gonna be using this, though. Unfortunately, not the Giants either. But thankfully, hopefully the Dodgers will be out soon. So, if we zoom in to these areas at the periphery, you can see irregular air spaces lined by bronchial epithelium surrounded by dense fibrosis. If we zoom in at the interface between the fibrotic and less involved lung, we can see these areas with bluish fibroblasts with an overlying, I used to say reactive epithelial cap, but now I use this to drive my diagnosis. These stain with senescent markers such as P16, these are likely the driving force or part of the driving force of fibrosis. They are in what's called secretory senescent phenotype and they secrete a lot of pro-fibrotic humors. And then centrally, here's some normal looking lung. So, the other thing you can do is what Dr. Talmadge King used to do at conference, which is the tip test. He would take a slide and just hold it up to the light and say, this looks like IPF. And that's because since it's a peripheral lobular pattern, you'll often see obliteration of the tip of the biopsy where the surgeons grabbed the fibrotic stuff and stapled it. Whereas NSIP, because it's normal looking, when they stable it, everything looks the same from the end to the edge. So, here are two cases at the same magnification. This is usual interstitial pneumonia with the peripheral fibrosis and this is NSIP. And you can see how one looks quite heterogeneous and one looks quite homogeneous. So, UIP pattern, when there is true temporal heterogeneity, the diagnosis is almost certainly gonna be IPF. You can use the tip test. There are rare cases, of course, of chronic or fibrotic HP and connective tissue disease that can show a UIP pattern. But in my experience, these are probably just overlapping physiologies and it's this abnormal senescence that's driving the disease. And with that, I will stop. Thank you for your attention. Thank you so much, Dr. Jones. So, you guys really got to see a great evaluation of clinical radiologic and pathologic. Dr. Jones, I still wish we had you at our institution. So, we have two cases now to present. The first was submitted by Dr. Abdul Ghani, who unfortunately was able to make it, but Dr. Lockwood will be presenting the case. Mary, come on up. Okay, so this is a 73-year-old female with a history of recently diagnosed B-cell lymphoma, was treated with R-CHOP, which is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone approximately two weeks before this presentation. First cycle was notable for rituximab hypersensitivity reaction, which responded well to acetaminophen and diphenhydramine. On follow-up, patient was noted to have an oxygen saturation of 82% on room air with some minimal dyspnea, no cough, productive sputum, pleuritic chest pain, fevers, chills, or night sweats. Patient was breathing easily and was in no acute distress. On exam, vitals were stable, again, not in any distress. Oxygen saturation 82% on room air, which improved with nasal cannula. The rest of the exam was normal, including the lung exam. Laboratory-wise, patient had a white count of 20,000 with a normal differential, some mild chronic anemia, which was similar to previous exams. And then for radiology, I'm gonna have Dr. Groner come back up. Thank you. Thank you, Mary. Okay, so this is a frontal chest X-ray. I think what I sort of notice off the bat is, well, the lungs are normally inflated, which is always good to note, but I do see just what looks like too many lines. So that could be related to interlobular septal thickening I see, it's very hard, but if you use your imaginoscope, you can probably see some curly lines. And oh, oh, oh, sorry, sorry. And I don't see effusions. The lungs are a little bit hazy, so that may be ground glass opacity, which, you know, unless it's dense can, is typically, you know, less radiographically apparent than consolidation. But, you know, certainly in a patient who has leukocytosis, I think atypical pneumonia, like a viral pneumonia would be on the differential. And of course, somebody who is being treated with chemotherapeutic agents, you have to think about drug-induced lung disease, so understanding kind of the temporality of the two diseases would be, or of the medication would be helpful. So this is an axial CT image, it's contrast enhanced, and you can see that there is, oh, the pointer, ah, sorry, okay, is it, is it this way? Okay, sorry guys, you probably had no idea what we were looking at. So we have ground glass opacity, well, I'm sure you did. Ground glass opacity, that sort of, it's diffused, there are areas that are, you know, some are worse than others. And, you know, there's areas of interlobular septal thickening you really never should normally see with the secondary pulmonary lobules. So, you know, I think the pattern is, you know, I still think atypical pneumonia, like a viral pneumonia is high on the differential, and then a drug-induced lung disease either in organizing pneumonia or potentially like a hypersensitivity, pneumonitis type of pattern. And then, I'm seeing kind of at the basis here actually, like what looks like perilobular opacity, so I certainly think that there is, you know, there's evidence of organizing pneumonia or some degree of organization as well. So, yeah, that's that, thank you. Thanks, Dr. Grona. So we will now get to our first interactive question. You saw the history, plus you have Dr. Grona's discussion of radiology, you have the clinical history. So what should be done from here? We'll get to our first interactive question, and you can again scan and put your responses in. Would you do a surgical lung biopsy? Would you do a bronchoscopic lung biopsy? Would you say, nah, I'm just gonna repeat a scan in three months? Or would you start prednisone 40 milligrams daily? Dr. Brown is casting his vote. Hopefully your vote matches his. Hey, I don't know where Alfred is, can we stop this? I think 16 is a good cutoff. Yes, so do I, I agree. Okay, good, so as would not be surprising, most pulmonologists, or at least in the room, I suspect primarily pulmonologists, 75% would have done a bronchoid or transbronchial. One would have supported your local surgical colleague and done a surgical biopsy. And we have a couple who would have started prednisone. Dr. Brown? Yeah, so I find this really interesting. So what do I take away from the history, right? So I'm always looking for clues here. So number one, despite being hypoxemia, the patient doesn't seem very sick. So what do I mean by that? Doesn't seem in distress, doesn't have a lot in terms of respiratory symptoms. Unless I missed something, there was nothing on examination that pointed to a particular problem, but is really hypoxemic. So trusting the peripheral pulse oximeter to be correct, we would say that there needs to be an explanation for that hypoxemia, but likely separate from being super sick. All right. Second, what are the underlying medical issues, right? So she's got underlying lymphoma. And she's got this whole cocktail of stuff that unfortunately each of the chemotherapeutic agents have been associated with significant lung injury, both acute and chronic, unfortunately, which is an easy default, particularly since she had a reaction to the rituximab with the first infusion. Now what I don't know is the likelihood of a second reaction after a first reaction that's adequately managed with acetaminophen, but diphenhydramine. I'm sure that somebody knows that answer, but it makes me nervous when you get the same drug again when they've had a previous reaction. And then, so we take that information and we drop it into the, with the chest imaging, right, which is a mixed ground glass and organizing pneumonia pattern. So yesterday, Suhail Raouf, that Dr. Saleh knows quite well, and I talked about organizing pneumonia and where you see that. And this mixed pattern of organizing pneumonia and ground glass opacity can be seen in a whole variety of places, obviously, but drug-induced lung disease is one of those places. So if we take the radiologist's concern and assume that we have a previous chest image that suggested that none of this was there before, so this is all new. So in terms of temporality, it's relatively acute. It's within two weeks or about two weeks from drugs that are known to be pneumotoxic, particularly one that was already toxic previously. Say, yeah, there's a pretty good chance that this is drug reaction. Now, why do I not default to that? Well, what are the things, right? Infection, number one, always, always, always, always in this setting, infection is number one. But the patient's not very sick, so we either have to assume that the infection is occurring in somebody who is unable to mount any kind of response that would make them sick. Or it's unlikely to be infection. Second is a drug reaction, I think, in this setting. Third is recurrence of the underlying lymphoma, we would argue, maybe not in this case, right? She's on good drugs, seems to have responded before, be a pretty quick response. So I'm nervous about infection because I'm always nervous about infection, particularly because the drugs we use in acute inflammatory disease always put you at high risk. But drug reaction would be okay, right? And under observation, I think it's reasonable to treat with steroids alone. I probably would have wanted to do a bronchoscopy with BAL and trans-bronch, and that's what my default would be. But with an otherwise healthy patient that looked okay, I'd be okay under observation treating with steroids. So you'd be okay with doing a bronch, a BAL, and if someone chose empirically to treat with steroids, if they got better, great, and then if they didn't get better, you would certainly go for a bronch. Yes, okay. So what happened here? Okay, so the patient was started on prednisone, 60 milligrams daily with improvement of her symptoms. No tissue or BAL was performed. She clinically improved and multidisciplinary decision was made to discontinue the cyclophosphamide and give 100 milligrams of prednisone when the Rituximab was administered. So for chemotherapy-induced lung disease, it's a vast topic with multiple presentations, Rituximab being used more frequently, starting to have more pulmonary complications. The main presentations are acute or subacute organizing pneumonia, which occurs usually within two weeks and causes hypoxemia, which responds very well to steroids. Less frequently, it could be rapidly progressing ARDS pattern. So can I ask a couple of questions? Why was the cyclophosphamide, why was the choice made to stop the cyclophosphamide? Was it considered part of the lung injury? That's what the, yes, that's what they told us, yes. That's why they stopped it. And so that brings a question to you. You know, we've seen in our institution a few cases of Rituximab-induced lung injury, and it's almost, as Dr. Groener eloquently said, this sort of mixed ground glass and organizing pneumonia-type pattern. In our institution, once it happened, we did not opt to resume it, but I guess that depends on oncology. Dr. Brown, how do you feel about resuming it and that whole basket? Yeah, that's an oncologic decision regarding whether there are alternatives that are likely to provide the same benefit with a much lower likelihood of the adverse reaction. I know that a lot of our oncologists will continue Rituximab in the face of something like this, pre-treating with steroids, essentially, prior. I have to say, having used a lot of cyclophosphamide in the past, but not with mixed regimens, both the acute and chronic lung injury from cyclophosphamide is really quite rare. So I think there's much more likely due to Rituximab than somebody who previously had a reaction. And I'm sure if the oncologist, you know, of course, many times they won't bend when it comes to Rituximab. That's an integral part. So all's well that ends well here. Thank you, Mary. So our next case is gonna be presented by Dr. Bopana, who comes to us from Rochester Regional. His colleague, Dr. Lube, was unable to come. Dr. Bopana's gonna graciously present. Welcome. Good morning, everybody. So my case is a 76-year-old male, past history of some coronary artery disease, hypertension, hyperlipidemia, GERD, had a laryngeal nodule post-excision, who presented to the pulmonary clinic because they had some abnormal CT scans, specifically abdominal CT scan, performed recently for abdominal pain, and it showed some ground glass capacities in the bilateral lower lungs. So continuing with the history, had a three to five pound weight loss over the past year, decreased appetite, but no clear signs of aspiration, did not have any fever, coughing, hemoptysis, dyspnea on exertion, orthopnea, and he was able to carry out his regular activities, and those involved strength training at the gym, and had no difficulty. So had a 30-pack year smoking history, but quit more than 30 years ago, worked in a manufacturing factory in the 60s with possible solvent exposure, retired from a sales manager job and lives alone right now, doesn't have any pets or any contact with animals regularly, and no pertinent traveling history was reported. So in terms of exam, vital signs normal, lung exam was normal, saturating well on room air. For lab data, HIV, serology, and limited autoimmune workup, including ANA, rheumatoid factor, ANCA, Sjogren's antibodies were all negative, and routine labs were normal. So I'm gonna hand over to Dr. Groner at this time. I know he doesn't live in New York City because he has no contact with any critters or animals, so you cannot walk more than a couple of steps without encountering somebody or something. So I am looking at a frontal chest radiograph. It looks like it's abnormal, and there's what looks like a basilar predominant process, so consolidation, left greater than right, and it also looks like there's maybe some lines, so like a reticular pattern or septal thickening. It's interesting, because I don't know how much the clinical history helped other than to tell me that this is probably not something that is acute. I know that he worked in a manufacturing plant, so thinking about things like occupational lung disease, but they didn't say what, and usually those are upper lung predominant with the exception of asbestos that causes UIP pattern that's lower lung predominant. I don't see pleural plaques here. So I think CT would be helpful potentially here. Other things that are lower lung predominant, he doesn't really seem to be infected, so pneumonia would be low on my differential, and organizing pneumonia, but no fever or leukocytosis are really many symptoms at all other than I think shortness of breath, and of course somebody who has, I think maybe they said GERD, so something like a recurrent or chronic aspiration is in the differential. So on our CT, it looks like we have a periprongovascular predominant abnormality with consolidation, a little bit of ground glass, so if you can see the underlying architecture, like the underlying vessels superimposed on the opacity, then it's ground glass. So we have consolidation ground glass, and then you definitely have what looks like airway-centered or central lobular nodules. So I do think the pattern is slightly atypical, but something like aspiration, I'd like to see maybe the mediastinal window to see what density this is, like if there's fat or something like that, but this looks like an airway-centered process, and so in the acute setting, I think something like aspiration, also in the chronic setting, I think like a lipoid pneumonia or something like that, and sarcoid, I think the fissures aren't involved, so I'm not really thinking anything perilymphatic, so this is really more of an airway-centered process. Organizing pneumonia could be on my differential, but I think I would stick more so to like aspiration. And kind of more of the same here with central lobular nodules. So again, so then I'm really thinking like an aspiration bronchiolitis and pneumonia, and then we have, it's actually hypermetabolic, which is interesting. So things that, you know, certainly organizing pneumonia can be hypermetabolic, but I don't think this looks like this. An acute pneumonia or an aspiration pneumonia absolutely can be hypermetabolic, and you know, this doesn't really look like cancer to me. If it was, you know, something like lymphoma potentially, but you really don't see a tree and bud with lymphoma, so you know, and he's not sick enough for an airway-centered, you know, aspiration, airway-centered fungal infection. So what do we think? Thanks, Dr. Grona. So let's get our automated responses. Who would do a surgical biopsy? Who would repeat or do a bronc with a BAL and transbronchial? Who'd repeat a CT chest? Who would start prednisone? I don't know if I would have gotten a PET scan, I don't think I would have. Just because it didn't look like cancer, but. I think it just confuses everybody. Cast those votes. We're gonna cut you off at 16. Three more. Running up to the next session. Okay, we're gonna cut it off now. Just a few more votes. Good, so again, not unexpected in a pulmonary critical care conference, a vast majority are choosing bronchoscopy. A couple wanted to repeat a CT chest, and one wanted to start prednisone. Dr. Brown, the floor is yours. I don't know what this is. That's right. So it doesn't sound like a patient's sick. He has no respiratory signs or symptoms. Ex-smoker, so the couple of things I would be interested in is, why did he have the abdominal CT scan, and what were the results of that evaluation? Do you know? So I think he had, he was having almost right upper quadrant pain, and they were trying to rule out cholecystitis, but it just turned out to be almost, he had NASH cirrhosis that they found, so they attributed it to that. Oh, okay, that's interesting. As far as I'm concerned, the patient needs additional evaluation. We need tissue in this setting to figure this out. So you would do a transbronchia? Yep, I would start with a transbronchia. Not a surgical biopsy? You know, this is airway-centered. It should, based on location itself, should lend itself to a diagnosis from a transbronchia. From a transbronchia. Or a cryobiopsy. Or a cryobiopsy. Hey, we've been there already. Okay, Dr. Bopana, tell us what happened. So we performed an E-Bus bronchoscopy with robotic navigational biopsy of the left lower lobe nodule, and a BAL and mediastinal node sampling, which were all non-diagnostic, and then a CT-guided biopsy was performed, and I will hand over to Dr. Jones now. It depends on what kind of time of year it is. So this is the core biopsy. It's a nice, generous core, and you can see that the biopsy's full of holes, which is different holes than we saw radiologically earlier, but instead, the pinkish stuff here is fibrosis. We've got these holes, and lining the holes, we have macrophages, and the macrophages have vacuoles that are a variable size, so having large and small vacuoles within multinucleotide histiocytes, within the interstitium, with these large vacuoles, this is exogenous lipoid pneumonia. The patient is aspirating something. It could be oily nose drops. It could be the mineral oil they take to keep themselves regular. There's a lot of different things that this could be. This is just another example showing that multinucleotide giant cell, so exogenous lipoid pneumonia. Yes, so the diagnosis is lipoid pneumonia, which is uncommon and likely underdiagnosed disease. Usually, it's diagnosed after a lot of work has been performed. Usually, a detailed history and a high suspicion index is needed when evaluating such a patient with unexplained pulmonary infiltrates, and so basically, this patient was ingesting mineral oil for about 30 years for constipation. He was taking about three to four teaspoons every night, and it turned out he had a swallow study and he was aspirating as well that he was not aware of. Yeah, so there was actually one clue in the history that might have got us closer. Actually, there were two clues. One was the laryngeal nodule, right, which people get with recurrent aspiration. Reflux just puts them in 100 million, right, 150 million Americans, so that doesn't get you very far, but the nodule would suggest ongoing if we understood what it actually was and it wasn't something else. It would suggest reflux, and the second thing is that the abdominal pain in the absence of another diagnosis, it's not a rare evaluation for somebody with chronic constipation, and some people with exogenous lipoid pneumonia are almost always taking something that they have not told you about, either because they've taken it for so long they don't consider it a medicine, or they're afraid. It's part of their normal routine. Yeah, they're afraid to comment on it, yeah. Thank you, okay, any questions from the audience? Great, if not, thanks so much, and we'll be starting our next session in just a couple of minutes, so stretch your legs and hopefully come on right back, thank you. Her partner said, what if we?

abdominal pain

ground-glass opacities

smoking

solvent exposure

weight loss

reticular pattern

peribronchovascular pattern

lipoid pneumonia

mineral oil

constipation

pulmonary infiltrates