Good afternoon, everybody. My name is Sohail Rauf, and I work at Lenox Hill Hospital in New York. It is truly my pleasure and privilege to welcome you all to the Interstitial Lung Abnormality Joint Chest Fleischner Session. I want to give you a bit of a historical perspective about the Fleischner Society. Some of you may have attended the morning session that we gave, so I'm sorry, this will be redundant. But the Fleischner Society was created in 1969 by a group of eight radiologists, chest radiologists, who were interested in furthering the art and science of chest radiology. Over a period of several decades, the society has evolved from those original eight to now about 80. We do have the vast majority of the members of the Fleischner Society are chest radiologists from all over the world, but we also have pulmonologists, we have some thoracic surgeons, we have chest radiologists, physicists, etc. And to discuss this topic of interstitial lung abnormalities, I want to introduce to you Dr. Kevin Brown, who is in the incoming leadership. He's one of the incoming presidents of the Fleischner Society. And I have to say that the Fleischner Society has truly made some wonderful, wonderful contributions. Many of you may recall the solitary pulmonary nodule white paper that had come out. So the Fleischner Society takes on topics which are of clinical relevance and where there is not evidence-based information available to generate guidelines. And so it's a group of individuals who have expertise from throughout the world in a multidisciplinary fashion. And I want to thank Kevin and others in the Fleischner Society for having brought these very useful guidelines to us. In this session, we will have Zane. Zane, if you could, is our chief pulmonary fellow at Lenox Hill Hospital. And Jenna Shulner, who is a PA and works in the advanced lung diseases clinic with me. And they have come out with a case that we will be discussing towards the end. So the objectives that we hope to achieve in this session are we want to define what interstitial lung abnormality is. There's a lot of confusion that exists. And we want to be able to utilize the Fleischner paper guidelines and the other literature that has come out to be able to say this is ILA. And very importantly, this is not ILA. We want to be able to highlight the importance. Why are we having this conversation about ILA if it is not clinically relevant and important? And finally, we will have Dr. Kevin Brown. He was part of the panel that developed the guidelines for ILA from the Fleischner Society, talk about an algorithm that we as clinicians can look at and utilize in our day-to-day practice. Once we have had these two didactic sessions, then Zane and Jenna will be presenting a case of interstitial lung abnormality that will be used to kind of amalgamate the discussions that we have and put it in the right perspective. So this is the interstitial lung abnormality paper, which was a position paper from the Fleischner Society that was published in Lancet Respiratory Medicine in July of 2020. And we will be referencing this paper several times during this discussion. I also wanted to bring into focus this paper that is actually ahead of print in the Blue Journal, which looks through a meta-analysis in the prevalence and outcomes of adult interstitial lung abnormalities. It's a systematic review and may be worthwhile for those interested to go over it. So let's begin first. And I'd like to ask you, which of these three is actually interstitial lung abnormality? The first panel on the left-hand side is a person who's a 60-year-old individual with scleroderma, sedentary, does not complain of any shortness of breath, has mildly reduced total lung capacity and diffusion capacity to 65%. Is this interstitial lung abnormality? And I would say to you that because this patient has scleroderma, the patient is at a high risk. And therefore, even though this sedentary patient does not complain of shortness of breath on exertion, the patient is going to be considered subclinical interstitial lung disease, ILD. The second patient pertains to, again, a 60-year-old patient taken in from the lung cancer registry, complains of mild dyspnea on exertion, has relatively normal total lung capacity, mildly reduced, 75%, and a diffusion capacity of 60%. Now, you could say that the mild dyspnea on exertion may be because of the smoking, and this is a point that we will bring out during the course of this discussion. So, at the outset, I would say to you that this patient being symptomatic, and we don't have answers as to whether the symptoms are emanating from COPD versus the abnormalities that you are seeing, because the patient is symptomatic, the patient would be considered to have mild ILD. And the third panel defines a person who is 60 years of age, has a history of smoking, has a definite diagnosis of COPD, sedentary, no dyspnea on exertion, has a total lung capacity of 75% of predicted, diffusion capacity 65%, and an FEV1-FVC of roughly 70%. So, amongst these three cartoons here, the third one is the one that has interstitial lung abnormality because it defines a person who has smoking-related interstitial fibrosis, and I'm going to go over this in a minute. So, for the purpose of this presentation, we have broken down the discussion into four or five questions. First question is, what are interstitial lung abnormalities? And I would submit to you that this definition begins from our chest radiologists' readings. There are specific CT findings that they come up with. These findings are potentially compatible with the diagnosis of interstitial lung disease. And all of this is in the context of a person who does not have a clinical suspicion of the disease. In other words, we are not suspecting that the patient has interstitial lung disease. So, important things are, it is asymptomatic and it is not suspected, so it is incidental. So, what are the CT findings? The CT findings include ground glass opacities, reticulation. The worst in terms of the prognosis is when there's traction bronchiectasis or bronchiolectasis, and especially if there's evidence of architectural distortion. The worst is obviously honeycombing. And what I would also like to submit to you that in addition to what we generally consider as interstitial lung disease, there are also, there's another category of non-emphysematous cysts. So, these are the CT findings. But in addition to these CT findings, empirically, at least 5% of a lung zone should be involved to say this is significant. And the 5% of the lung zone should not include only dependent areas of the lung. So, this is to give you an example. This is a person who has subplural curvilinear lines, which are present in the, these are present in the periphery, and they represent a thickening of the peripheral interstitial. So, this is reticulation, but then this patient was placed in the prone position, signifying that if these opacities are still persistent, then this is not gravity dependent. The next question is, is this occupying 5% or more? And most of our radiology colleagues will eyeball it and give you an estimate, which is fine. Now, if you really want to get more technical, then there is quantification methods. As we know, the normal lung is going to have a lung attenuation between minus 700 and minus 750 Hounsfeld units, whereas reticular opacities, ground glass opacities and reticulation, will have an attenuation of minus 250 to minus 600. And lower than this is dense consolidation. So, there are quantification techniques on the CT scan that will allow us to quantify how much is normal lung. This blue is the area that is being considered, which is interstitial lung abnormality, reticulation and ground glass. And utilizing a computerized algorithm, it will quantify and tell you how much is the blue portion. For instance, in this case, the aggregate is 9%. So, there are sophisticated techniques. I'm not saying that we need to acquire this, but there are sophisticated techniques other than eyeballing if there's a subtle prevalence of this. How did the Fleischner Society paper change and update the definition of ILA? Because ILA has been defined in the past, the Fleischner Society paper changed this. The first and the foremost thing is, sentry lobular nodules are no longer considered as part of the definition of ILA. Because this is a smoking-related condition, the patient may have respiratory bronchiolitis, and several studies have shown that it generally does not progress. And when we say the person has ILA, we are trying to define the patient population that is likely to progress. So, still included, as we mentioned, is the non-emphysematous cysts, which are seen in cigarette smokers. They generally will have a well-defined wall. They may or may not be associated with honeycombing, and I'll show you examples of that. There may be absence of subplural predominance. And let's see what it looks like. So, here you can see that there is an area of lucency. There is a sharply defined wall around it, which is not what you expect to see in a patient with emphysema. There is the presence of ground glass opacity and haziness adjacent to it. And in some areas, it is away from the subplural area, which is where typically honeycombing is seen. And so, this is an example of the non-emphysematous cysts. And this is an example of a person who has smoking-related interstitial fibrosis, because as you can see, there is paraceptal emphysema. There is ground glass opacities. There is evidence of reticulation that you can appreciate. There are dilated air spaces, and you see these cystic spaces that are present. So, this is SRIF, smoking-related interstitial fibrosis, and this is considered to be part of interstitial lung abnormality. Now, let's spend a moment talking about what is not ILA, because I think that that is very important for us. What is not ILA is one dependent lung atelectasis, and I gave you an example of that. If you have fibrosis adjacent to the thoracic spine, that is fibrosis that has been invoked as a result of osteophytes, that is not interstitial lung abnormalities. Pluroparenchymal fibroelastosis, which we have seen at the apices, etc., is not part of ILA. Smoking-related centrilobular nodularity has been taken out from the definition and is not part of it. Now, generally, ILA tends to be bilateral. It tends to be present on both sides. If there's mild focal unilateral abnormality, it could be a focal process and some fibrosis that may have been left behind from organizing pneumonia, from infective pneumonia, etc. So, focal unilateral abnormality, especially if it does not occupy more than 5% of the zone that you are looking at, does not constitute ILA. And similarly, if there is interlobular septal thickening, possibly from interstitial pulmonary edema, if there's evidence of aspiration, tree and bud opacities, that is not ILA. So, I wanted to give you this example. This is a person who has haziness at the bases. This is, of course, dependent, but is this gravity dependent or is it for real? And so, you put this patient in the prone position and now, in this case, you see that this area is here and we don't find the ground glass opacity persistent. So, this was dependent at electuses that you were able to show was circumvented when the patient was placed in the prone position. This is a person who has osteophytes and you can see that adjacent to the osteophytes, as a result of friction, there has been paraspinal osteophyte-induced frictional fibrosis. What is not included in ILA from a clinical perspective, those were radiographic findings. What is not included from a clinical perspective is if the patient has symptoms. If the individual has abnormalities on the CT of the chest, but is symptomatic, then ILA may represent mild ILD. If the patient is at a high risk for coming down with ILD and a typical example would be connective tissue disease or a person who has been exposed, occupational exposures, or a person who has familial interstitial abnormality. The patient has a family history of interstitial lung disease. These are all patients who are at a high risk for coming down with ILD and these are patients who are expected to have ILD. This would be considered pre or subclinical ILD if the patient is asymptomatic. Third, what are the subcategories of ILA? This is how we are dividing the ILA. If it is non-subplural or it is subplural. Non-subplural, generally, ground loss opacities away from the subplural areas are usually not progressive and studies, Framingham studies and others, have shown that they do not increase the mortality of the patients. Subplural, on the other hand, can be further categorized into looking at subplural non-fibrotic, which has a better outlook and a better prognosis, versus subplural fibrotic, which has the propensity to progress, which has the propensity to cause more advanced interstitial lung disease, can result in architectural distortion and has been shown to increase mortality. And this is an example taken from the Fleischner paper, which shows in cartoon A here, there is ground loss opacity, it is not subplural, it is diffuse and there is no evidence of reticulation. This has the best prognosis. Cartoon B here is subplural. You can see the ground loss opacity that is present more in the subplural areas, but there is absence of reticulation or linear lines that you can see. Whereas right here is subplural with, you can see, reticulation and there is also evidence of traction bronchiectasis and bronchiolectasis. And Hiroto, Hatabu, and others have shown that if there's the development of traction bronchiolectasis, that has a worse prognosis. Those are the patients in whom we have to closely monitor because those are the patients who don't do well in many instances. So now I want to just conclude by talking to you about the stepwise approach for the diagnosis of ILA and Kevin would talk to you, Dr. Brown would talk to you about the management. So step one, there are four different aspects that our chest radiologists are being called upon to help us with. There is an incidental finding. Is it one of these types of incidental findings that we talked about? If the answer is yes, we still have to ask them, can we exclude mimics of ILA, diffuse central lobular nodularity, dependent atelectasis, etc. If that has been done, then is it significant? And again, going back to this rough estimate of 5% of a lung zone or more. And then finally, when that has been done, we want to ask our radiology colleagues to help us stratify the risk. Subplural fibrotic is what we talked about. Correlate this with, is it a UIP pattern that they are finding? Is there evidence of traction bronchiolectasis? And if there are prior images, please correlate and tell us if there's been a progression in the last five years. So that's what the chest radiologist is called upon to do. Then there are two steps which we as clinicians have to fulfill. Is the patient symptomatic? If the answer is yes, then this is not ILA, this is preclinical ILD or subclinical ILD. The second, and if the patient is not symptomatic, then step three for us as clinicians is, is the patient at high risk for ILD? If the answer is yes as a result of occupational exposure, collagen vascular disease, familial pulmonary fibrosis, then this is likely representing early ILD. And only if the answer to this is no, we are dealing possibly with ILA. So let me stop here and request Dr. Kevin Brown to talk to you about the algorithmic approach for management. Thank you, Suhail. So for those of you who are at our morning session, you will have already heard this, but I, again, want to acknowledge that, for those of you who know him, that Professor Raouf is the consummate gentleman, and more importantly, clinician in this setting. And I learn something every time he speaks. So I'm going to talk to you about the algorithmic approach to how to deal with these things. So I still get confused about what ILA are, right? So every time we talk about this, somebody changes the definition just a little bit that makes me unsteady. But the way I think about it is that these are incidental findings, OK? They're radiographic abnormalities that are incidental findings, meaning you are not looking for these. They just show up. And that's different than if you take a patient with familial disease. Their brother, their father, their aunt has diffuse lung disease, often fibrotic diffuse lung disease. And they come to you worried about lung fibrosis. You're actually screening those patients for the presence of fibrosis. That's different than doing a CT angiogram looking for coronary artery disease and finding lung parenchymal abnormalities, or most importantly, lung screening, lung cancer screening, excuse me. So those of you who are in centers that already have lung cancer screening programs, you know what I'm talking about, because you're getting these patients referred already. For those who don't have them yet, you will. You'll either have a lung cancer screening program, or the radiologists are now going through an entire process to try to identify in a formalized way and to capture in a formalized way these incidental findings found on particularly chest imaging. That is going to bleed over into every other form of chest imaging, and you will see more of these patients referred to you going forward. All right, so here's my conflict of interest disclosure. None of these are relevant for this particular subject. OK, so here's the problem, right? So a patient has undergone lung cancer screening and has ended up with something that looks like this. So this is not normal, right? This is absolutely not normal. But what do you do with it? You know, 35 years ago, when we started looking at chest x-rays and we looked at retrospective chest x-rays of patients were sent to us with idiopathic pulmonary fibrosis, you could go back generally 10 years prior to the diagnosis and identify, even on a plain chest radiograph, with the benefit of hindsight that there were abnormalities there. But nobody ever commented on them, right? Because what are they, and what are you supposed to do with it? Better not to bring it up if you're not going to do anything about it, right? We're going to see the same thing, but at a much higher degree of sensitivity with high-resolution CT scan. And let me assure you, when machine learning starts to marry with the radiologists, you're going to see all sorts of stuff that we don't understand what to do with. But a lot of it is going to start right here with interstitial lung abnormalities. So these are common. In lung cancer screening programs, it's somewhere between 5% to 10%. Everybody's going to live around 7% of patients are going to have interstitial lung abnormalities. In a screening population of patients with familial disease in their family, and you screen those patients, about 25% are going to have radiographic abnormalities, right? So this is not rare. You can imagine how many patients who are eligible for lung cancer screening and take 7% of those. There are a lot of patients coming your way. All right. The important thing is that radiographic progression is common. So once identified, it turns out that these getting worse is not a rare event. It's actually a common event. And if you look at the bottom here, what you'll start to see is, for those of you that are quick with math, you'd say about 10% a year. Because in about five years, about 50% of patients who have interstitial lung abnormalities at baseline, particularly the fibrotic forms, are going to show evidence that they're more extensive on their chest imaging. Second, progression on imaging is likely associated with a declining FVC. So radiographic change, which is just the x-ray, right? Really, who cares? But now it starts to make sense, right? There may be physiologic correlates to that progression radiographically. And that physiologic correlate is a declining FVC. So in the Framingham study, radiographic progression was associated with an accelerated loss of FVC compared to those without. And this is more so in those with fibrotic disease. Oops. That excess decline in FVCs, about 30 ccs, are double normal. So the average adult loses about 30 ccs a year. Those with ILA, on average, are going to lose about 60 ccs a year. So that's much different than those with idiopathic pulmonary fibrosis, right? Which averages about 200 ccs a year. But it's clearly greater than normal, right? And as we age, this starts to have an effect, particularly if there's something else affecting our lung function. So what I can't tell you is whether those are the specific patients with fibrotic ILA that account for all of that progression of FVC, because the way it's been studied right now is at a population basis. So at a population basis, the average person loses 30 plus. All right? As we get more sophisticated and as we get more, and these studies are ongoing, we'll begin to start to look at specific subgroups of patients with ILAs and decide whether those patients are more likely to be progressive and at what rate. So Professor Roof already alluded to this with the issue of the fibrotic ILAs being more likely to progress, we don't know what rate, than those with the non-fibrotic. Those with the peripheral being more likely to progress than those with the non-peripheral. OK. And separately, ILAs are associated with increased mortality. There is no question about this. The odds ratio is about 4 for early mortality, and then you can look across general population and lung cancer screening cohorts and see the relative risk there. That is, it is clear, it is measurable, and it is real. All right? So if you've got ILA, you're in a group that's at higher risk for early mortality. What we haven't figured out yet is whether that early mortality is all respiratory related. OK? Well, we don't know that yet. It probably is, but it could be, like many other things, it could be cardiovascular mortality. We just don't know that the overall mortality is higher if you have interstitial lung abnormalities. OK. So what's the risk factor for having them at all? Male sex, increased age, certain specific genetic abnormalities, so the promoter region of the MUC5B is clearly associated. Others are really quite rare, so it's harder to sort out, but this is clearly associated with the prevalence of ILA, the presence of ILA, and then previous exposures, right? None of that's surprising. Tobacco smoke, air pollution, specific occupations associated with vapors, gases, dust, and fumes, all of those are associated. Now, not surprisingly, you will look at the inhaled exposures on the bottom, you say, gosh, those are the things that people with idiopathic pulmonary fibrosis are also exposed to and have a higher risk for. So there is clearly overlap between risk factors for ILA and the risk factors for progressive fibrosing lung disease, best defined as idiopathic pulmonary fibrosis. Because each of those, older age, male sex, the minor allele in the promoter region of MUC5B, tobacco smoke, air pollution, and occupational exposures are associated with the development of progressive fibrosing lung disease. All right, so that's to clean up the ILA story. So here's the proposed scheme for management, at least in my brain. All right, so you've identified ILA. I think about this sort of like the respiratory bronchiolitis. Respiratory bronchiolitis is extremely common. Every smoker probably has it. If you look hard enough, you find it. Almost always central lobular nodules. Most smokers don't have respiratory symptoms. It's just a radiographic abnormality. What are you going to do? You're going to tell them not to smoke anyway, right? It doesn't matter. But the issue is those may go away if they stop smoking, but they don't have to. It can be persistent, even when you stop smoking. But it's very rare for them to progress. So you identify it, you note it, you move on. ILA is a little bit different, because the risk of progression is real as we go forward. All right, so ILA are identified. Is the high-resolution CT scan adequate, right? Is it incomplete? Is it equivocal? How many folks routinely do prone chest CT scans, particularly when they're looking for ILA? And how many places is that a routine? OK, about 2% of you. All right, maybe 5% of you. All right, but Professor Roof showed you that particularly dependent atelectasis is going to confuse people, certainly confuses me. And I'm lucky, because at our place, we routinely do prone sections. But that may be necessary here, right? So you may need a dedicated CT scan now, right? Not a screening CT scan, a dedicated high-resolution CT scan to look for interstitial lung disease. Now, the key is, is there evidence of clinically significant disease? So what does that mean? Are there respiratory signs and or symptoms that are related to the presence of interstitial lung disease? He's already alluded to. Sometimes symptoms are related to something else, right? Progressive exertional breathlessness might be because you have a left main lesion, right? So let's not get caught up in that all of your symptoms may be related to very minor radiographic abnormalities. But sometimes there are. You've got to exclude other things. The extent on CT is important. So 5% is the threshold. But what if all five lobes have them, right? So the greater the extent, the more likely they are to progress in the future. And if you have impaired pulmonary function and gas exchange, possibly attributable to ILD. There could be other things, right, but possibly attributable to ILD. That's all evidence of clinically significance, right? So now you've got a radiographic abnormality in a clinical syndrome, right, that may match up. They may explain each other. And now you've gone from a radiographic finding to possibly a disease. All right, so what are those clinical context questions you're going to ask? Is there a medical condition recognized to be associated with development of ILD? So you have familial ILD. You've got scleroderma. You have rheumatoid arthritis. You're on amiodarone, right? There are all sorts of things that you would say, oh, yeah, that's why this radiograph is abnormal, right? So it doesn't get you out of asking the questions. Are there signs or symptoms of a previously unrecognized systemic disease that could explain what's going on here? Are there illnesses in the extended family, right, suggesting an underlying genetic defect? We think about this with particularly telomerase defects that could account for this. It doesn't all have to be in the lung, right? Telomerase defects can affect the entire body in a wide variety of ways, including weird things like osteoporosis or liver failure. Does the patient use anything, right? Do they take anything? Are they exposed to anything that might account for what's going on? What exposures do they have specifically in their job? And to what are they exposed to at home? So I get to tell this story in this setting because I don't have another way to tell it this time. So see the patient, go through the whole thing, spend 45 minutes with them, get the whole thing. Call them up the next day and say, I got your CT scan and your PFTs. I just want to let you know. Wait a minute, are those birds in the background? Oh, yeah, yeah, yeah, those are birds. But we talked about this. You said you didn't have any pets at home. So these aren't pets. These are my family. So I've learned to ask specific questions just because I've made a lot of mistakes over time. And so now I specifically ask about birds and if they have any non-human family members that they want to share with me. All right, so you've asked a question, right? So you asked all the questions. We're going to decide whether it's clinically significant disease. And if the answer is yes, then the radiologist, hopefully, or the primary care physician is going to say, this might be important. We need to refer you to the pulmonologist. And you need to go through the usual stuff that we think about when we think about interstitial lung disease. And you're going to end up with that after you see them, you're going to say, yep, this is actually clinically significant ILD. It might be extremely mild. But this is real. The likelihood of progression is real. And we need to follow you and give you a diagnosis of an interstitial lung disease. And then the management of that group of patients is as you would manage that particular diagnosis. Or you might say, you know something, this really is just a radiographic abnormality. You have asthma. You've got a little bit of emphysema. You've got respiratory bronchiolitis. I don't actually think this is real and likely to progress over time. We're just going to put you in that category of radiographic abnormalities, ILA. And it's not clinically significant, all right? So now we're just going to talk about the ILAs, meaning you don't have a clinically significant disease. Are there radiographic features that suggest an increased risk of progression? Just based on these findings, these are the risk factors for progression of ILA. Tobacco smoking, other exposures, certain medications, physiology, or gas exchange at the lower limit of normal. The distribution basal and peripheral predominant are important. And the presence of fibrotic features are really important. Those all are risk factors for the regression. All right. So you've got evidence of regression. If you don't have any of those things, then you actually can follow them expectantly. If they have central abnormalities, central lobular nodules that we're trying to exclude from ILA, et cetera, you're just going to tell folks, you should probably quit smoking. It'd be good if you used a mask at work. You should re-decide whether you want the birds or not to be part of your family. But you reassess, then, symptoms and other evidence for progression over time. Just think about it expectantly. However, if they have evidence of those features that are likely to be associated with progression, you should actively monitor them. So we made this up. There is no prospective data to say this is the right way to do it. But risk factor modification is, without question, a necessary part of this. But a reassessment, sometimes within a year, both physiologically and clinically, is appropriate. And we thought a CT scan at 24 months in the absence of any new clinical features, and sooner, if there's other evidence, symptomatic, by exam, or physiologic, that earlier evaluation is necessary. So in summary, ILAs are clinically relevant findings on HRCT scans. You're going to be getting more of these patients. Radiologists are going to be identifying more of them. They're going to be, in a standardized way, recognizing and identifying them in their reports. And we're going to have to deal with it. Distinguishing incidental radiographic findings from early significant interstitial lung disease, I think it's important because of the management implications. Risk factors for progression are important, and likely put you in a different progression, excuse me, a different follow-up scheme. And plans for follow-up evaluation are necessary. With that, I will turn the podium over to our young colleagues. Thank you very much. Hi, everybody. My name is Zane. I'm one of the fellows that works with Dr. Ayoub. So we wanted to share with you a patient case that we encountered that brings up a lot of the discussion points that Dr. Ayoub and Dr. Brown have brought up, and kind of do this as a panel discussion about what things we need to think about in this case. So we have a 72-year-old man who was born in France. He's a former smoker, quit in 2011. He has a 60-pack year history. And then the past medical history is only relevant for BPH and kidney stones. His internist ordered a low-dose CT scan because of his relevant smoking history. He complains of mild shortness of breath. That's been going on for about 30 years. And he has that shortness of breath when he walks upstairs, for example. He walks for exercise every day. He can get to about 5,000 steps, usually, which is better than I usually do. And then he had respiratory infection in October of 2022. His symptoms were mainly cough, which was initially dry and then became productive. His wife and kids were sick at that time. And he was sick for about three weeks. He has no inhalational exposures at work or at home. He has no pets or birds in the house. His review of symptoms was overall unremarkable. He does have GERD and heartburn, but that's generally managed with over-the-counter medications. His family history is relevant for a history of prostate cancer. He has no autoimmune or pulmonary diseases. He's a mathematician. He takes atorvastatin, tamsulosin, and famotidine. His physical exam was notable for normal vital signs, saturation of 96% on room air. His BMI was 30. Overall, he had a slightly elevated collar size of 16.5. His cardiac exam, he was mildly tachypneic. And then his pulmonary exam was relevant for crackles bilaterally, about 1 3rd of the way up, worse on the right. The crackles were described as early inspiratory fine crackles. Otherwise, he had 1 plus pitting edema, worse on the right than the left, and no other articular manifestations of rheumatologic diseases, no cyanosis, no clubbing. Skin exam was dry. The remainder of his examination was normal. So what would we expect to find on imaging? I'll ask Dr. Ayouf and Dr. Brown to comment on this and turn it over to Jenna. So this is a test of our imagination. Yeah. Go ahead. So I'll show you guys the imaging. So as it's scrolling down, you can start. The esophagus is mildly dilated. And then you can see, if I were to play it again. So you'll see in the right upper lobe, as the CT is scrolling, that there are cystic changes in areas of bronchiectasis. And I'll show you some still cuts on the following slide. And throughout, there's areas of bronchiectasis and dilated airways. So here you can see, on your left, that there are the cystic areas. And in the middle, also cystic areas within areas of bronchiectasis. And then on the right image, there's the dilated esophagus and the dilated airways, as well as the reticulation peripherally. So based on that, if you would like to comment. See if I can. Want to go back? Go back. To the other one? Here. Yes. No, it's OK. This is fine. Thanks, Jenna. Good job. So Jenna, you rightly mentioned that when we look at these three different levels of the CT scan, the findings that we find is this fine reticulation that is present in the sub-plural areas. And in the sub-plural areas, the other important thing is, is this predominantly reticulation or not? And I would submit to you that this sub-plural abnormality is predominantly reticulation. I don't find a whole lot of ground-gloss opacity. Some of us can say, perhaps this is ground-gloss opacities. But if ground-gloss changes are present in the area of reticulation, then that is generally early reticulation. And it is not ground-gloss. It's just so early that even with an HRCT, you don't have the resolution to pick up reticulation. And therefore, looking at this, I would say, yes, this is reticulation. Yes, this is sub-plural. And the other important thing is, is there a craniocaudal gradient which you mentioned exists? I would certainly like to see the coronal and the sagittal views to be able to see that. But you could convince me to say that there is perhaps more reticulation at the bases as compared to the upper lung zone. So that is one abnormality that we find. The part that is separate from this reticulation is the bronchiectasis. And again, if you were to look at mini-IPS, if you were to look at the images which you showed us up and down, this is not cystic changes. But this is bronchiectasis. And it can be tubular bronchiectasis or even cystic bronchiectasis. But this is a separate abnormality. This is not traction bronchiectasis. There's no way that with this limited reticulation, you would get this central bronchiectasis. So this is a separate finding that we have. The third thing that is important for us is, as we are looking in the areas of reticulation, do we find that there is some dilated bronchi? And I would submit to you that there is. If you look over here, there is an area that appears to be dilated. It has gone out in the outer 1 third of the lung, where generally bronchi should not be visible. And so I would say to you that there is traction bronchiolactasis that is separate from the central bronchiectasis that we are seeing. I'm not going to comment on the esophagus. There are criteria that have been defined to say that there's dilatation. And there have to be six sequential cuts 1 millimeters apart. So I think that the esophagus is relatively the same. So my question then, Kevin, to you is, as you were formulating the guidelines for ILA from the Fleischner Society, there is reticulation that you would agree with. And it is mainly subplural fibrotic type. But when you have a second abnormality like this, how would you put that in context? Nobody brought it up. Nobody brought it up. I think this is, as every patient, is a unique situation. So I consider this trying to determine whether that reticulation is responsible for symptoms and findings, or whether it's a completely separate issue. So we proceeded to get pulmonary function testing and a six-minute walk test. So on the PFT, the force vital capacity is mildly reduced, 78%. The FEV1 is normal, 82%. And the FEV1-FVC ratio is normal without any significant response to bronchodilator. The total lung capacity was mildly decreased, 73%. And the diffusion capacity was normal, 83%. So we can say that there is mild restrictive lung defect. And the six-minute walk test, he walked 566 meters. And he desaturated from 96% to 93%. So 3% desaturation, we felt, was significant. We got baseline labs, which were normal. And then we did an extensive College of Bachelor panel, including a hypersensitivity panel and myomarker panel. And they were all negative. So how would you on the panel all manage this patient? I would send the patient to Dr. Brown. Does he have IOA? Yeah, so I actually think this is a great patient to have this discussion, because this is obviously complicated. And I appreciate that you didn't clean up the case the way presenters sometimes do. So as you went through the case, the things that I thought about were, this patient has risk factors, has demographic risk factors for both ILD and ILA, 72-year-old male, ex-smoker, 30 years of breathlessness, 5,000 steps a day. I don't know how to take that. I guess I'm not going to consider that necessarily clinically significant. However, what I did find clinically significant was the finding of inspiratory crackles on examination. And I was good with saying, those inspiratory crackles, particularly if they're mid-to-end and if they're more prominent in the bases and bilateral, is probably related to radiographic abnormality until Professor Roof commented on the bronchiectasis that the patient had. And could those excultatory findings be associated with the bronchiectasis? And I would have to argue without the patient in front of me, yeah, that's possible, that those are related to the previous bronchiectasis. But I'm still leaning towards it being related to the peripheral ILA abnormalities. The physiology helps some. But as always, it's right on the edge, right? It's low normal in terms of all of those things. There's not a lot of obstruction. So I'm moving the bronchiectasis as a primary diagnosis down a little bit. It's primarily restrictive. So it's pushing me towards thinking that this is early interstitial lung disease rather than incidental radiographic abnormalities without other explanation. I will say that the gas exchange abnormality, so his DLCO is normal. So with a normal DLCO, I would normally consider a change in the walking oximetry at least of four absolute millimeters of mercury for it to be real, because there's lots of background noise in those tests, as you know. So with a normal DLCO, I would not consider that, quote, desaturation to be clinically relevant. So right now, I would consider this patient to be sort of either early interstitial lung disease or in a group of patients with ILA at high likelihood of progression and would plan on early follow-up. Yeah, so Kevin, that was what our thought was. We felt that the type of abnormality seen on the CT scan is the one that lends itself to progression. You very nicely showed the ratios from the Framingham study and other studies that in the next five years or so, the likelihood that the person will progress is 50%, 60% or so. And yes, we were also puzzled. Not very common to hear, I mean, in the absence of fluid in the cysts, I would tend to think that the crackles that we were hearing are more likely to be from the reticulation. And that was what our feeling was when we saw this patient. Would love to hear from the audience what their thoughts are and what you would do. Yes? Do we have any work on the physicalization of chronic aspiration? So the question is about chronic aspiration. Certainly, chronic aspiration needs to be looked at. We did inquire from the patient if there were any known risk factors, alcohol ingestion, et cetera, seizures. But again, in many instances, you ask the history, you don't get it. But that's a good point. It's almost the bronchiectasis that you see is central. And the question was, could this person have had infections in the past, aspergillosis, et cetera. We asked him about it. We asked him if he had had any childhood infections, has he had multiple infections in these 77 years. All of that came up non-contributory. But I think that the point of aspiration needs to be emphasized, as Dr. Kevin Brown mentioned earlier in the other session as well, that that has to be an integral part of our consideration in patients presenting with a fibrotic lung disease. Any other? Yes? I have two questions. Yeah. So you skipped right to the hard questions. So yeah. So what to do with these? So there are studies going on right now about the pure ILAs that are progressing, about intervening in that group. In this patient, because I'm thinking that this is early interstitial lung disease rather than just radiographic abnormality, that I would offer treatment early. If there was evidence of progression, particularly if there was physiologic decline, because that's the outcome measure, right, that we seem to be able to have an impact on separate from mortality, that I would offer therapy early. The second question about the combined emphysema and pulmonary fibrosis I think is a little bit tougher. I mean, he did quit smoking, right? So the question that I'm struggling with a little bit is that lots of people, if you look hard enough with COPD, particularly our active smokers, also have respiratory bronchiolitis, just because most smokers get respiratory bronchiolitis, and that's persistent. This patient does not have central lobular nodularity, right? So this is not the confusing additional features that we would think of. If they had this peripheral basal predominant reticular abnormality with the sculptatory findings of crackles and emphysema, yeah, I actually would think of them as probably combined disease. And hopefully I'm guessing this right, that you're asking that question, because that will have an impact on the physiology, particularly the overall size of total lung capacity and the FVC. And so you need to recalibrate how you're thinking about what the change might look like physiologically before triggering the questions about therapy. I think those are both really, really important questions and really hard questions. So we decided, just before another question, our plan, clinical management, was to repeat the CAT scan, pulmonary function test, six-minute walk in six months, along with the autoimmune serologies. Given that he did have that shortness of breath for 30 years and this 3% desaturation, we ordered a cardiopulmonary exercise test and also wanted to include just an annual echocardiogram. I want to be careful here because I have consulted for some of these companies, and so I don't want to drift off. I need to be very clear about this part if we're going to talk about therapy, because I have consulted for some of these companies. I do think that in real-world data there's probably a mortality benefit, but I accept absolutely your comment about adverse effects and who's going to benefit. I do not think that we are really good at knowing who's going to benefit, but we're pretty good at knowing who has the side effects. So I absolutely think it's reasonable in this patient, since we're talking about risk of progression rather than absolute confidence in progression, to look over shorter periods of time. But I would not wait one or two years. I would wait, as they're pointing out, I generally go three to four months or no longer than six months for my first follow-up, and I warn the folks what the questions are going to be when they come back. Because I want them to be thinking about, is my exercise routine more difficult? Not have I had to stop, but is it more difficult? Am I having a harder time getting upstairs to go to my bedroom? Are there things in my life that I've had to alter because of that? And combine those clinically relevant features with the physiology. Does that answer your question? Yeah. Again, there is no data on that. I mean, if you think about it, in a 77-year-old male patient who doesn't have any musculoskeletal signs of collagen vascular disease, it would be a very rare entity. It would – having seen – but you do come across individuals who can have autoimmune disease. So, in this particular instance, we chose to go ahead and do a one-time serological evaluation on the patient just to get it out of the way. But I agree with you that the yield is low in this instance. Kevin, would you have done that? You know, that's a decision with the patient, I think, about how important it is for them to get to a specific diagnosis. There are plenty of times that I would say we'll follow up in six months and see what's going on. Yeah. Yes. Can you repeat the question? So the question is that, you know, he's a 77-year-old male patient. He's walking 5,000 steps. Would it be appropriate for us to do a CPET and see if he's desaturating and then decide how we move forward, which is a reasonable approach, you know, which is a reasonable approach. The way we looked at it is that if you go back to the statistics and large-scale studies, the Framingham, et cetera, the likelihood that this person is going to progress is significant. And even if the CPET today doesn't show evidence that when the person exercises that there is desaturation, I would still want to get a follow-up CT scan done at a relatively early interval to see if the scarring and fibrosis is progressing. Because then if it is, I would have a shared decision-making discussion with the patient and say, this is progressing. It is likely to progress. And do we want to start you on antifibrotics? These are the consequences. These are some of the side effects that may happen. But the potential benefit is that in 50% of the people, there may be a 50% reduction in the rate of progression of fibrosis. So that's the kind of information that I would like to get across. And I don't think one would necessarily preclude the other. Well, seeing that there are none, no others, thank you so much. You've been a wonderful invitation. Thank you.

interstitial lung abnormalities

ILAs

clinical relevance

CT scans

reticulation

ground glass opacities

bronchiectasis

progression to interstitial lung disease

evaluation and management

treatment decisions