Okay, good morning. I think we'll go ahead and get started. I want to thank you for attending today Stephanie Levine, I'm a professor of medicine at UT Health San Antonio and the South Texas Veterans Healthcare system and welcome to session 2012 on eosinophilic lung disease Current knowledge and future directions. I think we'll get through all our talks and then hopefully with a few minutes remaining We'll be able to take questions afterwards Just a few Announcements all sessions can be evaluated through the mobile app and or the online program Please evaluate the session course and faculty when it is done and then see a me claiming will be open starting Wednesday October 11th at noon to claim see a me for this in any other session So I have no conflicts of interest as related to this topic Are the objectives are included in in the mobile app and Here's our outline. I'm going to start off with overview and idiopathic Overview of the idiopathic eosinophilic pneumonia is a pulmonologist perspective Then we'll go to dr. Goh from Mayo Clinic Rochester on hyper eosinophilic syndrome a hematologist perspective Then dr. Mustafa from University of Rochester allergic bronchopulmonary Aspergillosis and allergist immunologist perspective and then dr. Aaron will fung from Vanderbilt on eGPA a rheumatologist perspective and we want to thank the airway network and session for for section for designing this multidisciplinary session So with that we'll go ahead and get started. So here is our cell of interest eosinophil We know it contains granules including major basic protein eosinophil a cationic protein eosinophil derived neurotoxin and charcoal aden crystal protein and there are cytokines that stimulate growth and differentiation and production of eosinophils Including il-5 il-3 and GM CSF, but it is only il-5 that is specific for the eosinophil So one of the ways to define the eosinophil lung disease is is they're really a heterogeneous group of disorders They are characterized by increased eosinophils in one or more compartments of the lung and or the peripheral blood There are associated radiographic abnormalities impaired pulmonary function and they may or may not have peripheral eosinophilia and What's interesting is that the role of the eosinophil and these different disorders can vary they may be a pathogen Good guy, they may or a bad guy. They may be the good guy or they sometimes it's thought they're a bystander So here's just a spectrum of what we're going to be touching on today We're familiar certainly with parasites and fungal infections with some certainly some of these systemic diseases can have renal involvement as well and arthritides drugs and We'll try to touch on some of the major ones in this session So one of the classification system is based on anatomical location Diseases focus it focused on the airway such as asthma eosinophilic bronchitis ABPA bronchocentric granulomatosis and those on its focused in the parenchyma They can be idiopathic sometimes called primary disorders versus those due to a known cause or secondary Disorders and Of the primary they can be lung limited. So AEP acute eosinophilic pneumonia CEP Chronic eosinophilic pneumonia and those there could be some that are systemic such as the hyper eosinophilic syndrome and eGPA For the secondary meaning known cause airway centered ABPA Infections such as the parasites we were already talking a little bit amongst us about you know The fear of missing stronger loities and and you know immunosuppressant your patient further So that's a big one to think about bacterial and fungal coxies the most common there then certainly Vascularities we're here about some of those today drugs and toxins think about daptamycin has a black box warning for eosinophilic pneumonia Nitrofurantoin many antibiotics and non-steroidals as well some malignancies are associated with eosinophilic pneumonia lymphoma lung cancers leukemias and myelodysplastic syndromes and then in the interstitial lung disease category sometimes hypersensitivity pneumonitis LCH cryptogenic organized pneumonia or what we used to call boop and sarcoidosis can be associated So we're not audience response But I started with this case a 50-year-old patient woman Presents with two months of low-grade fevers cough a five-pound weight loss and progressive shortness of breath She does have a history of asthma her labs are notable for 45% eosinophils in the blood IgE is 300 her anka is negative PFT show obstruction, and this is her chest imaging and Then the question is the most likely diagnosis is eGPA Hyper eosinophilic syndrome chronic eosinophilic pneumonia or allergic bronchopulmonary Aspergillosis, so since this is my topic. I'm sure you can guess that this is actually chronic eosinophilic pneumonia But again, we're going to differentiate all of these in this in this hour, so let's start by talking about the idiopathic Eosinophilic pneumonia, so let's start with the acute form in in an idiopathic AEP it can be severe Younger patients slight male predominance. They're usually healthy before they develop AEP It's often associated with the recent onset of smoking if they have Stopped and then resume smoking it can be seen dust exposure environmental stimuli It was associated with the World Trade Center of bombings vaping has case reports and sometimes military exposure to to dust and toxins in the field as the name says it's acute and onset and It's defined as an acute febrile illness usually less than five to seven days in duration with cough chest pain myalgias They do progress to hypoxemic respiratory failure on imaging there's diffuse alveolar or mixed opacities and On BAL which is often done because this is in a way an unexplained cause of ARDS So a BAL can be helpful here, and you will see eosinophilia Usually greater than 25% but hot sometimes as high as 50% you rule out other diseases and infections drugs and asthma and In AEP they usually respond rapidly to corticosteroids What's interesting is at least early in onset? It's rare to have the peripheral eosinophilia Here's what the BAL might look like numerous eosinophils that you can see here The chest x-ray patchy opacities ARDS occasionally small effusions most often detected on CT The pathology is eos in multiple compartments of the lung alveoli bronchial walls the interstitium They do have diffuse alveolar damage on biopsy not that biopsy is often done And then in the BAL this elevated IL-5 and VEGF and IL-18 and in the serum elevated IGE and Treatment as we said is with corticosteroids usually with a complete and rapid response and relapse is rare with idiopathic AEP Here's what the imaging might look like often they're intubated because it progresses rapidly to respiratory failure and Here is what the biopsy might look like if it is done, and you can see that there's eosinophils in numerous compartments of the lung Now CEP is different most often middle-aged women are affected they are more often non smokers one-third to one-half have a to b 60% asthma and about half and as the name says it's a Subacute to chronic presentation over weeks to months cough fevers sweat sometimes weight loss dyspnea wheezing and In the peripheral blood there is eosinophilia Usually greater than 30% and that's present in almost 90% of patients the BAL also has eosinophils usually 30 to 40 percent in count they have elevated IGE and 50% and the PFTs can be mixed Restrictive obstructive or normal Here's what the imaging might look like it's the case I showed you from the beginning and better appreciated on CT is this peripheral nature of the opacities Often described as the photographic negative of pulmonary edema that being said is a classic presentation It's it's not it's only present in about 40 or so percent of patients So it's sometimes billed as a non-resolving pneumonia or what what they're referred to us for They have as I said the peripheral pleural base dense ground glass opacities and the photographic negative of pulmonary edema Pathology here is eosinophilic infiltrates in the interstitium and the alveolar spaces They can have an a component of bronchiolitis obliterans micro abscesses and occasionally non caseating granulomas Here the use of eosinophil is likely a pathogen Lots of IL 5 6 and 10 at play here elevated IGE as we mentioned and the treatment is corticosteroids Usually for three to six months, although they improve initially as you taper them They often relapse so relapse is common in up to one half of patients So just to summarize here we have AEP and CEP Acuity as the name says acute severe for AEP CEP chronic milder weeks to months AEP may have asthma but not as consistently as CEP where it's present in 30 to 60 percent Blood eos early on in AEP are absent but present in CEP In 90% of cases both have BAL eosinophilia the x-ray and AEP looks like ARDS May have some effusions the CEP has classically the photographic negative of pulmonary edema Treatment for both is corticosteroids It's rare to relapse in AEP, but quite common in CEP So to summarize the key points there are many disorders in the group of eosinophilic lung diseases Some are either you know, some are idiopathic which we talked about today some have known etiologies some have peripheral versus BAL eosinophilia or both and Fortunately most are corticosteroid responsive But again the the you know, the caution of the a patient who's immunocompromised when you have to think about strontuloides So with that I want to thank you and again, we'll save the questions for the end. Thank you So next we have dr. Mustafa Thank you so much, dr. Lund for kicking off this session and for the invitation to speak and for joining us this morning So I'm going to talk about ABPA I do allergy immunology. I love this multidisciplinary conference There's actually really great data There's a great article from JAMA that patients do better when you're taking care of complicated conditions and there's a multidisciplinary approach So I do allergy immunology in Rochester, New York. Dr. Goh is going to present later. He's Does Hematology the other Rochester. We're going to talk about a background of ABPA and I'm really going to focus on therapeutics Because I think that's where the world is changing the data is missing and the lack of data doesn't mean things don't work It just means we haven't learned enough yet negative data suggests things work. So I'm going to talk about that a little bit So ABPA Affects probably one to two percent of individuals with asthma. There's obviously significant overlap and a lot of the stuff we're talking about Dr. Levin mentioned and it used to feel like pneumonia is 50% have asthma. So that's obviously a common component There has there could be a component of cystic fibrosis These folks are colonized with aspergillus. Okay, so it's not a particularly an invasive infection, but they're colonized with aspergillus Starting an immune response IgG sweet class switching to IgE in an atopic population So you see both of those antibodies and I think that's important for diagnosis and we're not talking about asthma With sensitization to aspergillus. This is different, right? So we have lots of asthmatics 70 to 80 percent will have sensitizations to common allergens including molds This is different and we want to know about that We're going to talk about ABPA. But of course, this has been associated with a host of other molds as well So I just want to make that a point that this can ABPM ABPA We're going to use kind of interchangeably, but I'll focus on ABPA with aspergillosis But this can apply affect any other mold that you're also talking about So diagnosis is not straightforward and we're going to have a talk on eGPA here as well And there's a lot of overlap in these conditions. So we have to be thoughtful about it It becomes particularly challenging when our diagnostic criteria don't even agree on how to make the diagnosis, right and there's different Guidelines suggesting different criteria So I'm going to kind of distill this because I'm not smart enough to understand all of this stuff Distill it into kind of how I approach this diagnosis. You have to have asthma or cystic fibrosis You're not going to have ABPA in the absence of asthma or cystic fibrosis and in our population It's going to be more so asthma. Of course, if we take care of ATP folks with T2 high disorders eosinophilia You must have an elevated total IGE and this is where things start getting a little bit muddier, right? Elevated is not binary. What do you consider elevated in a primary care office? IGE of 100 is elevated in my office. That's like really low, right? I'm an allergist. So I think it has to be and most of the guidelines would agree above 500 And I think most people would argue in the setting of true ABPA. You're going to have above a thousand and even higher All right. I just want to make a comment on differential diagnosis here We see IGE is very very high particularly in children, but even in adults we see levels up to 13,000 14,000 20,000 We talk about hyper IGE syndrome, which is an immunodeficiency The differential there is you have to have recurrent infections. All right, typically staff typically skin We get a lot of referrals for hyper IGE syndrome with an IG of 2,000 or so and it usually ends up being ATP. So the differential you guys are working with there is recurrent infections, particularly skin And then you have to have sensitization to the mold that we're talking about in this case aspergillosis Additionally, you should probably meet some of these criteria. These guys are gonna have mild to moderate eosinophilia again How do you define mild to moderate right in my office 300 400 peripheral eosinophils is not how do I notice it? Really? It's very common But when you start getting up into higher numbers in America in the United States of America 1,500 and below is usually where we're working here once you get over that very arbitrary cut off of 1,500 which dr. Goh knows very well as a hematologist your differential changes number one cause in America by far and away is drugs Drugs drugs drugs drugs drugs drugs. So you're really looking at hypersensitivity reactions over 1,500, but the differential is broad malignancy Vasculitis all sorts of other things you do want to have precipitating antibodies when you're talking about this. So do you want to demonstrate IgG? You should have pulmonary infiltrates that are consistent with a BPA and often that includes bronchiectasis So these are the things I'm looking for when I'm making this diagnosis, which can be muddy at times So therapeutic options is really what I find most interesting There's a lot of talks at this wonderful conference on asthma and biologics and a BPA and asthma obviously has huge overlap And there's lots of targets that we're going to talk about with cytokines here that may work that we don't know if they work And there's going to have a lot of overlap with asthma as well So this is kind of the very the sciency slide all these cytokines that you may want to target This is a very high t2 condition. So you would think t2 Blocking t2 cytokines would be helpful And that's I think where we should be moving So dr. Levin mentioned as well oral corticosteroids will knock out eosinophils easily eosinophils are very steroid phobic All right, so it's very very easy to knock down eosinophils neutrophils For example in the setting of COPD less steroid phobic, right? So it's very easy to knock out eosinophils that help a lot of these conditions with corticosteroids But what happens long term right you want to use steroid sparing agents? We all know the side effects of steroids historically reviews oral steroids and folks with a BPA We've used high dose and health steroids and we've used oral antifungal medications, right? I trick on is all typically that's changing a little bit I think it's important to touch upon that data that I trick on is all work comes from a 2,000 article from New England Journal It was a very small study of 55 Individuals who are randomized to standard of care versus I trick on is all on top of standard of care and it was a positive Study, but again, we don't live in black and white. We live in shades of gray What is a positive study right a positive study is anyone who had a reduction in their daily oral corticosteroids by 50%? Was a responder So if these individuals were on inhalers and prednisone of 10 milligrams and with I trick on is all over 16 weeks They decreased their prednisone to 5 milligrams. That was a responder. That was a positive response. Is that good enough? Is it not? I think it lies in the eye of the beholder So it was a small study, but it was it was randomized. It was blinded So is the best done study and it shows us the paucity of information in this space, right? This is like one of the best studies done to date and that's why we used I trick on is all I Want to argue from an allergist perspective why this study may have worked So I trick on is all absolutely affects p450 drug metabolism and All of these folks were on systemic steroids So there's an argument that the I trick on is all didn't do anything for the disease It decreased steroid metabolism and essentially increased their endogenous steroid doses There is an argument that that is why this study had a modest positive result So something to think about I think here. It's something to consider We've certainly used it particularly before we had a lot of therapeutics, but is the juice worth the squeeze? Are you going to get much out of this? questionable the other drug we've used a lot of since it became FDA approved for Asthma in 2003 is omalizumab anti-IgE and that's that's why the best data today or the most data I wouldn't say the best data today. It is for omalizumab. It's simply a factor of time. It's been around for 20 years So there are good meta-analyses There's lots of studies that have published Case reports or some form of controlled studies and this meta-analysis took 42 and it distilled it down to just 14 Even though there were 14 studies. The total end there is just 180 So 14 studies and 180 these are small studies, right? And what is it? What does it show? It does show positive impact of omalizumab in the setting of ABPA decrease exacerbations Decrease oral steroid use like the itraconazole data. I think in the top right is the most important thing 53% of individuals were able to come off of their systemic steroids. So that's a win I think I think we would all argue with that win here, right? So this is absolutely a medication we can use we can consider we have used the challenge becomes some of these IgE levels are so High, are we going to be able to effectively block them with omalizumab at the doses? So that's the consideration. We've used this for a long time. There's some data not a home run Sometimes dosing is challenging but well tolerated medication that we're familiar with and Now I'm into a world of case reports, right? That's it Eosinophils, we talked about eosinophils. We talked about banging out eosinophils with anti-IgE therapies, right? So mepolizumab which is anti-il-5 or potentially benrolizumab which blocks the receptor for il-5 So anti-il-5 therapies this one study published in 2020 is on folks with ABPA treated with mepolizumab The N is 20. This is the biggest case series to date on any of these newer biologics 20 individuals And again, what you see here is there is improvement in asthma control scores They're obviously you knock out their eosinophils. These drugs are very very good at knocking out blood eosinophils So you see a system significant change there You do cut down on exacerbations, but the impact on steroids was modest All right, and I think that's important to know Very importantly when you're talking about asthma or AVPA, these folks are very t2 high They have a lot of exhaled nitric oxide. You guys should know if you even successfully treat someone with an anti-il-5 agent There's no data that they're gonna improve their exhaled nitric oxide So if you're using that as a marker of success, you're never gonna fail improve it Even if you improve symptoms cut down on steroids and be medication sparing So 20 individuals with mepolizumab showed modest improvement some degree of improvement in symptoms lung function testing Certainly peripheral eosinophils and slightly less steroids with no improvement and exhaled nitric oxide The Biggest study to date that's going on. It's called the Liberty study. It's for dupilumab anti-il-4 anti-il-13 They're recruiting right now. This is a double line randomized control multi-center trial on dupilumab in ABPA or ABPM This is again case series ends of three. There's a case series on the left of an individuals with ABPA treated with that Mepolizumab who failed therapy and you see that on the lots of steroid bursts, right? They were switched over to dupilumab and you kind of knock that out So three patients three individuals here treated with dupilumab And again, what you see here is you do see an improvement in symptom scores lung function decreased steroids Dupilumab is probably your most potent Medication to decrease exhaled nitric oxide no matter what condition you're working with. So that's your goal. Dupilumab is Probably your biologic of choice Very very interestingly. I think it's important to touch upon the peripheral eosinophils when you treat dupilumab If you're if your eosinophils are your end or affect your cell causing an organ damage you can knock them out, right? So il-5 dupilumab does not knock out your eosinophils. It affects eosinophil trafficking So it locks up your eosinophils in your bloodstream your vasculature keeping it from Chemotaxis to the end organ of choice, whether it's your airway your lungs wherever So often when you treat individuals with eosinophil with dupilumab you see a slight increase in their eosinophil count Which actually speaks to the mechanism of action and as you use more and more of these you're gonna see some folks bump up And an allergy peripheral eosinophilia as a drug hypersensitivity until proven Otherwise dupilumab is the only drug where it actually says the drugs mechanism of action is probably working So eosinophils in your bloodstream not so bad when they get to end organs, that's where we worry So I just want to notice when you're treating folks with t2 disease and your baseline eosinophils are starting at seven hundred eight hundred Thousand and you start them on dupilumab. It may creep up. It's something to be aware of which I'm sure this audience is and then lastly anti-tslp Tazepilumab Again, this is a potent t2 inhibitor. So are there studies there are not studies There's just a couple of case reports, but again similar outcomes of improved symptoms Potentially decreased steroids improved lung function not well studied and no ongoing trials right now But I've thrown at you a lot of options potentially that are probably more fruitful and worth considering beyond systemic steroids So in summary, we're talking about a BPA which it probably affects about one to two percent of our asthmatics You're gonna see a significantly elevated IgE. You'll be sensitized to the mold of what you're talking about Aspergillosis in the state and then radiographic findings We've historically used a lot of systemic steroids and maybe Atraconazole based on a double-blind randomized control trial from the New England Journal more than two decades ago that had pretty soft outcomes I really think we need to be moving to biologics in these individuals because this is not an acute condition This is chronic and relapsing. So you want to use steroid sparing therapies? Omalizumab we have the most experience with Mepilizumab has case reports I would argue we'll have the best data and maybe the best success with dupilumab over the next 12 to 24 months as that Data comes out from the Liberty trial And tezepilumab is actually probably a great option, but being the newest kid on the block We know the least about it in this setting But it's definitely something to consider and just to be thoughtful about which medications we pick in these individuals And with that, thank you so much. I hope this was helpful You can take something back to the office, and I think dr. Go Dr. Go is the anchorman. We're gonna go to eGPA next Okay, so I've been given the dubious task of talking to you guys about eGPA My approach is a rheumatologist and as disclosure. I'm also boarded in palm crit So I have seen the spectrum from both sides. I don't have any disclosures relevant to this talk. And the goal for me today is to really talk to you not only about the key manifestations of eGPA, but when should you think about it? When is the time to think about this disease? To understand how to evaluate a patient that you're thinking maybe this is in fact what they have and discuss treatment algorithms. And as we continue to come back to multidisciplinary approaches, right? Call your friends, this is a time to not treat alone. And I'm going to start with a case. And this is a case for perspective is the only patient with eGPA I have diagnosed in my career. I started my fellowship in 2014 and this is the time I diagnosed it, okay? So this was a 71-year-old woman and she had been diagnosed with asthma two years prior. She was on high-dose Advair, she was on prednisone on and off. And other than that, she was fine. Until one day she was working at the computer, and when she got up to get a glass of water and she went back to the computer, she couldn't type with her right hand because her hand wouldn't work. Over the next month, she developed left foot drop followed by right foot drop, followed by left hand not working, at which point she was seen by an outside hospital, had an LP that was negative, was diagnosed with Guillain-Barre and put on IVIG. And she's been wheelchair bound since that time. A month ago, she developed finger discoloration and she was actually admitted to another hospital when she left AMA to go to UCSF's neurology clinic who promptly sent her to the hospital. And these are her pictures from the night of admission. I wanna highlight a few things. One, I'm gonna try not to shoot anyone in the eye here. You can see this very purple finger here that's purely ischemic with an area of redness adjacent. That's kind of gonna be a medium vessel inflammation whenever you see that purpura with adjacent retiform changes, medium vessel. On the side of her tongue, it's not projecting well. There's actually a punched out ulcer right here. When you see vasculitic ulcers on the tongue, they're usually gonna be on the side. It's a really nice way to distinguish from canker sores, but it's punched out there. And then on her leg, she has two findings. One, here's her one little spot of palpable purpura. So all of us, when we think about palpable purpura, we think we need tons of spots. You need one. Okay, aside from cryo, you aren't gonna get just confluent palpable purpura. And we can also see this retiform changes again, this laciness of her skin that was levido reticularis. And these are her labs over the antecedent six months. And what I wanna highlight here is what Dr. Mostafa was just talking about. This isn't the eosinophil count of 1,000, right? Her eosinophil counts have been very, very high for a very long time, 11,000, 20,000. Elevated SEDs, elevated CRP. Her urine, yes, it's contaminated, but it had blood and protein. Her ANCO is actually positive at the outside hospital with an MPO of 400. She actually had severe sinusitis that had been previously demonstrated on an MRI. And she had had some diarrhea over the summer, and her colonic biopsy showed focal granulation tissue with acute on chronic inflammation. They did not mention eosin the tissue. We'd never asked for that path for review. And so that was a case where you walk in the room and you're like, hello, eGPA, it's nice to meet you again. But we don't wanna let it get to the point that they have literally every single manifestation of disease before we call it. And I also wanna highlight that we now have, and this is from Europe, eGPA-specific evidence-based guideline. So always before, the ACR lumped it in with the other ANCOs, and this group in Europe just published this review, which we're going to be working through, but I highly recommend you guys to look at, to really focus on eGPA. And their first statement was, when should I suspect eGPA? And you wanna think about it, who's somebody who has asthma, and chronic rhinosinusitis, and eosinophilia, and then do they have something else? Who then develops end-stage involvement, either with peripheral neuropathy, lung infiltrates, cardiomyopathy, skin, GI, you know, alveolar hemorrhage, right? But you need those first three, and then something else. Whenever you think about eGPA, we wanna think about what do we do? How do we work this person up? How do we approach it? Well, we're looking for other organ dysfunction, right? So let's start with some general labs. We're gonna talk with a CMP and CBC. We're gonna get some urine studies looking for is there glomerulonephritis? We can get sputum culture looking for some sort of infection. You want to look at the heart, and I'll talk about this more in a second, but D-dimer, troponin, BNP, you wanna get a fecal occult blood, right? Is there blood in their poo from GI inflammation? And a CRP can be helpful for disease activity. But we also wanna rule out other things. Lots and lots and lots of things cause eosinophilia. My diseases outside of eGPA also cause eosinophilia. 1,500 in a lupus patient? Okay. 1,200 in a myositis patient? Okay. This is really high levels. So we wanna get ANCAs to risk stratify organ involvement. We wanna get other causes of eosinophilia and vasculitis, right, is this just IGA vasculitis? And Dr. Agoa will talk about this more in a second, but we wanna rule out the hematologic issues. So get an LDH, tryptase B12 smear, flip one fusion, and we wanna rule out infection. I have diagnosed one patient with eGPA, and two of my fellows now have bronched worms out of lungs. So I have been involved in worms coming out of lungs in a BAL, then I have eGPA diagnoses, okay? Please think about strongi. Everyone has a story about someone they know who got rituximab for strongi. Also think about imaging, nasal endoscopy, evaluating for chronic rhinosinusitis. Realize, though, that the biopsy sensitivity, if you biopsy the sinus, may not be great. This is best established for GPA, 20 to 30%. So just because it's negative doesn't mean you're done. Look for pulmonary involvement. I don't have to tell this group that. Get an echo, I would argue an EKG2, and an abdominal ultrasound, although the ultrasound is more looking for hepatosplenomegaly. And it's critical to remember that the organ involvement varies by ANCA status. So why do we want that ANCA so that we know where our problems are going to be? If you are ANCA positive, kidney, kidney, kidney, kidney, the kidney's also a really convenient target for biopsy. Yes, there's a bleeding risk, but relative to some other things, it can be a really useful target to confirm your diagnosis, prove that you have vasculitis, so that moving forward, when you're giving more immunosuppression, there's not that thought in your head of do I have the right diagnosis? Neuropathy is gonna be very common in ANCA positive patients, as is palpable purpura. And the ANCA negative patients, cardiomyopathy, cardiomyopathy, cardiomyopathy, what is it like to do? It can do the ejection fraction, sure. The big thing it can also do is conduction system. So you wanna be very mindful of conduction abnormalities, work with your cardiology colleagues on cardiac MRI. Is there infiltrative disease? You do not want these patients going into complete heart block before you realize that they have conduction involvement. These are also the patients who tend to have more pulmonary involvement as well. So this is just a figure, again, highlighting our different manifestations. Not to sound like a broken record, but I think as adult learners, the more we hear that over and over, the better. Asthma, sinusitis, eosinophilia for everybody. ANCA is gonna be kidney, nerve, skin. Negative is gonna be lungs, cardiomyopathy, and GI. And how we treat varies by disease severity. We don't wanna treat severe disease not with enough immunosuppression. We don't wanna over-treat mild disease. So in rheumatology, we have the five-factor score. Now, this was developed for other vasculitities. This was not developed for eGPA, but it's borne out pretty well. And so you wanna say, do you have risk factors for a poor outcome? Do you have significant renal insufficiency? Do you have proteinuria? Do you have cardiomyopathy or conduction system? Do you have GI involvement? Do you have CNS or mononuritis multiplex? And then other risk factors, you know, ocular involvement, right? That's work and threatening. We don't wanna play around with the eye. And if patients have one of the five-factor score or another risk factor, they should be treated for severe disease. And the way our European experts are recommending that we treat this is outlined here. And again, this is stratified by disease severity. For non-severe disease, steroids alone, and maybe mepolizumab as a steroid-sparing agent, really good option. For severe disease, that will not be enough. Okay, we're gonna be doing pulse-dose steroids. This woman, we literally gave her a gram of steroids at one in the morning, because even though it had been going on for six months, we didn't want another nerve to fall overnight with us not having treated. You're gonna then transition to orals. I think historically, an ANCA-positive rituximab is used very prevalently. There's more data in ANCA-negative, but cyclophosphamide may be preferred in that setting. And then for maintenance of remission, glucocorticoids, rituximab, and then now mepolizumab and maybe some other DMARDS. So I keep talking about mepolizumab, and obviously you guys are well-versed in it for asthma, but what's our data for vasculitis? And this was a double-blind controlled trial in relapsed or refractory eGPA. Now, as some of my colleagues have already talked about, just as important is how did they define success and who was included in the trial. And notably, anyone with life or organ-threatening disease was excluded if that had been there in the last three months. So a lot of the sick patients that we're treating, this is not on the table, at least initially. But what you can see here is that patients did really well. We can see that our proportion of patients with remission rises, and then when the drug stops, it falls back down towards the placebo group, really showing almost a withdrawal of this agent led to relapse. And it's important to realize that historically, if somebody's on prednisone 7 1⁄2, which is kind of our arbitrary rheumatology standard for when it gets really bad for side effects long-term, that's considered remission. But now that we have better drugs, we should probably really be trying to get people off. Saying 7 1⁄2 is good enough is probably not good enough anymore. And a relapse is defined by new vasculitis, and not just sinus or asthma, but treat with topical steroids and then steroids and mepolizumab. And here is their highlight for this. So if it's, again, we wanna go back at the time that they relapse, what is their disease severity? If it's severe, IV steroids, oral steroids, cyclophosphamide or rituximab. And non-severe, you're gonna be looking at mepolizumab and really optimizing your inhaled agents, right? Is there anything else that we can do from an inhaled kind of topical perspective that we can use to treat these folks? And so with takeaway, what I really wanna emphasize is that this is a rare cause of vasculitis. There's a reason why the ACR has lumped it in with other groups. It's because it wasn't even prevalent enough to have its own guideline. Okay, so this is a rare thing and should be considered in steroid-dependent asthma with chronic rhinosinusitis neosinophilia. The treatment algorithm varies by disease severity and always call your friends. No one should treat things alone. And here's two key publications. And thank you for your attention and don't forget to evaluate the session. And Dr. Goh is up next and he'll talk to us about hematologic perspective. Thank you for being here today. I'm Ronald Goh, one of the hematologists. And thanks to the organizers for the invitation. So these are our objectives today. First to define the terminologies using eosinophilia evaluation. And then we'll discuss some practical workup strategy really based on the clinical presentation. The idea is not to do a full workup but also when to consult hematology and also a brief overview of treatment. So this is a case, this is not a hematology case, it's actually a pulmonary case. So an actual case was seen by my colleagues and then I saw the patient actually at the end. So this was three years ago, patient presenting with cough, shortness of breath and was diagnosed with bronchitis, got antibiotics, got steroids. Incidentally, the white count was mildly elevated with eosinophil count of 1.8. So the patient responded very quickly to treatment within a week. So let's start with some definitions here. So absolute eosinophil count. So normal is generally between zero to 0.4 cells per microliter. And just a tip is don't pay attention to the percentage, just pay attention to the absolute eosinophil count because that is what matters. For eosinophilia, anything about 0.5 up to one, anything about 0.5, but if you're beyond 1.5, then we call it hyper eosinophilia. So in general, when the eosinophil count is below 1.5, it's very, very unlikely to have a hematologic disorder. And even if your eosinophil count is above 1.5, it's still very, very unlikely it's a hematologic disorder. Maybe slightly more likely, that's all. And I'll see you some numbers shortly. So it can be confusing when you see HE and HES, hyper eosinophilia and hyper eosinophilic syndrome. The difference between the two is when you have the syndrome, there is end organ damage. So for hyper eosinophilia, eosinophil count of over 1.5, but also you can use tissue infiltration as a surrogate. If you're bone marrow, eosinophil count is over 20%, or extensive organ involvement by eosinophils. When we talk about the syndrome, you have to have the clinical findings, whether it's skin, inflammation of the gut, the heart, the lungs, or thrombosis. The phrase hyper eosinophilic syndrome is used very, very specifically for hyper eosinophilia with organ damage and no cause. So it has to be idiopathic. So these terminologies can be very confusing, unfortunately. So this patient came back a month later with the same pleuritic chest pain, shown as a breath, and this time has hypoxemia, chest infiltrates, and got similar treatment, antibiotics with steroids. Unfortunately, there was no eosinophil count. But one thing that I want you to pay attention to is that there's actually no anemia. The platelet count is normal. So there are no other cytopenias, and certainly no other physical findings that may suggest a hematologic disorder. In the same event, repeated a month later, and this time the eosinophil count was a little higher. So it's recurrent. So what are the causes of hyper eosinophilia? As a hematologist, I don't see things in black and white. I see things in red and white, and shades of red. All right, so either you're anemic or you're polycythemic, all right? So I think you'll probably see in reviews a lot of these terminologies that is also very confusing, even for me as a hematologist. I practice classical benign hematology, so very broad. But these terminologies can be confusing. So my suggestion here is to just to think about is this hematologic disorders or non-hematologic disorders? And earlier, our presenters earlier have discussed the non-hematologic conditions, which really is the vast majority, also called the secondary causes. But for the hematologic conditions, these are the main categories. And the point here is not to remember any of these. It's really, if you don't find any hematologic condition, just call the hematologist and we'll figure it out. But just short definitions, the myeloid lymphoid neoplasm with eosinophilia, typically they have fusion proteins or gene rearrangement in the platelet-derived growth factor, FGF, and JAK2, and chronic eosinophilic leukemia. These patients don't have these mutations or fusions, but they have chromosomal abnormalities, for example, abnormal karyotypes or other types of mutations beyond those listed above. Now, we hear about concerns about could the eosinophilia be secondary to another blood cancer, say Hodgkin lymphoma, MDS, and so forth. Those are very uncommon, but that's a category in itself. The lymphocyte variant, which is detected typically by flow cytometry, showing a barren T cell, suggesting maybe a clonal T cell disorder, that's also very uncommon. And when you rule all of those out, then you call it idiopathic hyper eosinophilic syndrome. The etiology is not yet known, but hopefully in the near future, we know what's the underlying problem. So this is just to highlight the incidences of various disorders that are associated with eosinophilia. And you can see these are incidences per 100,000 per year. And on the top, eosinophilic esophagitis, gastroenteritis, pneumonia, drugs, and so forth. And you can see, really, the hematologic disorders are way low. And I have to say that at our institution, you know, one of these reports, we reported 22 cases of these hyper eosinophilic syndrome, chronic eosinophilic leukemia. And those 22 cases were over 10 years. So it's 2.2 per year. So that rare. So, and these are other diseases associated with eosinophilia. And these are the more common ones. I was not able, really, to get very good data on the parasitic infections. Most of these came from the CDC website. But you can see, these are magnitude of order, more frequent than hematologic diseases. So this patient had another, about a few days after a local ER visit, and subsequently came to Mayo Clinic and was admitted to pulmonary service. Eosinophils were higher, 4.2. And guess what, hematology was consulted. Okay, so the question here is, when to consult hematology? So in general, if the absolute eosinophil count is less than 1.5, I would say no need to call hematology. If it's above three, yes. First talk to the hematologist, maybe before doing a full consult. And then if you're in between 1.5 to three, it depends. So anything above 1.5, of course, if you have unexplained organ damage, unexplained lymphadenopathy or cytopenias, I think it's fair to call hematology. So what do I do when I get called for eosinophilia? I generally start with some basic testing, CBC, blood smear chemistry, review the history, the usual, anybody would do this. And of course, if there are signs and symptoms specific to certain organs, esophagus, lungs, and so forth, it's generally a cue that this is one of those other eosinophilic disorders. The hyper eosinophilic syndrome that are associated with hematologic conditions generally present with other CBC findings, lymphadenopathy, maybe B symptoms, and also generally have multiple organ damage at the same time. So somebody with blood clot, heart failure together. Blood clot, heart failure, respiratory failure at the same time. That's when I would think of a hematologic disorder, not just isolated one organ issue. So when you get hematology consult, I think these are some of the cues when to get hematology. So this lady subsequently got a bronchoscopy and not surprisingly showed eosinophilia. Now I think the problem in this case was the patient was admitted to the pulmonary service, but the pulmonary service consulted hematology. I'm not a pulmonologist, but it sounded like based on the history, this was chronic eosinophilic pneumonia. Am I correct? Yeah, I'm looking at my experts here. So what happens is when you consult hematology, of course we do what a hematologist would do, a bone marrow biopsy. I mean, there's nothing else we would do. So I'm just showing you the futility of this work up here. But typically we would do a bone marrow biopsy and this lady showed 47% eosinophilia in the marrow, had a flow cytometry to look for the ovarian B or T cells, cytogenetics for a clonal evidence, T cell receptor for clonal, and then all these fusion proteins and also a kit mutation, which is associated with mastocytosis. And guess what? All were negative. So that's when I came in on the service. It was after everything. So the treatment, this is my last slide, the treatment for hyper eosinophilia. Certainly, I think if there is organ damage, you gotta act quickly. Is it life threatening? Yes, give the steroids. Of course, you don't want to have strong jaloides in the background. You may have to give prophylactic antibiotics. And if it's not life threatening, then you check, is this a reactive? Assuming you have time to do all the evaluation for the more common causes. And if you find an underlying problem, of course treat the underlying problem. And then if everything is negative, then that's when you probably have to call hematology and think about clonal disorder. And if we find a clonal disorder, then it depends on what clone, what mutations or fusions are found. And we may have specific targeted agents for this. And if you don't find a clonal condition, then treat as idiopathic hyper eosinophilic syndrome. Or same thing as what we do if there's no molecular target. So all of the drugs that were mentioned earlier, IL-5 related, biologic therapy. Sometimes we use chemotherapy, methotrexate, cyclophosphamide, hydroxyurea. So case conclusion, this patient was discharged on 60 milligram reprednisone daily. At the time of discharge, eosinophils went down to 0.4. And one cue is that this may be a hematologic disorder is when the patient don't respond well to high dose steroids. Then that may be a malignancy in the background. And then the patient was seen a year later in normal CBC, no symptoms. So just in summary, hematologic cause is unlikely if the absolute eosinophil count is less than 1.5. And I would argue even less than three or frequently even less than five. Now if you're getting above five, that's when we get very interested in hematology. And again, use clinical judgment when determining the extent of evaluation. You don't have to do the full panel. Just go targeted by symptoms, by organ. And then treat the syndrome, not the eosinophil count. There's a new concept nowadays. It's called hyper eosinophilia of unknown significance, similar to monoclonal gammopathy of unknown significance. We're still studying that to see really what it means. And then finally, the use of steroids in my experience, whether you're looking for lymphoma or hyper eosinophilic conditions, it's actually unlikely to mask or prevent you from getting a diagnosis. So meaning you give the steroids as clinically indicated, you call hematology, we get a bone marrow biopsy. If this is a malignancy, we're still gonna find it. So don't hesitate to give the steroid and treat the patient. Thank you.

eosinophilic lung disease

idiopathic eosinophilic pneumonia

hyper eosinophilic syndrome

allergic bronchopulmonary aspergillosis

eosinophilic granulomatosis with polyangiitis

role of eosinophils

classification systems

diagnostic criteria

biologic therapies