Episode 434: Schema Episode – Eosinophilia

(upbeat music) - Welcome back clinical problem solvers, Maddie and Yusuf here. At CP Solvers, our mission is to make clinical reasoning accessible to learners worldwide. We invite you to join us for our live virtual morning reports where we break down cases and sharpen our diagnostic reasoning together. Now over to you Yusuf. - Thanks Maddie. Just a quick reminder, this podcast is for educational purposes only and is not a substitute for medical advice. Patient details haven't modified to protect their privacy and the views expressed to our own, not those of our employers. Now let's dive into the case. - Enjoy the show. (upbeat music) - Hello everyone, welcome back to another schema episode. I'm so excited because I'm gonna be presenting a great case to my dear friends. Maddie, how have you been since last episode? - I've been great. That was such, I love the enthusiastic start. I'm so happy to be here with you guys. I'm on Mickey's rotation right now and so this is a nice kind of change of pace. And yeah, as we were talking about kind of before the show, I'm in the last weeks of pregnancy. So excited to meet this little boy soon and we're all feeling good. Mark, do you wanna share any updates in your life? How are you doing? - Yeah, I'm breathing. I was born and raised on the East Coast, so I'm like used to seasons and the winter season, but I've been in the Bay Area for like a year and a half and I'm learning that this is like the coldest it's been in like a hundred years and although that was just like some AI generated tweet on X or actually real, but it feels like really, really cold. So I feel like I'm already like getting away from my New Jersey roots and I can't handle the cold anymore. But besides that, I'm doing really well. My wife and I went to Mexico City for Thanksgiving break in her birthdays, which was wonderful. I highly recommend for all people that love food and nature. So yeah, how about you, you said? How you doing? - All good. I'm still in the slumps since Thanksgiving where there's like dinner every two days. So I feel like I've all I've been doing for the past two weeks is eat excellent food. So I'm just happy right now. - You said what is the best thing you've been in the past week? - That's a really hard question. I love a Lebanese meal called Fetty. It's like yogurt, eggplant, chickpeas and bread and with pomegranate syrup. So that's my favorite. Oh, I'm gonna share the recipe. So I don't know if I'm gonna share it in the episode description. My turn my phone depending how good it comes up. How about you, Manny? Best thing I've been eating in the last week? Oh gosh, what have I eaten in the last week? My husband made this really good like Bolognaise pasta dish the other night and we've just been eating that for leftovers and that's been really delicious. What about you Noah? What are the best thing you've eaten in the last week? - So this was my first true American Thanksgiving. I went up to say new work with my girlfriend to visit her parents and we had sweet potato casserole and then you get the sauce and you put on top of the mac and cheese and it was phenomenal. I ate it for like four meals in a row. What about you, Mark? - Yeah, I think I would get a lot of trouble if I didn't say my mother-in-law is Tsitankima that I just ate and as I was the best meal of the last week, I just had it like five minutes ago and I feel like it's really great brain food for Noah's case. So yeah, definitely is the best meal of the last week. - And that's a great tagway into the case, Mark. Thank you so much for that. All right, so this is gonna be a very simple case, you all. And it's an interesting story of this 50 year old woman that came into the hospital for weight gain and edema. Maddie, you know, I feel like it's very non-specific but I wanna hear kind of what your reflex thoughts on this initial presentation. - Yeah, I think my reflex thoughts in a 50 year old woman with weight gain and edema. So I think reflex thoughts when I hear that is of course, you know, I wanna step back and think about edema. I'm assuming this is lower extremity edema but of course we probably wanna clarify are we talking about lower extremity edema or are we talking about kind of anastarca and whole body swelling. For right now, I'm going to assume it's lower extremity edema but I acknowledge I'm making that assumption. And so clarifying the location is this like one leg or both legs or this whole body anastarca. But if we just assume that there's edema, that you need I'm translating to volume overload and assuming this is a volume overload state, I find it helpful to think of just the three main organ systems that can do that. And so that being the heart, the liver and the kidney. So I'm gonna be very interested when you give us more information on history to hear are there signs suggestive of heart failure? Is there orthochnia, for example, on exam or we're gonna see JDD, does she have a history of heart failure or risk factors for that? So the heart, so you can think of cirrhosis or chronic liver disease that can cause volume overload especially from, I think of it as like basically low albumin when you're liver, synthetically cannot make low albumin. You have low on clot at pressuring, can have this volume overload. And so we'll also be interested on exam or there are signs of chronic liver disease issues, risk factors for chronic liver disease, alcohol, things like that. And then the third organ system is the kidney. And this I generally think of nephrodics syndrome. So they'll be interested in, of course lab work. What is the UA, is there protein in the ear? And so my initial reflex is, is are you pointing us towards a volume overload condition? And I'm gonna be paying attention to those three organ systems and see if the history and on exam we can kind of clue into which of those three organs might be at play. You said do you have anything to add to that or did your mind go anywhere else when you heard weight gain and de dima? - No, I love your framework and the etiologies. One thing I'm thinking of is out of kidney liver heart, which is what I think of too. Usually if you have cirrhosis, you're not gonna present just with edema. You typically have other symptoms. You have abdominal swelling, sometimes jaundice. And obviously you can develop edema, but typically if the patient is in the hospital, you they will have other symptoms. So hearing the chief complaint of just weight gain and edema makes me want to prioritize heart and kidney. And like you said, in the photic syndrome causes anasarca. Sometimes you see swelling in the arms and the face, we don't hear that too. So I think out of this list, I'm maybe choosing heart one kidney to liver three, but obviously really eager to hear more information from you Noah. - Yeah, that was a great start to the discussion. So you go down to the ed, right? You talk to the patient and she tells you that she was in her usual state of health. She was actually working on weight loss earlier this year. She lost quite a bit of weight with exercise. And then over the last two weeks, she noticed that she's been gaining the weight back. She tells you that she always had edema in her lower extremities. Her PCP has her own frozen mind for that, but this has increased dramatically. She's not even able to fit into her usual pants. She also has noticed lie headiness when standing up. She's more tired than usual. And if she walks around too much, she gets a little short of breath. She hasn't had any fevers, no chills, no proxies, no nocturnal dyspnea, and no orthopnea. The weight gain was quantified 'cause she keeps a close eye on her weight. So 30 pounds in two weeks. And she also does take her blood pressure home 'cause she has hypertension. And her blood pressure has been ranging like into 70s over 50s or so. And that's kind of why she decided to come in 'cause she wasn't getting any better. Mark, with that information, how can you build upon the French and the median use of shared? - Yeah, this is a very interesting HPI. I think if I were gonna pick one piece of data, that's the most helpful for me. It would definitely be the blood pressure. And before I'd come on that, Nilla, just to clarify, was the blood pressure 70s over 50s for two weeks? Or is it like when it's just in the emergency room that it was 70s over 50s and it was at her base line at home? I just wanted to clarify that before I. So it wasn't in the emergency room that was just patient reported. The emergency room was a little bit higher than that actually. - God, so this is really helpful. I think one of the most important physical exam findings in trying to stratify like, is this gonna be more likely gonna be volume overload from the heart, their liver or the kidney, is really the blood pressure. Because really like most patients that have seen anything in a deem of from kidney disease, will typically be quite hypertensive, right? When the kidneys aren't working, you retain salt and water. Your rassus is really elevated. Now, maybe I shouldn't say, 'cause the rassus is also elevated for other reasons and heart and liver disease. But you're retaining a lot of salt and water. You're not peeing as well. And then your blood pressure gets elevated. Now, the only caveat to that is that if someone has an end stage nephrodic syndrome, right? And their albumin is so low, let's say their albumin is in the low twos, the ones. And you just start having so much third spacing. Then you can have a lot of Thursday. and become on the softer side and for blood pressures. But that's usually someone that has like established nephrodite syndrome and it just has really refractory disease and that becomes really, really tricky to manage. Now, you also have a situation that someone has kidney disease plus a reason to have a low blood pressure. The disease plus sepsis is gonna cause low blood pressure, right? But if we think this is all driven by one disease right now, that kind of makes kidney disease a little less likely, especially you can learn to afraid this, right? Serosis very commonly causes low blood pressures, right? All the evil tumors of the liver, when the liver is not working that well, you get released in nitric oxide, you get a lot of supply and type phasor dilation. I remember residency, like all the patients on the liver service, their books are solids were in like the 80s and I would just turn my head and like I got to find, that's normal, that's their based one. But I've had a patient on like another service where the stall get ADI, I'd be like running to their bedside. So, but when use of set is really important, like most patients with like liver disease, it's usually pretty obvious. It's not just that they have a little bit of lower extremia, Dima, if someone has blood pressures, it's the stocks in the 70s from cirrhosis, they should have a sitease, they should be jaundice, they should be confused, like that's pretty, pretty end-stage cirrhosis. So I always, I've had that interesting as well. And then, you know, in terms of the heart, now, the heart can go either way. I feel like liver disease, usually it's also blood pressures, kidney disease, usually higher blood pressures. Heart failure can kind of go either way. Like, it depends on the mechanism of the heart failure, right? If someone has hypertensive cardiomyopathy, they're probably going to be hypertensive, right? If someone has toxic induced cardiomyopathy from cocaine, they're probably going to be hypertensive, right? But outside of maybe a few of those hypertension mediator, more synpathomatic mediated, blood pressure is in patients with heart failure, maybe tend to be on the softer side, especially as they get more advanced heart failure and when their EF starts dropping. So, honestly, no, like, I'm very interested by that blood pressure. Does it point me towards a little bit towards cirrhosis? Maybe, but we're not getting a lot of other signal towards that. Is it maybe parts? You didn't give me a lot of orthopnea, PND, but those aren't perfect signals. I think at the end of the day, like, I'm going to want that evaluation labs exam that Maddie and Yusuf asked for in the first salic block, but I'm curious, does Maddie, would you think of the HDI? Yeah. I, it was so cool to hear how you use the blood pressure to kind of reason through those different organ systems. And I loved your reasoning there and totally agree with you. I think one, in addition to the organ system approach that I use when I hear of Adema, and it sounds like from, what I heard from you was like lower strontidium, but I think you said that she couldn't like sit in her pants. So, in addition to the organ systems, I also think about could there be some type of proximal compression of venous drainage of the legs? So, that's not isolated to the heart deliver the kidney. So, for example, I've seen cases where you have IDC compression for some reason, and then that causes, you know, low-work strombid demons. So, you'd initially start with the organ approach, but ultimately you need to think about is there a clot in the IVC? Is there some kind of external compression? So, I think that's just another part of the differential besides the organ system approach. I have nothing to add here, like brilliant breakdown at how the blood pressure affects it. Yeah. And Maddie, I was also thinking that the blood pressure is low at 7.50. And the pulse pressure is narrow. So, 70 minus 50 is just 20. So, what how do we make of that? We see that sometimes if a patient is very hypervolemic, let's say they're fluid down, you're like, "Okay, they just need some volume." But in this case, we hear that a patient is an acyclic, and they have low blood pressure, and the narrow pulse, and lightheadedness. So, could this patient be having early signs of shock? And is their EF really, really low? So, I agree with you both, and not only am I worried about heart failure, I'm also worried about a very low ejection fraction. So, this is one of those patients that would try to get a bedside ultrasound, physical exam, JVP, check that, get early testing, like the NP, et cetera. And I think I want to look for signs of quite the genic shock. So, these include things like coldness and extremities. So, if their extremities are cool, especially in the proximal regions, you want to consider, if you see signs that are either ridiculous, altered mental status, aka eye signs of low organ profusion, then I would think about that as well. I'm just keeping that in the back of my mind, because we're really, really good at detecting shock when the patient's really sick, but this is early shock as hard as the detect. So, my antennas are up. Back to you, Noah. That was wonderful, especially like, you're a teaching point, shoesive of our early shock. I feel like, you know, we have to prioritize what's more morbid, right? What's going to kill the patient first? And that's kind of what the ED did. So, to give a little bit of background, and then tell you what the ED did, she has hypertension, type 1 diabetes. She actually has total cytos and verses. And she has a history of melanoma in her lower shemini that was completely treated, finished treatment earlier this year. For meds, lasics, insulin, and statin, her physical exam, her vitals were relatively stable. She wasn't techicardic. Her blood pressure in the ED was 100 over 70. She was having a well-dramar. Cardiovascular, no murmur, lungs were clear to excitation. Kind of the most notable finding was pitting a dima. It was up to her abdomen, like men abdomen. You know, I love a focus. The ED did focus her. And you could see that the heart had a good squeeze. So, no obvious, you know, decrease ejection fraction. And as they all do, they get a CMP and a CBC. So, the CMP was stone-cold normal. So, LSTs were completely fine. Billy Ruby was negative. Except for protein of 4.8. And her albumin was 2.7. And then you can clearly look back 'cause she follows with oncology for that melanoma. We have like very frequent labs for her in the alpacin setting. And you see that the albumin has been dropping for the past month or so. Her CBC comes back with leukocytosis to the tune of 14, a hemoglobin of 12 in platelets of 300,000. And then for the differential on that CBC. That was kind of the most interesting finding. Her using the fills, the absolute count was around 6,000. And you can also see that it was slowly rising in the alpacin setting over the past couple of months. Initially it was normal, then like 600 and then 6,000. And they also got a UA. So, the UA was normal. Had trace blood, but no obvious protein on it. Use if, I give you a lot of information. And I feel like I threw kind of a curveball 'cause we were talking about edema and all of a sudden we see those elevated using the fill counts. I want them to hear from you kind of what are you making of this case so far. But also, how do you usually go from a diagnostic reasoning perspective when you have such, you know, more bid and serious complaints which are kind of unrelated? How do you reason through them? - Yeah, I love it Noah. So to summarize, we have a history of melanoma, cytosine versus and found to have a demod exam, focus looked okay, a low serum albumin and a using a full count at a whopping 6,000 in a normal year analysis. When choosing your problem representation, you can choose either symptoms that present in the same timeframe, for example, or symptoms that are mechanistically close to each other. Like for example, low albumin and edema, go hand in hand. Well, if I told you low albumin and using a fill the other connection is not direct immediately. It takes more than one step. The other option is you can exclude the most morbid diagnoses. That's like a third category. And then the frame to think of is which symptom has the now narrowest differential or most unique differential. And I will, through initially the albumin and I'll give the hand over the mic to Maddie to touch on his and affiliate in Mark. I think in general when we think about albumin, we think of it as the patient, for example, malnutrition, or they're losing so much weight that the albumin is very, very low. Or is there like acute inflammation and albumin is a negative inflammatory marker. And then the other categories you think of is their protein loss. And the urine or is it in the form of nephrodix syndrome or loss of protein in the stools and the form of protein losing and terrapathy? These are the big categories I'm thinking of. The way I would want to think about that further is checking the urinalysis and checking a urine protein to creatinine ratio. A urine protein creatinine ratio correlates really, really well with a 24-hour protein collection. So in the past, we used to always have a 24-hour urine collection for protein and then quantified that way. But now they've shown that the urine protein to creatinine ratio, which is a spot sample, correlates really, really well, at least as a screening test. So it's a really handy tool to immediately think of how much patient is losing protein in their urine. And then in terms of the EOS, I'll throw the mic to Maddie to give us her impressions on the 6,000 EOS. Yeah, that's a lot of EOS, Noah. And so I find it helpful to kind of just start with definitions because it will help anchor us, I think, as we go forward. And look this up kind of every time I get a case of EOS, anophilia, but helpful to kind of define the degree of eosinophilia. And so eosinophilia is defined when you have greater than 500 eosinophiles per microliter. And that's eosinophilia. Then you get into the hyper eosinophilia space when you have greater than 1500 eos per microliter. Hyper eosinophilia. And then what we'll talk about is we need to understand what is the cause of the eosinophiles? And is there a consequence of having such a high amount of eosinophiles? So there's something called hyper eosinophilic syndrome. And that's when you have eosinophiles in the hyper eosinophilic range, so greater than 1500 plus an organ damage that you have pinned on the eosinophiles. And what I mean by that is first we need to understand we absolutely need to have an explanation for why this person has hyper eosinophilia, where that's what I'm labeling this as, because this person has greater than 1500 cells per microliter. So we need to understand what is the cause, but also what is the consequence of this high of eosinophiles. And so my understanding is that eosinophiles, they can infiltrate organs and they are also can weed to a hyper-quagible state. And so you know you don't always need to have end organ consequences when you have hyper eosinophilia, but you are more likely to end organ consequences when you have such high eosinophiles. So I would be very concerned that with eosinophiles in the 6000's, they are going to be wrecking some kind of havoc on various organ systems. And the main organ systems I generally think of are like the lungs, the skin, the GI tract, and the heart. And what's interesting is even regardless of the cause of the eosinophilia, when you just have that many eos they can cause all sorts of organ damage and cause like hyper-quagibility. So Mark, maybe I'll pass on to you to go through, I kind of talked about like the definition and the consequences you need to think about, how do you think of the different causes of eosinophilia? And is there any particular category that's coming to mind based on the HPI that Nila is talking about? Yeah, that was awesome. I mean you and you just sent me out for success and maybe I'll just kind of put a Venn diagram over, you know, I'll talk about eosinophilia, but kind of put a Venn diagram over like severe hypo-obby minimia and zollim overlobe and severe eosinophilia. It's a very interesting space. Like you used to say, it sounds something that right away comes to you, but I think that's what you did, it's a systematic approach. So that like severe hypo-obby minimia, as the user said, it's helpful when you have something that has a pretty short differential diagnosis because you can really make progress quickly. And in this case, we've made a lot of progress, right? So Nila's giving us this exam that's not consistent with heart failure. We're gonna, you know, we're gonna check out the heart with an echo, but he's giving us an exam and labs that are not consistent with a cardiomyopathy. He gave us a year analysis, didn't have any, any protein. Like you said, we're still gonna get the urine protein to creatinine ratio because the urine analysis only picks up an albumin in the urine. So non-albumin cause of protein area will be totally missed by your analysis. You know, we're not really getting a strong signal for an euphrodite syndrome right now. And then the liver labs look pretty good and the patient doesn't look like and they're in decompensated sources. So we're already kind of getting to the very end of the algorithm for hypo-obby minimia. And I'm very curious about the GI tract, right? Because we don't have a patient that at least for a long time has been severely inflamed or severely now nourished. So we also think their albumin would be a little. So I'm very curious, I was saying, if the patient is at any GI symptoms and, you know, about the entity of protein losing enteropathy, that you can test with a stool alpha-1 and a T-tripsin. So if I'm working with a hypothesis, like I'm working up the heart and the kidney. I'll wait for those labs and the echo to come back. But if I'm anchoring myself in maybe GI causes of albumin, how can I marry the severe eosinophilia and possible protein losing enteropathy or GI loss? Well, there's a few ways you can think about that. Like one is from severe parasitic infections, right? Anytime you have a severe eosinophilia, which Maddie defined, the one of the first things you could think you should think about is the severe parasite infection. One of the most common ones we see that impacts the GI system, really worldwide is trangela diastas. You know, there's, I've been surprised by patients that have had disseminate trangela and even have serologies that are positive for trangela. When you do a good social history, you're not really picking up anything. So it's just something I really, in these cases, I just order very quickly. So that's one. A lot of parasites can impact the GI tract. So I'd kind of do like a stool over in parasites, you know, as well to see if it's causing a defect in the GI in women leading to protein loss. So that's one, you know, the history of melanoma is, you know, it's interesting. Like I don't really think of melanoma as it can, I mean, it can go anywhere. Honestly, like metastatic melanoma is a devastating disease. So would I be surprised if it's kind of infiltrated the GI system and lead the protein losing enteroopsy? Probably not. The other thing to think about too, it made it brought up is like, is this a cause of primary eosinophilia? I've experienced a phyloxendrom. That's not just attacking the GI tract. Again, I'm going to, I would really like know, it hasn't given us any GI symptoms yet, but maybe he'll tell us some soon. Like especially just having a lot of diarrhea or other GI symptoms, but it's totally possible that all those eos are just in the in the small bowel large bowel. There's having a lot of protein loss. So that's totally possible. The other thing to think about when someone's eos are that high and the 6000's right? Because there's like things that can cause a mild eosinophilia, right? In like the 500, for instance, adrenal insufficiency. You know, so it's on all the list of eosinophilia, but adrenal insufficiency does not cause an eosinophilic count. The 6000 just doesn't happen. That would be very surprised. The other thing that can possibly be severe is the syphilis severe drug reactions. We haven't heard about any new drugs that patient has been given. It would be really weird for a severe drug reaction than the cause of the protein losing and to drop the thing. But again, is it just the eos or infiltrating the GI tract? That's the big thing. I'm really on the look out for parasites. I'm really curious that the patient possibly has a primary clonal high-periodceinophilic syndrome and we're just getting an organ manifestation in the GI tract or does this patient have a not either metastatic disease from their melanoma or a new occult malignant sciner GI tract that's causing a parasyneoplopsychias and affiliate and protein losing that drop the thing. I know it just rambled for a lot, but I'm really just trying to create a vent diagram between the GI system and the GI. I guess no. Any GI symptoms at all? I know I said that like 15 times. Beautiful discussion. So talking in a little bit more about the edema, and the investigations for it. The urine analysis, no protein. The UPCR was actually negative. It was like 85, which is negligible. They did go ahead and collect the 24-hour anyway, which was also unremarkable. Formal alcohol came back and it was completely fine. She had the cytosine versus, but the EF was fine. They got a CT, A, chest, abdomen, pelvis, which was normal. Had some mild lymphed anopathy, but even the radiologist commented that it could be in the setting of the diffuse edema. They did do a very thorough GI history because they were concerned about protein losing a theropathy, given that, as you mentioned before, the differential is quite short. She denied any changes in bowel movement at all. Regardless of that, GI was consulted and they were more than happy to do bidirectional scopes with random biopsies to investigate further. The scopes were unrevealing in terms of the macroscopic examination, and the biopsies came back relatively fast and they were actually normal. So no eosinophilic infiltration in the GI tract. Meanwhile, some other investigations for the eosinophilic cooking, but I'm interested to see where we are in terms of the anazarka. Maybe use it. What do you think so far? What now that the GI tract is not the culprit? Wow, incredible case Noah. Like Maddie said, whenever you have eos you want to see visit in an organ specific, and are the eos causing a syndrome and that's it? Or is there a secondary etiology that's causing both the eosin and the anazarka? How can we connect the two? I think big categories. I think the kidney has been exonerated with the longer-year and protein. I think the GI tract has mostly been exonerated through no eos on biopsy. I expect them to be some of eos on biopsy, but we hear that there's potentially no eosinophilic gastroenteritis or colitis, which is most exonerated. So next thing I'm thinking of, could there be a vascular leach syndrome, where the patient is actually having permeable blood vessels and that's causing the anazarka and the eosinophilia? In general, the whooping eos of 6000, you need to explain this. If your eos were between 500 and 1500, even though they're high, you will not always find an answer. You can try, you can send some work up, but you don't necessarily find an answer. While the eos are severely elevated, like more than 5000, then you need to explain this because it's so unique. So what would I do next? So I think the categories I think of like Maddie and Mark mentioned primary hyper-exinterimics syndrome, the secondary syndromes. The secondary syndromes are the things you want to rule out first, and the primary hyper-exinterimics syndromes are on the malignancy spectrum. You think of myeloperative of neoplasms, leukemias, lymphomas. or proliferation of eels. So I usually start with the secondary etiologies first. Strangie is a really good one. Other things is like parasites that are just luminal. Like do you have an example? Usually it should not cause eels in a failure. And most parasites usually don't have a very long incubation period. Usually get them shortly thereafter, but Strangie has a very long incubation period. It's one that you always have to consider. Other things like dimorphic fungi, we didn't hear about any other findings on the cross-sectional imaging, which is good. Viruses like HTLV, we also don't hear about, like an endemic error, anything like that, but we still consider it. But then the big categories you want to consider are eels in a phylegranial autosis with poly and GI-dys. So it's a vasculitis that has also associated with elevated eels in efflose. The serologies for EGPA are not always positive. They're positive in about 50% of cases, so it's not the most sensitive test. But this is a test that you will be ordering very early on alongside the Strangie and get that going. And then there are rare syndromes associated with vascular leak and eosinophilia like glyc syndrome, which is a syndrome associated with a monoclonal like a mapefili vascular leak and eosinophilia, IgG-4 related disease as well, but we don't hear about lymphatic anopathy. We hear about mild lymphatic anopathy, but we don't hear about any other manifestations like retro-persi-neocybrosis or anything like that. I think I'm thinking of all the studies we can get before we can get a bone marrow viopsy, which is the rule out of primary hybrids, epilixendroms. And I think the studies I would want to get are a S-PEP, because we mentioned that syndrome, e-encacerology, Strangie-cerology, maybe a peripheral smear, and then if nothing there, then maybe considering a flow cytometry. But I'm not confident in one diagnosis. Mark, where's your mind at? - Hey, I'm also not confident in one diagnosis. I think this case is very puzzling. I think that we have a pretty, like you mentioned, you outlined a beautiful streamlined approach to severe eosinophilia, but again, the severe eosinophilia was severe hyplobiuminemia with anasarca, despite, I mean, no, it didn't give us the stool, alpha-1 antitirpsin, I don't believe yet. And colonoscopy biopsies, EGD biopsies, are limited, right? So you can have patchy disease. Biopsies can be negative. I've seen so many times that they go back in for another scope and something that becomes positive. So I'm definitely not ruling out protein-losing entropathy, even in the absence of no GI symptoms. There are many cases of protein-losing entropathy that just present in this malabsorbed way. So I still want that stool alpha-1 antitirpsin. And I think if we have that as being elevated, we can make a lot of progress. But let's say that's not elevated. You said, honestly, I think this case would be screaming capillary leaks to germ, right? Like a lot of these capillary leaks in germ, some of them actually have hyperalbuminemia and hemoconsentration because you're just foreign-fluated to the interstition. But it actually is a hallmark of carcassons, the kind of idiopathic systemic capillary leaks in germ to have hyplobiuminemia and intermittent hypotension. So I definitely am very curious about those capillary leaks in terms of what you mentioned, or a lot of times are S-cap positive. So it's a good idea to send the paraprotene workup, because a lot of them are hematological diseases. Like you mentioned, they get all poems and tempe and all those diseases. So yeah, very curious about that kind of heen world in the capillary leaks syndrome and the alpha-1 antitirpsin. But yeah, this is a very interesting space. If the protein-losing entropathy workup is negative, I think it's just has to be-- I think I'm trying to think of what else it really could be besides a capillary leaks syndrome. Yeah, Maddie, what do you think? I'm right there with you guys. And I think maybe what I'll try to do is just kind of give a summary right now to try to orient us, orient myself, basically. Nose told us about a 50-year-old woman, pertinent history that's kind of like sending out to me of hypertension. She is coming in with weight gain and anastarca. And pertinent labs include an albumin of, I believe, 2.7, hyper-use anaphylia. And the workup so far has shown basically normal kidney function without protonuria and a normal evaluation of the GI tract so far. That's kind of what's standing out to me. And so I think-- I don't have too much to add, Mark and Usa to your discussion, but I agree that I think we need to-- we need to get to the bottom of why there is hyper-use anaphylia. And as Usa said, we need to understand if this is a primary monoclonal process or a secondary reactive process. And then we need to understand, are the Usa and Aphyls infiltrating anywhere? We don't have any signs of the Usa and Aphyls infiltrating any organ right now. And we're actually not even seeing signs of any organ dysfunction, right? We're not seeing any signs like the kidney being dysfunctional, right? There's no protein in the urine. There's no evidence that the GI system is being infiltrated. The heart, no concerns there. And so I think it really does come down to the low albumin in the hyper-use anaphylia. And I think right now we need to chase any secondary causes and rule those out before landing on the primary monoclonal process. And I totally love the work out use if that you outlined that agree with that. But one thing I just wanted to mention that I was thinking about is that, this is obviously being going on for two weeks. And the patient doesn't look too sick based on Noah's description, but we've mentioned the word capillary leach syndrome. And I guess the most important first step when someone has a capillary leach syndrome is to make sure they don't have like a devastating cause of a capillary leach syndrome and that being an infection, right? So besides, obviously, sepsis, another that being the most one was classic causes of capillary leach. There's very unique infections like hauntavirus, viral hemorrhagic fevers like dengue, all those infections. They can cause capillary leach, but most of those are viral. And it would be very odd for those to cause severe hyper-use anaphylia. And I'll see Noah hasn't really given us a social history yet, but didn't give us a social history that would suggest exposures to those. So it definitely would not fit with how well the patient looks besides their antisperca and their severe antisperia. But I guess I just want to mention that as one of the first steps when you see someone that comes in the center of the caulking, can turn for capillary leach. Off to you know. - All right, a lot of information, beautiful discussion. And I'll give you what you're asking for Mark. So the stool, menta-tripsing, the alpha-entatripsing was negative. So completely exonerated the GI system. At least the GI doctors felt so. In terms of social history, so, this patient is from Missouri. She was dealing with the melanoma. It was actually, you know, it was not as malmelonoma. It had be excised first and then it had positive margins. So they went for like a bigger surgery and I was like a year ago. And then she got some adjuvant therapy for a year. And then while she was getting the adjuvant therapy, she didn't travel much. She was just kind of nursing herself. And after that treatment ended in July of this year, she had a small trip to celebrate just to Florida. And that was kind of a little bit after her symptoms started. So it wasn't before the symptoms started. Otherwise, no international travel or anything like that. In terms of further investigations. So they got ESR and CRP. ESR was normal and CRP was elevated at 40. They got an A and A, which was one to 80. A and A was initially in the terminate, but then MPO and PR three were negative. A trip days was sent somewhere along the way and it was 5.4. The strange loyades antibodies were sent and they came back negative. At this point, the primary team felt they had exonerated causes of secondary is unaffilia enough or the concern for primary is unaffilia was high enough that they consulted hematology and they agreed that a bone neurobiopsy wouldn't be unreasonable. So that was done and that was pending. Other things that happened during the hospital stay, they got a PET CT for her given the history of melanoma and the recent treatment. It didn't show any avid lesions in her body. And the SPAP was ordered and came back negative. Or eye friends, Maddie, what do you make of all those negative information that I'm giving you? - This is so fascinating. You know, I think some of the things that stand out to me from what you said is when I gave that summary statement, I had forgotten to include the history of melanoma but I think that's really key here. Because if we just kind of lay out the summary of, both Mark, you said, if I can't do that, but if we just lay it out to be clear, when you're thinking of causes of eosinophilia, you really want to break it down to, is it driven by a clone, a monoclonal process? Or is it reactive to, and then you name all these categories of disease infections, autoimmune drugs, allergic processes and even male-evimancies? And so the reason why that history of cancer comes up is because I'd be curious exactly what type of treatment that she was on. And then I would probably be searching all the different resources to see could she have had almost like a drug-induced hypersensitivity reaction to that that could have led to this significant use in affiliate. So I think that is one thing I would be looking up and kind of clarifying exactly what she got. In terms of kind of like going through those categories, right, we have primary or secondary. We are going to ask about kind of the treatment that she was on for the cancer to see if that could be an allergic or drug-induced component. Infections, you know, we've sent strong G, I'm not getting a flavor, you know, generally the infections you think of like parasitic and fungal. And you know, maybe you could send kind of markers for the endemic fungi that I'm also, I would say that's lower on my differential. That's infection, so kind of parasites, fun guys, especially. Malignancies, the thing that I want to mention about that is that you can obviously have a primary monoclonal process driving use in affiliate, like acute use in affiliate, like Kenya, but you can also have some cancers that cause like a secondary non-clonal process. And so I'm wondering, I would be looking this up, I don't know right now. Like can you have use in affiliate as a like reactive process to the melanoma is something I would be considering. And then ultimately kind of does ultimately come back, do we need to rule out a colonel process with flow cytometry and a bone marrow biopsy. So I think that's, you know, I don't have a great argument or picture, clear picture in my mind for any secondary process driving this, you know, there's a hypothesis of the melanoma and the treatment that you got, and maybe we're still investigating some infections, but I don't have a clear picture for a secondary driver. So I think I'm becoming more and more concerned for a primary colonel process driving this. And so I'm really eager to hear the results of the bone marrow and flow cytometry. Mark, I'm curious where your mind is at and how you interpreted the data that no gave us. - Yeah, no, I totally agree to you. I think my mind is going towards a primary colonel process just because such a good secondary evaluation and then just based on like the time course of symptoms of like two weeks and based on really not that many B symptoms or systemic symptoms besides obviously the end of the circuit of the patient. That's kind of odd. But I guess the issue with the primary colonel hypothesis is that I'm really struggling to kind of marry that with the end of circa unless it was a primary colonel process that triggers a capital-led syndrome. So that's what I'm struggling with. In cases like this, I do think about just splitting all the different problems. In medicine, we like to lump everything into one nice neat diagnosis. And it's really nice when it works out that way, but that's not always how it is in real life. In today, a set NOAA presented to us on our other podcast series where it was actually two diagnoses were the final answer. So I guess I'm thinking like is could there be something driving the yeast and the philia and then something separately driving the iPod or evenemia or is abscessional anusarca or is like the cause of the anusarca also triggering the hybrides of the philia. So let me give you an example. Say like on the DDX for anusarca is cushing. So rarely can cause very severe volume overload through like increased cell dosterum. Cushing makes you like innately immunosuppress, right? Your body is secreting a lot of cortisol. There's actually cases of new presentations of cryptococcal meningitis and intations that have newly found to have cushing syndrome because it's like you're on like a big dose of prednisone every day so you're very immunosuppress. So what's this patient has cushing syndrome? They're essentially getting equivalent of like prednisone 20 to 40 milligrams every day and they have a very invasive parasitic infection that we have not yet identified because there's a lot of parasites out there. That's possible. So I'm kind of just thinking sure that we are also working up everything independently. I think at the end of the day, I probably won't be able to make much more progress until I know the bone marrow biopsy results and I can pull in a roll out of primary process. You know, a lot of me is a primary fibrousinophilic syndromes are associated with like platelet-degrived PDGF-RA and D. That's one of the mutations. And a lot of times they're also associated with mass cells as well. I know, no, did you mention that the drip days was normal? - The drip days were normal. Okay, got to. 'Cause that obviously can cause like capillary leak as well. So yeah, I think I don't know. I'm curious for you to think too. So I think I'll be able to make more progress once I have that bone marrow biopsy results. - Yeah, I think at this point, I want flow cytometry and amperein panel and bone marrow biopsy, thinking of primary hyperecinophilic syndromes. And then the secondary causes the malignancies, like you also have the PET-seats-dees negative, which reassures me for like less likely to be like recurrence or lymphoma, especially with that like small lymphadenopathy that we saw earlier that don't seem to be PET-avid, which is reassuring. So I think the next step is bone marrow biopsy, based on those results, I think I'll take it from there. So I'm with you all on the same page. So Noah, can I wait to hear more? - Or I can ask, just one thing. Can you mind telling us kind of the therapy that she was on and then like once she received her last dose of therapy in relationship to her symptoms, started? 'Cause as many times it doesn't matter so much, it's our fault and we, the symptoms that patients experience her medications we give them. So I'm just curious of this. - I'm thinking of BDL1 inhibitors too, that's how I was like, oh, 100%. - Yeah. - So she actually got BD1 inhibitor. She got an Nivolumab and she got it for a year. So her last dose was three months prior to symptom onset. But if you look at her chart, on the month that she got her last dose, her using a fills went from 0.4 to 0.57. And then at the end of that month, it was as high as 0.9. So using a fillet like Maddie was mentioning, more than 500. And then at the end of next month, it was already 1.8. And then slowly climbed all the way to 7,000, which was kind of the peak like we mentioned. And then the album ends, started to drop in the end of the month that she got the last dose of Nivolumab. It was 4.3, a month later was 3.8. And then on presentation it was 3.3. So it was low drop there too. And then for the bone marrow biopsy, which I'm sure everyone's waiting for. So it showed a normal cellular bone marrow with multi-lineage hematopoases and mild multi-lineage ATPA with increased using a fills. No blast observed. The cytogenic analysis revealed no evidence of this alphabet soup. So the plate of the rye of growth factors that Mark was mentioning, plus FGFR1, PCR-ABL arrangements. And then the growth factor FIP1L1 fusion. They also did a Milosec, which is a more comprehensive sequencing of the bone marrow. And it showed two variations, which were not compatible with her picture of eusonophilia. So the final hematological diagnosis was that there was no clonal process in the bone marrow normal pregnancy that would explain her eusonophilia. During the hospitalization, she got a post dose of steroids. She did develop a rash. It was biopsyde, showed some eusonophilus infiltrating the skin. And at that time, her eusonophilus were as high as 7,000. So they decided to treat it. So they treated those steroids and her eusonophilus dropped to zero in like three days or so. So that's kind of where things were. And the diagnosis was made. She got a treatment and she got better. And I'm curious to hear what you all think it is. - No, it can ask clarify questions. So that it sounds like the eusonophilia and the hypoalbumemia worsened after she stopped the melanoma treatment. Is that accurate, Tosa? - Yeah, I think it's accurate. I think it's like they started to worsen on the last month that you got the treatment, basically. - And then is the, it was an immune checkpoint inhibitor that she was on, is that right? - Yes, Nivalomab. So I hate to always pin things on the immune checkpoint inhibitors, but immune checkpoint inhibitors can cause a lot of, you know, the eye rays, immune-related adverse effects. And given that we have seen two exoners, we are like not really thinking this is a primary clonal process. We're in the secondary. Infections have become less likely. I'm just, I'm wondering if the, I'm worried that the immune checkpoint inhibitor may be playing a role here. I'm not a tyrosher in what way, but could this be a, like, immune reaction to that or an allergic reaction to the immune checkpoint inhibitor? So I would, that's what I would be googling, truly. I would be googling like hybrid use in affiliate and this immune checkpoint inhibitor, given that the timing seemed to have really worsened after that. And you know, you can have, I was, other cases that I've had with immune-related adverse effects. You can have those after the immune checkpoint inhibitor. has been stopped. So generally, you know, you have these mean related adverse effects, I think most commonly within the first three months, but you can have these delayed irase after you stop that. So I think I would really, I think I would be investigating that hypothesis at this point. You stuff where are you at? Yeah, I would say that I'm not confident and like one diagnosis, this is like a really hard case. But the L1 inhibitor associate like side effect, a good idea, a really good idea because it can cause like side effects even months later. We think of like endocrine side effects and we also think about solid organ disease, but it can also probably cause like immune activation causing the a's in a failure. Is there anything else that I would want or is there any form of cryptic infection that I'm thinking of? Not really, to be honest, Strangely is the most common one. All the other causes will not be pan CT negative, PET scan negative without like exposure and chronic. So I'm in the space of like, oh, could this be a min checkpoint in the related and do they just need like more more even like adjunance efficiency? We see that with pdr1 inhibitors, although we don't see eos that are this high. To be honest, this is where I would be just talking to my specialist colleagues and picking their brain. What those steroids is high enough? Mark, what are you thinking? Yeah, I'm a hospital. So I always love to blame the checkpoint inhibitors for all things bad. You know, I actually had a case recently, a patient that was on a checkpoint inhibitor for bladder cancer, I believe, and came in with severe hypersinophilia. And that patient actually wound up having disseminated Strangely. But there is very, very, I remember reading this at one specific or like rare associations between like checkpoint inhibitors and capillary leak syndrome. It's definitely not a common immune related adverse effect at all. But at this point, the only thing I can do is blame the checkpoint inhibitor for all the baddest that's happened to the patient. So I wonder and same thing even with the acid affiliate, actually, I was surprised when I read this that actually, eosinophilia is kind of a rare man have a see immune related adverse effect. And severe eosinophilia is actually very, very rare. So even though we always think medication, you know, causing eosinophilia, it's always good to look for something else when someone's on a checkpoint inhibitor like noist team did. But honestly, this is, it's possible that this this checkpoint inhibitor is is triggering severe anesthetylianic capillary leak syndrome. It is described definitely rare. But no, this, we're stopped. What's going on here? Yeah, I feel like everyone was stumped taking care of this patient because I feel like that's why medicine is so crazy sometimes, right? You have a patient that's clearly very sick, clearly has an azarka and hypobinemia. And you know, you should be able to find an answer. He has eosinophilia of 7,000. How can you not find an explanation? And you look, you look, you look, you don't find anything. And in those moments, that's kind of where you have to use your best judgment, use time and use therapeutic response to see if you got a right or wrong. So the allergy team was consulted and, you know, they felt like we had exonerated enough. They causes a secondary in primary eosinophilia. They did blame the checkpoint inhibitor. It is exceedingly rare with nivolumab specifically. I think there are three or four case reports of capillary leak. They recommended treating the eosinophilia with steroids and then tapering off in the outpatient setting and monitoring weekly the levels of eosinophiles and seeing how the patient responds. And they recommended those of IVIG for the capillary, capillary leak syndrome component of the reaction. And the patient responded great to those treatments. So the hypoganymia resolved, the anazarka resolved using the philzer staying down. She's like doing the prolonged taper now. And interestingly enough, like you mentioned, I wasn't aware of that. I thought that the temporal relationship would be more tightly linked. But I guess it is well described that side effects can happen months later. And I mean, nivolumab, the half-life is 26 days, right? So if you have taken nivolumab for a year, who knows how long for all of the drug to be completely eliminated from your system? So in this case, it was checkpoint inhibitors. They were the bad guys. What do you all think? No, fascinating case. Thank you so much for sharing. I will always be humbled by medication adverse effects, especially with checkpoint inhibitors. Incredible. Thanks for that journey. Yeah, no, this was my mind is still processing all of this. But I was not, you know, I've seen several immune-related adverse effects from checkpoint inhibitors. And I've, you know, generally I've seen a lot of like, generally you get kind of like nausea and vomiting and are as the most common like effect. And then they can infiltrate glands. So you can have what like endocrine issues. But I was not aware of the capillary weak phenomenon related to this. And that was really interesting. I'm curious how you was the, was the hyper-use and affiliate basically just a immune reaction to the checkpoint inhibitors that how you were framing it. And then the hyperalbuminemia was from capillary leak. Is that how you were putting it together? Yeah. So like, user was mentioning the way we connected the dots was we gave something that caused two different side effects. So both of them were connected by cause, but they weren't connected by, you know, by themselves. So I thought the journey, the diagnostic journey was great. I really liked how you all emphasized, you know, the basic approach in Nazarika with heart liver kidney. Then look for GI. And then if that's negative, capillary leak is the next step. And I really like how simple you made using affiliate B, especially you Maddie with why does this patient have use in affiliate? Right. Is it a clonal process or is it a multi clonal? And it's multi clonal is reacting to something right to checkpoint inhibitor to a drug to an infection. And you always have to look and see what's the consequence. So look at the heart, deliver the kidney and the skin to make sure the patient isn't having side effects from all those nasty use in the foes. So I really appreciate you all discussing this case. Thank you. Thank you for taking us down the journey of like Nazarika all the way to the end is an affiliate all the way. A lot of learning. Thank you. No, can't wait to read more about this. All right, everyone. That's a wrap. Thanks for tuning in. We'll see you next time. That's a wrap, everyone. 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