Episode 19 – Eosinophilia

Hey folks, just a quick reminder that this podcast is not meant to be used for medical advice. Just good old fashioned education. Hi folks, welcome to the clinical problem solvers. My name is Robbie G.H.A. a clinician educator at UCSF. We also have Arslan here. Arslan, what's good with you? Robbie, I'm feeling really good man. I spent a while since we recorded. Just the other day I was talking to my intern working in the CCU and I asked her if she was doing, she said, "You know I'm really tired. Came to give her some words of encouragement about February and intern year being hard this time of year." She said, "Oh yeah, a little bit of that, but I ran 20 miles yesterday." I was like, "Oh my God, I really got to reevaluate my life." So, Sharmeen, how are you doing? I'm good Arslan. I'm just coming up with a vacation, which was really, really fun and relaxing and I did not run 20 miles. I feel pretty bad about myself now. How are you doing, Resa? I'm doing great. Thanks for asking, Sharmeen. I'm really excited for tonight's topic, which is Eosenephilia. Alright, let's take it off. So a seven year old man with a history of asthma presents with six weeks of fatigue, reduced extra-dice tolerance and low grade fevers. At baseline, he placed Tennyson pinkpong, but now gets fatigued when he walks more than a few blocks. He denies any chest pain, lightheadedness, shortness of breath, myalgia's abdominal pain, nausea, vomiting or headaches. In the last three months, he has had three asthma exacerbations all requiring oral steroids. So for his medical history, he was diagnosed with asthma at the age of 60. He also has hypertension, gird and nasal polyps. He takes a meprosol, albuterol, aspirin, bidesanide and a torvostatin. He has never smoked and drinks alcohol socially. He has never used any marijuana, cocaine or amphetamines. He lives in California and has never traveled outside the region. So this is a 70 year old man with history of nasal polyps and adult-uncilled asthma with multiple recent exacerbations, presenting with subacute decrease in exercise tolerance and low grade fevers. So in keeping with the recurrent theme of this podcast, I want to distinguish the foreground of this case from the background. The foreground being what is the main presenting features for this patient, while the background is the relevant past medical history or exposure that can help us frame the foreground. Here I would say the foreground is exercise intolerance and low grade fevers. Exercise intolerance is very non-specific and difficult to build a differential round. But I would ask clarifying questions to gauge whether this intolerance stems from short and subbrathe, weakness, gate instability or simply fatigue. Fevers reflect an inflammatory process which would prioritize infections, autoimmune processes or malignancies. And the subacute nature here makes pyogenic bacterial infections less likely. Let's clarify the background a little bit more and review the illness script for asthma. And just as a reminder, illness script is how I think of as a mental representation of a disease and has the who, what, when and what. So it includes the epidemiology and risk factors, clinical syndrome, time course and the pathophysiology of the disease. So for asthma, it's a common chronic condition that is characterized by four features, variable and recurrent symptoms, airflow obstruction, underlying early inflammation and bronchial hypersensitivity. It is interaction between these features that determines the patient's presentation and the severity of the disease, usually diagnosed in childhood or young adulthood. And episodic symptoms include weezing, shortness of brass, chest tightness or cough. Triggers often include smoking, allergens or infections. Hey folks, make sure to check episode 71 from our friends and curbsiders for a terrific all-round discussion of asthma. Let's now talk about diagnosing this episodic disorder. Before we do that, we're going to take a step back and talk about episodic disorders in general. Diagnosing these conditions is really tough. And think about examples that range from common syndromes like migraines and biliary colic to rare and esoteric things like fiochromocytoma. Most patients with these syndromes don't present with active symptoms. And thus the diagnosis is plagued by the inherent decay in the precision of the history and the generally lower sensitivity of additional testing when your patient sitting in front of you is completely asymptomatic. The same is true of asthma. Most patients have completely normal PFTs when they're feeling good. This of course is helpful in ruling out other causes of respiratory complaints. But renders asthma as a working diagnosis, not a confirmed one. So anytime I see a patient with a pass medical history of COPD or asthma who presents to the hospital with shortness of breath, cough, dysmere or wease, I reflexively ask what did their PFTs show? It is helpful if they have PFTs while they're symptomatic that confirms the diagnosis. And I'll highlight this point through a high coup. A high coup consists of three lines. The first line is five syllables. The second line is seven. And the third line is five syllables. The reason I'm telling you this is because I had a YouTube what a high coup is. And I hope I'm pronouncing that correctly. But I'm there with you. All wease, not asthma. All wease is our obstruction. Centurres tweets are beautiful. We learn from group reed Dollywall and Kelly Arps in episode nine that one third of cell you lightest diagnosed in the hospital is incorrectly diagnosed. In a recent multi-centered jammer publication in 2017, one third of patients with physician diagnosed asthma had their asthma diagnosis ruled out on re-evaluation. So in that study, the patients most likely to have a diagnosis of asthma excluded included patients who weren't using their daily asthma medications and patients who didn't have a PFT at the time of diagnosis. So when what are mimics of asthma? What do we mistake for the diagnosis of asthma? The most common includes upper airway cough syndrome, which includes allergic and non-allergic rhinitis or sinusitis and girt. Other diagnoses include chronic cough due to an ACE inhibitor, a post viral cough, bronchi ectasis, interstitial lung disease, eschemic heart disease, and paradoxical vocal cord motion. We'll have the complete list on the show notes for you. Alright, let's get his exam. So he was a febrile, had a heart rate of 80, a blood pressure of 150 over 70, breathing 98% on room air, and breathing comfortably at 14 breaths per minute. He was comfortable in a no acute distress. His lung exam was notable for diffuse expatory weasers. His belly was soft and non-tender. His neurology exam was normal and his skin was without any rash or a dima. His CBC came back with a white blood cell count of 20,000, 15,000 of which were neutrophils, and 1200 of which were eocenophils. His hemoglobin was 11 with a normal MCV and his platelets were 300. Alright, let's update our problem representation here. So we have a seven-year-old man with a past medical history of nasal polyps, adult onset asthma, with multiple recent exacerbation, who presents with subacute decrease in exercise tolerance, low grade fevers, who was found to have diffuse weasening, leukocytosis, and esenophilia. Alright, let's talk about esenophilia. So we define it by absolute esenophila count, which is just a number of esenophiles in peripheral blood. And when it's greater than 500 eos per microliter, that's considered abnormal. There are three buckets that we usually think of for elevated eos. Mild, which is 500 to 1500, moderate 1500 to 5000 and severe, which is greater than 5,000 eos in microliter of blood. Although breaking down the degree of esenophilia can be helpful to narrow the differential diagnosis, it's not enough to establish the diagnosis. At the end of the day, all it tells you is that your patient has elevated eos, but not why. It's important to remember that the degree of the peripheral blood eos does not always accurately predict the risk of organ damage, because eos are primarily tissue-dueling cells. Although complications are more common with higher levels, like greater than 1500, some patients with mild eos can have organ involvement. The three organs that are most often involved include skin, lung, and GI tract. It may be a complete coincidence, but I'd like to remember them as the organs that are most exposed to the outside world. Hard and nervous system can also be involved, and that can be more concerning and life-threatening. As we mentioned, any T-Share. you can be infiltrated by the EOS as there are t-shirt dollars after all. Alright folks, it's that time in the case. You know this. It's time when you get to lie in a river full of red blood cells. Except there's one change this time that rivers full of EOS. Learners, what is your approach to eosinophilia? Okay, so the approach to eosinophilia is similar to the approach to any cell line abnormality which is increased. You're asking the question, is this primary due to a clonal expansion or is it secondary due to a stimulus? So the primary causes include eosinophilic leukemia which comes in two flavors, acute and chronic and primary hyper-eosinophilic syndrome. The reactive causes I think of in five categories but think of the top three categories we often consider on our show. This includes cancers, infections, autoimmune diseases. And the autoimmune reminds me that the other two categories start with A which includes allergic disorders and adrenal insufficiency. I'll name a few common examples in each category but we'll have a much more extensive list on our schema which will be located on the website. So for malignancy that resultant eosinophilia, this includes hematologic cancers like CML and systemic mastocytosis or any B or T cell lymphoma. Solid tumors include adenocarcinoma of the gastrointestinal tract. The one infection to consider our parasitic helmets that may be endemic worldwide. For example, Strangeloidiocese. And this is an important one because if you treat someone with eosinophilia with steroids and they have Strangeloidiocese, this can result in disseminated hyper-infection and that's why we send this serology while we're evaluating someone with eosinophilia. The other infection I want to highlight are fungi including disseminated coxidiumicosis, histoplasmosis and cryptococosis. The autoimmune disease worth noting is eosinophiliate granulomatosis, poly and gytis. As far as allergic disorders, they can be organ specific like atopic dermatitis or a drug reaction like dress. And the one I include at the bottom, the fifth category is adrenal insufficiency, which results in a mild in eosinophilia and usually in a sick patient. Remember the eosinophils are extremely sensitive to steroids. So in someone who's adrenalin insufficient and doesn't have endogenous corticosteroids, they may have a mild the eosinophilia. And this might be your clue to a patient who's hypotensive with eosinophilia in the ICU. So just to summarize, five categories, the three main ones, cancers, infection, autoimmune and the autoimmune reminds you to say allergic disorders and adrenalin sufficient. All right, let's get some more data. So his creatinine returned at 1.2 and his baseline is 0.7. His LFTs were normal. His ESR was elevated at 62. His urinalysis showed four white blood cells, one plus protein, one plus blood and 13 red blood cells. These red blood cells were non-dismorphic, but there were several RBC casts. His urine protein to creatinine ratio was 1.2. An AM-corazole returned to 24. Estrangea-Loydese antibody was negative, and a stool ONP was negative. On review of his imaging last few months, he has had several x-rays and CTs showing multifocal waxing and waning peripheral infiltrates. So to summarize, this is a 70-year-old genomin with adult onset asthma, presenting with subacute decreased exercise tolerance and low-grade fievers found to have elevated inflammatory markers, moderate asinophilia, migratory peripheral pulmonary infiltrates in AKI with hemissuria and protein urea. AKI, I can't wait to have a full episode on AKI, but here's the summary. You know that I love to localize a lesion, and a large fraction of kidney injury does not localize the kidney itself, but rather to the plumbing of this incredible organ. And there are really two plumbing systems. The first, the vascular system responsible for getting blood to and from the kidney. The problems here are too little volume like hypovolemia, too much volume like congestive heart failure, and some cool things like shunting as occurs in a paterino syndrome. The other plumbing is of course the collecting system that drains the urine, and the main problem here is obstruction. Most causes of plumbing issues will leave you with a relatively normal ua. This of course is an this all is an oversimplification of the AKI schema, which I can't wait to talk about. But back to our patient. The abnormal ua makes a problem with the plumbing less likely. Specifically here, the hematuria, protonuria, and rbccast are suggestive of glomerion of fredus. Hey Robbie, before we continue let's update that problem representation. So here we have a 70 year old man with a history of nasal polyps, adult onset asthma who presented with subacute decrease in exercise tolerance and low grade fevers, and was found to have moderate eosinophilia, migratory peripheral pulmonary infiltrates, and glomerulin of fredus. So at this juncture of the case, I would have two vendigraps, one for eosinophilia, and one for glomerular nephritis. And then I would try to identify what diagnosis links these two problems together. Remember we've talked about the return of investment for your mental effort, and these two will reveal a diagnosis. Just to talk a little bit about glomerular nephritis, we will for sure have an episode where we'll dive into Robbie's river of Gahand and discuss it very elaborately. But just very briefly, the clutiglomerular nephritis is nephritic range progenuria, hematuria, and the clinical manifestation might include AKI hypertension and edema. I like to categorize it based on three mechanisms of disease, which includes immunocomplex mediated like lupus, anti-GBN, or ANCA associated. So we'll talk more about the ANCA associated category as this case unfolds. The lab's return with a negative an A, a C3 and a C4 that are normal, and an ANCA that is positive for MPO in a perinuclear pattern. These findings prompt a renal biopsy, which showed chrysentic, necrotizing, and posse immune glomerular nephritis. Hey, I'm John Stockton with the Assist here. Sharmeen, let's tackle ANCA associated vasculinity. Only for you, RC. Let's take a step back. A small vessel vasculatus is usually divided into two categories. Immune complex mediated and posse immune. The most common cause of posse immune is ANCA associated with vasculitis. So what's ANCA associated with vasculitis? It's a necrotizing vasculitis affecting most often the small blood vessels like arterioles, capuaries, and demanules that can lead to multi-organ disease. Lung, kidney, and skin are the organs that are most commonly affected. Patients often have systemic signs of inflammation like fever and evidence of end-organ damage to skin. Papua, purpra, and glomerular nephritis is common. Remember that some drugs like chrysendic can cause drug-induced ANCA associated with vasculitis, but this is pretty rare. So the three ANCA associated with vasculitis that we want you guys to think about, and these are rare diagnoses, are GPA, MPA, and EGPA. So a granulomitus with polyangitis, GPA, is best known for granulomitus inflammation of upper and lower respiratory tracks, like the destructive sinusitis that it can happen with this disease. It's associated with C-AnCA, and capuary lung regions is pretty unique to GPA. Microscopic polyangitis, MPA, is associated with P-AnCA. Branketosis, and ILD, is unique to MPA, and diffuse alveolar hemorrhage that can be life-threatening is more common in MPA. However, MPA and GPA show many clinical features. Often, what distinguishes MPA from GPA is lack of granulomitus inflammation on path. Okay, I see. I'm getting tired of my own voice. Do you want to suck with an GPA? Sure, but I'm never tired of your voice, Charmeen. So, E-Synophilic granulomitosis with polyangitis, or EGPA, shares a lot of the symptoms of the other ANCA associated vasculities that Charmeen went over, such as B symptoms. But less commonly involves the kidney. The distinctive features of EGPA include adult onset asthma, allergic rhinocyanusitis, edicinephilia, and a higher frequency of vasculitis involving the GI tract, nerves, and heart. And the ANCA is positive in about 30 to 60 percent of patients, but it's not needed for the diagnosis. diagnosis. So owing to the constellation of refractory asthma, ESinophilia, a positive NPO in glomerion of fritis, he was diagnosed with ESinophilic granulomatosis with polyngiatus. He was treated with cyclophosphamide and prednisone and was discharged with plans for a close follow-up. Alright, so let's look back at our clinical journey. We had a patient who presented with exercise intolerance and low-grade fevers. His background was significant for nasal polyps and adult onset asthma. On further work up, we discovered moderate ESinophilia, transient peripheral lung infiltrates and glomerular linofritis, which landed us on the diagnosis of EGPA. I just want to make the point that when you have ESinophilia, make sure to look at the absolute ESinophilic count and try to categorize as mild, moderate, and severe and build a differential based on that. Yeah, absolutely. Categorizing the amount might be helpful, but just remember to always look for evidence of an organ damage because it often doesn't correlate to the level of ESinophilia. Remember, they're tissue-dwelling cells. Alrighty folks, make sure to check out our schemas on our website, clinicalproblems solving.com. There you can subscribe to our weekly email, summarizing the schemas and other awesome pearls. Email us at the clinicalproblems [email protected] and check us out on Twitter @CPSolvers and our YouTube channel, the clinicalproblems solvers. We can't wait to hear from you guys. And I can't wait for this week's teaser. Oh, well, this week's teaser is really tricky. And I think that as we talked about, ESinophilia is incredibly daunting and there are so many causes. And unfortunately, with this teaser, we're going to have you dive down to the absolute bottom of that ESinophilic river. And the question for today is, can you name not one, but two causes of ESinophilia and angiodema? Why angiodema? I have no idea. But two causes of ESinophilia and angiodema. Hint, one of them may be a perfect description of the show.