Time Stamps

  • 02:34 Pearl 1: Why Do We Care About Eosinophilia?
  • 10:24 Pearl 2: Eosinophilia and Atopy
  • 18:57 Pearl 3: Eosinophilia and Drugs
  • 27:29 Pearl 4: Eosinophilia and ID 
  • 33:54 Pearl 5: Eosinophilia, Steroids, and Neoplasms

Show Notes

PEARL 1: Eosinophilia Thresholds and Why We Care

  • Two main reasons we care about eosinophilia:
    • Direct end-organ damage: 
      • Too many circulating eosinophils → can directly cause tissue injury regardless of underlying cause
    • Diagnostic clue: 
      • Elevated eosinophil count! 
        • Can be a sign  of a serious underlying process that needs attention (parasites, malignancy, EGPA)
  • Definitions:
    • Eosinophilia = absolute eosinophil count (AEC) > 500 cells/μL 
      • (or 0.5 × 10⁹/L in many electronic medical record systems, EMRs)
    • Hypereosinophilia = AEC > 1,500 cells/μL on repeat measurements
      • (or 1.5 × 10⁹/L in EMR) 
    • Hypereosinophilic syndrome (HES): Hypereosinophilia PLUS end-organ damage
      • (AEC > 1,500) 
    • NOTE:  we use absolute eosinophil count
      • NOT the percentage of eosinophils 
      • pay attention to the units! (most guidelines utilize cells/μL)
  • Almost every organ system can be affected by HES. 
    • Be vigilant and monitor for end-organ complications when AEC > 1,500 cells/μL*. 
      • Cardiac involvement 
        • Highest cause of morbidity and mortality in HES. 
          • Obtain troponins, EKG, and ECHO to evaluate for eosinophilic myocarditis and its sequelae regardless of symptoms, 
            • Watch Out! t can be clinically silent. 
      • Other organ involvement:
        • GI
          • Check LFTs
        • Renal
          • Check BMP
        • Skin
        • Neurologic 
  • *CRITICAL CAVEAT: Peripheral eosinophilia ≠ tissue eosinophilia
    • There is NO perfect correlation between magnitude of peripheral eosinophilia and risk of end-organ damage!
      • Eosinophils are tissue-dwelling cells. 
    • You can have tissue eosinophilia (e.g., eosinophilic esophagitis) WITHOUT peripheral eosinophilia, 
      • AND you can have peripheral eosinophilia without tissue damage!

PEARL 2: Diagnostic Framework & Eosinophilia and Atopy

  • CAMP-E(osinophilia) = Mnemonic for Etiology of Eosinophilia
    • C: Cancer
    • A: Atopy AND Adrenal insufficiency
    • M: Medications
    • P: Pathogens (including parasites)
    • E: EGPA (Eosinophilic Granulomatosis with Polyangiitis, formerly Churg-Strauss)
  • What if your patient has mild eosinophilia?
    • consider whether they have an atopic condition that is known to be associated with eosinophilia!
  • The mechanism: 
    • epithelial damage in atopic diseases → inflammation and recruitment of eosinophils → Type 2 helper T cells → IL-5 production → continued eosinophil maturation and survival
  • Eosinophil count ≠ atopic disease activity and is not a marker of disease severity. 
    • You can still have elevated eosinophils with well-controlled asthma
  • PEARL: Adult-onset asthma with eosinophilia can be the first sign of a more systemic process like EGPA vasculitis
    • Be suspicion for EGPA if:
      • adult-onset asthma and eosinophilia PLUS any of the following:
        • chronic sinusitis and nasal polyps 
        • pulmonary opacities on imaging 
        • mononeuritis multiplex
        • glomerulonephritis
    • EULAR criteria and the help of your rheumatology colleagues to make the diagnosis!

PEARL 3: Medications and Drug-Induced Eosinophilia

  • Drug-related eosinophilia 
    • extremely common in both outpatients and inpatients!
    • To make the diagnosis, you need to conduct a thorough medication history
      •  prescriptions 
      • over-the-counter medications 
      • supplements. 
  • Any medication can cause eosinophilia! 
    • MOST most common culprits are: 
      • antibiotics (vancomycin, penicillins, linezolid) 
      • anticonvulsants 
      • NSAIDs 
      • allopurinol
  • Drug-induced eosinophilia is NOT an IgE mediated reaction, 
    • SO time from drug initiation to onset can vary based on drug and past exposure. 
      • Always ask what new medications were started in the last month.
    • Time from drug initiation to isolated peripheral eosinophilia = typically 1 to 21 days
    • Time from drug initiation to DRESS syndrome = typically 2-6 weeks 
  • Medication management:
    • CONTINUE the medication if: 
      • eosinophilia is relatively mild with NO signs of end-organ damage 
      • patient is asymptomatic
      • medication is medically necessary (e.g., treating endocarditis, osteomyelitis)
    • STOP the medication IMMEDIATELY if:
      • signs of DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) such as: 
        • fevers 
        • morbilliform rash 
        • facial edema 
        • lymphadenopathy 
        • hepatitis 
        • AKI
  • Continue monitoring patients with drug-related eosinophilia to assess for development of DRESS with troponins, LFTs, BMP, urinalysis (eval for interstitial nephritis), and skin exam

PEARL 4: Infections and Parasites

  • Infectious causes of eosinophilia
    • Parasitic infections (especially helminths/worms) = MOST common
    • HIV 
    • Fungi 
    • Allergic bronchopulmonary aspergillosis (ABPA) 
      • Hypersensitivity immune response to aspergillus (environmental mold) is associated with eosinophilia
  • Take a proper travel and exposure history is critical to evaluate for pathogens: 
    • Immigration history
      • Parasites can persist for decades after exposure
        • Example: Strongyloides (the parasite that causes Strongyloidiasis can complete its whole life cycle in human host)
          • Immunocompetent = low-grade eosinophilia
          • Immunosuppressed = life-threatening hyperinfection
        • Test for strongyloides = serology (NOT ova & parasite)
    • Travel history (including layovers, brief visits, and activities)
    • Dietary history (undercooked foods, wild meats and seafood)
  • All patients should be evaluated with HIV testing and stool ova & parasites (collect from multiple days for better sensitivity)
    • Further testing should be guided by patient symptoms and geographic considerations unveiled by your travel travel history. 
      • See linked CDC website for further guidance 
      • Involve your infectious disease colleagues for decisions regarding best diagnostic testing. 
    • Example: Patient with eosinophilia recently returned from West Africa, you should consider sending testing for Loa Loa! 

PEARL 5: Eosinophilia, Steroids, and Malignancy

  • Higher the cortisol = Lower the eosinophils (inverse relationship!) 
    • absolute eosinophil count (AEC) is lowest in the morning, (when cortisol is the highest), and fluctuates throughout the day based on endogenous cortisol production
  • In critical illness, such as sepsis, eosinophils should be LOW, given the body’s stress response and increase in endogenous steroids
    • Pearl: in critical illness, a normal or elevated AEC is ABNORMAL and warrants workup for hypereosinophilia! 
  • Adrenal insufficiency is an etiology of eosinophilia 
    • loss of cortisol = removes suppressive effect on eosinophils!
  • Cancer and eosinophilia
    • Suspect cancer as a possible etiology of eosinophilia if: 
      • AEC is severe (AEC > 5,000 cells/μL, or 5.0 × 10⁹/L in EMR) 
      • eosinophilia is refractory to steroids. 
        • In these cases, involve your hematology and allergy & immunology.
    • Cancers causing eosinophilia can be divided into: 
      • solid tumors (typically adenocarcinomas) 
      • lymphoid malignancies
      • myeloid neoplasms (which often have additional CBC abnormalities)
      • Chronic eosinophilic leukemia, a type of myeloid HES, is an etiology of eosinophilia that does NOT respond to steroids. 
        • It is associated with a FIPL1: PDGFRA mutation 
    • Workup for suspected neoplasm: 
        • Flow cytometry (peripheral blood) 
        • FISH testing for PDGFRA 
        • Next-generation sequencing for myeloid mutations (JAK2, etc.) 
        • B12 level (elevated in myeloproliferative disorders) 
        • Tryptase (systemic mastocytosis) 
        • CT chest/abdomen/pelvis (lymphadenopathy, masses)
      • Bone marrow biopsy is NOT essential for initial workup
  • Why DON’T we always empirically treat hypereosinophilia with steroids? 
    • Infection risk: 
      • Giving steroids to undiagnosed Strongyloides → hyperinfection syndrome → severe illness/death
    • Diagnostic interference: 
      • Steroids can affect ability to diagnose malignancies (especially lymphoma) and can cause temporary improvement that masks underlying malignancy
  • When do you give urgent and empiric steroids?
    • Patients who are sick and have end-organ damage as a result of eosinophilia (such as eosinophilic myocarditis) 
      • This is typically a multidisciplinary decision. 
    • Before giving steroids obtain:
      • CT chest 
      • flow cytometry 
      • FISH for PDGFRA translocation 
      • next-generation sequencing for myeloproliferative disorders 
      • tryptase
      • B12 
    • Do NOT wait for the results of these tests before giving steroids
    • Evaluate epidemiologic risk for parasites based on travel/ exposure history.
      •  If at risk for strongyloides, treat empirically with ivermectin

Transcript

Dr. Peter Weller: I think one has to be vigilant that on occasion, this curious cell can indeed contribute to and cause tissue damage. And it’s up to us to be cognizant of that risk, and then ameliorate it in an intelligent and rational manner if we can.

Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. I’m Dr. Shreya Trivedi, and I’m joined by

Dr. Hila Ghersin: Hi, I’m Hila Ghersin, an internal medicine resident at Beth Israel Deaconess Medical Center. Today’s episode is all about peripheral eosinophilia.

Dr. Shreya Trivedi: Yes. And to help us sort through this, we spoke to experts in the world of allergy and immunology, hematology, and pulmonology. And to dig into this topic in a way that I’m biased, but I feel like is way more approachable than what I knew before.

Dr. Hila Ghersin: Agreed. 

Dr. Peter Weller: Hi, I’m Dr. Peter Weller, Chief of the Allergy Division at the former chief of the ID division at the BI Deaconess. And I’ve had a longstanding interest in eosinophilia.

Dr. Jason Freed: Hi, I’m Jason Freed. I’m a hematologist at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

Dr. Praveen Akuthota: I’m  Praveen Akuthota from Pulmonary and Critical Care at University of California, San Diego. I’m a professor of medicine there. I have a practice that focuses us on eosinophilic diseases.

Dr. Shreya Trivedi: And as always, please pause after each of the following pearls and test yourself.

Dr. Hila Ghersin: Because the more you test yourself, the deeper your learning gains.

Dr. Shreya Trivedi: Pearl one, thresholds, and why we care. Why do we care about eosinophilia, and when does the eosinophilia become dangerous?

Dr. Hila Ghersin: Pearl two, eosinophilia and atopy. When can asthma, allergic rhinitis, or eczema explain eosinophilia? And when should you worry something more systemic is going on?

Dr. Shreya Trivedi: Pearl three, medications. Which medications most likely cause eosinophilia, and when is it safe to monitor versus when you need to stop?

Dr. Hila Ghersin: Pearl four, infections and parasites. How do travel, immigration history, and diet guide your infectious workup?

Dr. Shreya Trivedi: And finally, Pearl five, steroids, and malignancy. How do steroids affect that eosinophil count? And why do we need to think about neoplastic causes of eosinophilia before we treat? 

Pearl 1: Why Do We Care About Eosinophilia? 

Dr. Shreya Trivedi: Okay. Let’s start big picture here, Hila, and maybe the elephant in the room. Why should we even care about eosinophils to begin with?

Dr. Hila Ghersin: Shreya, I had the exact same question, and that was a big motivation behind why I wanted to learn more about this. So we care about eosinophilia for two main reasons. First, if the eosinophils get high enough, they can cause direct organ damage, regardless of why they’re so high. The second reason is that an elevated eosinophil count can be that first clue that something more serious is going on in the body.

Dr. Shreya Trivedi: Amazing. Okay. So before we get into the clues about what that eosinophilia might be telling us, let’s make sure we’re all in the same shared language. What is eosinophilia? And then when should we pause? And  particularly, , can you help me understand the numbers in the EMR? There’s percentages, there’s absolute values, there’s decimal places.

Dr. Hila Ghersin: Definitely. Eosinophilia is an absolute eosinophil count greater than 500 eosinophils per microliter. Unfortunately, in most electronic medical record systems, this will not show up as 500, but rather 0.5. So, since the units are different, you’ll need to multiply by a thousand anything you see in the EMR to get the eosinophils per microliter.

Dr. Shreya Trivedi: I’m so glad you said that because I also even get confused. Do I look at the percentage or do I look at the absolute one? And it’s so sensitive. I’m looking at the absolute EO count, and we kind of ignore the percentage and then yeah, I guess we just have to translate decimal points.

Dr. Hila Ghersin: Right. So for absolute eosinophil count greater than 500 or greater than 0.5 in our electronic medical record system, we’re starting to put on our detective hats. But when we’re reaching an absolute eosinophil count greater than 1,500 or 1.5, we get into hypereosinophilia territory, and that’s when we need to get vigilant and do more than just put on our detective hats.

Dr. Jason Freed: Hypereosinophilia just means their absolute eosinophil count is above 1,500. We just arbitrarily decide if it’s above that, it’s hyper. Okay, fine. But what’s hypereosinophilic syndrome? Hypereosinophilic syndrome means you have an absolute eosinophil count above 1,500, and you have some end-organ manifestation that is being caused by the elevated eosinophils. It’s pretty rare to have sort of end-organ manifestations with an absolute eosinophil count less than 1500. Between 1,500 and 5,000, it gets tricky because you can definitely have some life-threatening manifestations in that category. And then when you get above 5,000, and then especially the higher you get, the more likely that you are to develop some serious end-organ manifestations from the non-specific effects of having super high eosinophil count.

Dr. Shreya Trivedi: Okay. So sounds like if the eosinophil count is high enough, particularly above 1,500 per microliter or 1.5 in the EMR, then we worry about that directly causing some end-organ damage regardless of the cause.

Dr. Hila Ghersin: Exactly. Hypereosinophilia is just the number, just the absolute eosinophil count greater than 1,500 or 1.5. Now, hypereosinophilic syndrome, that’s a clinical diagnosis. That’s hypereosinophilia plus end-organ damage, which is more likely to occur when the eosinophil count is above 1.5.

Dr. Shreya Trivedi: Okay. So it sounds like when there’s too many eosinophils, these crowded eosinophils degranulate in the blood and in the tissue, and that can lead to end-organ damage. And unfortunately, that end-organ damage can be in any organ, the heart, the skin, the lungs, the GI system.

Dr. Hila Ghersin: Yeah. I once had a patient who presented with right-sided weakness and was found to have embolic strokes. Her eosinophil count was 17,000 or 17.0 on Epic, and her troponins kept rising. She never had any chest pain, shortness of breath, but as part of her workup, we got a cardiac MRI. That showed signs of fibrosis, which was really concerning for eosinophilic myocarditis. Because of all the inflammation in her left ventricle, she developed a thrombus that then embolized to her brain and led to these stroke symptoms.

Dr. Shreya Trivedi: Oh my. You know what I’m so struck by is that patient had no symptoms, right? That eosinophilic myocarditis was clinically silent. Gosh, there was no symptoms related to that cardiac dysfunction.

Dr. Hila Ghersin: Exactly. And my takeaway from that is when patients have an eosinophil level above 1500 or 1.5, we need to be vigilant in evaluating for eosinophilic myocarditis, regardless of the symptoms. We should get troponins and EKGs. And I even spoke to some cardiologists who recommend getting an echo upfront too to evaluate for that thrombus formation.

Dr. Shreya Trivedi: So helpful. So trop, EKG +/- echo when the eosinophil count is greater than 1,500 per microliter or 1.5. Okay. What about the other organs? Do we do anything else to screen for other end-organ damage in the body when the EO count is that high?

Dr. Hila Ghersin: We should definitely get a basic metabolic panel and liver function tests to evaluate for any renal or liver involvement, but the rest of the body, it’s really having that vigilance, like you need to do a thorough review of systems to identify any new pulmonary or GI symptoms, do a physical exam to look for any rashes or any neurosigns.

Dr. Shreya Trivedi: Okay. So that’s helpful in the context of anyone who has an EO count greater than 1,500 or so. But I guess the other question is, does it matter how high the eosinophil count is above that 1,500 threshold? Is someone with an eosinophil count greater than 3,000 more likely to have end-organ damage in someone than 1,500 eosphils per microliter?

Dr. Hila Ghersin: Shreya, only was that straightforward. Though there is a higher risk with more elevated eosinophilia, there’s not a one-to-one relationship. This number, caught off of 1,500 gives us an idea of a patient’s risk of end-organ damage, but peripheral eosinophil counts, which is what we measure on a CBC, does not correlate with the damage that eosinophils can cause in the body.

Dr. Peter Weller: There’s no perfect correlation between magnitude of blood eosinophilia and risk of cardiac damage or other eosinophil-mediated grief. With the imprecision of measuring eosinophil numbers and the fact that what we can sample is the circulating blood pool of eosinophils. We don’t know what’s going on in the marrow. We don’t know what’s going on in tissues.

Dr. Hila Ghersin: Understanding the life cycles of eosinophils is really helpful to explain this. EOs spend only about 25 hours of their lifespan in peripheral circulation, but then spend days or even up to weeks in the tissues. They call it eosinophils tissue-dwelling cells for a reason. So you can imagine the sample that you’re getting in your AM labs is only a snapshot in time and misses the full distribution of eosinophils in the body.

Dr. Shreya Trivedi: Yeah. Man, that idea that the EO count that we see in our EMR is just a snapshot and that these eosinophils are mostly, as you said, tissue-dwelling. They’re mostly in the tissues and not in the blood. I guess that makes sense, why in conditions like eosinophilic esophagitis, they’re basically eosinophils that are just in the tissue in the esophagus, but there’s no peripheral eosinophilia.

Dr. Hila Ghersin: And at the same time, there can be peripheral eosinophilia without tissue damage. This adds another layer of complexity to the already complicated topic of eosinophilia.

Dr. Shreya Trivedi: Oh, man. Awesome. I’m with you. I’m getting this. Thank you so much, Hila, for doing this. So maybe if I can summarize our first chunk or first pearl, it’s that we care about eosinophilia, particularly that’s defined by greater than 500 eosinophils for a microliter or 0.5 in the EMR. We care about for two reasons. One, if the eosinophils get high enough, usually above 1,500 or 1.5 in the EMR, that can directly cause end-organ damage regardless of the cause.

Dr. Hila Ghersin: And the second reason we care is that the absolute eosinophil count is a clue that something else more serious is going on. So let’s put our detective hats on for the rest of these pearls.

Pearl 2: Eosinophilia and Atopy 

Dr. Shreya Trivedi: All right. So let’s say we have a patient whose eosinophil count is 750. So in an EMR, it would show up as 0.75. To be on the safe side, we think about end-organ damage. There’s no symptoms, there’s no lab abnormalities, nothing scary. Hila, can we just ignore this 750 eosinophil count? Can we just close our eyes and hope it goes away?

Dr. Hila Ghersin: Short answer, no. As we mentioned, even without end-organ damage, eosinophilia can still be a signal that something else is going on. So we still need a framework to figure out why the eosinophils are so high.

Dr. Jason Freed: There is a very popular mnemonic for the causes of eosinophilia that I have actually found very helpful in my practice, and that is NAACP. 

Dr. Hila Ghersin: Okay. So, NAACP is a helpful mnemonic, but it misses an important etiology of eosinophilia and also includes a name for EGPA we don’t use anymore. So I propose a new mnemonic, CAMP-E or camp eosinophilia.

Dr. Shreya Trivedi: Awesome. Tell me more, Hila.

Dr. Hila Ghersin: So envision five tents around a bonfire in the woods of Camp E or Camp eosinophilia. Each of these tents represents a different etiology. So C is for cancer. A is an extra-large tent with room for both Atopy and adrenal insufficiency, M is for medications, P is for pathogens, and E is EGPA. The bonfire in the middle represents the inflammation that is caused by having too many circulating eosinophils.

Dr. Shreya Trivedi: I love that. But also humbling, right? Because everything from cancer, atopy, adrenal insufficiency, meds, parasite. I mean, I appreciate a good list, keeps us from missing stuff, but lists are also just lists. And how do we prioritize one thing from another?

Dr. Hila Ghersin: I feel you on that on such a deep level. So I thought it would be a really good idea to go through the most common causes of eosinophilia and dig through some nuances within each.

Dr. Jason Freed: When I’m seeing an outpatient for peripheral blood eosinophilia, one of the first questions I’m asking myself is, do they have a disease known to be associated with peripheral blood eosinophilia? Number two, is the eosinophilia mild? And therefore, I can just probably connect it to that disease known to be associated with eosinophilia. And number three, is there anything else going on with them that needs to be explained, or is this really just an incidental abnormality that we’re trying to connect? And if it’s just an incident or abnormality, they’re doing fine otherwise, and we’ve got a diagnosis we can connect to, and it’s mild, I’m usually done there.

Dr. Shreya Trivedi: Okay. So if we’re meeting a patient in clinic who has mild eosinophilia, and then the conditions I’ll be thinking about are the things that fall in that atopic bucket, right? Allergic rhinitis, asthma, atopic dermatitis. And one thing that I learned from our peer reviewer was that even eosinophilic GI diseases like eosinophilic esophagitis falls under the atopy umbrella.

Dr. Praveen Akuthota: For relatively not high-grade eosinophilia, like in the kind of that 500 to 1500 reach, I’d say top things that they often are in those patients are some sort of atopic cause. Atopy is very common in the population. So that’s what common things being common.

Dr. Hila Ghersin: As I was learning more about this topic, I kept seeing this relationship between eosinophils and allergic conditions, and I kept wondering why. Turns out atopic diseases are driven by damage to the epithelium, which leads to inflammation. This inflammation leads to the migration of type two helper cells, and they produce a ton of IL-5. If you remember from boards, IL-5 is super important for eosinophil maturation and their survival.

Dr. Praveen Akuthota: So IL-5 is also produced by lymphocytes, CD4 type two lymphocytes that those cells that are kind of canonically or classically regulated in allergic conditions. And that’s why eosinophils are up in these atopic conditions in many patients with atopy is that that’s driven by some excess IL-5.

Dr. Shreya Trivedi: IL-5, wow. I have not thought about that in a minute, but makes me think if someone has a really bad allergy flare or an asthma exacerbation, maybe their IL-5 will go crazy and then their eosinophil count will be proportionally that much higher.

Dr. Hila Ghersin: That’s a good thought, but unfortunately, no.

Dr. Peter Weller: You can be well-controlled asthma and still have an eosinophilia.

Dr. Hila Ghersin: You can have eczema or atopic dermatitis or eosinophilic gastritis that is relatively well controlled and still have eosinophilia. So eosinophilia is not a marker of disease activity, and IL-5 is not a helpful lab to send.

Dr. Shreya Trivedi: What a humbling cell in our bloodstream. I just wish it was a one-to-one with the eosinophilic count interpretation. And I guess what I’m worrying about is that say I have a patient who has a mild eosinophil count and they have something in their chart like asthma, allergies, atopic dermatitis, then my worries that I’m just going to write off that eosinophil count and not think of the other things, and that can’t be pneumonic. I don’t want to miss parasite. I don’t want to miss cancer.

Dr. Hila Ghersin:  I don’t either, and I live with those same anxieties, but common things are common. What you do bring up though is a really great point that we need to keep a healthy dose of curiosity because systemic conditions like EGPA or eosinophilic granulomatosis with polyangitis often start with eosinophilia and asthma.

Dr. Peter Weller: But I think one still has to keep in mind that is there something else developing? An example would be what used to be called the Churg-Strauss syndrome, EGPA. That can be a process where, for adults that manifest by adult onset asthma, sinusitis, and then the vasculitis manifests later. So it’s a situation where I think you can say, “Yeah, can asthma give you eosinophilia?” Yes. But can you close the book necessarily in that individual? Not if something else is developing that makes you worried about a vasculitic process. 

Dr. Hila Ghersin: So when there are multiple systems involved with signs of glomerulonephritis and asymmetric neurologic findings like mononeuritis multiplex, it raises the possibility of vasculitis. And if those are present, you need to consider EGPA, formerly known as Churg-Strauss disease as a potential etiology.

Dr. Peter Weller: I had called in MICU on a weekend night and it was a gentleman who ended up perforating his bowel. And in retrospect, it was a vasculitis. It was EGPA. He had been referred about a year and a half before. He probably had some abdominal pain, but he had a CT scan, and he had a hypernephroma. So he was sent to us for a surgical resection. At that time, he had eosinophilia. People said hypernephroma eosinophilia, it’s no link, let it be. But in retrospect, he had Churg-Strauss syndrome, EGPA, and what did him in ultimately was small bowel vasculitis. The eosinophilia in retrospect, was a clue to that. And probably some of his abdominal pain was his incipient GI vasculitis that then led to the CT scan, which gives you the diagnosis of hypernephroma, true, but not related.

Dr. Shreya Trivedi: Wow. That case really highlights that mantra of “staying curious”. So I guess what I’m taking away is in a patient with asthma or sinusitis and other unexplained symptoms like that vague abdominal pain in the case we just heard, or the classic polyp on exam, or maybe there’s unexplained opacities on lung imaging or abnormalities in their neuro exam or in their urine studies, we can think about EGPA. And Hila actually found this, there’s these EULAR criteria that can help us think through the diagnosis. And of course, we can always reach out to our rheumatology and allergy colleagues that can help us make this very complex diagnosis.

Dr. Hila Ghersin: And so to recap, when someone has unexplained eosinophilia without localizing symptoms, one of the first question to ask is, do they already have a condition that’s known to be associated with eosinophilia? Atopy really is one of the most common causes of eosinophilia driven by damage to the epithelium and subsequent inflammation, but eosinophil counts are not associated with disease activity.

Dr. Shreya Trivedi: I still can’t get over that. I wish it was a one-to-one. And then the other thing is that when the explanation seems benign, I think we can all stay a bit curious. Make sure we’re monitoring over time, watch out for any red flags that kind of come up. And of course, eosinophilia might be a first clue that something bigger might be developing down the line.

Pearl 3: Eosinophilia and Drugs

Dr. Hila Ghersin: So we’ve talked about atopy as a potential source of eosinophilia, but our third pearl is truly something we see all the time.

Dr. Shreya Trivedi: Medications.

Dr. Jason Freed: I think one of the most important things that you can do as a generalist is to take a very thorough medication history because medication-related eosinophilia is so extraordinarily common, both in terms of outpatients and both in terms of inpatients. And the diagnostic test for that is a really good medication history, which is not easy to do. And it’s actually like, sometimes it’s so, so easy to click, click, click, order, order, order, echo, order this, order that, order referral. But you know what’s hard? Spending 15 minutes in the chart looking at when they got each different antibiotic over the past two weeks and seeing which one might make sense timing-wise as the cause of their DRESS syndrome. But guess what? That’s actually what’s really going to solve the case, not necessarily sending off this million-dollar workup for a bunch of things that don’t make sense. Because if they acquired eosinophilia in the hospital, it is almost certainly related to a drug you gave them. And so doing a really good drug history is so essential.

Dr. Shreya Trivedi: There is nothing like a good history and chart review to figure it out, but yes, it takes time. And we do have to be thorough because that eostophilia might not happen in front of our eyes, but after discharge.

Dr. Jason Freed: The group at MGH looked at 824 consecutive patients where they were going to be getting extended courses of IV antibiotics, often about six weeks. And when they looked, 25% of their patients developed some degree of peripheral blood eosinophilia, absolute eosinophil count greater than 500. They saw eosinophilia with basically every antibiotic. Of course, vancomycin, linezolid, like penicillins. But essentially, if you think about what antibiotics are, they’re large natural products.They end in Mycin, like we got them from microorganisms. And our bodies are sort of trained to treat such things as foreign, right? These large macromolecules, like we of course want to be having an immune response to these large macromolecules. And so drug-related eosinophilia is really common with these large macromolecules like antibiotics.

Dr. Hila Ghersin: So antibiotics are a big cause of drug-related eosinophilia, but they’re not the only ones. Some commonly implicated medications besides antibiotics include NSAIDs, anticonvulsants, and allopurinol.

Dr. Peter Weller: Homeopathic preparations at times have elicited eosinophilia. The example, notable example from some years ago is batches of contaminated L-tryptophan that people took for a number of reasons for sleeping and this and that. And they developed the eosinophilia myalgia syndrome mechanism, which is still not understood. It was the L-tryptophan that they were taking. And in some of those individuals, the medication history was not volunteered because they weren’t thinking about their nocturnal  L-tryptophan dose as a medication. Doctor didn’t prescribe it, took it on their own.

Dr. Shreya Trivedi: So yes, ask about supplements, ask about over-the-counter meds or quote-unquote natural products, whatever will jog our patient’s memory on the other things that they’re taking. But I got to say, Hila, it seems like almost every medication can cause eosinophilia. And the hard part is to figure out which one. I can imagine a situation where someone’s on antibiotic, but also taking natural products.

Dr. Hila Ghersin: Very fair. And most of our patients are on more than one medication at a time. So you’re right that any number of meds can be the culprit. And on top of that, it’s sometimes tricky to pin down which one because drug-related eosinophilia isn’t an immediate allergic reaction.

Dr. Peter Weller: In most cases, the mechanism that drives eosinophilia elicited by medications is really not well understood. It’s not an IgE-type allergic reaction, probably some manifestation of cell-mediated immunity. And it can develop after someone’s been on a medication for a period of time, may not become apparent right away.

Dr. Hila Ghersin: So, because of this cell immunity, the time from when you start a medication to when you develop peripheral eosinophilia can really vary by what medication it is and whether a patient has seen that medication before.

Dr. Shreya Trivedi: That variation is so annoying to me because I wish, again, it was like a clean timeline, drug exposure, and then one week later, eosinophilia.

Dr. Hila Ghersin: We have some rough guidelines from one of the studies that showed that the median time from medications start to isolated peripheral eosinophilia is anywhere from one to 21 days, but even that’s quite a big range.

Dr. Shreya Trivedi: Right? So I guess maybe the practical kind of takeaway is to ask our patients, “Hey, what medications have you changed in the past month or so?”

Dr. Peter Weller: If something was started recently and we know they didn’t have an eosinophilia a year ago, but now they have one, it begins to point the finger potentially the newly started medication.

Dr. Shreya Trivedi: Okay. So let’s say the timing of a new medication starting and that trend of the absolute eosinophil count going up kind of works out and we have a good sense of, okay, it was this medication doing it. Does that then mean automatically we have to stop it?

Dr. Hila Ghersin: Not necessarily.

Dr. Jason Freed: If they just have isolated peripheral blood eosinophilia that is relatively mild, those patients can usually just be followed. And if that’s really the best antibiotic for them, we’ll often just continue the antibiotic because that’s the safest course of action is to actually treat their infection, not which worry about an asymptomatic lab abnormality.

Dr. Peter Weller: As long as it’s not eosinophil-mediated damage to tissues, I can continue to monitor that patient and follow them, balance the need for the medication versus the easy choice who’s terminating it. At times, hopefully patients were started on a medication for a reason, so that again comes up in patients who say on long-term antistaphycocal agents, semisynthetic penicillins, they not infrequently will develop a low-grade eosinophilia. They need it for what is potentially a life-threatening endocarditis or whatever osteomyelitis, and one would like to continue to ride with that. One can, as long as one’s not missing something that is a reflection of eosinophil-mediated tissue damage.

Dr. Shreya Trivedi: Okay. So isolated, asymptomatic eosinophilia, we can often monitor,

Dr. Hila Ghersin: But that isolated qualifier really matters because what we’re always watching for is DRESS, which stands for Drug Reaction with Eosinophilia and Systemic Symptoms.

Dr. Shreya Trivedi: And those systemic symptoms, the SS and DRESS is not subtle. Our patients are going to be having fevers, morbiliform rash, facial edema, lymphadenopathy, hepatitis, AKI, a whole storm.

Dr. Hila Ghersin: Right. But it’s just important to note because DRESS is treated very differently than isolated eosinophilia. In DRESS, the offending agent has to be stopped immediately and patients often require further immunosuppression with steroids or other medications.

Dr. Shreya Trivedi: Yeah. I think this is why we have to closely monitor for end-organ damage. And I think for space repetition, we’re going to be looking for troponins. We’re going to get an EKG to see if there’s any low voltage or any new arrhythmias. We’re going to get LFTs. We’re going to look at the kidney function and of course do a careful skin exam.

Dr. Hila Ghersin: And if you’re suspecting a drug-related eosinophilia, I’m going to add that list a urinalysis. We’re going to be looking for sterile pyuria or white cell cast that would be concerning for interstitial nephritis.

Dr. Shreya Trivedi: Yeah, thanks for adding that.

Dr. Hila Ghersin: And so now that we’re going through it, I’m really starting to understand why our patients on long-term antibiotics aren’t ”safety labs”. It’s one of the reasons at least is to monitor for this development of DRESS syndrome from peripheral eosinophilia. DRESS, we should just keep in mind, develops around two to six weeks after medication initiation.

Dr. Shreya Trivedi: Okay. So maybe to summarize the takeaways when it comes to medications causing eosinophilia, I think we know our usual culprits that can do it, antibiotics, anti-seizure meds, allopurinol, NSAIDs, those are the typical ones, and then it can happen days to weeks from starting.

Dr. Hila Ghersin: And it’s important to remember that mild isolated eosinophilia doesn’t always require stopping the drug, but you really have to be vigilant and monitor for end-organ damage or DRESS.

Pearl 4: Eosinophilia and ID

Dr. Shreya Trivedi: Okay. So now onto my favorite pearl, and I think the most practice changing one for me. We did atypic, we did medications now onto the P of the Camp E pneumonic, P for pathogens, and here we’re really talking about infectious causes.

Dr. Hila Ghersin: I’ll be honest Shreya, before this episode, I thought I was doing such a good job with travel history. I’d ask any recent travel, get a no, and move on.

Dr. Shreya Trivedi: Oh, same. But Dr. Weller taught us that that is not enough.

Dr. Peter Weller: In terms of travel history is, we often will ask where people have been recently. We also have to remember that we should ask about the immigration history because there are people that have come from areas where some of the, especially the GI parasites, may be endemic, who have not gone back to their home. They haven’t been in Costa Rica for 10 years or Puerto Rico for 10 years. So travel history is negative. No, they have to include immigration history because especially Strongyloides, which can be a chronic infection that uniquely auto-infects. So it can perpetuate its life cycle at times subclinically or palsy clinically, and that is germane, and occasionally someone will develop disseminated Strongyloidiasis when they’re immunosuppressed, and that distant immigration history has been overlooked, and the nominal travel history last couple years, no, I haven’t gone back to my native country, so history is important.

Dr. Shreya Trivedi: Okay. So a good travel history isn’t just about, okay, did you having traveled recently, especially because of a parasitic worm, Strongyloides that can perpetually autoinfect.

Dr. Hila Ghersin: Yes, strongoids is special in that it can complete its whole lifecycle in the human host. That’s why the infection can persist for decades after the exposure, and it can cause this low-grade eosinophilia in immunocompetent patients.

Dr. Shreya Trivedi: Yeah. And then if a patient does become immunosuppressed, then the Strongyloides can turn into a very life-threatening hyperinfection.

Dr. Hila Ghersin: So we need to ask about where they were born, where they lived, and every stop along the way.

Dr. Peter Weller: And also in terms of travel, where in the world have they been? One patient I got called on in marked eosinophilia, who’s a PhD student who had been working in Madagascar, which curious, but marked eosinophilia and try to think about the parasites that caused marked eosinophilia in Madagascar, nothing jumps right out, but it turned out he has spent time in West Africa where some of the filareal parasites are present and indeed he had what is loa loa

Dr. Hila Ghersin: And then there’s another part of the history we often forget, diet.

Dr. Peter Weller: A corollary of a travel history is a dietary history. If they’ve been traveling or even if they haven’t been traveling, anything that they might have consumed. Trachinosis would be an example of a parasite that causes marked eosinophilia. And if they had consumed say wild bear meat in Canada, in Maine, or still in central Europe, they can develop trichinosis.

Dr. Shreya Trivedi: That is a great point. We need to ask our patients, have they eaten any undercooked foods like seafoods, wild meats, or anything else? This is not something our patients are going to volunteer unless we directly ask them.

Dr. Hila Ghersin: So parasitic infections, especially helminths or worms, account for most infectious causes of eosinophilia. But it’s really important to keep in mind that viruses like HIV and fungi can also cause eosinophilia.

Dr. Peter Weller: Our patient that I was called about started on an antibiotic for pneumonia, had an eosinophilia. So the question to me, does antibiotic X cause eosinophilia? So I started reading up. I didn’t think so, but it couldn’t find case reports. But it turned out what was not given to me was the patient’s travel history. He’s a middle-aged male, a resident town north of Boston. And lo and behold, he had recently come back from Arizona, where he was helping tidy up around his father’s house. And he ended up coming to a bronchoscopy, and his diagnosis was not a parasite, but coccidiotomycosis.

Dr. Hila Ghersin: That last story really highlights how easily it can be for us to anchor on medications. Yes, it could be the antibiotics, but my takeaway is that even if there is a common cause of eosinophilia, I should still do my due diligence and get a more complete travel history.

Dr. Shreya Trivedi: Exactly. So, thinking about the workup then of the infectious causes, it’s going to be HIV testing for everyone. Stool testing for ova and parasites, and then the rest of the workup is really guided by the history and specific travel destination. So, for example, if a patient travels to West Africa and has eosinophilia, then we should be getting specific testing for a loa loa.

Dr. Hila Ghersin: Yes. And about the ova and parasites, the more days we have stool samples from, the better the sensitivity is for picking up helminths. But it’s really important to know that ova and parasite is not the test of choice for Strongyloides. That’s because Strongyloides has low and irregular larva output in the stool. So that’s why we really want to get the serology.

Dr. Shreya Trivedi: Yes, exactly. Okay. To sum up this pearl, the next time we see eosinophilia, we want to do a thorough infectious history. It’s really about where were you born? Where have you lived? Where have you traveled? Even if it was years ago, and did you have any stopovers?

Dr. Hila Ghersin: And we want to really think about what kinds of food have patients eaten. Were they exposed to any undercooked or wild meats? The CDC travel website, I will link below for you guys, is an amazing resource at linking what infectious exposures are related to where in the world and when you need to think about them.

Dr. Shreya Trivedi: Oh, that sounds really helpful. And the last thing to ran out, the P and the CAMP-E pneumonic stands for pathogens. And we can say parasites per se because helminths or worms are the majority of it, but we need to also remember that viruses and fungi, like for example, coccyoides, can also cause eosinophilia.

Pearl 5: Eosinophilia, Steroids, and Neoplasms

Dr. Hila Ghersin: So we covered the three big causes of eosinophilia, Atopy, meds and pathogens. Let’s round out our discussion with some potpourri of high-yield points on eosinophilia

Dr. Peter Weller: Eosinophil number fluctuates. There’s subtle fluctuation over the course of the day, which reflects the endogenous circulating rhythms of corticosteroids. You start pumping out some steroids in the morning. Eosinophil tends to be lower. Also, stress can suppress the eosinophil numbers. There’s an old study on medical residents presenting at grand rounds and eosinophil levels before and after. The stress of presenting at grand rounds, they were eosinopenic.

Dr. Shreya Trivedi: Oh man, that is wild. So if the eosinophil levels actually fluctuate throughout the day, what about those 6:00 AM labs that we’re so used to? How do we interpret those?

Dr. Hila Ghersin: So those AM labs are probably when eosinophils are at their lowest because that’s when we make most of our cortisol. The rule is more stress, more endogenous corticosteroid production, the lower the eosinophil counts.

Dr. Jason Freed: All your patients with sepsis in the hospital have neutrophilic leukocytosis; they’ll have suppressed eosinophil counts. I mean, go to the ICU census. You’ll see everyone’s got to suppress the eosinophil count. Anyone who doesn’t, there’s probably some reason for that.

Dr. Shreya Trivedi: So here’s the pearl. In a patient who’s septic, a normal eosinophil count or a mildly elevated one is actually abnormal, right? Even though our EMR is not flagging that for us. A normal or elevated EO count in a sick patient is a clue that there might be some other underlying process.

Dr. Peter Weller: I remember doing an ID consult and a complicated guy who had a motor vehicle accident in New Hampshire, was transferred down here, was in the MICU pre-op and sick, febrile and he had normal years on his diff. I said, “That’s curious. You always teach that sepsis and stress suppress eosinophils.” Yeah, until his CT scan showed that he’d bled into his adrenals. So he had adrenal insufficiency from trauma.

Dr. Hila Ghersin: I love me good Peter Weller eosinophilia story. So that patient in the ICU had adrenal insufficiency. That brings us back to our camp eosinophilia pneumonic. That A, it stands for both atopy and adrenal insufficiency.

Dr. Shreya Trivedi: Yeah. And so in this case, with adrenal insufficiency, there was a loss of cortisol, right? That removes that normal suppressive effect that steroids have on the eosinophil, so hence his eosinophil count was normal on the CBC.

Dr. Hila Ghersin: I’m so glad we talked about stress, steroids, and how those impact the eosinophil levels. We spent a lot of time on causes, and so the next natural question for me is how do we actually manage eosinophilia?

Dr. Jason Freed: One of the really weird things about eosinophilia is that it’s often easier to treat than it is to figure out what people actually have. Because honestly, steroids work for basically everything on that giant list of causes of eosinophilia.

Dr. Shreya Trivedi: Okay. So if steroids work so well on all our eosinophilia woes, then Hila, why don’t we spend this whole episode going over etiology? I mean, I know we’re good internal medicine doctors, but did that really matter?

Dr. Hila Ghersin: It does matter, Shreya. We have two big reasons. First is infection. Giving steroids to someone who has an undiagnosed strongyloides infection can trigger a hyperinfection syndrome and make our patients very, very sick. The second is diagnostics. Giving steroids can really muddy the data and interfere with our diagnosis of cancers like lymphoma. They can also lead to temporary improvement in eosinophils, which can masks an underlying malignancy that’s going on.

Dr. Shreya Trivedi: Ah, right. Yeah. Cancer was at C in the camp E pneumonic. That’s something I’m always worried about missing.

Dr. Hila Ghersin: I’m also worried about it, but the good news is that it’s a really rare cause of eosinophilia. There’s a subset of myeloid neoplasms that we really don’t want to miss, and it’s one of the causes that does not respond to steroids. 

Dr. Jason Freed: Steroids will make the eosinophils go down for basically every single cause, except for this one thing, chronic eosinophilic leukemia, aka MHES. And that’s because in this case, these are actual clonal eosinophils. The eosinophils are part of the malignant clone. They’re no longer responding to growth signals or things that try and suppress their growth, meaning they will continue to grow and replicate independent of you trying to suppress them with steroids. And they will continue to grow and replicate, independent of you cutting off their supply of interleukin-5, because they are actually the cancer.

Dr. Shreya Trivedi: That is good to know. So then how do we think about the neoplastic workup? I mean, we’re not going to be sending it off on everybody, of course.

Dr. Hila Ghersin: And you definitely shouldn’t. You should really think about sending it though, when the eosinophilia is severe, like above 5,000 eosinophils per microliter or five in the EMR, and persistent. Eosinophilia that does not respond to steroids or eosinophilia that initially improves with steroids, but then comes back with a vengeance, is also concerning for malignancy.

Dr. Shreya Trivedi: And this is where we’re like, yes, hematology or allergy immunology colleagues, please help us.

Dr. Hila Ghersin: Yes. And just to give you a heads up of what their workup might include, they will probably send things like flow cytometry, FISH testing for this mutation called PDGFRA, next generation sequencing, B12, and tryptase to look for systemic mastocytosis and full body imaging.

Dr. Shreya Trivedi: And then I know sometimes bone marrow biopsy is a part of that initial heme workup.

Dr. Jason Freed: A bone marrow biopsy is not an essential part of the initial workup for eosinophilia, and you can proceed with just sending off all these tests off the blood.

Dr. Shreya Trivedi: Okay, nice. One less procedure in that initial workup for our patient. Wonderful. So I know we said hold off on steroids, especially if we’re ruling out strongyloides or cancer, but what if our patient’s really sick and maybe there’s a concern of even and organ damage?

Dr. Hila Ghersin: Like my patient who had that eosinophilic myocarditis and stroke.

Dr. Jason Freed: For a sick patient in the hospital who’s got an elevated troponin and an abnormal EKG and you’re like, “This person could die of their eosinophilia.” I do not have a week to wait for all these tests to come back. So before I’m empirically giving steroids to someone who’s really sick with peripheral blood eosinophilia, I want to make sure I have a CT torso that has identified any lymphadenopathy or other possibilities of some other cancer that I want to go after a biopsy before I give any steroids. I’m checking a tryptase, but I’m not waiting for the results because the reality is that’s unlikely to be helpful. I am sending off flow cytometry of the blood to look for LHES, and I often will also send off the testing for myeloproliferative hyperosinophilic syndrome, AKA chronic eosinophilic leukemia. And so that’s going to be the translocations, the FISH testing for the PDGFR translocation, as well as doing next-generation sequencing for myeloid type mutations to identify things like JAK2 mutations that may drive another subset of cases.

Dr. Hila Ghersin: That was some good space repetition for the heme workup of malignant neoplasms. So for clinically sick patients, we send off testing and start empiric steroids while we’re still waiting for the results.

Dr. Shreya Trivedi: Yeah. And then earlier we also discussed that giving steroids could precipitate like a disseminated hyperinfection of Strongyloides. So how do we think about that in a sick person?

Dr. Jason Freed: My general approach is I ask the question, are there any parasites or other pathogens that it makes any sense for this patient to have? And I just think about that epidemiologically in terms of their travel and exposure history. And if there are essentially none, then I treat them for Strongyloides because everyone in the US is at risk for Strongyloides with ivermectin, and then I give them steroids. And I don’t even wait because that person has a life-threatening situation. I just give them steroids to sort of like shoot first, ask questions later.

Dr. Shreya Trivedi: So I guess when somebody is sick, particularly if we’re thinking about the patients in the ICU, I think the order of management definitely changes. And so our main takeaways when it comes to steroids and malignancy, we know steroids is an effective treatment for lowering eosinophils, but there’s a worry of the hyperinfection of strongyloides and also reducing our diagnostic yields in neoplasms like lymphoma.

Dr. Hila Ghersin: And one of my absolute favorite pearls is that in critically ill or septic patients, a normal eosinophil count is actually really abnormal and should make you concerned about causes of hypereosinophilia. That could be anything that we just talked about, like drug exposures, adrenal insufficiency, et cetera,

Dr. Shreya Trivedi:. Coming back full circle, everything we just talked about. So that is a wrap for our episode. I hope you guys had fun taking a trip on Camp Eosinophilia with us. Hila, thank you so much for putting this together and leading the ship. I learned a ton.

Dr. Hila Ghersin: Thank you so much, Shreya. And if you want to add any of your own tips, listeners, please leave a comment on our website page on Instagram or Facebook. Thank you so much to our peer reviewers, Dr. Paneez Khoury and Dr. Jonathan Berry.

Dr. Shreya Trivedi: And always, we love hearing feedback. Please email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you and take care. 

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