When the Count is High: Eosinophilic Diseases

Podcast Transcript

Raed Dweik, MD:

Hello and welcome to the Respiratory Exchange Podcast. I'm Raed Dweik, MD, chairman of the Respiratory Institute at Cleveland Clinic. This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease, and related disciplines. We will share information that will help you take better care of your patients today as well as the patients of tomorrow. I hope you enjoy today's episode.

Hello everyone and welcome to this episode of the Respiratory Exchange Podcast. I'm Raed Dweik, MD, chairman of the Respiratory Institute and your host today, and my guest is Fred Hsieh, MD. He is the director of the Allergy and Immunology Fellowship Program and vice chair of the Department of Allergy in the Respiratory Institute at the Cleveland Clinic. Our topic today will be focused on eosinophilic-related diseases. This is an area that Dr. Hsieh is a world expert in, and we look forward to his insights. Welcome to the podcast, Fred.

Fred Hsieh, MD:

Raed, thanks you very much for inviting me.

Raed Dweik, MD:

All right. So, the eosinophil, this is a mysterious blood cell. I would say most of us who don't deal with the day-to-day, only worry about it when the number shows up on the CBC or something. So, tell us more about the eosinophil? What is it? What does it do?

Fred Hsieh, MD:

So, eosinophil is a granulocyte. Like other granulocytes, that you're probably very familiar with, like the neutrophil, for example. It is a cell that is chock full of granules, and it has a notable staining characteristic that it's very eosinophilic when you stain with H and E, and that gives it its name. It is notable in the sense that it's usually found in very low concentrations in the peripheral blood, but can be elevated with various conditions, some of which are related to infection, others related to allergic disease, and then others related to a primary or defect in the eosinophil itself.

I think what's notable about this granulocyte it is has a very short half-life. So, it exists in the peripheral blood with a half-life of less than 24 hours. So, this is very different than some other cells of the immune system like lymphocytes and macrophages, for example. And what's notable about this is that when it traffics into the tissues, it can have a dramatically different phenotype, and also has an extended half-life. So, tissue eosinophils may behave in a slightly different way than peripheral blood eosinophils. And the function of eosinophils in the various tissues are very different than that of what you might harvest from the peripheral blood.

Raed Dweik, MD:

That's great. So, most of us, as I mentioned, only think about the eosinophils when it pops up on a CBC complete blood count differential. So, what does that mean when I see that in my report?

Fred Hsieh, MD:

Well, I think that the first question to ask would be what is the context in which you have ordered the complete blood count or CBC, and what are you expecting to find? So certainly, the elevation in the use of the full count can be, you know, stable and incidental. It can be secondary to some other disease, it can be primary, or reflect some defect within the eosinophil itself.

Raed Dweik, MD:

So, what would be the most common to say, if I want to see the most common things that cause the high eosinophil count, what would that be?

Fred Hsieh, MD:

So here in the developed world, we would say the most common cause would be allergic disease. Things like asthma, allergic rhinitis, eczema, and other classic atopic diseases. In the developing world, it's postulated the most common cause would be parasitic infection. So various parasites can trigger peripheral blood and tissue eosinophilia, and the cells are felt to be key in the host defense against parasitic infections in the developing world.

Raed Dweik, MD:

When I see this on the blood count, do I have to kind of say, "Oh, this is an urgent and I have to deal with it right away," or this is something that we just can figure it out over time? You know, how urgent is it like?

Because usually patients like now these days they see it on MyChart or, you know, some way or another, and they call, freaking out about a high number of eosinophils. How urgent is this?

Fred Hsieh, MD:

No, that's an excellent question. It all depends upon, again, on what context you order the test. It can be sort of an incidental finding. It can be something that is totally asymptomatic, if they have some symptoms, but the symptoms are chronic and relatively stable. They can be symptomatic related to the eosinophils count. But if you're checking it when the patient is acutely ill, for example, then it can certainly require more urgent workup and intervention.

Raed Dweik, MD:

Yeah. Which brings me to another related question. We hear about hypereosinophilia, which is kind of a descriptive term like just high eosinophils count, I assume, but also the hyper eosinophilic syndrome, is that the same or is it different and how is it different?

Fred Hsieh, MD:

So, it is very different. Eosinophilia simply refers to an eosinophil count that's greater than the upper limit of normal in your laboratory. Hypereosinophilia has a specific definition. It is an absolute eosinophil count greater than the value of 1500. So, if you see the absolute count greater than 1500, that would be hypereosinophilia. Hypereosinophilic syndrome then requires that someone has hypereosinophilia, then the current diagnostic criteria suggest you want to see this absolute count greater than 1500, for at least two different bloods drawn over a 30-day period.

So, an extended period of time, at least one month's time with absolute count greater than 1500, with evidence of eosinophil-related target organ damage, and all other causes of eosinophils or hyper eosinophilia ruled out. So hypereosinophilic syndrome has a very specific diagnosis. This is distinguished from hypereosinophilia alone where it's just a number.

Raed Dweik, MD:

Okay, so when you talk about organ damage, what kind of organs are we worried about here?

Fred Hsieh, MD:

Almost every organ system can be involved with eosinophils and the hypereosinophilic syndrome. Some of the more common ones would include the skin. So, you can have various types of skin manifestations. You can have gastrointestinal involvement, that's not uncommon. You can have a cardiovascular involvement, either with the vessels, with clotting, and the clotting can be either arterial or venous, or you can have infiltration of the myocardium itself. And that's certainly cardiac involvement is considered to be the most fearsome, um, manifestation of hypereosinophilic syndrome. The peripheral nervous system can be involved, the central nervous system can be involved, especially if they have thrombotic, or embolic disease. And then you can have manifestations in other organs as well, including the lung. So, it certainly can be a multi system disease.

Raed Dweik, MD:

So how common is this? This seems very ominous.

Fred Hsieh, MD:

Well, it's, I would say that the prognosis has improved with, over the past 30 years, but it's not common per se. So certainly, if you do see an individual with eosinophilia, the count that you've seen in the CBC can sort of direct how urgent you think the evaluation should proceed. But it's certainly not the first thing that one should think about when you get the CBC with differential back from your patient, and you see that the eosinophils count is elevated.

Raed Dweik, MD:

So, I know we focus about the hyper eosinophilic syndrome, because to me, like it sounds very serious, but maybe go back and talk about hypereosinophilia in generally, that can be symptomatic or asymptomatic as well. So, what kind of symptoms do we expect from hyper eosinophilia, you know, that is not, does not make it to be the Hypereosinophilic syndrome. Yeah.

Fred Hsieh, MD:

So, I think a lot of that depends upon why the patient has hyper eosinophilia and think that touches upon what are the conditions that could be associated with an elevated eosinophil count or even hypereosinophilia. So, I think there are a number of things that, you know, a clinician would work through in the differential diagnosis, certainly could this be a paraneoplastic phenomenon? So, was there an as an affiliate related to a concurrent malignancy? It was it could the patient have an adrenal disorders, such as adrenal insufficiency that is commonly or no, perhaps not commonly, but can be associated with peripheral blood eosinophilia to workup for atopic disease, like we mentioned, allergic rhinitis, asthma, eczema, other atopic disease, atopic dermatitis, drug reactions that are, you know, allergic "in nature" can certainly give you a peripheral blood eosinophilia.

Many collagen and vascular diseases, autoimmune disorders, including some very common ones. Rheumatoid arthritis, for example, can be associated with eosinophilia. Depending on the patient's travel history, and other exposures, it could be related to parasitic infection, tuberculosis, and other types of infections. And then if all of those conditions have been evaluated, and "ruled out," then you would be worried about hypereosinophilic syndrome. So just elevated eosinophils in the peripheral blood shouldn't really cause you many symptoms, per se. It is what are the target organs that are involved with eosinophils that may give you the symptom.

Raed Dweik, MD:

With all the disorders that you listed that are associated with hypereosinophilia, like this is like the kind of the differential diagnosis, if you will, how would you approach a patient like that? It's like it could be malignancy, it could be rheumatoid arthritis, it could be allergy, it could be parasites. Is there like, if you see it, like, Of course I can understand maybe referring it to an allergist or somebody who's an expert. But before you do that, what are the... maybe for a provider and either, uh, a specialist or a generalist who sees this, what would be the first few things they could do just to figure them out? Are we dealing with something serious, or is it something that we need to refer to, or is this something, "Okay, I can try to figure it out over time"?

Fred Hsieh, MD:

Well, I think the, you know, first would be to take a step back and try to identify why you checked the CBC in the first place and what you were expecting it to be.

Raed Dweik, MD:

Let's say it's incidental, I do a CBC on somebody, and they have a high eosinophilic count.

Fred Hsieh, MD:

All right. So, then I think statistically speaking, could say, Does the patient have atopic allergic disease? Do they have allergic rhinitis? Do they have asthma? Do they have atopic dermatitis or eczema? Sort of those would be the conditions that would be more commonly associated with eosinophilia. So, an eosinophil counts greater than the upper limit of normal in your laboratory, but perhaps approaching or, at/or around the level of 1500? That would be considered hyper use and affiliate. So, I think that that would be the first thing statistically speaking to say, "Okay, does the patient have any of these very common conditions that are commonly associated with eosinophilia here in the developed world?"

I think that if, you know, they truly have persistent hyper eosinophilia with a count greater than 1500, then I think that, you know, you can work through the differential looking for some of these other conditions. I think that, you know, many of them adrenal disease, you can see of do they really have, you know, metabolic findings that are suggestive. Do they have, you know, blood pressure issues, things like that, that might be suggestive of an adrenal problem? You know, often clinicians will send screening laboratories for autoimmune disease and rheumatoid factor. So, I'd rate things like that, you know, careful history to see the patient has joint symptoms, specific rashes, that are consistent with various autoimmune conditions.

You know, so I think that a lot of the workup can be done by the general internist or the, you know, the practitioner that has, you know, the appropriate skill set to take the history, ask appropriate questions, order some straightforward laboratory studies.

Raed Dweik, MD:

I'm hitting the number 1500 now, multiple times? So, would it be fair to say, if it's above 1500, just send them to somebody who knows what they're talking about, dealing with? If it's below that, you can take your time to figure it out by history, physical, some preliminary tests, but if it is about 1500, maybe it's best just to kind of send them to a specialist who deals with this. Is that fair?

Fred Hsieh, MD:

Well, I think that's not unreasonable.

Raed Dweik, MD:

Yeah.

Fred Hsieh, MD:

I think that, you know, the data beyond 1500 is interesting. How did that number come up, is it really a threshold like 1499? You're you know, safe, and 1501, now you're at risk of cardiovascular complication. And it's interesting in the sense that that is sort of a number that's been developed, since, you know, the 1970s, where people sort of proposed this diagnosis of hypereosinophilic syndrome.

And that sort of has been carried in the literature ever since. And so even with the most recent update to the diagnostic consideration for hypereosinophilic syndrome that occurred a couple of years ago, they still maintain the 1500 cutoff. So, I think that for whatever reason, 1500 is here to stay. I think that if, you know, you have an individual that has clear allergic disease, they have atopic term, they have allergic rhinitis, they have asthma, or symptoms suggestive of those conditions, and the number is around 1500, it's 1400s, it's 1550, it's 1300, I think you're reasonably safe and assuming that it's related to atopic disease. But, you know, clearly, if you follow these patients with time, and the number continues to increase, that's one thing or if they have some active disease, for example, patient has a new onset rash of some sort, then you look at, it could be a drug rash, you do the complete blood count with the front show and the eosinophil count is elevated, especially if you've been following for, the patient for a while. And it's much greater than their baseline study, then this does suggest that maybe this rash is a drug rash, and you just send them to dermatology allergy, some service for, you know, trying to figure out what it might be.

Raed Dweik, MD:

Yeah. And we've talked so far about the number of eosinophils in the blood. But initially, you mentioned something you're going to come back to that there's a difference between the [inaudible 00:14:31] in eosinophils and the tissue in eosinophils. So, is it possible that you can have an eosinophilic disease without an elevated peripheral account or is it, you have to have an elevated count?

Fred Hsieh, MD:

That's a very incisive question. And I would say that this is one I think the key points in evaluating eosinophilic disease that you can certainly have prominent tissue eosinophilia with target organ damage due to eosinophils with a normal peripheral blood eosinophil count and there are many, many such cases. One case that I saw here early in my career was an individual who was a firefighter who had participated in putting out a fire at the warehouse downtown, and then came into the emergency room, several hours later with hypoxemic p- respiratory failure, was intubated in the emergency room, brought to the ICU. A chest X ray showed white out of both lungs and the patient was not getting, was not improving and required a high degree of oxygen supplementation and bronchoscopy was done, which showed florid eosinophils in the lung. And the peripheral blood eosinophil count was undetectable.

Raed Dweik, MD:

Wow.

Fred Hsieh, MD:

And so, the treatment in that case was to treat the patient with corticosteroids. Corticosteroids rapidly lead to the apoptosis of eosinophils. And the patient gradually, you know, rapidly improved and could be excavated with this therapy. And clearly this is a case where there was no peripheral blood eosinophil count, there was target organ damage due to eosinophils in the lung, leading to respiratory failure and in the diagnostic procedure of choice, the bronchoscopy demonstrated, sheets of eosinophils in the lung. And this then led to the institution of the correct therapy in the corticosteroids to treat the disease.

Raed Dweik, MD:

Yeah.

Fred Hsieh, MD:

So certainly, you can have lung only eosinophilic disease, and then many other conditions can also present like this. So, for example, eosinophilic gastrointestinal disease, eosinophilic esophagitis. A lot of clinicians probably are familiar with this, these individuals can have strictures, dysphasia, required, uh, delectation other invasive interventions due to esophageal eosinophilia. The peripheral blood count can be totally normal.

Raed Dweik, MD:

Yeah. And as a pulmonologist, myself, I think that, yeah, the disease that I deal with is like eosinophilic pneumonia and the chronic eosinophilic pneumonia. It sounds like the case you described is more of an acute eosinophilic pneumonia which kind of gets better very quickly, as you said with steroids and does not come back. But there's the chronic eosinophilic pneumonia, which is kind of a recurring requires long-term. Can you just comment on that a little bit?

Fred Hsieh, MD:

Well, you probably know more about chronic eosinophilic pneumonia than I do. But certainly, it's a very different disease.

Raed Dweik, MD:

Yeah.

Fred Hsieh, MD:

I completely agree that chronic eosinophilic pneumonia or CP, you know, does tend to recur, there is a higher incidence in individuals that have atopic disease and asthma. And some individuals with asthma, chronic eosinophilic pneumonia is the first presentation of their lung disease. And it can certainly wax and wane. And this is one area where they... these patients, because they typically do have a topic disease, they can have peripheral bloody eosinophilia. And I think the sort of clinical situation that sometimes we confront is an individual that has a history of asthma, that has pulmonary infiltrates, and does have some peripheral blood eosinophils, and does this patient just have asthma, with some kind of pulmonary infection and peripheral blood eosinophilia or do they have chronic eosinophilic pneumonia?

Raed Dweik, MD:

Yeah.

Fred Hsieh, MD:

And so, I think that this is sometimes an area where the pulmonary service and the allergy service may have some disagreement where in terms of whether a bronchoscopy or other definitive tests, meaning a biopsy or something like that in the lung, that really required to guide the therapy in working up potential pulmonary use and affiliate.

Raed Dweik, MD:

Yeah, thank you. I've taken care of a few of those in my career, and they are very difficult to treat, because they keep recurring, you taper it with steroids, they come back find those of steroids. Let's come back to the general topic of eosinophilia, and your approach. Somebody gets referred to you for eosinophilia, what does your kind of initial workup look like?

Fred Hsieh, MD:

Well, I think there's no escaping the importance of the history and physical examination to look for, you know, the tempo and the conditions that are associated with the development of the peripheral blood as an affiliate and what symptoms what organ systems might be involved. And then I think that, you know, you can utilize a number of tests to rule in or rule out various conditions based on what the current symptoms are, but I think it's not unreasonable to, you know, check the blood count to do some sort of workup for parasitic infection, especially if there is a travel history or other history like that.

Depending on when the organ system is involved, you might do an echocardiogram of the heart, you might look at the skin or ask for a skin biopsy from your dermatology colleagues. If there are a lot of GI symptoms or pulmonary symptoms, you would, you know, direct the imaging or consultations based on, you know, what organs are involved. And then if there is some consideration of hypereosinophilic syndrome, really the key test is to ask your colleagues and hematology oncologist to do the bone marrow examination.

Raed Dweik, MD:

So, what does that tell you, a bone marrow exam?

Fred Hsieh, MD:

Oh, well, so the eosinophil being a white blood cell is birthed in the bone marrow and then is released as mature granulocyte and will then move to through the peripheral circulation to the various tissues. So, it is the birthplace of the eosinophil. And that is where you would look to see whether or not there is a clonal or molecular defect that you can identify that is driving the eosinophil-related disease. So, I think it's really critical to look at the bone marrow and then the other key point which is articulated well in your question is that there are individuals who have a concomitant hematologic malignancy, where the malignancy is releasing eosinophils poietin such as interleukin 5, interleukin 3, GM-CSF, that then is driving the hypereosinophilia.

So many types of malignancies that you can identify in the bone marrow like AML, for example, can be associated with a paraneoplastic eosinophilia, but the paraneoplastic eosinophilia is not isolated to hematologic malignancies, certainly solid tumors, we have a number of cases of patients that had, you know, lung tumors that all had a concomitant paraneoplastic eosinophilia. So, it can be seen, but practically any kind of solid tumor as well.

Raed Dweik, MD:

Yeah, that's beyond just a simple infiltration of bone marrow and release of eosinophilic actually they release factors that stimulate the production of eosinophils.

Fred Hsieh, MD:

That's correct. So right, I mean, if you think about the mechanism by which you can get abnormal proliferation of eosinophils and hypereosinophilic syndromes, there really are two broad categories. One, there's a molecular defect in genes that are responsible for eosinophils pathogenesis, there are a number that have been identified in many involving PDGRF, a platelet derived growth factor receptor signaling, and a lot of these you can identify with the appropriate tests both from the peripheral blood in the bone marrow.

And then you have situations where there are abnormalities in other cell types for the e- hypereosinophilic disorder classified as lymphocytic variant hypereosinophilic syndrome. These patients actually have a T-cell defect, where the T-cells are clonal and release TH2 cytokines such as interleukin 3 and are interleukin 5 GM-CSF, and this drives eosinophilia. So even though the patients have you as eosinophilia, and eosinophils are responsible for some of the target organ damage, the clonal defect is actually in T-cells. And this is something that it is possible to identify by looking for T-cell receptor gene rearrangements in the specimens from the peripheral blood or from the bone marrow.

Raed Dweik, MD:

Yeah, wow. It's getting more complicated than I thought. Thank you for explaining and breaking this down for us. So, let's go, move on to treatment a little bit. So, I know, a high eosinophilic count is enough of a disease per se, you mentioned it could be multiple things. But what's your approach to treatment in assuming it's kind of underlying whatever the causes, there's eosinophilia you have to treat? Are there any specific things you look into as you treat these patients?

Fred Hsieh, MD:

No, it's a great question. So exactly as you said, if you identify a parasitic disease, then treat the parasitic disease, eosinophilic account will improve or resolve. But if you're specifically focused on reducing hypereosinophilia, as, you know, in disorders like hypereosinophilic syndrome, then certainly the first line therapy is to use corticosteroids. Corticosteroids reliably re- induce apoptosis of eosinophilia... eosinophils, both with secondary eosinophilia and with primary hypereosinophilic disorders. And then when you reduce the steroids, you expect the symptoms, whatever symptoms that the patient is suffering from, to improve.

The problem often is that as you tried to taper the steroids, then the eosinophilic count comes back, the tissue and filtration comes back, and maybe the symptoms can recur. So, then you're looking for steroid sparing agents, and the newest kid on the block, so to speak, is mepolizumab or NUCALA. That was approved by the FDA here just in 2020 for the treatment of hypereosinophilic syndrome, not associated with other known hematologic disease. And this represents, say, important advancement in the treatment of this condition, the ability to use this eosinophil targeting biologic to reduce the eosinophils in the blood.

As you probably know, there are other biologics that are targeting eosinophils that currently are used, are FDA approved for other conditions, but currently only this one, the mepolizumab or the NUCALA is approved for hypereosinophilic syndrome.

Raed Dweik, MD:

Yeah. So, which brings me to kind of maybe my final question to you, is about the prognosis. And again, since many things can cause eosinophilia, the assumption is that underlined disease, but for isolated is eosinophilia, what's the prognosis for these patients?

Fred Hsieh, MD:

So, it's difficult to sort of just say, eosinophilia in general, but to specifically target hypereosinophilic syndrome, I would say that, you know, with the first major review that was done probably 15 years ago, the mortality was like 40 percent. So, in many cases it was worse than many malignancies. And that was predominantly due to the fact that clinicians would often watch the eosinophil count for some time, until the patient had some kind of catastrophic event, some myocardial disease or something like that. And now, with advanced recognition, improved therapeutics, use of, you know, prompt use of corticosteroid therapy to reduce the eosinophil count, the mortality has markedly improved. So, I think that with a lot of the agents that are available today, and the approaches that have been recommended by the major national societies, there are more ways to properly treat and reduce the eosinophil account as opposed to watching and waiting. And then that certainly can lead to improved mortality.

Raed Dweik, MD:

It's great. So, thank you for really breaking this down for us today, Fred. Anything else you'd like to share with our audience before we close?

Fred Hsieh, MD:

Yeah. I think the one thing that I've sort of neglected to mention in terms of in the category of treating hypereosinophilic syndrome is that if you do identify a particular molecular defect in PDGR, associated with aggressive or so-called mild proliferative variant hypereosinophilic syndrome, then tyrosine kinase inhibitors such as imatinib, have been FDA approved to treat this condition. So, there are a number of "steroid" or non-sparing agents or non-stored agents that can be utilized, of which at least to the imatinib and the mepolizumab have been FDA approved for this indication.

Raed Dweik, MD:

Wonderful, thank you. I learned a lot today, more than I expected. So, thank you for sharing your knowledge with us. I'm just going to try to close with a few takeaway points for our audience, one, to say that high eosinophilic count interpretations should be taken in context, why you order the test in the first place, and also appropriate history and physical examination, including travel. You have to differentiate between eosinophilia, hypereosinophilia, and the hypereosinophilic syndrome, they are really quite distinct entities.

And hypereosinophilic syndrome is the more serious because it's involved with organ damage. And that's something we have to pay attention to because it's also treatable. You know, we have effective therapies for it. And so my at least recommendation, and it may not be yours, is that if you have eosinophilic count more than 1500 with no obvious cause, somebody doesn't have asthma, clear reporting, allergies, just refer it to a specialist so that they can really get on it right away because early treatment saves organ function, and there are results in better prognosis. Is that fair?

Fred Hsieh, MD:

I totally agree.

Raed Dweik, MD:

Okay, thank you so much, Fred. Then thank you to our audience for listening to this episode today. Again, this is your host, Raed Dweik, MD, chairman of the Respiratory Institute. And my guest today was Fred Hsieh, MD, who is the director of the fellowship program of allergy/immunology and the vice chair of the Allergy and Immunology Department in the Respiratory Institute at the Cleveland Clinic. Thank you, Fred, and have a great day everyone.

Fred Hsieh, MD:

Thanks for having me.

Raed Dweik, MD:

Thank you for listening to this episode of the Respiratory Exchange Podcast. For more stories and information from the Cleveland Clinic Respiratory Institute, you can follow me on Twitter @RaedDweikMD.