[SPEAKER_01]: I have a colleague who's based in the UK who as a medical student in the UK had anemia from heavy mental periods, very common in women, and then also has the decino phenotype.
[SPEAKER_01]: And so her PCP saw two cytopenias, a low neutrophilic out, and referred her to a hemapologist, right?
[SPEAKER_01]: And that called her that it might be leukemia.
[SPEAKER_01]: So she's a stressed out medical student, you know, just trying to get by and thinking that she had leukemia.
[SPEAKER_02]: That was Dr. Lauren Hurtz.
[SPEAKER_02]: a hematologist at the University of Michigan.
[SPEAKER_02]: Welcome to the core of him, Thye Perl's podcast, bringing you high-yield evidence-based pearls.
[SPEAKER_02]: This is Dr. Schreacher Betty.
[SPEAKER_03]: And I'm Dr. Casey Kim, a hematology oncology fellow at Tufts Medical Center.
[SPEAKER_03]: And today we're bringing you before I am at the note on Neutropenia and febrone utropenia.
[SPEAKER_02]: I'm so thankful that you brought this episode to life because I think I learned so much about the nuances of neutropenia.
[SPEAKER_02]: And I think there's a lot of guiding principles that can help us try to figure some of this out a bit better.
[SPEAKER_03]: So everyone keep calm and we'll carry on with our newest episode on neutropenia and February on neutropenia with the following five pearls.
[SPEAKER_03]: Make sure to test yourself by pausing after each of the five questions.
[SPEAKER_02]: I remember the more you test yourself, the deeper you're learning games.
[SPEAKER_03]: Pearl one, risk stratification of neutropenia.
[SPEAKER_02]: What level of neutropenia increases your risk of infection?
[SPEAKER_02]: And what of the types of neutropenia that gives you the highest risk of infection?
[SPEAKER_03]: Pearl two, work up of neutropenia.
[SPEAKER_02]: What do you consider when working up new neutropenia and what patterns matter the most?
[SPEAKER_03]: Pearl three, timeline of neutropenia recovery.
[SPEAKER_02]: How long does it take for a patient to recover their neutral counts?
[SPEAKER_02]: And what should you counsel patients to do during that process?
[SPEAKER_03]: Perl four, febral neutropenia?
[SPEAKER_02]: What is febral neutropenia?
[SPEAKER_02]: And how do you assess and triage these patients?
[SPEAKER_03]: Perl five, management of febral neutropenia?
[SPEAKER_02]: How long do you treat febral neutropenia with antibiotics?
[SPEAKER_02]: and when do you consider adding treatment like anti-fungles?
[SPEAKER_03]: I was about to discharge a patient who was feeling pretty well after his pneumonia was treated and on the day of discharge his CBC and absolute neutrophil count was nearly about seven hundred.
[SPEAKER_02]: What a tough place to be in.
[SPEAKER_02]: What'd you do?
[SPEAKER_03]: I just did charge to him.
[SPEAKER_03]: He was feeling fine, but honestly, I felt a little uneasy, sending him out when I knew he was in a trapeñac.
[SPEAKER_02]: I know, I feel like, especially when we see a new trapeñac, I think a lot of us think, okay, this is like high risk of infection, but I think as we learned, it's a lot more nuanced than that.
[SPEAKER_01]: We really like the rules.
[SPEAKER_01]: We like that we have to transceuse at seven and we always transceuse at seven, whether you're in patient or in surgery or outpatient.
[SPEAKER_01]: I think we often try to apply the same rules to neutropenia.
[SPEAKER_01]: I think a lot of us learned that an absolute control count of fifteen hundred or lower
[SPEAKER_01]: And then many of us also learned those subdivisions of, you know, less than five hundred is severe between, you know, five hundred and a thousand is moderate and that's, I wasn't the fifteen hundred is mild.
[SPEAKER_01]: I think that we need to step away from a lot of those rigid definitions.
[SPEAKER_01]: And instead, first look at the patient in front of us and look at their clinical context and look at the numbers themselves lab.
[SPEAKER_01]: Wait, so where are these numbers come from?
[SPEAKER_01]: I really tried to look into the where did we come up with the number, fifteen hundred and I couldn't find a good answer and all of my research.
[SPEAKER_01]: The best I can find is that in the nineteen eighties, we were trying to figure out how to quantify toxicity from chemotherapy.
[SPEAKER_01]: And you'll back in the nineteen eighties, we were giving some very intense chemotherapy that was totally my little blade of really big doses.
[SPEAKER_01]: And we were trying to define toxicity in a way that we could all agree with.
[SPEAKER_01]: And that's for that number of fifteen hundred came from.
[SPEAKER_03]: So essentially we've been applying a threshold developed for cancer patients getting intensive chemotherapy to everyone.
[SPEAKER_03]: And I've had seems like a pretty big leap to me.
[SPEAKER_02]: Right, and then on top of that, what we're measuring in the blood is actually just a tiny snapshot of what's happening in the body.
[SPEAKER_01]: White blood cells only live in the bloodstream for three to twenty four hours.
[SPEAKER_01]: You're only seeing one to five percent of the mature neutrophils in the blood at any one time.
[SPEAKER_01]: And so I think appreciating that what we see in the blood is an imperfect proxy.
[SPEAKER_01]: It was actually going on in the body.
[SPEAKER_01]: Nothing's going to be a ton of fluctuation and variation, even on an hour by hour basis.
[SPEAKER_01]: And just kind of allow the to appreciate the art of medicine.
[SPEAKER_03]: You know, I think the variation that we see our by our brings up a never keep point that you can see variation on the population level as well, too.
[SPEAKER_03]: And in particular, something called Duffy no associate in utopina.
[SPEAKER_02]: I'll be honest here.
[SPEAKER_02]: I've heard that term once or twice, but never had a really good grasp on what that actually means clinically.
[SPEAKER_03]: So, Duffy Null is genetic variant in different proteins on different blood cell types that develop primarily as an evolutionary adaptation to malaria, specifically conferring resistance to plus modium Vax.
[SPEAKER_03]: But people with his variant typically have lower neutral count in their peripheral blood, even though their total body neutral filth count is completely normal.
[SPEAKER_01]: So we can see in mouse model, it hasn't proven in humans, we see in mouth models that when you don't have the expression of dussy, it result in neutrophils that just a phenotypically different and tend to go to the spleen rather than hang out in the periphery.
[SPEAKER_01]: And so the total body and nutritional are the same.
[SPEAKER_01]: What we see in the bone marrow is exactly the same.
[SPEAKER_01]: But the way that we measure blood by taking it from the periphery is going to be different for people who are definitely know versus definitely not know.
[SPEAKER_02]: Wait, so these patients with Duffy Null have a completely normal immune function, but we've just been labeling them as neutropenic because their neutrophils are hanging out in the spleen and not in the periphery, which is where we're taking blood from.
[SPEAKER_03]: So you can imagine the sort of anxiety and that work of that patients and even clinicians go through with having these well-are neutrophil counts.
[SPEAKER_01]: And medical school, I remember as a teenager who was quite a soccer star, like in the era
[SPEAKER_01]: Andrea, he did an ACL repair and the surgeon's decline to do the ACL repair until he had a hematology work up because neutrophils were at like one hundred.
[SPEAKER_01]: Right, so what we know is normal for someone with the dusting all phenotype.
[SPEAKER_01]: It was out of the reference ranges at the institution.
[SPEAKER_01]: So there is a delay in his surgery.
[SPEAKER_01]: It took a while to get the hematology.
[SPEAKER_01]: We said everything was okay.
[SPEAKER_01]: But at the time, he got back to the surgeons.
[SPEAKER_01]: He had missed a lot of his season, right?
[SPEAKER_01]: And especially about high schoolers who's thinking about college prospects, the really big deal.
[SPEAKER_01]: The time to quantify these things.
[SPEAKER_01]: How you quantify that stress or the
[SPEAKER_01]: time off work, or even just that sense of other being told that you're not normal or having your values always be red, but someone tells you you're fine.
[SPEAKER_01]: Your values are red and you're just like that disconnect.
[SPEAKER_01]: It's distressing.
[SPEAKER_01]: There's evidence that people with a defy null variant get more bulamero biopsies.
[SPEAKER_01]: That is not a benign or easy thing to go through, right?
[SPEAKER_01]: It's fine if you need it and it's essential for your clinical care, but that's not a casual test to get.
[SPEAKER_01]: We also see things like either biopreneuse for lupus or other autoimmune disease.
[SPEAKER_01]: There is higher rate of discontinuation for people with the duffy null phenotype.
[SPEAKER_03]: You know, that's crazy.
[SPEAKER_03]: I can see a bunch of patients who have duffy null phenotype and who get medications like their closipine stat because of neutropenia.
[SPEAKER_03]: Anyway, it's not the closipine that's causing the neutropenia of a rabbit just the fact that they have this duffy null phenotype and a normal ANC fluctuation.
[SPEAKER_02]: Yeah, it just makes me wonder, like how many patients I've seen with Newsphenia, and how many of those cases I might have missed a Duffy Nelfino type.
[SPEAKER_01]: So, I'm Sarah and Africa, and into the Arabian Peninsula.
[SPEAKER_01]: In West Africa, we often see eighty to a hundred percent of the population with the null phenotype.
[SPEAKER_01]: An alienated states among people who will self-identify as black or African-American, we typically see two and every three people with the null phenotype.
[SPEAKER_02]: Oh, that demographic is definitely helpful because I think at the back of my mind is I'm thinking, you know, who should I send off a duffy null on?
[SPEAKER_02]: Is it everyone?
[SPEAKER_02]: And to speak to that a bit more, we set down with Dr. Jason Fried, a hematologist at BIDMC, and who's most you may recognize very well from our gray matter segment.
[SPEAKER_04]: So the way I approach isolated neutropenia is that if absolute neutral count is a thousand to fifteen hundred, and there are African or Middle Eastern ancestry,
[SPEAKER_04]: I send duffy engine testing.
[SPEAKER_04]: And if they're duffy null, which two thirds of African Americans are, I reassure them.
[SPEAKER_04]: I do no further testing, no bone marrow biopsy, no invasive testing, fast the answer.
[SPEAKER_02]: So that's helpful on who to send off that test on.
[SPEAKER_02]: What else should we be looking for when we try to distinguish?
[SPEAKER_02]: Is this a normal variation?
[SPEAKER_02]: Like duffy nulls, so it's in Spina, or some other ideology in Spina that gives a really higher risk of infection.
[SPEAKER_03]: You know, even though we just spoke about not placing too much value on the absolute number for, you know, with past couple minutes, it's still good to keep an ANC of five hundred in mind.
[SPEAKER_03]: Usually you wouldn't expect to see an ANC of five hundred or below in a patient with the Duffy Nell phenotype.
[SPEAKER_03]: and being below that particular threshold makes me think that you may just not have enough neutrophils in your body to find out an infection.
[SPEAKER_01]: So when neutrophilter, five hundred or less, and what we can measure in the blood, we worry that the total body-neutral counts
[SPEAKER_01]: are low, which means that a person is not going to be able to robustly cite off any sort of infection or disease and might need things like IV antibiotics or a closer monitoring more than someone who has an ANC that's two thousand are higher.
[SPEAKER_04]: Being below five hundred is one of my variables for worry, duration of time that they're going to be less than that because every day is a dice roll as far as a risk that you're going to get an infection.
[SPEAKER_02]: Okay, summarize what I'm taking away from this pearl.
[SPEAKER_02]: I think before diving into this, I had a knee-jerk response whenever I see an absolute neutral count less than fifteen hundred.
[SPEAKER_02]: Oh, they're in Japanic increased risk infection.
[SPEAKER_02]: But we learned that that number came from patients on chemotherapy in the nineteen eighties and not real world diverse non-cancer patients.
[SPEAKER_02]: And I think definitely can take away the fact that two thirds of black patients in U.S.
[SPEAKER_02]: have a doffy and alfino type and they can naturally have
[SPEAKER_02]: lower ANC's, but have a normal immune function.
[SPEAKER_02]: The other big shift for me is to not let the number drive the plan really asking myself, is this new for the patient, could a definitely not the energy and be a play, especially if they are from an African American or male eastern ancestry?
[SPEAKER_02]: And of course, if that ANC number is under five hundred, then my worry about infection goes up much higher.
[SPEAKER_03]: So say your patient is not definitely no and but they are still neutropenic, you know, let's go through how our distance doesn't think through neutropenian, how they would work out these cases.
[SPEAKER_04]: And so the first thing I'll say is that the standard approach that you use for other side of eanias, it doesn't work as well here.
[SPEAKER_04]: So there's other general thing that we use to talk about is it a production problem, is it a destruction problem,
[SPEAKER_04]: or is it splinic sequestration, like the cells are hiding?
[SPEAKER_04]: That's great for anemia and thrombocytopenia, but for neutropenia, it's a little bit more limited in terms of actually getting to a specific diagnosis.
[SPEAKER_03]: So we can talk about the first branch point in the neutropenia workup.
[SPEAKER_03]: Is this isolated neutropenia, or is this pancydopenia?
[SPEAKER_03]: If it's pancydopenia, then you're looking at an entirely different differential, and most of a time that's straight to bone marrow biopsy.
[SPEAKER_02]: But what did you just have isolated in your opinion?
[SPEAKER_02]: The red blood cells will prove it's fine.
[SPEAKER_02]: How do we think through the isolated Nishpina?
[SPEAKER_04]: If Nishpina is isolated, meaning that's really the only CBC abnormality that you're seeing, it's an entirely different set of causes.
[SPEAKER_04]: hematologic malignancies are not common causes at all.
[SPEAKER_04]: And in fact, here, even doing a bone marrow biopsy is rarely important because most of the time, doing a bone marrow biopsy won't even give you the diagnosis.
[SPEAKER_01]: Nine-hime but a ten in a neutropenia evaluation is about the history and it's rarely about the lab tests that you send off.
[SPEAKER_01]: I think a lot of times in our busy health care system were very dependent on just wanting to send tests and have the tests tell us.
[SPEAKER_01]: Neutropenia is one of those entities where it's we about the history more than about the test that you sent out.
[SPEAKER_02]: All right.
[SPEAKER_02]: So for Neutropenia, it's really our time to turn up our internal medicine, history taking skills, and really try to figure out the cause.
[SPEAKER_04]: Well, the list is pretty long, but you can narrow it down pretty quickly based upon paying attention to a few factors.
[SPEAKER_04]: One is their medications.
[SPEAKER_04]: Two is other diseases they have.
[SPEAKER_04]: Three is other symptoms they have that you might not have made a specific diagnosis round.
[SPEAKER_04]: Four is the severity of the neutropenia because completely different things cause you'd have severe neutropenia from mild neutropenia.
[SPEAKER_04]: And five is the pattern of the neutropenia.
[SPEAKER_04]: And so here's where having multiple CBCs the differential can be really helpful.
[SPEAKER_02]: So with those five, thinking through meds, what other diseases they have, other symptoms, like rheumatologic ones that might seem to find that's the cause, the severity of the naturopenia, and the pattern of the naturopenia thing, who those five things, it was really when we just spoke to our experts that the money is really in that first one, the medications.
[SPEAKER_02]: And that is what we're going to focus on.
[SPEAKER_04]: And just to take step back, if you've ever been working on a patient for a naturopenia,
[SPEAKER_04]: And you're like, okay, well, I know meds are a cause.
[SPEAKER_04]: Let me, you know, go online and see which medications this patient saw on, cause Neutropenia.
[SPEAKER_04]: It's crazy making because you look it up at every single medication has Neutropenia listed as a possible side effect.
[SPEAKER_04]: So it's like, what am I supposed to do with that?
[SPEAKER_04]: There are two types of medication related neutropenia, but the same two types of medication related problems that exist for everything, which is the problem can be dose and duration dependent, or it can be idiosyncratic, also known as immune-mediated.
[SPEAKER_04]: And the reason why that distinction is so important is because the patterns are entirely different, and what you do is entirely different.
[SPEAKER_02]: All right, so the foundation we need to really cement and dive into when we're thinking about the overwhelming medications category is asking ourselves, is this either a problem due to the duration and dose of a medication or is this a problem because of an immune-related problem?
[SPEAKER_03]: So, you know, we can start with the first category of dose and duration dependent medications and these medications tend to give you a gradual neutropenia.
[SPEAKER_04]: And there are probably medicines you already know about.
[SPEAKER_04]: So, these are medications like micro-phenolate.
[SPEAKER_04]: like azethioprin, like gansite clover, like six more captive puring.
[SPEAKER_04]: What do all those drugs have in common?
[SPEAKER_04]: They're all nucleotide analogs, right?
[SPEAKER_04]: They're like basically like the same thing as chemo, right?
[SPEAKER_04]: They obviously affect DNA replication.
[SPEAKER_04]: Now, that should affect all your cell lines, but for whatever reason, they tend to cause nutrient-eat as a big problem.
[SPEAKER_04]: So those medications, if you're on those and you're nutrient-eat, there's a good chance.
[SPEAKER_04]: It's at least contributing.
[SPEAKER_03]: You know, I think that's a really good point about dose-dependent effects of medications, but we can also think about duration as well.
[SPEAKER_03]: Take one nasal ed, for example, which can cause dose-enderation-dependent utropemia.
[SPEAKER_03]: If you use one nasal ed for one week course for cellulitis, you almost never see any significant cytopenias, but it's not the case if you do it for like a six-week course for endocarditis.
[SPEAKER_03]: In that case, you'll actually see cytopenias in like a third of patients who receive that treatment course.
[SPEAKER_02]: Yes, a duration definitely can matter.
[SPEAKER_02]: I guess it is fine if you have a patient on one of the notorious medications for a short term course, but say this patient needs it long term.
[SPEAKER_02]: Say there you have autoimmune disease or solid organ transplants.
[SPEAKER_02]: What do we do with that?
[SPEAKER_03]: You know, I feel like in those situations, it can be really tricky because, you know, you want to treat the neutropenia, but those medications are also super important.
[SPEAKER_03]: But the good news is that, you know, because a lot of this is context dependent and, you know, we're talking about dose dependent medications, you might actually just be able to get away with lowering the dose of a medication first.
[SPEAKER_02]: Nice, okay.
[SPEAKER_02]: So say, this is not a dose dependent neutropenia.
[SPEAKER_02]: It's an immune-media in your opinion.
[SPEAKER_02]: How do we think about that a little differently?
[SPEAKER_03]: So for these medications that cause immune-mediated neutropenias, you see a much more abrupt and often much more severe neutropenia.
[SPEAKER_04]: When you have neutropenia, for example, from Clauseopine, you start Clauseopine, you're fine, you're fine, you're fine, you're fine, and all of a sudden one day your ANC is zero.
[SPEAKER_04]: Okay, your absolute neutrop account is zero.
[SPEAKER_04]: You have severe life-threatening neutropenia.
[SPEAKER_04]: So immune-mediated neutropenia has this very different pattern to it.
[SPEAKER_02]: I guess I now understand why Dr. Fried calls it idiosyncratic, right?
[SPEAKER_02]: These meds can cause your immune system to just hijack your neutrophils.
[SPEAKER_02]: All of a sudden, and it kind of happens randomly in idiosyncratically.
[SPEAKER_02]: The other common offenders in addition to a chozopine is going to be an endocrine world with them as all ptu, and then other meds like depsone or sulfazilin can also abruptly drop your neutrophils.
[SPEAKER_04]: And the reality is that I think people are already familiar with this concept because they know about heparin induced rhombocytopinia, right?
[SPEAKER_04]: Where the first time you are exposed to heparin, you don't get hit until at least five days, right?
[SPEAKER_04]: It's like the five to ten day, because it takes time to make the antibodies.
[SPEAKER_04]: Whereas if you've been exposed to heparin recently, you may have already been primed.
[SPEAKER_04]: Then you can see it in less than twenty four hours.
[SPEAKER_04]: Same thing is true for drug related isolated neutropinia through immune-mediated mechanisms.
[SPEAKER_04]: And it's idiosyncratic, meaning it's unpredictable.
[SPEAKER_04]: The idiosyncratic immune mutated.
[SPEAKER_04]: You have to stop the drug and never restart it because if you even give them a little bit of that drug again, their ANC is going to plummet to zero again.
[SPEAKER_02]: And our experts did recommend that if the patient's ANC less than five hundred, that definitely requires a hematology evaluation, but if it's more mild or moderate, you know, ANC the five hundred, twelve hundred, more of a gradual process, then you do have time to work it up to say that loud.
[SPEAKER_03]: Yeah, yeah, it's good not to have to rush some time.
[SPEAKER_03]: But in summary, you know, start your work up of Neutropenia with the question, is there a pancyteopenia or isolated Neutropenia?
[SPEAKER_03]: If it's isolated Neutropenia, you can forget the bone marrow biopsie and just do a good medication and symptom review.
[SPEAKER_03]: Pay attention to a trend of Neutropenia, you know, especially regarding medications, as if it's gradual, it might be a dose dependent or duration effect versus a quick drop is more likely immune-mediated.
[SPEAKER_03]: So, once you diagnose the likely cause of neutropenia, I feel like the next question my patients often have is will my neutrophil count recover?
[SPEAKER_03]: And if so, when?
[SPEAKER_02]: Yeah, I believe that's a great question.
[SPEAKER_02]: When will the neutrophil recover?
[SPEAKER_02]: I feel patients ask it all the time too, especially if they've severe neutropenia, especially considering what we learned earlier that every day is a disrole at times infection and they can, and are at the risk for serious infection.
[SPEAKER_03]: But you know, I think the neutrophil count recovery has a lot to do with what's causing the neutropenia in the first place.
[SPEAKER_01]: A lot of that you come down with how fast neutrophils are made.
[SPEAKER_01]: It takes you to seven to ten days to make a mature neutrophil.
[SPEAKER_01]: So I'm a hematicoidic stem cell to mature neutrophil.
[SPEAKER_01]: And they live in the periphery for three to twenty four hours.
[SPEAKER_01]: So a lot of it is based on that.
[SPEAKER_02]: So it takes about seven to ten days to make a mature neutrophil.
[SPEAKER_02]: And I guess that's what I've seen when it comes to a patient who has a viral infection and that causes neutropenia.
[SPEAKER_02]: It often does take, you know, ten days, two weeks for that neutropenia count to really get better and things not to be so, so run in the EMR.
[SPEAKER_03]: Yeah, and I feel that ten to fourteen-day timeline of recovery is true for a lot of medications as well, you know, especially if it's medications that are inducing like an immune-mediated neutropenia.
[SPEAKER_04]: But if you take away the drug, the antibodies don't do anything to your neutrophils.
[SPEAKER_04]: It requires the combination of the drug plus your neutrophils to have an effect.
[SPEAKER_04]: And the good news is that in drugs without long half lives, once you stop the drug, they are usually relatively rapid recovery.
[SPEAKER_03]: But we do have a slightly delayed timeline for one big category of medications, you know, dose dependent medications.
[SPEAKER_04]: If you remember from your oncology rotations, when you give chemo, you give it on day one.
[SPEAKER_04]: And then there's usually a nater in their Nutriple account between days, fourteen and twenty one, depending on the regimen.
[SPEAKER_04]: And then it starts coming back, back up around three to four weeks after you gave Bikimo.
[SPEAKER_04]: So the same thing happens with Nutripeania from Michael Fennelade, or Gansite Kovier, or these other things that are causing dose and duration dependent.
[SPEAKER_04]: You stop the drug.
[SPEAKER_04]: But it could be several weeks before it comes back up.
[SPEAKER_04]: And a lot of times, it's even longer if the way that you're managing this is by dose reduction.
[SPEAKER_04]: Because with dose and duration dependent in the trapenia, it doesn't mean you can't use the drug at all a lot of times.
[SPEAKER_04]: It just means that you need to give them less because it's dose dependent.
[SPEAKER_02]: It's like human therapy induced utropina, you know, say if it's drug really like Michael Fennellet induced utropina, it's going to really peak that utropina is going to really peak at two to three weeks post treatment and then start to recover around week four.
[SPEAKER_03]: I think the general just has stopped the medication causing the neutropenia.
[SPEAKER_03]: Your bone marrow will cover after some time like three or four weeks.
[SPEAKER_02]: What about neutropenance caused from chronic disease?
[SPEAKER_02]: Like, neutropenia related to autoimmune disease.
[SPEAKER_03]: So that can be a little bit of a tricky situation.
[SPEAKER_03]: You know, on the one hand, you want to treat autoimmune diseases that are causing penetropenia, but a lot of the medications you use to treat these diseases can also cause an ultropenia.
[SPEAKER_03]: So, you know, it feels like a little bit of a ketocone too.
[SPEAKER_04]: I almost think about that situation, like in cardiorenal syndrome, where like they have AKI and your afraid to use diuretics, and then everyone's like, you know, you've got to push through, you've got to diarise them, and then they're supposed to
[SPEAKER_04]: They're creating thoughts getting better despite the diaries and you're like, yes, it's like, I knew this could happen, but I'm always so worried it's not going to work how I wanted to write the same thing is true when you use immunosuppressives that can cause new travenia in patients who have autoimmune diseases is that.
[SPEAKER_04]: It gets better once you get them on treatment.
[SPEAKER_04]: The same thing is true.
[SPEAKER_04]: When we treat people with LGL leukemia with severe leukemia, we give them methotrexate, we give them cyclophosomy medicines that can potentially cause leukemia, but it gets better as it starts treating the actual disease.
[SPEAKER_04]: So you have to sort of trust slash hope that it's going to be more likely to cause the benefit that it is to cause the harm.
[SPEAKER_02]: All right, so say our patient has a chronic illness that's causing an utropenia.
[SPEAKER_02]: We're hoping that the new sugar account will get better with treatment, but to put on my worst case scenario hat, I guess, what if it doesn't get better?
[SPEAKER_02]: What if the new sugar pills don't get better?
[SPEAKER_03]: You know, to be honest, like sometimes it doesn't.
[SPEAKER_03]: That's a point that our third discussion, Dr. Eric Poe, a hematologist oncologist infectious disease physician at University of Manitoba and Cancer Care Manitoba brought up.
[SPEAKER_00]: There are going to be cases, however, where you don't expect the ANC to recover, where myloid recovery is not going to occur, such as myloid dysplastic states.
[SPEAKER_00]: And giving high dose chemotherapy on the context of myloid dysplastic states, the physician shouldn't be waiting around for that ANC to recover that may never recover.
[SPEAKER_00]: And knowing that context can help the clinician manage the patient safely.
[SPEAKER_02]: Yeah, so then what do we do for these patients, you know, when we don't expect the neutrophils to recover or there's a prolonged neutropenia?
[SPEAKER_03]: You know, I think the fact of the matter is that these patients of prolonged neutropenia are at higher risk or serious infections.
[SPEAKER_03]: So I think in that case, the most important thing to do for them is to counsel them about new fever, mouth ulcer, diarrhea, or really any of our symptoms concerning for infection.
[SPEAKER_02]: Yeah, and then I can imagine patient scarring the internet, really finding all these things like wearing special masks or in a drapeenic diet, I think I have a patient to ask me, hey, can I eat fruit?
[SPEAKER_02]: Can I sell it?
[SPEAKER_03]: I struggle with that question, you know, I never want to tell people like they can't have food or salad, but actually they've looked into interventions such as footwear exchange, protective environments like positive pressure rooms, respiratory or surgical mass, neutropenic diets, which is basically, you know, no fruits or vegetables and nutritional supplements.
[SPEAKER_03]: But none of those are clearly recommended because there's mixed evidence that they don't really prevent infections for neutropenic patients.
[SPEAKER_03]: And actually a lot of the data tends to side towards that these precautions are not more effective at preventing infections.
[SPEAKER_03]: You know, so let your neutropenic patients eat fruit.
[SPEAKER_02]: Nice, nice yellow underneath.
[SPEAKER_02]: Let's summarize what we've learned so far with the neutral recovery.
[SPEAKER_02]: It's really seems like the timeline can vary based on what the cause is.
[SPEAKER_02]: If it's something viral, immune-mediated cause, then the recovery can be relatively more quick, ten to fourteen days.
[SPEAKER_02]: Depending on that, that half life of the drug, that's causing an immune response, and then as long as the neutrals are being made, it's going to be around that ten day to leak timeline.
[SPEAKER_02]: If it's from chemotherapy or drug dependent,
[SPEAKER_02]: Nishipinia, it could take longer three to four weeks.
[SPEAKER_02]: And then autoimmune causes can improve a treatment, but might never fully normalize.
[SPEAKER_02]: And then there are some conditions like, well, dysphasic syndrome, you might not expect to recover.
[SPEAKER_02]: Let's move on to February on a chupinia.
[SPEAKER_02]: I feel like we've all been taught, you know, February on a chupinia.
[SPEAKER_02]: It's a clinical emergency times of the essence, but to be honest, sometimes I like, you know, get all on edge, like, okay, February on a chupinia patients here, or I'm admitting this person, and I go in the room and I'm like, this person doesn't look at that sick.
[SPEAKER_03]: Yeah, I think appearances can be deceiving.
[SPEAKER_03]: You know, I think there are some patients who are fine with the Browner Tupinia, but for those patients who do the develop the Browner Tupinia and severe steps is their septic shock.
[SPEAKER_03]: The in hospital mortality rate can be as high as fifty percent as documented by some retrospective studies.
[SPEAKER_02]: That is a lot.
[SPEAKER_02]: And I guess the take away is like, you know, if a Browner Tupin patients, if they get sick, they get really, really sick.
[SPEAKER_03]: Yeah, so, you know, different societies and guidelines are pretty clear about the timeline for work up and management for Fabrano, Trapina, you know, most recommended finishing work up within fifteen minutes of triage and starting antibiotics within one hour of determining Fabrano, Trapina.
[SPEAKER_02]: work up in fifteen minutes, that is fast.
[SPEAKER_02]: But here's like my challenge, my devil's advocate to that, because in reality, you know, patients come to the ED with the fever.
[SPEAKER_02]: You don't know if they're a new drapeenic and lab sick a while to come back or see somebody calls you or epic chats using they have a fever.
[SPEAKER_02]: You might not know and won't have access to, you know, blood work for a while and don't know how quickly to act.
[SPEAKER_00]: given a history, we have done in our guidelines, is to use a very simple sensitive question that's not very specific.
[SPEAKER_00]: This is if you've had any chemotherapy or can't he catch treatment at any time in the last six weeks?
[SPEAKER_00]: Yes or no?
[SPEAKER_00]: And the answer is yes.
[SPEAKER_00]: Then it puts the likelihood that this could be a neutrapinic episode.
[SPEAKER_00]: And I think that's quite a unique for any of the different syndromes that you and I look at and manage over from day to day.
[SPEAKER_02]: Wow, a simple question of did you have chemotherapy in the last six weeks?
[SPEAKER_02]: Can we this helpful?
[SPEAKER_02]: And I guess that goes back to what we learned in our last Pearl that Newsphenia can be predictable in these patients.
[SPEAKER_00]: I think it's predictable if we know the date of the incident that got it going in the first place or the Puget incident.
[SPEAKER_00]: And usually chemotherapy, when did you get your treatment last?
[SPEAKER_00]: Oh, well, yes, Dr. Bo gave me my chopped chemotherapy, twelve days ago.
[SPEAKER_00]: And this is day twelve.
[SPEAKER_00]: Well, then I know that pretty much from one patient to another with some significant exceptions, that when you get that cytotoxic therapy, that the nadir of that neutrophil count is going to be somewhere between day twelve and day fourteen.
[SPEAKER_02]: Yeah, but say my patients, you know, did have chemotherapy in the last six weeks or so.
[SPEAKER_02]: Does that mean straight inpatient mission for viral on a leukemia or cancer is being managed outpatient, especially if they're seemingly well peering?
[SPEAKER_00]: For the lower risk patients, I mean by risk, in this context is risk for medical complications that would either get you into hospital or keep you in hospital if you're already there.
[SPEAKER_00]: For those that would be considered low risk, and that's usually the solid tumor population getting cytotoxic therapy in a cyclical fashion.
[SPEAKER_00]: In that population, we can often, as I mentioned earlier, treat them as an outpatient.
[SPEAKER_00]: And our duration is different because the time to they'd have for residents, at least in clinical trials and in our own experience, is only two to three days.
[SPEAKER_03]: Yeah, so, you know, I think patients with solid tumors who are neutropenic are generally considered lower risk because they're neutropenic for a shorter time.
[SPEAKER_03]: I think especially comparing them to say like a patient who has leukemia and is getting chemotherapy.
[SPEAKER_03]: I think the other reason that breast cancer patient is lower risk is because
[SPEAKER_03]: It's really only the chemotherapy that's affecting very bone marrow as opposed to leukemia patient who has both cancer and chemotherapy affecting very bone marrow.
[SPEAKER_03]: So, you know, given that double hit, you would expect a leukemia patient to be more severely neutropenic for a longer period of time.
[SPEAKER_02]: Hmm, interesting on that, that makes sense.
[SPEAKER_02]: I think like the next step is to send off infectious work up, but I feel like often the testing comes back negative most of the time and what happens if we can't find a source.
[SPEAKER_03]: Dr. Bo actually broke down Neutropenic fever into three categories that can help guide your thinking.
[SPEAKER_00]: When I think about neutropenic fever syndromes, I've always classified them in three ways.
[SPEAKER_00]: I'm oversimplifying it.
[SPEAKER_00]: They're either microbiologically documented infections where I've got a pathogens and I have a place where the pathogens coming from, like the blood or the blood.
[SPEAKER_00]: And the next, of course, is the clinically documented infection, which is, by definition, we have a focus of infection, but I don't have a pathogen.
[SPEAKER_00]: And then the last one, which is almost the common, is the unexplained fever, where I have a surge syndrome, that is, since a semiconductor response syndrome.
[SPEAKER_02]: Oh, so that's helpful.
[SPEAKER_02]: It's basically thinking through, is it a microbiologically documented infection?
[SPEAKER_02]: Or is it a clinically documented infection where, say, you have a pass that is on a chest x-ray, but no pathogen?
[SPEAKER_02]: And then, last but not least, is an unexplained fever with a source syndrome?
[SPEAKER_02]: And might as well say, it feels so validating to hear someone say that, that is the most common scenario, because sometimes, if you're like a son of a pretty broad workup, and I'm thinking, okay, am I missing anything for this February on Japan patient?
[SPEAKER_03]: I feel like it can drive you crazy thinking about whatever test to order for these patients.
[SPEAKER_03]: So just to summarize her four, which is work up a fat brown utropina and how do you move through that fifteen minute window to get these patients to treatment and the first step is to ask patients if they've had chemotherapy in the last six weeks.
[SPEAKER_03]: as your screening question and remembering that neutropinia typically occurs ten to fourteen days after cytotoxid therapy and then you know thinking about risk stratification you can probably more comfortably manage solid tumor patients who don't have their bone marrow affected as an outpatient if they have stable vitals and then you know for patients who you do have that bone utropinia or sending that infectious work up
[SPEAKER_03]: You can classify them as having infections that are microbiologically documented, clinically documented, or an unexplained fever.
[SPEAKER_02]: So let's say we completed the work-up of the wrongish pinia in that critical first-hour, especially because the mortality is so high with their septic hypotensive.
[SPEAKER_02]: But I think the other big question that comes up is what's the right animal I ought to start.
[SPEAKER_03]: I think thankfully if the guidelines are produced straightforward here, you need something that covers pseudomonas.
[SPEAKER_03]: So the typical three to reach out for would be sephatine, piprocylind, taste-of-backedum, or marropanum.
[SPEAKER_02]: Hmm, what about Link of Ice?
[SPEAKER_02]: And I feel like I've seen that added pretty frequently.
[SPEAKER_03]: Oh, yeah, the classic combination of vanks, suffope, or vanks, those in.
[SPEAKER_03]: It's a great point.
[SPEAKER_03]: Vingo Misen isn't actually recommended as the first line.
[SPEAKER_03]: It's generally only recommended if you have an epidemic instability or known versus colonization and the infection source that's likely to be mercy.
[SPEAKER_03]: So something like gram positive, coxide, the blood cultures, pneumonia, soft tissue infection, or severe mucositis.
[SPEAKER_02]: So it sounds like Thinkhamisen is not routine standard of care for the Brown and Gopinia.
[SPEAKER_02]: It's only based on specific clinical scenarios where there is a high suspicion of Versa.
[SPEAKER_02]: The other thing Casey, I feel like I've seen people do when they're really worried about patient, is add fungal coverage.
[SPEAKER_03]: Yeah, you know, I think your patient's not doing well, you're like, what else can I add on?
[SPEAKER_03]: But I think the question of adding anti-fungal is actually where the neutrophil count in duration can play a big role as well too.
[SPEAKER_01]: Yeah, need to filter our workhorse.
[SPEAKER_01]: They, you know, the cell that's the most common.
[SPEAKER_01]: It really fights off like all the infections.
[SPEAKER_01]: And again, bacteria is like the main one, but fungal is common.
[SPEAKER_01]: If you want to emphasize though, that are concerned about fungal infection, really isn't there until need to filter two hundred or lower.
[SPEAKER_01]: And again, that's really in the context of multiple days.
[SPEAKER_02]: Yeah, I really appreciate hearing this rule of thumb for fungalities.
[SPEAKER_02]: It's an absolute drill countless and two hundred and a duration being at least more than two days of neutropenia.
[SPEAKER_03]: That also generally lines up with guidelines that will link to in the show notes that generally recommend adding anti-fungal coverage if patients aren't responding to antibiotics within three to seven days.
[SPEAKER_00]: It's not really the neutrophil count that I'm thinking about, even though the neutrophil count is a risk factor for opportunistic infections.
[SPEAKER_00]: But it's a context, the patient with acute myloid leukemia, and given the kind of treatments that such patients have, the expectation is that they're going to be at risk as a function of severe neutropenia for a lot longer than other kinds of other patient groups.
[SPEAKER_02]: So the risk of fungal infection isn't just about neutrophils being less than two hundred or more than two to three days of that low-neutral count.
[SPEAKER_02]: It's really also the context, right?
[SPEAKER_02]: And it seems like the highest risk is going to be malignant heat patients, like someone with AML.
[SPEAKER_02]: All right, Casey, I'm sorry to feel better about kind of what to start in federal and European.
[SPEAKER_02]: I think maybe the teaching, and more importantly, I think what not to start right away.
[SPEAKER_02]: But I think the other big thing that we often hum and hum about is how long to keep these patients on antibiotics.
[SPEAKER_03]: It is a question that I feel like I've struggled with a lot, and that I've also seen practice a lot of different ways as well.
[SPEAKER_03]: But all the major society guidelines tend to agree that antibiotics can be discontinued when patients show a trend towards recovery, and are AFEBrel and asymptomatic for at least four to eight hours with negative blood cultures.
[SPEAKER_02]: You know, that first part you said were, you know, trending towards recovery.
[SPEAKER_02]: What does that even mean?
[SPEAKER_02]: Is it just like, oh, you have two days of neutrophil's going up or is there a certain absolute neutral count threshold that we feel comfortable?
[SPEAKER_02]: Okay, I'm going to discontinue antibiotics and this patient who had febriol neutropenia.
[SPEAKER_03]: I mean, it's a great question because there's no strict definition of recovery, which is why actually, I think you can see a variety of responses.
[SPEAKER_03]: Some clinicians will step in a biodex based on clinical response and time a febrile.
[SPEAKER_03]: Well, others might use like a threshold of neutral recovery of ANC above one thousand.
[SPEAKER_00]: We maintain them on anti-bacterial therapy until they're a febral for four to five a febral days and then consider discontinuance.
[SPEAKER_00]: Now typically, now this is where it gets predictable again.
[SPEAKER_00]: In a patient with an AML patient who has a neutropenic fever syndrome,
[SPEAKER_00]: and you give them whatever regimen you have.
[SPEAKER_00]: And if it's effective, it'll take a median of five days for them to death or vests.
[SPEAKER_00]: It's just an empirical observation from our clinical trials.
[SPEAKER_00]: So it's a median of four to five days before they'll death or vests.
[SPEAKER_00]: And if you treat them for another four to five days, a federal add that up.
[SPEAKER_00]: Now you're getting close to ten days.
[SPEAKER_02]: So it sounds like either way the body recovers when it recovers in most patients.
[SPEAKER_02]: with intrapenic fevers get roughly about seven to ten days of antibiotics total.
[SPEAKER_03]: You know, the other cool thing about seven to ten days is that that's also the expected time for gut mucosal recovery as well too.
[SPEAKER_00]: The other organ system that is pertinent to the conversation is the lining of the gastrointestinal tract from the bromideon border to the anal border.
[SPEAKER_00]: And again, a patient getting cytotoxic therapy may have cytotoxic therapy induced epithelial damage of the gut, which again allows for the translocation of colonizing organisms into the
[SPEAKER_00]: subucosal tissue and causing systemic infection.
[SPEAKER_00]: And so part of my thinking here is I have to do account when I wait to recover.
[SPEAKER_00]: And it typically recovers about the same time as the ANC recovers.
[SPEAKER_02]: Wow, how cool and convenient that gut mucosa and the ANC recovery go hand-to-hand.
[SPEAKER_02]: So let's say we do have an infection source, you know, does that change then how many days we're putting this patient on antibiotics?
[SPEAKER_03]: Yeah, absolutely.
[SPEAKER_03]: You know, if you identify a specific pathogen or source, that kind of supersedes everything we just said about our seven to ten-day rule of thumb, you should actually follow the standard guidelines for the infection that you identified.
[SPEAKER_00]: If you knew it was a pseudomonasarogenosobacteremia, you would then be using the guidelines for bacteric patients as a guideline for a duration of antibiotic therapy.
[SPEAKER_02]: All right, last thing to run out of discussion that I've been thinking about a lot as we're talking is GCSF, granalsite colony simulating factor.
[SPEAKER_02]: Why don't we just give our patient some of this to estimate some neutrophils and reduce the time of neutropenia, right?
[SPEAKER_02]: We learned time is infection.
[SPEAKER_03]: You think it would work, but actually it's like the one area where there's pretty strong consensus against routine use of GCSF for patients with neutropenic fever.
[SPEAKER_02]: I think GCSF would improve outcomes now.
[SPEAKER_03]: Yeah, so they did randomize control trials and giving GCSE for patients with chemotherapy induced febral neutropenia, which did note decreased hospitalization times and decreased periods of neutropenia, but there were no changes in overall mortality or mortality from infection.
[SPEAKER_02]: Hmm, people who care about length of stay will, like Juicy SF then.
[SPEAKER_02]: But yeah, I guess, you know, the fact that there's a strong condos again.
[SPEAKER_02]: So I guess, maybe that goes back up to like Dr. Bowie's point that he made earlier that the timeline for a new Drupionia recovery, especially if it's chemotherapy induces relatively predictable.
[SPEAKER_02]: And if you're already close to that timeframe for recovery, then Juicy SF might not give you much benefit for the cost.
[SPEAKER_03]: You know, I think again, like there's always some caveats and in the right context, like you can consider GCSF or high-risk patients.
[SPEAKER_03]: So these are patients who have prolonged neutropenia over ten days, really profound neutropenia under a hundred cells per microliter or other factors that really increase your mortality from infection, like age over sixty five, severe sepsis, or really bad invasive fungal disease.
[SPEAKER_02]: All right, so let's summarize what we learned so far about antibiotics.
[SPEAKER_02]: In terms of starting antibiotics, we're going to reach for in federal Wikipedia and a suitable antibiotics within that first hour.
[SPEAKER_02]: And consider anti-fungal coverage if that absolutial count is less than two hundred for more than at least two days.
[SPEAKER_02]: And it's a patient who is at higher risk of infections, like blood cancers.
[SPEAKER_02]: And then we're going to continue antibiotics and stop it based on the absolute control count recovery.
[SPEAKER_02]: You know, some people do have a threshold of, you know, if it's above a thousand for at least forty hours, which again, also falls usually within the seven to ten day range anyway.
[SPEAKER_02]: And then of course, just to say, if you do have a specific infection source, then you would let that ride your antibiotic choice duration and not as much the seven to ten day rule.
[SPEAKER_03]: So that wraps up our episode on your Trappinian Feverone, Trappinia.
[SPEAKER_03]: If you want to add any of your own chips or shared challenges, tweet us and leave a comment on our website page on Instagram or Facebook.
[SPEAKER_03]: Thank you to our peer reviewer, Dr. Honeyelle, some curry.
[SPEAKER_02]: And as always, we love hearing feedbacks who email us at helloacorianpodcast.com.
[SPEAKER_02]: The opinion you can express to our own and do not represent the opinions of any affiliate institutions.
[SPEAKER_02]: Thank you.
[SPEAKER_02]: Take care.