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Time Stamps

• 02:24 Pearl 1: Risk Stratification of Neutropenia
• 11:38 Pearl 2: Workup of Neutropenia
• 19:46 Pearl 3: Timeline of Neutropenia Recovery
• 26:56 Pearl 4: Febrile Neutropenia
• 33:02 Pearl 5: Management of Febrile Neutropenia

Show Notes

PEARL 1: Risk Stratification of Neutropenia

• Don’t use the classic definition of neutropenia of absolute neutrophil count (ANC) < 1500 as the primary determination of risk in neutropenia
  • Neutropenia can be subdivided into mild (1000-1500 ANC), moderate (500-1000 ANC) and severe (< 500 ANC)
  • The threshold of ANC < 1500 came from studies in 1980s to quantify chemotherapy toxicity in cancer patients receiving intensive, myeloblative treatment and may not apply to all patients
  • Our measurements are imprecise: neutrophils live in the blood stream for 3-24 hours and peripheral blood only captures about 1-5% of total mature neutrophils
• Duffy Null Associated Neutropenia (previously known as benign ethnic neutropenia) is a type of neutropenia without change in immune function
  • Caused by a genetic variant that provides evolutionary advantages to malaria caused by Plasmodium Vivax
  • Patients with Duffy Null have lower peripheral neutrophil counts but completely normal total body neutrophil counts and immune function
    • This is because neutrophils sequester in the spleen as opposed to the peripheral blood
  • Highly prevalent in Subsaharan Africa and into the Arabian peninsula (80-100% population in West Africa with null phenotype) and ⅔ of self identified black individuals in the US have the Duffy null phenotype
  • Test for the Duffy Null phenotype for ANC 1,000-1,500 in patients of African or Middle Eastern ancestry
• Patients with ANC < 500 are at higher risk of inadequate total body neutrophils and infection risk
  • Other factors such as longer duration of neutropenia and concurrent immunosuppression (with chemotherapy, rituximab, T cell suppressants) will also increase infection risk in these patients

PEARL 2: Workup of Neutropenia

• First Question: Is this isolated neutropenia or pancytopenia?
  • For isolated neutropenia (without anemia or thrombocytopenia), hematologic malignancies are uncommon causes and bone marrow biopsies are usually not recommended
• History, not lab tests, often reveals cause of isolated neutropenia
  • Medications
  • Comorbidities (Ask about autoimmune diseases, conditions like gastric sleeve surgery or celiac disease that may cause nutritional deficiencies or malabsorption)
  • Symptoms (Rheumatologic, infectious)
  • Severity of neutropenia
  • Pattern of Neutropenia (chronic neutropenia often less concerning than acute neutropenia)
• There are two distinct patterns of medication induced neutropenia: Dose and duration dependent vs. immune mediated/idiosyncratic
  • Type 1: Dose and duration dependent medication induced neutropenia is often gradual onset and can be managed with dose reduction
    • Medications: mycophenolate, azathioprine, ganciclovir, linezolid
  • Type 2: Immune mediated/idiosyncratic medication induced neutropenia usually causes abrupt, severe neutropenia as a result of development of antibodies
    • Medications: clozapine, methimazole, PTU, dapsone, sulfasalazine
    • These medications must be stopped and cannot be restarted
• Obtain urgent hematology referral for any new ANC < 500

PEARL 3: Timeline of Neutropenia Recovery

• It takes 7-10 days to produce a mature neutrophil from hematopoietic stem cell
• Neutrophil recovery depends on the cause, which affects bone marrow recovery
  • 10-14 days: Viral Infections and Immune mediated drug neutropenia
    • For immune mediated neutropenia, there is rapid recovery once drug is stopped as antibodies need both drug + neutrophils to cause neutropenia
    • Timeline depends on drug half-life – shorter half-life drugs recover faster
  • 3-4 weeks: Dose dependent drug neutropenias
    • Similar to chemotherapy induced neutropenia, lowest point of neutropenia usually occurs 14-21 days after drug exposure
    • Recovery may take longer if there is dose reduction vs complete cessation of the causative agent
  • Variable: Autoimmune diseases & myelodysplastic syndromes (MDS)
    • Treatments for autoimmune disease (such as azathioprine or cyclophosphamide) can sometimes cause neutropenia, but if neutropenia is from autoimmune disease, using these treatments can sometimes paradoxically improve the neutropenia
    • Some conditions such as MDS, even with treatment or chemotherapy, there may not be neutrophil recovery
• Counseling and precautions while patients are neutropenic
  • It is very important to counsel on infectious symptoms such as fever, mouth ulcers, and diarrhea
  • Other precautions are more mixed in their efficacy on preventing infections in neutropenic patients: footwear exchange, positive pressure rooms, respiratory and surgical masks, or neutropenic diets
• Antimicrobial prophylaxis while neutropenic is only recommended when patients are expected to have ANC ≤100 cells/mm3 for >7 days by IDSA guidelines
  • These are usually hematologic malignancy patients undergoing chemotherapy
  • Antibacterial Prophylaxis: Most commonly fluoroquinolone (to cover Pseudomonas)
  • Antifungal prophylaxis: Usually an -azole that can cover yeast and molds, like posaconazole or isavuconazole

PEARL 4: Diagnosis of Febrile Neutropenia

• Febrile neutropenia is a clinical emergency with potentially high mortality, but risk stratification can guide management approach
  • In-hospital mortality can reach 50% in patients who develop severe sepsis or septic shock
  • Guidelines recommend workup within 15 minutes of triage, antibiotics within 1 hour
• Key Screening Question for febrile neutropenia: “Have you had any chemotherapy or anti-cancer treatment in the last 6 weeks?”
  • If answer is yes, assume potential neutropenia until proven otherwise
  • Highest risk period: 1-2 weeks post-chemotherapy (expected nadir in ANC at days 12-14)
• Risk Stratification: Who can potentially be treated as an outpatient?
  • Lower risk and potential outpatient management
    • Overall, patients who are expected to have functional bone marrow, short durations of neutropenia, and stable vital signs
    • These are more commonly solid tumor cancer patients receiving cyclical chemotherapy
  • Higher risk and often require inpatient management
    • Usually hematologic malignancy patients (leukemia, lymphoma) will have prolonged, more severe neutropenia as they have “double hit ot their bone marrow: cancer and chemotherapy
  • Risk calculators such as CISNE and MASCC have been developed and validated to identify low risk patients
• Classification of Neutropenic Fever syndromes
  • 1. Microbiologically documented infection: identified pathogen with source (blood, urine, etc.)
  • 2. Clinically documented infection: clear focus of infection (Pneumonia on chest XR, cellulitis) but no pathogen identified
  • 3. Unexplained fever: SIRS syndrome without identified source (which is the most common scenario)

PEARL 5: Management of Febrile Neutropenia

• What should you start for treatment for febrile neutropenia?
  • First line treatment: Antipseudomonal antibiotic (cefepime, piperacillin-tazobactam, meropenem)
  • Vancomycin is NOT considered standard of care, but added in specific clinical scenarios
    • Hemodynamic instability
    • Known MRSA colonization AND infection source likely to be MRSA (Gram positive cocci in blood, pneumonia, soft tissue infection, severe mucositis)
  • Antifungal coverage depends on specific risk factors and situations
    • High risk for fungal disease: ANC < 200, Duration of neutropenia >2-3 days, and hematologic malignancies like AML
    • Guidelines generally recommend adding antifungal coverage if patients are not responding to antibiotics in 3-7 days
• Duration of antibiotic therapy in febrile neutropenia
  • Antibiotics can be discontinued when patients show trend towards recovery, which there is no strict definition for, but can include:
    • ANC threshold > 1000
    • Clinical response and time afebrile
    • There have been a few randomized clinical trials, such as HOW LONG (2017) that suggest shorter duration of antibiotics could be implemented, as patients with neutropenic fever had antibiotics discontinued after 72 hours and clinical recovery regardless of neutrophil count, but overall, they have not been adopted into official guidelines or recommendations given variability in trial/study design and evidence (Cochrane Reviews).
  • Usually, regardless of definition of clinical recovery, most patients are on antibiotics for 7-10 days
    • Median time to defervescence: 5 days + additional 4-5 days afebrile = ~10 days total
    • This timeline also coincides with gut mucosal recovery, as the gut mucosa can be damaged with cytotoxic therapy and allow for bacterial translocation that can cause systemic infection
  • But if an infection source is identified, this supersedes the 7-10 day rule and one should treat the specific infection identified (example: Pseudomonas bacteremia should be treated per bacteremia guidelines, not as unexplained neutropenic fever)
• Consensus is against routine Granulocyte Colony Stimulating Factor (GCSF) to treat febrile neutropenia
  • Metaanalysis of randomized control trials showed G-CSF decreased hospitalization time and neutropenia duration, but no improvement in overall mortality or infection-related mortality
  • Consider GCSF in high risk patients: Prolonged neutropenia >10 days, profound neutropenia <100 cells/μL, Age >65 years, Severe sepsis, Invasive fungal disease

Transcript

Dr. Lauren Merz: I have a colleague who’s based in the UK, who, as a medical student in the UK, had anemia from heavy menstrual periods, very common in women, and then also has the Duffy null phenotype. And so her PCP saw, you know, two cytopenias, a low neutrophil count, and referred her to a hematologist, right? And told her that it might be leukemia. So she’s a stressed out medical student, you know, just trying to get by and thinking that she had leukemia.

Dr. Shreya Trivedi: That was Dr. Lauren Merz, a hematologist at the University of Michigan. Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. This is Dr. Shreya Trivedi.

Dr. Casey Kim: And I’m Dr. Casey Kim, a Hematology Oncology Fellow at Tufts Medical Center. And today, we’re bringing you the Core IM episode on neutropenia and febrile neutropenia.

Dr. Shreya Trivedi: I’m so thankful that you brought this episode to life, because I think I learned so much about the nuances of neutropenia, and I think there’s a lot of guiding principles that can help us try to figure some of this out a little bit better.

Dr. Casey Kim: So everyone keep calm, and we’ll carry on with our new episode on neutropenia and febrile neutropenia with the following five pearls. Make sure to test yourself by pausing after each of the five questions.

Dr. Shreya Trivedi: And remember, the more you test yourself, the deeper your learning gains.

Dr. Casey Kim: Pearl 1: Risk Stratification of Neutropenia

Dr. Shreya Trivedi: What level of neutropenia increases your infection risk? And what are the types of neutropenia that gives you the highest risk of infection?

Dr. Casey Kim: Pearl 2: Workup of Neutropenia

Dr. Shreya Trivedi: What do you consider when working up new neutropenia and what patterns matter the most?

Dr. Casey Kim: Pearl 3: Timeline of Neutropenia Recovery

Dr. Shreya Trivedi: How long does it take for a patient to recover their neutrophil counts? And what should you counsel patients on during this process?

Dr. Casey Kim: Pearl 4: Febrile Neutropenia

Dr. Shreya Trivedi: What is febrile neutropenia? And what is febrile neutropenia, and how do you assess and triage these patients?

Dr. Casey Kim: Pearl 5: Management of Febrile Neutropenia

Dr. Shreya Trivedi: How long do you treat fibroid neutropenia with antibiotics? And when do you consider adding treatment like antifungals?

PEARL 1 – Risk Stratification of Neutropenia

Dr. Casey Kim: 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 700.

Dr. Shreya Trivedi: what a tough place to be in. What’d you do?

Dr. Casey Kim: I just discharged him. He was feeling fine, but honestly, I felt a little uneasy sending him out when I knew he was neutropenic.

Dr. Shreya Trivedi: I know that feeling, especially when we see neutropenia. 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.

Dr. Lauren Merz: We really like the rules. You know, we like that we have to transfuse at seven, and we always transfuse at seven, whether you’re inpatient or in surgery or outpatient. I think we often try to apply the same rules to neutropenia. I think a lot of us learned that an absolute neutral count of 1500 or lower counts as neutropenia. And then many of us also learned those subdivisions of, you know, less than 500 is severe, between, you know, 500 and 1000 is moderate, and 1000 to 1500 is mild. I think that we need to step away from a lot of those rigid definitions, and instead, first look at the patient in front of us, and look at their clinical context, and look at the numbers themselves last.

Dr. Shreya Trivedi: Wait, so where are these numbers come from?

Dr. Lauren Merz: I really started to look into the where did we come up with the number 1500, and I couldn’t find a good answer in all of my research. The best I can find is that in the 1980s we were trying to figure out how to quantify toxicity from chemotherapy. Back in the 1980s, we were giving some very intense chemotherapy that was totally myeloablative, really big doses, and we were trying to define toxicity in a way that we could all agree with, and that’s where that number of 1500 came from.

Dr. Casey Kim: So essentially, we’ve been applying a threshold developed for cancer patients getting intensive chemotherapy to everyone! …. That seems like a pretty big leap to me.

Dr. Shreya Trivedi: 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.

Dr. Lauren Merz: White blood cells only live in the bloodstream for 3 to 24 hours. You’re only seeing one to 5% of the mature neutrophils in the blood at any one time. And so I think appreciating that what we see in the blood is an imperfect proxy of what’s actually going on in the body and that there’s going to be a ton of fluctuation and variation even on an hour by hour basis just kind of allows us to appreciate the art of medicine.

Dr. Casey Kim: I think the variation we see hour by hour brings up another key point : that you can see the variation we may see on a population level as well too, and in particular something called Duffy Null Associated Neutropenia.

Dr. Shreya Trivedi: I’ll be honest here, I’ve heard of this term once or twice but never had a really good grasp on what that actually means clinically.

Dr. Casey Kim: So Duffy Null is a genetic variant in different proteins on different blood cell types that develop primarily as an evolutionary adaptation to malaria, specifically conferring resistance to Plasmodium vivax. But people with this variant typically have lower neutrophil counts in their peripheral blood, even though their total body neutrophil count is completely normal.

Dr. Lauren Merz: So we see in mouse models hasn’t proven in humans that we see in mouse models that when you don’t have the expression of duffy, it results in neutrophils that just a phenotypically different and tend to go to the spleen rather than hang out in the periphery. And so the total body Neutrophils are the same. What we see in the bone marrow is exactly the same, but the way that we measure blood by taking it from the periphery is going to be different for people who are Duffy Null versus Duffy Non Null.

Dr. Shreya Trivedi: Well. so these patients with Duffy Null have completely normal immune function, but we’ve been labeling them as neutropenic because their neutrophils hanging out in their spleen and not in the periphery where we take blood from.

Dr. Casey Kim: So you can imagine the sort of anxiety and the workups that patients and even clinicians go through with, you know, having these lower neutrophil counts.

Dr. Lauren Merz: In medical school, I remember as a teenager, who was quite a soccer star, like in the area, needed an ACL repair, and the surgeon declined to do the ACL repair until that he had a hematology workup, because neutrophils were at like 1200 right? So what we know is normal for someone with the Duffy Null phenotype, but was out of the reference ranges at the institution, so there is a delay in his surgery. It took a while to get the hematology. We said everything was okay, but by the time he got back to the surgeons, he had missed a lot of his season, right? And especially of a high schooler who’s thinking about college prospects, the really big deal. It’s hard to quantify these things. How you quantify that stress, or the time off work, or even just that sense of othering, being told that you’re not normal, or having your values always be red, but someone tells you you’re fine, your values are red you’re just like that disconnect. It’s distressing. There’s evidence that people with a Duffy null variant get more bone marrow biopsies. That is not a benign or easy thing to go through, right? It’s fine if you need it and it’s essential for your clinical care, but that’s not a casual test to get. We also see things like azathioprine use for lupus or other autoimmune disease. There is a higher rate of discontinuation for people with the Duffy null phenotype.

Dr. Casey Kim: You know, that’s crazy. I can see a bunch of patients who have Duffy Null phenotype and who get medications like their Clozapine stat because of neutropenia, even though it’s not the Clozapine that’s causing the neutropenia, but rather just the fact that they have this Duffy null phenotype and a normal ANC fluctuation.

Dr. Shreya Trivedi: Yeah, it just makes me wonder, like, how many patients I’ve seen with neutropenia, and how many of those cases I might have missed a Duffy Null phenotype.

Dr. Lauren Merz: So Sub Saharan Africa and into the Arabian Peninsula. In West Africa, we often see 80 to 100% of the population with the null phenotype. And in United States, among people who will self identify as Black or African American, we typically see two in every three people with the null phenotype.

Dr. Shreya Trivedi: Oh, that demographic is definitely helpful, because I think at the back of my mind, as I’m thinking, you know, who should I send off a Duffy null on? Is it everyone? And to speak to that a bit more, we sat down with Dr Jason Freed, a hematologist at BIDMC, and whose voice you may recognize very well from our gray matter segment.

Dr. Jason Freed: So the way I approach isolated neutropenia is that if absolute neutrophil count is 1000 to 1500 and they’re of African or Middle Eastern ancestry, I send Duffy antigen testing, and if they’re Duffy null, which two thirds of African Americans are, I reassure them. I do no further testing, no bone marrow biopsy, non invasive testing. That’s the answer.

Dr. Shreya Trivedi: So that’s helpful on who to send off that test. On what else should we be looking for when we try to distinguish Is this a normal variation, like Duffy Null Associated Neutropenia or some other etiology of neutropenia that, you know, gives a really higher risk of infection?

Dr. Casey Kim: You know, even though we just spoke about not placing too much value on the absolute number, for you know, the past couple minutes, it’s still good to keep an ANC of 500 in mind. Usually you wouldn’t expect to see an ANC of 500 or below in a patient with the Duffy null phenotype, and being below that particular threshold makes me think that you may just not have enough neutrophils in your body to fight off an infection.

Dr. Lauren Merz: So when Neutrophils are 500 or less, and what we can measure in the blood, we worry that the total body neutrophil counts are low, which means that a person is not going to be able to robustly site off any sort of infection or disease, and might need things like IV antibiotics or closer monitoring more than someone who has an ANC that’s 2000 or higher.

Dr. Jason Freed: Being below 500 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.

Dr. Shreya Trivedi: Okay, summarize what I’m taking away from this pearl. I think before diving into this, I had a knee-jerk response whenever I see an absolute neutrophil count less than 1500 Oh, they’re neutropenic, increased risk of infection. But we learned that that number came from patients on chemotherapy in the 1980s and not real world diverse non cancer patients. And think definitely gonna take away the fact that two thirds of black patients in us have a Duffy Null phenotype, and they can naturally have lower ANCs, but have a normal immune function. 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 Duffy Null antigen be at play, especially if they are from an African American or Middle Eastern ancestry? And of course, if that ANC number is under 500 then my worry about infection goes up much higher.

PEARL 2- Workup of Neutropenia

Dr. Casey Kim: So say your patient is not Duffy Null and but they are still neutropenic. You know, let’s go through how our discussants think through neutropenia, and how they would work up these cases.

Dr. Jason Freed: And so the first thing I’ll say is that the standard approach that you use for other cytopenias, it doesn’t work as well here. So this other general thing that we use to talk about, is it a production problem? Is it a destruction problem, or is it splenic sequestration, like the cells are hiding, like, 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.

Dr. Casey Kim: So we can talk about the first branch point in the neutropenia workup. Is this isolated neutropenia, or is this pancytopenia? If it’s pancytopenia, then you’re looking at an entirely different differential, and most of the time that’s straight to bone marrow biopsy.

Dr. Shreya Trivedi: But what if you just have isolated neutropenia? The red blood cells, the platelets, are fine. How do we think through that isolated neutropenia?

Dr. Jason Freed: If neutropenia is isolated, meaning that’s really the only CBC abnormality that you’re seeing. It’s an entirely different set of causes here, hematologic malignancies are not common causes at all. 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.

Dr. Lauren Merz: Nine times out of 10 in a neutropenia evaluation is about the history, and it’s rarely about the lab tests that you send off. I think a lot of times in our busy healthcare system, we’re very dependent on just wanting to send tests and have the tests tell us neutropenia is one of those entities where it’s we about the history more than about the tests that you send out.

Dr. Shreya Trivedi: All right. 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.

Dr. Jason Freed: Well, the list is pretty long, but you can narrow it down pretty quickly based upon paying attention to a few factors. One is their medications. Two is other diseases they have. Three is other symptoms they have that you might not have made a specific diagnosis. Around four is the severity of the neutropenia, because completely different things cause you’d have severe neutropenia. From mild neutropenia, and five is the pattern of the neutropenia. And so here’s where having multiple CBCs of differential can be really helpful.

Dr. Shreya Trivedi: So with those five thinking through meds, what other diseases they have, other symptoms, like rheumatologic ones that might signify that. The cause, the severity of the neutropenia, and the pattern of the neutropenia. I think those five things, it was really, when we spoke to our experts, that the money is really in that first one, the medications, and that is what we’re going to focus on.

Dr. Jason Freed: And just to take a step back, if you’ve ever been working up a patient for neutropenia, and you’re like, Okay, well, I know meds are a cause. Let me go online and see which of the medications this patient’s on cause neutropenia. It’s crazy making, because you look it up at every single medication has neutropenia listed as a possible side effect. So it’s like, what am I supposed to do with that? There are two types of medication related neutropenia, but they’re the same two types of medication related problems that exist for everything. Which is for everything. Which is the problem can be dose and duration dependent, or it can be idiosyncratic, also known as immune mediated. And the reason why that distinction is so important is because the patterns are entirely different, and what you do is entirely different.

Dr. Shreya Trivedi: 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 the duration and dose of a medication, or is this a problem because of an immune related problem?

Dr. Casey Kim: 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.

Dr. Jason Freed: And they’re probably medicines you already know about. So these are medications like mycophenolate, like azathioprine, like ganciclovir, like six mercaptopurines. What do all those drugs have in common? They’re all nucleotide analogs, right? They’re like, basically like, the same thing as chemo, right? They obviously affect DNA replication. Now, that should affect all your cell lines, but for whatever reason, they tend to cause neutropenia as a big problem. So those medications, if you’re on those and you’re neutropenic, there’s a good chance it’s at least contributing.

Dr. Casey Kim: 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. Take linezolid, for example, which can cause dose and duration-dependent neutropenia. If you use linezolid for a 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;, in that case, you’ll actually see cytopenias in like a third of patients who receive that treatment course.

Dr. Shreya Trivedi: Hmm, yeah, so duration definitely can matter. 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, say they have autoimmune disease or solid organ transplants. What do we do with that.

Dr. Casey Kim: 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. But the good news is, 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

Dr. Shreya Trivedi: Nice, okay, so say this is not a dose dependent neutropenia. It’s an immune mediated neutropenia. How do we think about that a little differently?

Dr. Casey Kim: So for these medications that cause immune mediated neutropenias, you see a much more abrupt and often much more severe neutropenia.

Dr. Jason Freed: When you have neutropenia, for example, from Clozapine, you start Clozapine, you’re fine, you’re fine, you’re fine, you’re fine, you’re fine. And all of a sudden, one day, your ANC is zero, okay, your absolute neutrophil count is zero. You have severe, life threatening neutropenia. So immune mediated neutropenia has this very different pattern to it.

Dr. Shreya Trivedi: I guess I now understand why Dr. Freed calls it idiosyncratic, right? These meds can cause your immune system to just hijack your neutrophils all of a sudden. It kind of happens randomly and idiosyncratically. The other common offenders, in addition to Clozapine, is going to be in the endocrine world, methimazole, PTU, and then other meds, like dapsone or sulfasalazine can also abruptly drop your neutrophils.

Dr. Jason Freed: And the reality is that I think people are already familiar with this concept, because they know about heparin-induced thrombocytopenia, right? Where the first time you’re exposed to Heparin, you don’t get hit until at least five days, right? It’s like the five to 10-day thing, because it takes time to make the antibodies. Whereas, if you’ve been exposed to heparin recently, you may have already been primed, then you can see it in less than 24 hours. Four hours. Same thing is true for drug related isolated neutropenia through immune-mediated mechanisms, and it’s idiosyncratic, meaning it’s unpredictable. The idiosyncratic immune mediated 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.

Dr. Shreya Trivedi: And our experts did recommend that if the patient’s ANC is less than 500 that definitely requires a hematology evaluation. But if it’s more mild or moderate, you know, ANC in the 500 1200 more of a gradual process, then you do have time to work it up, just to say it out loud.

Dr. Casey Kim: But in summary, you know. Start your workup of neutropenia with the question, is there pancytopenia or isolated neutropenia? If it’s isolated neutropenia, you can forget the bone marrow biopsy and just do a good medication and symptom review. Pay attention to a trend of neutropenia, 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.

PEARL 3- Timeline of Neutropenia Recovery

Dr. Casey Kim: 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? And If so, when?

Dr. Shreya Trivedi: Yeah, I feel like that’s a great question. When will the neutrophils recover? 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 dice roll, time is infection, and they can and are at a risk for serious infection.

Dr. Casey Kim: But, you know, I think the neutrophil count recovery has a lot to do with what’s causing the neutropenia in the first place.

Dr. Lauren Merz: A lot of that, too, comes down with how fast Neutrophils are made. It takes, you know, 7 to 10 days to make a mature neutrophil, from hematopoietic stem cell to mature neutrophil, and they live in the periphery for 3 to 24 hours. So a lot of it is based on that.

Dr. Shreya Trivedi: So it takes about 7 to 10 days to make a mature neutrophil. And I guess that’s what I’ve seen when it comes to a patient who has a viral infection and that causes neutropenia. It often does take, you know, 10 days-two weeks, for that neutropenia count to really get better, and things not to be so so red in the EMR.

Dr. Casey Kim: Yeah and I feel that 10 to 14 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.

Dr. Jason Freed: But take away the drug, the antibodies don’t do anything to your neutrophils. It requires the combination of the drug plus your neutrophils to have an effect. And the good news is that in drugs without long half lives, once you stop the drug, there’s usually a relatively rapid recovery

Dr. Casey Kim: But we do have a slightly delayed timeline for one big category of medications, you know, dose-dependent medications?

Dr. Jason Freed: If you remember from your oncology rotations, when you give chemo, you give it on day one, and then there’s usually a Nadir in their neutrophil count between days 14 and 21 depending on the regimen, and then it starts coming back, back up around three to four weeks after you gave the chemo. So the same thing happens with neutropenia from mycophenolate or ganciclovir or these other things that are causing dose and duration dependent. You stop the drug, but it could be several weeks before it comes back up. And a lot of times it’s even longer, if the way that you’re managing the managing this is by dose reduction, because with dose and duration dependent neutropenia. It doesn’t mean you can’t use the drug at all. A lot of times it just means that you need to give them less because it’s dose dependent.

Dr. Shreya Trivedi: It’s like chemotherapy induced neutropenia, you know, say, if it’s drug related, like mycophenolate induced neutropenia, it’s gonna really peak. That neutropenia is gonna really peak at two to three weeks post treatment, and then start to recover around week 4.

Dr. Casey Kim: No, I think the general jist is stop the medication causing the neutropenia, your bone marrow will recover after some time, like three or four weeks.

Dr. Shreya Trivedi: What about neutropenia is caused from chronic disease like neutropenia related to autoimmune disease?

Dr. Casey Kim: So that can be a little bit of a tricky situation. You know, on the one hand, you want to treat autoimmune diseases that are causing the neutropenia, but a lot of the medications used to treat these diseases can also cause neutropenia. So, you know, it feels like a little bit of a catch 22.

Dr. Jason Freed: I almost think about that situation in Cardiorenal syndrome where they have AKI and you’re afraid to use diuretics, and then everyone’s like, you got to push through, you got to diurese them, and then all of a sudden their creatinine starts getting better despite the diuresis, and you’re like, ah, yes, I knew this could happen, but I’m always so worried it’s not going to work how I want it to. Right. The same thing is true when you use immunosuppressives that can cause neutropenia in patients who have autoimmune diseases is that it gets better once you get them on treatment. The same thing is true when we treat people with LGL leukemia who have severe neutropenia, we give them methotrexate, we give them cyclophosphamide medicines that can potentially cause neutropenia, but it gets better as it starts treating the actual disease. So you have to sort of trust slash hope that it’s going to be more likely to cause the benefit than it is to cause the harm.

Dr. Shreya Trivedi: All right, so say our patient has a chronic illness that’s causing neutropenia. We’re hoping the neutrophil count will get better with treatment, but to put on my worst case scenario hat, I guess. What if it doesn’t get better? What if the neutrophils don’t get better?

Dr. Casey Kim: You know, to be honest, like sometimes it doesn’t. That’s a point that our third discussant, Dr. Eric Bow, a hematologist, oncologist, and infectious disease physician at the University of Manitoba, in cancer care Manitoba brought up.

Dr Eric Bow: There are going to be cases, however, where you don’t expect the ANC to recover, where myeloid recovery is not going to occur, such as myelodysplastic states and giving high dose chemotherapy in the context of high dose myelodysplastic states, the physician shouldn’t be waiting around for that ANC to recover, that may never recover, and knowing that context can help the clinician manage the patient safely.

Dr. Shreya Trivedi: Yes, 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?

Dr. Casey Kim: You know, I think the fact of the matter is that these patients with prolonged neutropenia are at higher risk for serious infection. So I think in that case, the most important thing to do for them is to counsel them about new fevers, mouth ulcers, diarrhea, or really, any other symptoms concerning for infection.

Dr. Shreya Trivedi: Yeah, and then I can imagine patients scouring the internet really finding all these things like wearing special masks or a neutropenic diet. I think I’ve had patients ask me, Yeah, can I eat fruit? Can I eat salad?

Dr. Casey Kim: I struggle with that question. You know, I never want to tell people like they can’t have fruit or salad, but you never know. But actually they’ve looked into interventions such as footwear exchange, protected environments like positive pressure rooms, respiratory or surgical masks. Neutropenic diets, which is basically, you know, no fruits or vegetables and nutritional supplements, but none of those are clearly recommended because there’s mixed evidence that they don’t really prevent infections for neutropenic patients. And actually, a lot of the data tends to side towards that these precautions are not more effective at preventing infections, you know. So let your neutropenic patients eat fruit.

Dr. Shreya Trivedi: Nice, nice, yeah. Let me eat. Let’s summarize what we’ve learned so far with the neutrophil recovery. It’s really seems like the timeline can vary based on what the cause is, if it’s something viral, immune mediated cause. Then the recovery can be relatively more quick, 10 to 14 days, depending on that half life of the drug that’s causing an immune response. And then as long as the Neutrophils are being made, it’s gonna be around that 10 day, two week timeline. If it’s from chemotherapy or drug dependent neutropenia, it could take longer, three to four weeks. And then autoimmune causes can improve a treatment, but might never fully normalize. And then there are some conditions, like myelodysplastic syndrome that you might not expect from recovery.

PEARL 4- Febrile Neutropenia

Dr. Shreya Trivedi: Let’s move on to febrile neutropenia. I feel like we’ve all been taught, you know, febrile neutropenia, it’s a clinical emergency. Time is of the essence. But to be honest, sometimes I like, you know, get all on edge, like, okay, febrile patients here are admitting this person, and I go in the room and I’m like, This person doesn’t look that sick.

Dr Casey Kim: Yeah, I think appearances can be deceiving. You know, I think there are some patients who are fine with febrile neutropenia, but for those patients who do develop febrile neutropenia and severe sepsis or septic shock, the in hospital mortality rate can be as high as 50% as documented by some retrospective studies.

Dr. Shreya Trivedi: That is a lot. And I guess the takeaway is like, you know, febrile neutropenia patients, if they get sick, they get really, really sick.

Dr Casey Kim: Yeah, so you know, different societies and guidelines (the American Society of Clinical Oncology or ASCO and Infectious Diseases Society of American or IDSA) are pretty clear about the timeline for workup and management for febrile neutropenia. You know, most recommend initial workup within 15 minutes of triage and starting antibiotics within one hour of determining febrile neutropenia.

Dr. Shreya Trivedi: Workup in 15 minutes. That is fast. But here’s like, my challenge, my devil’s advocate, to that. Because, in reality, you know, patients come to ED with a fever, you don’t know if they’re neutropenic, and labs take a while to come back or see somebody calls you, or epic chats you saying they have a fever. 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.

Dr Eric Bow: Given a history we have done in our guidelines is to use a very simple, sensitive question that’s not very specific. It says, if you’ve had any chemotherapy or anti cancer treatment at any time in the last six weeks, yes or no, and the answer is yes, then it puts the likelihood that this could be a neutropenic episode, and I think that’s kind of unique for any of the different syndromes that you and I look at and manage over from day to day.

Dr. Shreya Trivedi: Wow. A simple question of, did you have chemotherapy in the last six weeks? Can be this helpful. And I guess that goes back to what we learned in our last Pearl, that neutropenia can be “predictable” in these patients.

Dr. Eric Bow: I think it’s predictable if we know the date of the incident that got it going in the first place, or the prudent incident, then usually chemotherapy. When did you get your treatment last? Oh, well, yes, Dr. Bo gave me my chop chemotherapy 12 days ago, and this is day 12. 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 12 and day 14.

Dr Casey Kim: So to summarize, I think you know which is really, how do you work up febrile neutropenia, and how do you think about things to be able to move quickly through that 15 minute window, to be able to get these patients to treatment within one hour. So ask your patients if they had chemotherapy in the last six weeks as your screening question, remembering that neutropenia typically occurs to 10 to 14 days after cytotoxic therapy. You know, and thinking about risk stratification, I would say that, you know, solid tumor patients who don’t have their bone marrow is affected may be candidates for outpatient monitoring if they have stable vitals. And then once you’re you know, kind of established febrile neutropenia, you can then start to categorize it as an infection that could be microbiologically documented, clinically documented or an unexplained fever.

Dr. Shreya Trivedi: Yeah. But say my patients, you know, did have chemotherapy in the last six weeks or so. Does that mean straight inpatient admission for febrile neutropenia, or can some of this be managed outpatient, especially if they’re seemingly well appearing.

Dr. Eric Bow: 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. For those that are would be considered low risk, and that’s usually the solid tumor population getting cytotoxic therapy in a cyclical fashion. In that population, we can often, as I mentioned earlier, treat them as an outpatient. And our duration is different, because the time to effervescence, at least in clinical trials and in our own experience, is only two to three days.

Dr Casey Kim: 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, I think especially comparing them to say like a patient who has leukemia and is getting chemotherapy. I think another reason that breast cancer patient is lower risk is because it’s really only the chemotherapy that’s affecting every bone marrow, as opposed to the leukemia patient who has both cancer and chemotherapy affecting their bone marrow. So you know, given that double hit, you would expect the leukemia patient to be more severely neutropenic for a longer period of time.

Dr. Shreya Trivedi: Hmm, interesting, and that makes sense, I think, like the next step is to send off infectious workup. But I feel like often, the testing comes back negative, most of the time. And what happens if we can’t find a source?

Dr Casey Kim: Dr. Bow actually broke down neutropenic fever into three categories that can help guide your thinking.

Dr. Eric Bow: When I think about neutropenic fever syndromes, I’ve always classified them in three ways. I’m oversimplifying it. They’re either microbiologically documented infections, where I’ve got a pathogen and I have a place where the pathogen is coming from, like the blood or the lung in that case. Then 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. And then the last one, which is almost the common, is the unexplained fever, where I have a SIRs syndrome, that is Systemic Inflammatory Response Syndrome.

Dr. Shreya Trivedi: Okay, so that’s helpful. It’s basically thinking through, is it a microbiologically documented infection, or is it a clinically documented infection where, say, you have a pasta use on chest X ray, but no pathogen? And then last but not least, is an unexplained fever with Sir syndrome. And might I say? It feels so validating to hear someone say that that is the most common scenario, because sometimes I feel like I send off a pretty broad workup and I’m thinking, okay, am I missing anything for this fibromain patient?

Dr. Casey Kim: I feel like it can drive you crazy thinking about whatever test to order for these patients. So just to summarize Pearl four, which is work up a febrile neutropenia. And how do you move through that 15 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 as your screening question, and remembering that neutropenia typically occurs 10 to 14 days after cytotoxic 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 febrile neutropenia or sending that infectious workup, you can classify them as having infections that are microbiologically documented, clinically documented or an unexplained fever.

PEARL 5 – Management of Febrile Neutropenia

Dr. Shreya Trivedi: So let’s say we completed the workup of febrile neutropenia in that critical first hour, especially because the mortality is so high with their septic, hypotensive but I think the other big question that comes up is, what’s the right antibiotic to start?

Dr. Casey Kim: Thankfully, the guidelines are pretty straightforward here. You need something that covers Pseudomonas. So the typical three to reach out for would be cefepime, piperacillin-tazobactam or meropenem.

Dr. Shreya Trivedi: Hmm. What about vancomycin? I feel like I’ve seen that added pretty frequently.

Dr. Casey Kim: Oh yeah, the classic combination of vanc cefepime or vanxosin. It’s a great pPoint, vancomycin isn’t actually recommended as the first line. It’s generally only recommended if you have hemodynamic instability or known MRSA colonization and an infection source that’s likely to be MRSA, so something like gram positive cocci in the blood cultures, pneumonia, soft tissue infection or severe mucositis.

Dr. Shreya Trivedi: So it sounds like vancomycin is not routine standard of care for fibronopenia. It’s only based on specific clinical scenarios where there is a high suspicion of MRSA. The other thing Casey, I feel like I’ve seen people do when they’re really worried about patient, is add fungal coverage.

Dr. Casey Kim: Yeah, you know, I think your patient’s not doing well. You’re like, what else can I add on? But I think the question of adding antifungals is actually where the neutrophil count and duration can play a big role as well, too.

Dr Lauren Merz: Yeah. Neutrophils are our workhorse. They you know, the cell that’s the most common, it really fights off like all the infections. And again, bacteria is like the main one, but fungal is common. Did you want to emphasize, though, that our concern about fungal infection really isn’t there until Neutrophils are 200 or lower? And again, that’s really in the context of multiple days?

Dr. Shreya Trivedi: Yeah, I really appreciate hearing this rule of thumb for fungal disease, it’s an absolute neutral count less than 200 and the duration being at least more than two days of neutropenia.

Dr. Casey Kim: That also generally lines up with guidelines that we’ll link to in the show notes that generally recommend adding antifungal coverage if patients aren’t responding to antibiotics within three to seven days.

Dr. Eric Bow: It’s not really the neutrophil count that I’m thinking about, even though the neutrophil count is a risk factor for opportunistic infections, but it’s a context the patient with acute myeloid 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.

Dr. Shreya Trivedi: So the risk of fungal disease isn’t just neutrophils <200 or more than 3 days of that low of neutropenia, its the context of the patient and it seems the highest risk is gonna be malignant heme patients like someone with AML. Casey, I’m starting to feel better about kind of what to start in febrile neutropenia. I think maybe the teaching and more importantly, I think what not to start right away, but I think the other big thing that we often hum and haw about is how long to keep these patients on antibiotics.

Dr. Casey Kim: It is a question that I feel like I’ve struggled with a lot, and that I’ve also seen practiced a lot of different ways as well, but all the major society guidelines tend to agree that antibiotics can be discontinued when patients show a trend towards recovery and are afebrile and asymptomatic for at least four to eight hours with negative blood cultures.

Dr. Shreya Trivedi: You know that first part you said, where you know trending towards recovery, like, what does that even mean? Is it just like, Oh, you have two days of neutrophils going up, or is there a certain absolute neutrophil count threshold that we feel comfortable? Okay, I’m going to discontinue antibiotics in this patient who had febrile neutropenia.

Dr. Casey Kim: I mean, it’s a great question, because there is no strict definition of recovery, which is why, actually, I think you can see a variety of responses. Some clinicians will stop antibiotics based on clinical response and time afebrile, while others might use like a threshold of neutrophil recovery of ANC above 1000.

Dr. Eric Bow: We maintain them on antibacterial therapy until they’re afebrile for four to five afebrile days, and then Consider discontinuance Now, typically, now, this is where it gets predictable again, in a patient like an AML patient who has a neutropenic fever syndrome, and you give them whatever regimen you have, and if it’s effective, it’ll take a median of five days for them to defervace. It’s just an empirical observation from our clinical trials. So it’s a median of four to five days before they’ll defervace, and if you treat them for another four to five days, afebrile, add that up now you’re getting close to 10 days.

Dr. Shreya Trivedi: So it sounds like either way, the body recovers when it recovers, and most patients with neutropenic fevers get roughly about 7 to 10 days of antibiotics total.

Dr. Casey Kim: You know, the other cool thing about seven to 10 days is that that’s also the expected time for gut mucosal recovery as well, too.

Dr Eric Bow: The other organ system that is pertinent to the conversation is the lining of the gastrointestinal tract from the vermilion border to the anal border, 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 submucosal tissue and causing systemic infection and. So part of my thinking here is I have to take into account when I wait to recover, and it typically recovers about the same time as the ANC recovers.

Dr. Shreya Trivedi: Wow, how cool and convenient that the gut mucosa and the ANC recovery go hand in hand. Okay, 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?

Dr. Casey Kim: Yeah, absolutely. You know, if you identify a specific pathogen or source, that kind of supersedes everything we just said about our seven to 10 day rule of thumb, you should actually follow the standard guidelines for the infection that you identified.

Dr Eric Bow: If you knew it was a Pseudomonas aeruginosa bacteremia, you would then be using the guidelines for bacteremic patients as a guideline for duration of antibiotic therapy.

Dr. Shreya Trivedi: All right. Last thing to round out our discussion that I’ve been thinking about a lot as we’re talking is G-CSF, granulocyte colony stimulating factor. You know? Why don’t we just give our patients some of this to stimulate some neutrophils and reduce the time of neutropenia? Right? We learned time is infection.

Dr. Casey Kim: You think it would work, but actually, it’s like the one area where there’s pretty strong consensus against routine use of G-CSF for patients with neutropenic fever.

Dr. Shreya Trivedi: Hmm really? I think G-CSF would improve outcomes now, yeah.

Dr. Casey Kim: So they did randomized control trials in giving G-CSF for patients with chemotherapy induced febrile neutropenia, which did note decrease hospitalization times and decreased periods of neutropenia, but there were no changes in overall mortality or mortality from infection.

Dr. Shreya Trivedi: People who care about lymphocytes, length of stay will like G-CSF men, but yeah, I guess you know the fact that there’s a strong consensus against it, I guess maybe that goes back up to like, Dr Bowie’s point that he made earlier, that the timeline for neutropenia recovery, especially if it’s chemotherapy induced, is relatively predictable, and if you’re already close to that timeframe for recovery, then G-CSF might not give you much benefit for the cost.

Dr. Casey Kim: You know, I think again, like there’s always some caveats, and in the right context, like you can consider G-CSF for high risk patients. So these are patients who have prolonged neutropenia over 10 days, really profound neutropenia, under 100 cells per microliter, or other factors that really increase your mortality from infection, like age over 65 severe sepsis or really bad, invasive fungal disease.

Dr. Shreya Trivedi: All right, so let’s summarize what we learned so far about antibiotics. In terms of starting antibiotics. We’re going to reach for in febrile neutropenia, antipseudomonal antibiotics within that first hour, and consider antifungal coverage if that absolute neutral count is less than 200 for more than at least two days, and it’s a patient who is at higher risk of infections like blood cancers, and then we’re going to continue antibiotics and stop it based on the absolute neutral count recovery. You know, some people do have this threshold of you know, if it’s above 1000 for at least 48 hours, which again, also falls usually within the seven to 10 day range anyway. And then, of course, just to say it, 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 10 day rule

Conclusion

Dr. Casey Kim: So that wraps up our episode on neutropenia and febrile neutropenia. If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on Instagram or Facebook. Thank you to our peer reviewer, Dr. Daniel Samkari,

Dr. Shreya Trivedi: And as always we love hearing feedback, email us at [email protected]. Opinions expressed for our own and do not represent the opinions of any affiliated institutions. Thank you. Take care.

References

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