.Hello..My name is Anthony Sung..I'm a hematology oncology fellow.at Duke University Medical.Center..And I'll be talking.about neutropenia...I'll begin today talking.about the definition.of neutropenia, followed.by a discussion of its causes,.how to work up neutropenia,.how to treat it,.and end by discussing.the management.of febrile neutropenia...Neutrophils, also known.as polymorpho nuclear cells.or polys or segmented cells,.are the most abundant.white blood cell in the body.and crucial to fighting.infections..The Absolute Neutrophil Count.can be calculated.as the total number.of white cells multiplied.by the percentage of neutrophils.and bands.which are an immature form.of neutrophils..If the ANC is less than 1,500,.this is defined as neutropenia..Some people will break up.neutropenia into mild, moderate,.or severe,.based on an ANC of 1,000.to 1,500; 500 to 1,000;.or less than 500..However, more.important than the actual number.of cells is the body's ability.to fight infection..After all, this number.only mentions the number.of neutrophils in the blood,.but does not take into account.the number of neutrophils.in the bone marrow,.reticuloendothelial system,.tissues, et cetera..What matters is whether someone.is functionally neutropenic--.that is, more.susceptible to infections...neutropenia can be caused.by four broad categories.of problems--.decreased production.of neutrophils, where.your body's not making them;.ineffective granulopoiesis,.which is a problem.in the development.of neutrophils; a shift.to tissue pools-- that is, out.of the blood--.and increased destruction..You can see how some.of these causes,.such as shifting of neutrophils.to tissue pools,.may not cause a functional.neutropenia, while other causes,.such as decreased production,.can make a big difference...There is a long list of causes.of neutropenia--.main division is into acquired.and congenital causes..The most common acquired cause.is infection, followed by drugs,.which we'll talk about later..Primary immune or autoimmune.neutropenias can occur when.the body makes antibodies.against neutrophils..neutropenia has also been found.in association with collagen.vascular diseases, such as lupus.and rheumatoid arthritis,.as can be seen in Felty.syndrome, the triad.of rheumatoid arthritis,.splenomegaly, and neutropenia..Complement activation,.such as by a dialysis or ECMO.can also result in increased.destruction of neutrophils..Whereas hypersplenism causes.neutropenia by increased.sequestration and clearance..Nutritional causes,.such as low B12, folate,.or copper, can cause production.problems, as can bone marrow.disorders,.such as MDS or leukemia..Finally, there are idiopathic.cases where the cause cannot be.found..Congenital cases include.benign familial neutropenia,.which is a neutropenia found.in certain ethnic populations,.such as West Africans.and their descendants,.Yemeni Jews, Cretens, and so.forth..In this patient population,.the neutropenia is mild.and usually not.a functional neutropenia..There are also.a lot of congenital neutropenia.syndromes,.such as cyclic neutropenia,.Kostmann's,.Shwachman-Diamond-Oski,.Chediak-Higashi, Myelokathexis,.Reticular dysgenesis,.Dyskeratosis congenita, glycogen.storage disease-- such as von.Gierke's disease,.and X-linked syndromes,.such as Wiskott-Aldrich.and Bruton's agammaglobulinemia..The most important thing.in distinguishing acquired.from congenital causes.is whether the patient has.a history of neutropenia.or if this is a new development...Although infections typical.cause a leukocytosis.in increasing neutrophils,.many viruses, such as HIV, EVB,.CMV, the hepatitides, HHV6,.measles, rubella, varicella,.and dengue can all cause.neutropenia..neutropenia can also be seen.in bacterial infections,.particularly with brucella,.shugella, and mycobacteria,.as well as.in rickettsial diseases,.such as typhus, Rocky Mountain.Spotted Fever, and ehrlichia, as.well as parasitic diseases,.such as leishmania and malaria...Drug-induced neutropenia.requires the offending drug.to be administered within four.weeks of the development.of neutropenia..However, it typically develops.within the first three.to six months of drug.administration and resolves 30.days after discontinuation.of the offending agent..Drugs can cause neutropenia.in many ways..The first and most obvious form.is myelosuppressive drugs.for chemotherapy,.such as cyclophosphamide.or anthracyclines,.exert a direct effect.on the bone marrow.and impair production.of neutrophils..This can be also seen.with the immunosuppressants,.such as azothioprine,.antivirals, such as ganciclovir,.or rheumatalogic,.such as colchicine..Immune-mediated destruction.of neutrophils can also occur,.such as with thyroid.medications,.like propylthiouracil,.or with direct toxicity.to neutrophils from a metabolite.of drugs, such as clozapine...There is a very long list.of drugs that can cause.neutropenia, and so I'm not.going to spend time going.over each one of these..But I do want to point out.a few common drugs.that we all use, such as NSIDs,.H2 blockers, diuretics,.penicillins.and other antibiotics,.and many psychotropic drugs...The investigation of neutropenia.starts with taking a history;.asking.about comorbid conditions,.such as rheumatoid arthritis;.new medications,.such as propylthiouracil..Or recent infections can point.to the cause of neutropenia..Symptoms, again,.such as recurrent infections.or abdominal pain,.can suggest a severity.and degree.of functional neutropenia..The exam should focus.on the oral cavity and skin.or of catheter sites, where.ulcerations, abscesses, or signs.of infection are prominent..A large spleen can suggest.hypersplenism..Avoid doing a rectal exam,.as this may introduce bacteria..Lab work, such as a CBC,.is essential to establishing.neutropenia..And a peripheral smear can give.insight into whether there is.a bone marrow disturbance..LDH and ESR can give a sense.of inflammation..Viral studies can look.for a cause of neutropenia..Autoimmune workup, such as ANA,.C3-C4, rheumatoid factor,.and anti-neutrophil antibodies.can work up.autoimmunity-ologies..I should point out that caution.should be taken in interpreting.anti-neutrophil antibodies,.as they have.a high false negative rate..B12, folate, copper,.and ceruloplasmin studies look.for nutritional deficiencies..And flow cytomestry, test.of T-cell gene rearrangements.and bone marrow.biopsy can evaluate.for a malignancy, such as LGL.or MDS..It should be stressed.that this laboratory workup is.not a list of tests that should.be ordered anytime someone is.neutropenic,.but a set of guidelines.for working someone up..For example, if a patient has.arthralgias.and other rheumatalogic.syndromes, ANA compliment and so.forth would be perfectly.appropriate..Whereas, someone.with megaloblastic changes.should have B12 and folate sent..Finally, a cause may not.be readily apparent..And it is important to follow.these patients over time.to see how they develop...Treatment of neutropenia.depends on the cause..If neutropenia is.secondary to an underlying.problem, such as an infection,.treat it with antibiotics..If secondary to drugs,.withdraw the offending agent..If an autoimmune phenomena,.start or increase.immunosuppression..If from hyper-splenism,.consider splenectomy..If nutritional deficiency is.present, supplement this..And if a bone marrow disorder,.such as MDS or leukemia--.treat with chemotherapy..However, primary or idiopathic.neutropenia is trickier..Watchful waiting.is the main approach that should.be taken..As it was mentioned.in the beginning of this talk,.what's important.is not just a patient's.neutrophil count but also.whether they are functionally.neutropenic..Do they have increased.infections and hospitalizations?.Antibiotics are not generally.recommended for prophylaxis.in neutropenia.except in special cases,.such as prolonged neutropenia.following chemotherapy,.such as induction chemotherapy.for leukemia..Growth factors can be used.to increase the neutrophil count.in platelets who.are functionally.neutropenic.with frequent infections.and may result in decreased.infections in use.of antibiotics..Granulocyte transfusions.can directly boost a patient's.neutrophil count,.but are associated with a number.of immune complications.and are generally avoided..Finally,.for severe refractory.neutropenia, bone marrow.transplant can be considered...Febrile neutropenia.is a special circumstance that.is important to address..Again, a response depends,.in part, on the severity.of neutropenia..Some guidelines recommend.that someone with an ANC.of greater than 1,000.can actually be treated.normally, as if they were not.neutropenic..Whereas, fever in a patient.with less than 500 neutrophils.warrants.immediate hospitalization.and the administration of IV.antibiotics..However, again, it.is important to look.at the clinical context..The importance of febrile.neutropenia stems from the fact.that a patient lacking.neutrophils cannot put up a good.response to infection,.particularly from gram-negative.rods, and is at increased risk.of infection-related mortality..With regard.to empiric antibiotic therapy,.patients who are febrile.neutropenic should be covered.with an anti-pseudomonal.beta-lactam,.such as ceftazidime, cefepine,.or zoxyn..For severe sepsis,.animoglycoside and vancomycin.can be added..Vancomycin should also be added.in cases where.a skin or oral source.is suspected,.such as Lyme infections..Although antifungals are.typically not initiated.in the beginning,.unless other factors are.present, such as nodular.infiltrates on a CT..There should be a low threshold.to start antifungals if patients.remain febrile after 48 to 72.hours.of adequate antibiotic coverage,.as above...In summary, neutropenia.is defined as ANC less.than 1,500,.although it is important to take.into account whether someone is.functionally neutropenic.and at increased risk.of infections..Acquired.versus congenital causes.can be separated based.on whether there is a history.of neutropenia..Common acquired causes include.infection,.drug-induced neutropenia,.autoimmune phenomenas,.nutritional deficiencies,.and bone marrow disorders..History is.essential to determining.the etiology of neutropenia.and how secondary causes.of neutropenia can be treated..For primary neutropenia that.results in multiple infections,.consider growth factor support..And remember the importance.of empiric anti-pseudomonal.antibiotics.in febrile neutropenia...Below, you can find.some references for more reading.on neutropenia...And I would like to conclude.by thanking Dr. Carlos DeCastro.as well as Duke Hematology.Oncology...Thank you...
