Neutropenia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term leukopenia. However, neutropenia is more properly considered a subset of leukopenia as a whole. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression may present as a medical emergency.

Neutropenia was first noted around the start of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities.^[1]

Calculated based on blood count differential, neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).

• Mild Neutropenia: ANC 1,000-1500 cells/microliter
• Moderate Neutropenia: ANC 500-1000 cells/microliter
• Severe Neutropenia (Agranulocytosis): ANC <500 cells/microliter

Neutropenia develops as a result of one of the three following mechanisms:

1. Impaired granulocyte production
   • Hematologic malignancy with bone marrow infiltration
   • Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow
   • Nutritional deficiencies
2. Margination: (process where free flowing blood cells exit circulation)
   • Splenic sequestration
   • Adherence to the vascular endothelium
3. Peripheral destruction
   • Autoimmune hemolysis
   • Drug-induced hemolysis

The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia. While the former is typically benign, as the title suggests, and not associated with significant complications, drug-induced neutropenia is often related to underlying cancer or medications that can suppress the bone marrow and can be severe and life-threatening if not identified and treated urgently.

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN). This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the Duffy antigen on red blood cells that helps to confer resistance to malaria. As the name suggests, these cases are typically mild and do not result in immunosuppression.

There are no routine screening recommendations for neutropenia. Neutropenia is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.

Neutropenia is a frequent finding on blood differential. When identified, attention must be placed on identifying underlying medication toxicities, autoimmune disorders or hematological malignancies, or various infections. While most patients with mild neutropenia recover quickly and without complications, severe medication-related neutropenia can be fatal in up to 10%.^[2] Close attention must be given to identifying poor prognostic indicators, early signs of infection, and any cyclic pattern to this hematologic abnormality to avoid potentially fatal complications.

Febrile neutropenia is an often fatal complication of severe neutropenia, with fever often being the only presenting symptom of an underlying infection.

In patients with severe neutropenia, the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.

Per 2002 IDSA ^[3] and 2013 ASCO ^[4] guidelines, febrile neutropenia requires both of the following criteria:

1. Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour.
2. Severe neutropenia: ANC< 500 cells/microliter.

Neutropenia can go undetected until the patient develops secondary, and often severe, infections or sepsis. Some common infections can take an unexpected course in neutropenic patients; formation of pus, for example, can be notably absent, as this requires circulating neutrophil granulocytes. History should focus on symptoms suggestive of malignancy or infections, patient or family history of autoimmune or immunodeficiency disorders, risk factors for infections including HIV and hepatitis, and any unusual dietary practices or history of bariatric surgery. Medications should be reviewed with particular attention to chemotherapeutics, antibiotics, antiepileptics, and psychoactive drugs as well as documenting any new medications started within the preceding few months.

Common presenting symptoms in neutropenic patients include:

• Fever
• Frequent infections due to lessened ability to fight bacterial infections
• Mouth ulcers
• Diarrhea
• Burning sensation when urinating
• Unusual redness, pain, or swelling around a wound
• Sore throat
• Shortness of breath
• Shaking chills

Physical examination should focus on identifying any potential signs of infection and is directed by the patients’ presenting symptoms. A rectal examination should not be performed in a patient with neutropenia.

Neutropenia is detected on a full blood count. A peripheral blood smear is often useful to evaluate for abnormal morphology of the visible cells, which may help suggest the underlying cause. Additional laboratory studies include evaluation of metabolic abnormalities, genetic causes neutropenia, and toxic causes.

Neutropenia is not identified on or correlated with any particular imaging. In the cases of neutropenic fever, imaging findings are dependent upon the source of the fevers. Initial evaluation for neutropenic fever should include chest radiography to evaluate for pulmonary infiltrates or effusions. Further imaging, such as CT or MRI scans, are indicated depending upon presenting symptoms and physical examination findings.

Other diagnostic studies for neutropenia include bone marrow biopsy, which may be helpful when the etiology is uncertain, or serious causes such as malignancy and marrow replacement are suspected.

There is no specific therapy for neutropenia itself aside from removing the offending agents in drug-induced cases and treating the underlying disease in other, however recombinant G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia as described in detail above. Offending medications are often held and the patient is monitored for response to discontinuation while evaluating for alternative, more concerning etiologies. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.

Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment. Offending medications must be discontinued as drug-induced agranulocytosis presents up to a 10% mortality and is very likely to recur if the offending agent is restarted.

There are no intrinsic complications of neutropenia, however people who are neutropenic are at risk for infections and febrile neutropenia.

Low risk patients: ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.

• Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID

High risk patients: Hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy as below.

• Cefepime 2 g IV Q8H
• Meropenem 1 g IV Q8H
• Imipenem/cilastatin 500 mg IV Q6H
• Piperacillin/tazobactam 4.5 g IV Q6H
• Ceftazidime 2 g IV Q8H (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)

Indications for resistant Gram-positive coverage: Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection.

• Hemodynamic instability
• Suspected catheter-associated infection
• Mucositis or cellulitis
• Pneumonia
• History of MRSA infection or colonization
• Gram-positive bacteremia prior to final culture results
• Recent fluoroquinolone prophylaxis

Persistent Fever: Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve. The median time to defercescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period further work up is suggested.

1. Re-evaluate sources of infection
2. Re-evaluate indications for resistant Gram-positive coverage and consider adding vancomycin or linezolid.
3. Re-evaluate indications for resistant Gram-negative organisms and anaerobes and consider broadening to carbapenem antibiotics.
4. Consider fungal coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days. :Consider the following antifungals.
   • Caspofungin 70 mg IV x 1 dose, then 50mg IV daily
   • Liposomal Amphotericin B 3 mg/kg/day
   • Voriconazole 6 mg/kg IV Q12H x 2 doses, then 4 mg/kg IV Q12H

Caspofungin provides excellent coverage for Candida and is well tolerated, however nodular pulmonary infiltrates warrant coverage of Aspergillus with Voriconazole or Amphotericin B as echinocandins do not provide adequate coverage of Aspergillus or endemic fungi.

Duration of Antimicrobials

• Documented infection: Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data.
  
• Negative Cultures: Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) and continue until myeloid recovery.

There are no surgical treatments for neutropenia. In patients’ with neutropenic fever, surgical intervention may be necessary depending on the sources of their infections.

Prevention of neutropenia is dependent upon avoiding certain medications or treatment of underlying conditions.

Secondary prevention of neutropenia relies on careful avoidance of triggers, such as certain medications, or treatment of underlying conditions. Further discussion of the causes of neutropenia are reviewed above.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia was first discovered around the start of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities. With the advent and growing use of multiple myelosuppresive drugs – namely chemotherapy – the incidence of neutropenia has increased.^[1]

Neutropenia was first discovered around the start of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities. With the advent and growing use of multiple myelosuppresive drugs – namely chemotherapy – the incidence of neutropenia has increased.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia may be classified according to severity based on absolute neutrophil count on blood cell count differential into three sub-types: mild, moderate, and severe.

Neutropenia may be classified according to severity into three sub-types: mild, moderate, and severe. Neutropenia is calculated based on blood count differential and is defined as an absolute neutrophil count (ANC) less than 1500 cells per µL. Neutropenia is calculated by multiplying the total white blood cell count by the percentage of neutrophils (including both mature neutrophils and band forms). For example, in Caucasian patients, neutropenia severity may be graded as:

• Mild Neutropenia: ANC 1000-1500 cells/µL
• Moderate Neutropenia: ANC 500-1000 cells/µL
• Severe Neutropenia (Agranulocytosis): ANC <500 cells/µL

In other populations, such as African Americans, mild neutropenia may be present without increased risk of complications. Neutropenia in African American individuals is defined as an absolute neutrophil count < 1200 cells/µL.

Neutropenia may be classified according to etiology into two subtypes: congenital (severe, chronic, present at birth) and acquired. Congenital neutropenia may be further classified into the following subtypes:

• Severe congenital neutropenia: A rare inherited form of the disease usually detected soon after birth. It affects children mainly and may result in premature tooth loss and peremptory gum infections. The most severe form of chronic congenital neutropenia is known as Kostmann’s syndrome. It is genetically heterogeneous. Most commonly, it arises as a result of new, autosomal dominant mutations in the gene ELA2, encoding the neutrophil granule protease, neutrophil elastase. Additionally, HAX1, the gene responsible for many cases of autosomal recessively inherited severe congenital neutropenia, may also be affected. The mechanism for congenital neutropenia is not well-understood. There is evidence that mutations in neutrophil elastase, or in other genes associated with syndromic forms of neutropenia, disrupt its intracellular trafficking. Apoptosis may be a final effector for neutropenia.^[1]
• Cyclic neutropenia: Generally, cyclic neutropenia tends to occur every 3 weeks and lasts between 3-6 days, due to changing rates of cell production by the bone marrow. It is often present among several members of the same family. Cyclic neutropenia is also the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase.^[2]
• Idiopathic neutropenia: A rare form of neutropenia which develops in children and adults usually in response to an illness. It is diagnosed when the disorder cannot be attributed to any other diseases and often causes life-threatening infections.
• Myelokathexis: A rare form of inherited autosomal dominant disease associated with severe neutropenia. Some, but not all patients present with warts, hypogammaglobulinemia, and recurrent infections. Myelokathexis is also known as the WHIM syndrome. In spite of severe neutropenia in peripheral blood of myelokathexis patients, their bone marrow is hypercellular and is densely packed with mature neutrophils, indicating an impaired mobilization of hematopoietic cells in this disorder. Truncating mutations in the human cytokine receptor CXCR4 gene were identified in most of the families afflicted by myelokathexis. The molecular mechanism is not yet defined. Recent reports demonstrate that CXCR4 mutations appear to result in an increased sensitivity of bone marrow hematopoietic cells to its ligand, a stromal-derived growth factor SDF-1 that provides proliferative and survival signals.^[3]
• Autoimmune neutropenia: Most common in infants and young children where the body identifies the neutrophils as foreign bodies and generates antibody to destroy them. This form usually lessens in severity within two years of diagnosis.
• Drug-induced neutropenia: Often concurrently occurring with agranulocytosis, many anti-neoplastic drugs cause neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or complement-mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About 75% of all cases of agranulocytosis in the United States are related to medication. For example, clozapine, procainamide, anti-epileptic, and anti-thyroid drugs (e.g. methimazole, and sulfasalazine) are often implicated.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia may develop as a result of one of the three mechanisms: impaired granulocyte production, margination, and peripheral destruction. Genes involved in the pathogenesis of neutropenia include ELA2, HAX1, and CXCR4.

Neutropenia may develop as a result of one of the three mechanisms:^[1]

1. Impaired granulocyte production
   • Hematologic malignancy with bone marrow infiltration
   • Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow
   • Nutritional deficiencies
2. Margination (process where free flowing blood cells exit circulation)
   • Splenic sequestration
   • Adherence to the vascular endothelium
3. Peripheral destruction
   • Autoimmune hemolysis
   • Drug-induced hemolysis

Genes involved in the pathogenesis of neutropenia include ELA2, HAX1, and CXCR4.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2], Daniel A. Gerber, M.D. [3]

Neutropenia may be caused by drugs, cancer, radiation, vitamin B12 deficiency or folate deficiency. Marginalization and sequestration of neutrophils also can cause neutropenia following procedures such as hemodialysis.

The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia.

Malignancy is often associated with neutropenia, due to impaired production from myelodysplastic syndromes and hematological malignancies with bone marrow infiltration, hemolysis and impaired production from cytotoxic chemotherapy, and antibody-mediated destruction of neutrophils.

Alternative etiologies include post-infectious neutropenia resulting from bacterial, fungal, or viral infections. While bacterial infections typically cause leukocytosis, salmonella, shigella enteritis, brucellosis, tularemia, tuberculosis, and rickettsial diseases, such as Rocky Mountain spotted fever can present with neutropenia.^{[1] [2] [3] [4] [5]}

Parasitic diseases with neutropenia include leishmaniasis with hemolysis and splenic sequestration and malaria due to hyperreactive malarial splenomegaly (HMS).^[6] Viral etiologies include HIV, EBV, CMV, HHV-6, viral hepatitis, dengue fever, yellow fever, measles, varicella, and rubella.^[7]

Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, severe neutropenia can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty’s syndrome.^[8]

Finally, nutritional deficiencies resulting in neutropenia are typically attributed to vitamin B12, folate, and copper and are related to inadequate dietary intake, pernicious anemia, bariatric surgery, and malabsorptive syndromes.

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Aplastic anemia
• Cancer
• Cytotoxic chemotherapy
• Hemodialysis
• Medications^[9]
• Radiation therapy
• Vitamin deficiencies e.g. folate, Vitamin B12

Cardiovascular	No underlying causes
Chemical / poisoning	Arsenic trioxide, gold salts, strontium-89
Dermatologic	Chediak-Higashi disease, dyskeratosis congenita, x-linked, Elejalde syndrome , reticular dysgenesis, reticular dysplasia
Drug Side Effect	5-azacytidine, acetophenazine, aclarubicin, actinomycin D, acyclovir, aflibercept, albendazole, alemtuzumab, allopurinol, amantadine, amiloride, aminoglutethimide, aminoglutethimide, aminopyrine, amiodarone,amodiaquine, ampicillin, amsacrine, anakinra, anidulafungin, anti-thymocyte globulin, antibiotics, antipyrine, aprepitant, aripiprazole, arsenic trioxide, asenapine, atazanavir, atovaquone, auranofin, azacitidine, azathioprine, aztreonam, barbiturates, belinostat, benazepril, bendamustine, bevacizumab, blinatumomab, boceprevir, bortezomib, bosutinib, brentuximab, busulfan, cabazitaxel, cabozantinib, canakinumab, candesartan, capecitabine, captopril, carbimazole, carboplatin, carfilzomib, carmustine, cefaclor, cefadroxil, cefazolin, cefepime, cefixime, cefoperazone, cefotetan, cefotiam, cefoxitin, ceftaroline, ceftriaxone, cefuroxime, cephalexin, cephapirin, cephradine, cetuximab, chemotherapy, chlorambucil, chloramphenicol, chloroquine, chlorpromazine, chlorthalidone, cidofovir, cilazapril, cimetidine, cisplatin, cladribine, clarithromycin, clindamycin, clofarabine, clopidogrel, clozapine, colchicine, crizotinib, cromolyn, cyclophosphamide, cytarabine, cytosine arabinoside, dabrafenib,dacarbazine, daclatasvir, dactinomycin, dasatinib, daunorubicin, decitabine, deferasirox, deferiprone, delavirdine, desipramine, dexrazoxane, diatrizoate, diazepam, diazoxide, dicloxacillin, Diethylpropiondiflunisal, dipyrone, docetaxel, dolutegravir, doripenem, dothiepin, doxorubicin, doxycycline, efavirenz, eflornithine, elvitegravir, enalapril, enalaprilat, enfuvirtide, enzalutamide, epirubicin, eprosartan, eribulin, etanercept, ethacrynic acid, ethambutol, ethosuximide, ethotoin, etodolac, etoposide, everolimus, felbamate, fentanyl, fidaxomicin, flucytosine, fludarabine, fluorouracil, fluoxetine, fosamprenavir, foscarnet, fosinopril, ganciclovir, gefitinib, gemcitabine, gemifloxacin mesylate, glyburide, golimumab, griseofulvin, guanidinium, haloperidol, hydroxycarbamide, hydroxyurea, ibuprofen lysine, ibritumomab tiuxetan, ibrutinib, ibuprofen, idarubicin, idelalisib, iloperidone, imatinib, imipenem cilastatin, indinavir, indomethacin, infliximab, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, interferon beta-1b, irinotecan, isoniazid, isotretinoin, itraconazole, ixabepilone, lamivudine, lamotrigine, lansoprazole, lenalidomide, levamisole, levetiracetam, levomepromazine, lincomycin, linezolid, lisinopril, loxapine, lurasidone, maprotiline, maraviroc, meclofenamate, mercaptopurine, meropenem, mesalamine, methazolamide, methimazole, methotrexate, methyldopa, metolazone, mexiletine, mianserin, micafungin, mifamurtide, milnacipran, minocycline, mirtazapine, mitotane, mitoxantrone, moexipril, moxalactam, mycophenolate, mycophenolic acid, nafcillin, naproxen, nefazodone, nelarabine, nelfinavir, nevirapine, nilotinib, nilutamide, norfloxacin, nortriptyline, obinutuzumab, ofatumumab, ofloxacin, olanzapine, olaparib, olsalazine,omacetaxine, omeprazole, oprelvekin, oxacillin, oxaliplatin, paclitaxel, palbociclib, paliperidone, panobinostat, pantoprazole, pazopanib, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed, penicillamine, penicillin, penicillin G, pentamidine, pentostatin, peramivir, perazine, perindopril, pertuzumab, phenylbutazone, phenytoin, piperacillin, piperaquine, pipothiazine, piroxicam, pixantrone, pomalidomide, ponatinib, posaconazole, pralatrexate, prednisone, probenecid, procainamide, procarbazine, prochlorperazine, proguanil, propylthiouracil, pyrimethamine, quetiapine, quinapril, quinidine, quinine, radium chloride, raltitrexed, ramipril, ramucirumab, ranitidine, rasagiline, rasburicase, regorafenib, remoxipride, ribavirin, rifabutin, rifapentine, rifaximin, rilonacept, riluzole, risperidone, ritodrine, ritonavir, rituximab, romidepsin, ruxolitinib, saquinavir, satraplatin, secukinumab, sirolimus, sodium aurothiomalate, sofosbuvir, sorafenib, stavudine, stiripentol, succimer, Sulfacetamide, Sulfamethoxazole/Trimethoprim (oral), sulfasalazine, sulfonamide, sulindac, sunitinib, suramin, tacrolimus, tedizolid, teicoplanin, temozolomide, temsirolimus, teniposide, tenofovir, terbinafine, teriflunomide, thalidomide, thiothixene, ticarcillin, ticlopidine, tipranavir, tocilizumab, tofacitinib, tolazamide, tolmetin, topotecan, tositumomab, trabectedin, trametinib, trandolapril, trastuzumab, trimethadione, trimethoprim, trimetrexate, valganciclovir, valproic acid, valrubicin, valsartan, vancomycin, vandetanib, vesnarinone, vincristine, vindesine, vinflunine, vinorelbine, zidovudine, zileuton, ziprasidone, ziv-aflibercept, zoledronic acid
Ear Nose Throat	No underlying causes
Endocrine	Hyperthyroidism
Environmental	No underlying causes
Gastroenterologic	Glycogen storage disorder, hypersplenism, Shwachman-Diamond syndrome
Genetic	Barth syndrome, cartilage-hair hypoplasia, Chediak-Higashi disease, Cohen syndrome, Dubowitz syndrome, Elejalde syndrome , familial histiocytic reticulosis, Fanconi syndrome, fumarate hydratase deficiency, Griscelli syndrome type 1, methylmalonic aciduria, myelokathexis, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, Shwachman-Diamond syndrome, WHIM syndrome
Hematologic	Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, aplastic anemia, autoimmune neutropenia, chronic lymphocytic leukemia, cyclical neutropenia, familial histiocytic reticulosis, Hermansky-Pudlak syndrome, histiocytosis X, hypersplenism, Kostmann disease, myelodysplastic syndrome, myelofibrosis, pancytopenia, paroxysmal nocturnal haemoglobinuria, Shwachman-Diamond syndrome, x-linked agammaglobulinemia
Iatrogenic	Hemodialysis, radiation therapy
Infectious Disease	Brucellosis, cytomegalovirus, dengue, Epstein-Barr virus, hepatitis A, hepatitis B, hepatitis C, hepatitis, human granulocytic ehrlichiosis, human immunodeficiency virus, human monocytotropic ehrlichiosis, kala azar, Kostmann disease, lassa fever, Lyme disease, malaria, measles, rickettsiae, rickettsial infections, rocky mountain spotted fever, rubella, salmonella infection, sepsis, severe acute respiratory syndrome, shigellosis, tuberculosis, tularemia, varicella, visceral leishmaniasis, WHIM syndrome
Musculoskeletal / Ortho	Cartilage-hair hypoplasia, metaphyseal chondrodysplasia, Mckusick type
Neurologic	Fumarate hydratase deficiency
Nutritional / Metabolic	Copper deficiency, glutathione synthase deficiency, glycogen storage disorder, glycogenosis type 1b, hereditary orotic aciduria, isovaleric acidemia, methylmalonic aciduria, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, vitamin deficiencies
Obstetric/Gynecologic	No underlying causes
Oncologic	Chronic lymphocytic leukemia, hairy cell leukemia, histiocytosis X, leukemia, myelodysplastic syndrome, myelofibrosis
Opthalmologic	No underlying causes
Overdose / Toxicity	Alcoholism
Psychiatric	No underlying causes
Pulmonary	Severe acute respiratory syndrome
Renal / Electrolyte	Fanconi syndrome
Rheum / Immune / Allergy	Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2, autoimmune neutropenia, common variable immune deficiency, Felty’s syndrome, histiocytosis X, hyper-immunoglobulin M syndrome, lupus, rheumatoid arthritis, secondary autoimmune neutropenia, WHIM syndrome, x-linked agammaglobulinemia, x-linked hyperimmunoglobulin M syndrome
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia is diagnosed on a complete blood count differential and the severity is classified based on neutrophil count. Neutropenia is diagnosed when the absolute neutrophil count (ANC) is less than 1500 cells/µL.

Neutropenia is a laboratory diagnosis based off of the complete blood count differential, however the differential diagnosis for the etiology of neutropenia is quite important in diagnosing and treating these patients.

Consider the following broad differential when evaluating a patient with neutropenia:

• Congenital neutropenia: rare, inherited mutations in the genes ELA2 or HAX1.^[1]
• Cyclic neutropenia: 3 week cycles of neutropenia due to changing rates of neutrophil production by the bone marrow. Also the result of hereditary ELA2 mutations.^[2]
• Idiopathic neutropenia
• Myelokathexis: rare, inherited mutations in CXCR4 result in warts, hypogammaglobulinemia, and recurrent infections.^[3]
• Autoimmune neutropenia: antibody-mediated neutrophil destruction.
• Drug-induced neutropenia: 75% of all cases of agranulocytosis in the United States.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia is most commmon in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications, however a benign form of mild neutropenia is commonly identified in certain ethnicities (blacks, Yemenites, West Indians, Arab Jordanians) that does not impair the immune system.

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN). This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the Duffy antigen on red blood cells that helps to confer resistance to malaria. As the name suggests, these cases are typically mild and do not result in immunosuppression.

BEN is more often seen in blacks, Yemenites, West Indians, and Arab Jordanians with up to 4.5% prevalence in these populations. ^[1] In these individuals, a mutation in the Duffy antigen gene – a gene which encodes a red blood cell receptor used by malaria to enter these cells – both confers a protective effect against this parasite and, for unclear reasons, lowers the circulating neutrophil count. While quite common, the neutropenia is typically mild (ANC 1,000-1500 cells/microliter) and does not predispose to increased risk of infection or increased risk of febrile neutropenia in the setting of chemotherapy as these individuals have normal bone marrow neutrophil reserves.^{[2] [3] [4]}.

Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, severe neutropenia can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty’s syndrome. ^[5]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

At-risk populations include those undergoing cytotoxic chemotherapy or other myelosuppressive medications, however a benign form of mild neutropenia is commonly identified in certain ethnicities (blacks, Yemenites, West Indians, Arab Jordanians). This latter group rarely develops complications from their neutropenia.

• Medications^[1]
• Cytotoxic chemotherapy
• Hematologic malignancies
• Autoimmune disorders
• Infections
• Hemodialysis
• Radiation therapy
• Vitamin deficiencies e.g. folate, Vitamin B12
• Black, Yemenite, West Indian, or Arab Jordanian ethnicity

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

There are no routine screening recommendations for neutropenia.

Neutropenia is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Neutropenia is a frequent finding on blood differential. When identified, attention must be placed on identifying underlying medication toxicities, autoimmune disorders or hematological malignancies, or various infections. While most patients with mild neutropenia recover quickly and without complications, severe medication-related neutropenia can be fatal in up to 10%.^[1] Close attention must be given to identifying poor prognostic indicators, early signs of infection, and any cyclic pattern to this hematologic abnormality to avoid potentially fatal complications.

Febrile neutropenia is an often fatal complication of severe neutropenia, with fever often being the only presenting symptom of an underlying infection.

Neutropenia is a frequent finding related to various infections, cytotoxic chemotherapies or medication toxicities, autoimmune disorders, hematological malignancies, and certain ethnic groups. It is often asymptomatic and the neutropenia often normalizes quickly and without complications, however evaluation for an underlying cause is necessary when the neutropenia is severe or there are associated findings to prevent complications that can often be fatal.

For those without severe neutropenia and without clinical, serological, or radiographic evidence of underlying diseases contributing to neutropenia, regular blood count monitoring up to a few times each week is recommended to monitor the course of neutropenia. During this time, particular attention should be paid to any symptoms of infection or malignancy and any contributing medications as infectious complications carry a mortality rate of up to 10%.^[1]

A small fraction of neutropenic patients are found to have cyclic neutropenia, where 4-6 day periods of neutropenia occur approximately every 3 weeks and, like other forms of severe neutropenia, predispose the patient to complicated infections. Screening these individuals requires serial monitoring of neutrophil counts a minimum of 3 times per week for a minimum of 6 weeks to reveal the 3 week cycles.^[2]

Neutropenia is classified as “chronic” when lasting for greater than 3 months.

There are no intrinsic complications of neutropenia itself, however neutropenia is a complication of many cytotoxic medications and chemotherapy and other conditions described and can increase the risk of infections. Neutropenic fever is a potentially life-threatening condition associated with neutropenia that is described in detail in its own chapter and reviewed briefly below.

In patients with severe neutropenia, the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.

Per 2002 IDSA ^[3] and 2013 ASCO ^[4] guidelines, febrile neutropenia requires both of the following criteria:

1. Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour
2. Severe neutropenia: ANC< 500 cells/microliter

Despite prompt and thorough evaluation, a source of infection is identified in less than 1/3 of patients. Bacteremia, present in up to 25%, often serves as the only source of positive culture data. ^[3] As such, rapid risk stratification and appropriate empiric treatment is necessary.

Prognosis for low risk neutropenia is excellent – >90% probability of complete resolution without complications – however, high risk patients have >40% risk of complications. Risk assessment for patients with neutropenia is defined as below.

Low risk: typically patients with solid tumors on chemotherapy plus the following:

• Anticipated neutropenia (ANC<500 cells/microliter) <7 days
• No significant hepatic or renal dysfunction
• No significant comorbidities**
• MASCC Risk Score >21 (PPV 91%, specificity 68%, sensitivity 71%)

High risk

• Anticipated neutropenia (ANC<500 cells/microliter) >7 days
• Significant hepatic or renal dysfunction
• Significant comorbidities**
• Disease progression
• MASCC Risk Score <21 (PPV 91%, specificity 68%, sensitivity 71%)

**Significant comorbidities: Hemodynamic instability, mucositis, GI symptoms, acute neurological changes, intravascular catheters, pulmonary infiltrates, or underlying chronic lung disease.

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