Neutropenia overview

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

Overview

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.

Classification

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

NOTE: These ranges are based on Caucasian patients, whereas African Americans and some ethnicities have mild neutropenia without increased risk of complications. Neutropenia in African American individuals is defined as an ANC < 1200 cells/microliter. This often overlooked fact results in overdiagnosis of neutropenia in African American population.[1]

Severe chronic neutropenia may be present at birth (congenital neutropenia) or may occur at any stage in life (acquired neutropenia). There are several types of severe chronic neutropenia:

Severe congenital neutropenia — a rare inherited form of the disease usually detected soon after birth. It affects children mainly and may result in premature loss of teeth 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, NE. The gene responsible for many cases of autosomal recessively inherited severe congenital neutropenia is HAX1. 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, but the original studies from Dale and Aprikian supporting this pathway were retracted.

Cyclic neutropenia — tends to occur every three weeks and lasting three to six days at a time 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.

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 have warts, Hypogammaglobulinemia, and recurrent Infections. Therefore myelokathexis is also known as the W.H.I.M. syndrome. In spite of severe neutropenia (low number of neutrophils) in peripheral blood of myelokathexis patients, their bone marrow is hypercellular and it is 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.

Autoimmune neutropenia — most common in infants and young children where the body identifies the neutrophils as enemies and makesantibody to destroy them. This form usually lessens in severity within two years of diagnosis.

Drug-induced neutropenia — Many drugs can cause agranulocytosis (complete absence of white cells) and neutropenia. Manyanti-neoplastic drugs cause agranulocytosis and 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. Clozapine, File:Example.jpgprocainamide, anti-thyroid drugs (e.g. methimazole, and sulfasalazine are at the top of the list of drugs causing this problem, but many others (such as antiepileptics) have been implicated.

Pathophysiology

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

Causes

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

BEN is more often seen in blacks, Yemenites, West Indians, and Arab Jordanians with up to 4.5% prevalence in these populations . 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 .

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 and Shigella enteritis, brucellosis, tularemia, tuberculosis, and rickettsial diseases such as Rocky Mountain Spotted Fever (RMSF) can present with neutropenia. Parasitic diseases with neutropenia include Leishmaniasis with hemolysis and splenic sequestration and malaria due to hyper-reactive malarial splenomegaly (HMS). Viral etiologies include HIV, EBV, CMV, HHV-6, viral hepatitis, dengue, yellow fever, and common childhood exanthematous viruses including measles, varicella, and rubella where ANC nadirs around the time of the onset of rash.

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 syndrome .

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

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

Common Causes

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

Causes by Organ System

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

Causes in Alphabetical Order

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