Neutropenia causes

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

Overview

Various mechanisms and factors come to play with respect to the causes of neutropenia which could arise from decreased production of neutrophils in the bone marrow; commonly from drugs, cancer, radiation and vitamin B12 deficiency or folate deficiency or could be caused by increased destruction (for example from aplastic anemia and chemotherapy. Marginalisation and sequestration of neutrophils also cause neutropenia following procedures such as hemodialysis.

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 ^[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].

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 ^[5].

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

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, Diethylpropion diflunisal, 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

3

References

↑ Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP (2007). "Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences". Ann. Intern. Med. 146 (7): 486–92. PMID 17404350.
↑ Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988). "Benign familial leukopenia and neutropenia in different ethnic groups". Eur J Haematol. 41 (3): 273–7. PMID 3181399.
↑ Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J (1985). "The outcome of bacterial infection in subjects with benign familial leukopenia (BFL)". Biomed Pharmacother. 39 (1): 23–6. PMID 4027348.
↑ Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF (2009). "Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?". J Clin Oncol. 28 (10): 1633–7. PMID 20194862.
↑ Bucknall RC, Davis P, Bacon PA, Jones JV (2009). "Neutropenia in rheumatoid arthritis: studies on possible contributing factors". Ann Rheum Dis. 41 (3): 242–7. PMID 6979979.

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[pmid17404350-1] Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP (2007). "Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences". Ann. Intern. Med. 146 (7): 486–92. PMID 17404350.

[PMID3181399-2] Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988). "Benign familial leukopenia and neutropenia in different ethnic groups". Eur J Haematol. 41 (3): 273–7. PMID 3181399.

[PMID4027348-3] Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J (1985). "The outcome of bacterial infection in subjects with benign familial leukopenia (BFL)". Biomed Pharmacother. 39 (1): 23–6. PMID 4027348.

[PMID20194862-4] Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF (2009). "Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?". J Clin Oncol. 28 (10): 1633–7. PMID 20194862.

[PMID6979979-5] Bucknall RC, Davis P, Bacon PA, Jones JV (2009). "Neutropenia in rheumatoid arthritis: studies on possible contributing factors". Ann Rheum Dis. 41 (3): 242–7. PMID 6979979.

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