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Agranulocytosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [3] Nazia Fuad M.D.

Synonyms and Keywords: Agranulosis, granulocytopenia, neutropenia

Overview

Overview

Agranulocytosis is defined as marked reduction in the number of granulocytes (Neutrophils, Basophils, Eosinophils) below an absolute count of 500 cells/mcL. It is a rare condition with incidence of 1 to 5 cases per million population per year. Agranulocytosis results in frequent chronic bacterial infections of skin, lung, and throat. Patients can present with sepsis and fever. Among many risk factors, medications, combination therapy with ACE inhibitors and interferon, cytotoxic chemotherapy, hematologic malignancies, and autoimmune disorders are the more common. On the basis of etiology agranulocytosis can be classified as congenital and acquired. Common causes of acquired agranulocytosis include medications like clozapine, sulfasalazine, and thioamide, infections, nutritional deficiencies, myelodysplasia, collagen vascular diseases, and white cell aplasia. Agranulocytosis needs to be differentiated from bacterial sepsis, aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, cytomegalovirus, folic acid deficiency, and Hodgkin lymphoma. The negative prognostic factors in the course of agranulocytosis are age > 65, septic shock, bacteremia, systemic infections, renal, cardiac and respiratory diseases.The mainstay of treatment of agranulocytosis is medical therapy, including, discontinuation of offending agent, treating infections with broad spectrum antibiotics, and using granulocyte-colony stimulating factor.

Historical Perspective

Historical Perspective

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

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

Overview

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]

Historical Perspective

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]

References

  1. ↑ 1.0 1.1 Dameshek W. (1944). “Leukopenia and Agranulocytosis”. Oxford University Press. 1: 841–52. Text “NLM ID 39120200R” ignored (help)
Classification

Classification

Agranulocytosis can be classified as congenital or acquired. Each class can be classified to further subgroups as follows:

Congenital
Acquired
Pathophysiology

Pathophysiology

Agranulocytosis develops as a result of the following mechanisms:[2]

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

Overview

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.

Pathophysiology

Pathogenesis

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

  1. Impaired granulocyte production
  2. Margination (process where free flowing blood cells exit circulation)
  3. Peripheral destruction

Genetics

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

References

  1. ↑ Schwartzberg LS. (2006). “Neutropenia: etiology and pathogenesis”. Clin Cornerstone. 8 (5): 5–11. Text “pmid 17379162” ignored (help)
Causes

Causes

Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:[4][5]

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]

Overview

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.

Causes

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

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, 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

References

  1. ↑ James J, Dutta TK, Jayanthi S. (1997). “Correlation of clinical and hematologic profiles with bone marrow responses in typhoid fever”. Am J Trop Med Hyg. 57 (3): 313–6. Text “pmid 9311642” ignored (help)
  2. ↑ Fried D, Maytal J, Hanukoglu A. (1982). “The differential leukocyte count in shigellosis”. Infection. 10 (1): 13–4. Text “pmid 7068229” ignored (help)
  3. ↑ al-Eissa Y, al-Nasser M. (1993). “Haematological manifestations of childhood brucellosis”. Infection. 21 (1): 23–6. Text “pmid 8449576” ignored (help)
  4. ↑ Syrjälä H. (1986). “Peripheral blood leukocyte counts, erythrocyte sedimentation rate and C-reactive protein in tularemia caused by the type B strain of Francisella tularensis”. Infection. 14 (2): 51–4. Text “pmid 3710592” ignored (help)
  5. ↑ Hall GW, Schwartz RP. (1979). “White blood cell count and differential in Rocky Mountain spotted fever”. N C Med J. 40 (4): 212–4. Text “pmid 286884” ignored (help)
  6. ↑ Dale DC, Wolff SM. (1973). “Studies of the neutropenia of acute malaria”. Blood. 41 (2): 197–206. Text “pmid 4575057” ignored (help)
  7. ↑ Schooley RT, Densen P, Harmon D, Felsenstein D, Hirsch MS, Henle W, Weitzman S. (1984). “Antineutrophil antibodies in infectious mononucleosis”. Am J Med. 76 (1): 85–90. Text “pmid 6318560” ignored (help)
  8. ↑ 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.
  9. ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). “Idiosyncratic drug-induced agranulocytosis: Update of an old disorder”. Eur J Intern Med. 17 (8): 529–35. Text “pmid 17142169” ignored (help)

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Differentiating Agranulocytosis from Other Diseases

Differentiating Agranulocytosis from Other Diseases

Consider the following differential when evaluating a patient with agranulocytosis:

Epidemiology and Demographics

Epidemiology and Demographics

  • Agranulocytosis is an extremely rare condition.
  • The overall incidence rate is 7.2 per million per year.[6]
  • It can occur in all races and any age group.
  • The acquired type of agranulocytosis is more common in older individuals. While inherited type is commonly seen in children.
  • The risk of agranulocytosis is seen higher in women.[7]

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

Overview

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.

Epidemiology and Demographics

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]

References

  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.
  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.
  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.
  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.
  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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Risk Factors

Risk Factors

Risk factors for agranulocytosis include:

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

Overview

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.

Risk Factors

References

  1. ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). “Idiosyncratic drug-induced agranulocytosis: Update of an old disorder”. Eur J Intern Med. 17 (8): 529–35. Text “pmid 17142169” ignored (help)

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Screening

Screening

There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.[13]

Natural History, Complications, and Prognosis

Natural History, Complications, and Prognosis

Natural History

Complications

The major complications of agranulocytosis are as follows:[14]

Prognosis

The negative prognostic factors for agranulocytosis are:[15]

Diagnosis

Diagnosis

Diagnostic Study of Choice

The diagnosis of agranulocytosis is based on the laboratory finding when the number of granulocytes (Neutrophils, Basophils, Eosinophils) is below an absolute count of 500 cells/mcL.

History and Symptoms

History of patients with agranulocytosis should focus on any history of:[16]

Common symptoms include:[16]

Physical Examination

Common signs of agranulocytosis may include:

Laboratory Findings

The following tests should be performed after careful medication history:

Some patients may need:

Electrocardiogram

There are no ECG findings associated with agranulocytosis.

X-ray

There are no x-ray findings associated with agranulocytosis. However, an x-ray may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with agranulocytosis.

CT scan

There are no CT scan findings associated with agranulocytosis. However, a CT scan may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

MRI

There are no MRI findings associated with agranulocytosis. However, a MRI may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

Other Imaging Findings

There are no other imaging findings associated with agranulocytosis.

Other Diagnostic Studies

There are no other diagnostic studies associated with agranulocytosis.

Treatment

Treatment

Medical Therapy

  • Discontinuation of the offending agent
    • Identifying and removing the offending agents
    • It takes about 1-3 weeks for neutropenia to resolve after stopping the offending drug.
  • Bone marrow transplant
    • When other treatments do not work, bone marrow transplant is an option.
    • It is more successful in patients aged <40 years old in good health.

Surgery

There are no surgical treatments for agranulocytosis. However, in patients with neutropenic fever, surgical intervention may be necessary depending on the source of infection.[13]

Primary Prevention

Primary prevention of agranulocytosis is dependent upon:

Secondary Prevention

Effective measures for the secondary prevention of agranulocytosis include early detection and treatment of underlying conditions.

See also

See also

References

References

  1. ↑ Dameshek W. (1944). “Leukopenia and Agranulocytosis”. Oxford University Press. 1: 841–52. Text “NLM ID 39120200R” ignored (help)
  2. ↑ Pontikoglou, Charalampos; Papadaki, Helen A. (2010). “Idiosyncratic Drug-Induced Agranulocytosis: The Paradigm of Deferiprone”. Hemoglobin. 34 (3): 291–304. doi:10.3109/03630269.2010.484791. ISSN 0363-0269.
  3. ↑ Uetrecht, Jack; Zahid, Nasir; Tehim, Ashik; Mim Fu, J; Rakhit, Suman (1997). “Structural features associated with reactive metabolite formation in clozapine analogues”. Chemico-Biological Interactions. 104 (2–3): 117–129. doi:10.1016/S0009-2797(97)00017-3. ISSN 0009-2797.
  4. ↑ Andersohn F, Konzen C, Garbe E. (2007). “Systematic review: agranulocytosis induced by nonchemotherapy drugs”. Ann Internal Med. 146(9): 657–65. Text “PMID 17470834” ignored (help)
  5. ↑ Andersohn, Frank; Konzen, Christine; Garbe, Edeltraut (2007). “Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs”. Annals of Internal Medicine. 146 (9): 657. doi:10.7326/0003-4819-146-9-200705010-00009. ISSN 0003-4819.
  6. ↑ Strom, Brian L. (1992). “Descriptive Epidemiology of Agranulocytosis”. Archives of Internal Medicine. 152 (7): 1475. doi:10.1001/archinte.1992.00400190095018. ISSN 0003-9926.
  7. ↑ Alvir, Jose Ma. J.; Lieberman, Jeffrey A.; Safferman, Allan Z.; Schwimmer, Jeffrey L.; Schaaf, John A. (1993). “Clozapine-Induced Agranulocytosis — Incidence and Risk Factors in the United States”. New England Journal of Medicine. 329 (3): 162–167. doi:10.1056/NEJM199307153290303. ISSN 0028-4793.
  8. ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). “Idiosyncratic drug-induced agranulocytosis: Update of an old disorder”. Eur J Intern Med. 17 (8): 529–35. Text “pmid 17142169” ignored (help)
  9. ↑ Levy M, Kelly JP, Kaufman DW, Shapiro S (October 1993). “Risk of agranulocytosis and aplastic anemia in relation to history of infectious mononucleosis: a report from the international agranulocytosis and aplastic anemia study”. Ann. Hematol. 67 (4): 187–90. PMID 8218540.
  10. ↑ Casato, Milyia; Pucillo, Leopoldo P.; Leoni, Marco; di Lullo, Luca; Gabrielli, Armando; Sansonno, Domenico; Dammacco, Franco; Danieli, Giovanni; Bonomo, Lorenzo (1995). “Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: Evidence for a synergistic hematologic toxicity”. The American Journal of Medicine. 99 (4): 386–391. doi:10.1016/S0002-9343(99)80186-7. ISSN 0002-9343.
  11. ↑ Corzo D, Yunis JJ, Salazar M, Lieberman JA, Howard A, Awdeh Z, Alper CA, Yunis EJ (November 1995). “The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups”. Blood. 86 (10): 3835–40. PMID 7579351.
  12. ↑ Tamai, Hajime (1996). “Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease”. Annals of Internal Medicine. 124 (5): 490. doi:10.7326/0003-4819-124-5-199603010-00005. ISSN 0003-4819.
  13. ↑ 13.0 13.1 Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. (2011). “Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america”. Clin Infect Dis. 52 (4): e56–95. PMID 21258094.
  14. ↑ Andrès, Emmanuel; Maloisel, Frédéric; Zimmer, Jacques (2010). “The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis”. British Journal of Haematology. doi:10.1111/j.1365-2141.2010.08104.x. ISSN 0007-1048.
  15. ↑ Andrès, Emmanuel; Maloisel, Frédéric; Zimmer, Jacques (2010). “The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis”. British Journal of Haematology. doi:10.1111/j.1365-2141.2010.08104.x. ISSN 0007-1048.
  16. ↑ 16.0 16.1 16.2 Andrès, Emmanuel; Zimmer, Jacques; Mecili, Mustapha; Weitten, Thierry; Alt, Martine; Maloisel, Frédéric (2014). “Clinical presentation and management of drug-induced agranulocytosis”. Expert Review of Hematology. 4 (2): 143–151. doi:10.1586/ehm.11.12. ISSN 1747-4086.
  17. ↑ Tesfa, Daniel; Keisu, Marianne; Palmblad, Jan (2009). “Idiosyncratic drug-induced agranulocytosis: Possible mechanisms and management”. American Journal of Hematology. 84 (7): 428–434. doi:10.1002/ajh.21433. ISSN 0361-8609.
  18. ↑ Schimpff S, Satterlee W, Young VM, Serpick A (1971). “Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia”. N Engl J Med. 284 (19): 1061–5. PMID 4994878.
  19. ↑ Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M (2006). “Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock”. Crit Care Med. 34 (6): 1589–96. PMID 16625125.
  20. ↑ Rosa RG, Goldani LZ. (2014). “Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia”. Antimicrob Agents Chemother. 58 (7): 3799–803. PMID 24752269.

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