Agranulocytosis

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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] Nazia Fuad M.D.

Synonyms and Keywords: Agranulosis, granulocytopenia, neutropenia

Overview

Agranulocytosis is a hematological disorder characterized by the acute-onset of severe neutropenia. Neutrophils - a subset of white blood cell - normally make up 50-70% of circulating white blood cells and serve as the primary defense against infections. Hence, patients with neutropenia are more susceptible to infections, mainly bacterial; without prompt medical attention, the condition is often life-threatening. Similar to severe neutropenia in the setting of infection, cases related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression are considered a medical emergency.

Agranulocytosis is defined as severe neutropenia with an absolute neutrophil count (ANC) <500 cells/microliter.

While agranulocytosis technically refers to a reduction in all cells in the leukocyte lineage (neutrophils, eosinophils, and basophils), the vast majority of cases refer to neutropenia as neutrophils constitute the majority of leukocytes and the primary defense against infection.

Historical Perspective

  • Agranulocytosis 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]

Classification

Agranulocytosis is often used interchangeably with severe neutropenia. Calculated based on complete blood count differential, agranulocytosis is loosely defined as an absolute neutrophil count (ANC) less than 500, 200, or 100 cells per microliter, with mild and moderate neutropenia defined below.[2] The ANC 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 or Agranulocytosis: ANC <500 cells/microliter

This distinction is important diagnostically and prognostically. Patients with ANC <500 cells/microliter are at a markedly increased risk for severe infections and those <100 cells/microliter have just over a 3-fold increased risk of mortality[2] Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.

Pathophysiology

Agranulocytosis develops as a result of the following mechanisms:[3]

  • Immune mediated destruction of granulocytes
    • The drugs or its active metabolite act as hapten, and binds to neutrophil membrane.
    • Autoantibodies are produced as a result of this binding.
    • This results in destruction of sensetized neutrophils by phagocytosis.
    • Most common drugs are, propylthiouracil, amodiaquine , mono-desethyl amodiaquine, and flecainide
  • Direct damage of granulocytes
    • Some drugs releases chemically active metabolites.
    • These metabolites bind to cytoplasmic proteins or proteins in the nucleus.
    • This results in direct toxicity and destruction of granulocytes.
    • Chlorpromazine. dapsone, clozapine and procainamide are few examples of the drugs.
    • Granulocytes oxidize clozapine releasing nitrenium ions.[4]
    • Nitrenium ions bind irreversibly to granulocytes and its precursor cells resulting in toxic destruction of these cells.

Causes

Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:[2][5]

  • Medications
    • Clozapine
    • Deferiprone
    • Thionamides
    • Sulfasalazine
    • Ticlopidine
    • Rituximab
    • Quinine
    • Trimethoprim-sulfamethoxazole
  • Chemotherapy
  • Bone marrow transplant
  • Systemic Lupus erythramatosis
  • Rheumatoid arthritis
  • HIV
  • Hepatitis
  • Leukemia
  • Myelodysplasia

Differentiating Agranulocytosis from Other Diseases

Agranulocytosis is a laboratory diagnosis based off of the complete blood count differential, however the differential diagnosis for the etiology of neutropenia and agranulocytosis is quite important as patients can deteriorate rapidly without appropriate treatment.

Consider the following differential when evaluating a patient with agranulocytosis:

  • Drug-induced: An idiosyncratic (dose-independent) reaction. Accounts for 65-75% of all cases of agranulocytosis in the United States. More commonly presents with isolated neutropenia in the absence of anemia or thrombocytopenia.[6]
  • Malignant: Typically, a dose-dependent reduction in neutrophils to cytotoxic chemotherapy, malignant infiltration of the bone marrow, or immune-mediated hemolysis. Often seen concurrently with severe anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy.
  • Autoimmune: Antibody-mediated neutrophil destruction.[7]

Epidemiology and Demographics

  • Agranulocytosis is extremly rare condition
  • The overall incidence rate is 7.2 per million per year[8]
  • It can occur in all races and any age group
  • The acquired type of agraulocytosis is more common in older individuals
  • Inherited type is commonly seen in children.
  • The risk of agranulocytosis is seen higher in women[9]

Risk Factors

Risk factors for agranulocytosis include:

  • Acquired conditions

Screening

There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.[15]

Natural History, Complications, and Prognosis

Natural History

  • Neutropenia, and progression to agranulocytosis, occurs in either a dose-dependent or idiosyncratic process dependent upon the etiology.
  • Neutropenia caused by cytotoxic chemotherapy or malignant bone marrow infiltration is typically dose-dependent or related to tumor burden, as opposed to
  • Idiosyncratic, and immune-mediated neutopenia occur independently.

Complications

The major complications of agranulocytosis are as follows[16]

  • Septicemia
  • Bacterial infections
  • Fungal infections
  • Pneumonia
  • Fever
  • Mouth ulcers

Prognosis

The negative prognostic factors for agranulocytosis are:[17]

  • Neutrophil count at the time of diagnosis <0.1 × 109/l
  • Age > 65yrs
  • Advancement in to severe infections like se[tic shock, bacteremia
  • Pre existance of systemic infections, renal, cardiac and respiratory diseases.

History and Symptoms

History

History of patients with agranulocytosis should focus on any history of:

  • Malignancy
  • Infection
  • Autoimmune disorders
  • Medications

Symptoms

Common symptoms include:

Physical Examination

Common signs of agranulocytosis may include:

Laboratory Findings

Treatment

Medical Therapy

  • Discontinuation of the offending agent
    • Identifying and removing the offending agents,
  • Treat the associated infections and conditions
    • In cases of febrile neutropenia, empiric antibiotics should be implemented as early as possible after cultures are drawn and within 60 minutes of presentation
    • .[18][19][20] Initial antibiotic selection should provide broad bactericidal coverage of the most common, virulent, and likely pathogens so as not to rely on assistance from the host's impaired immune system
    • . Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.
  • Use of granulocyte-colony stimulating factor

There is no specific medical therapy for agranulocytosis. Treatment is directed at identifying and removing the offending agents, treating the underlying disease, and monitoring closely for signs of infection and treating quickly and aggressively. Recombinant granulocyte-colony stimulating factor (G-CSF) may be considered to accelerate myeloid reconstitution.[21] These patients often warrant urgent hospitalization for close monitoring and treatment. Furthermore, in cases of drug-induced agranulocytosis, reinitiating the offending agent is contraindicated as this reaction is likely to recur.

In cases of febrile neutropenia, empiric antibiotics should be implemented as early as possible after cultures are drawn and within 60 minutes of presentation, as there is significantly higher mortality when antibiotic administration is delayed.[18][19][20] Initial antibiotic selection should provide broad bactericidal coverage of the most common, virulent, and likely pathogens so as not to rely on assistance from the host's impaired immune system. Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.

Surgery

There are no surgical treatments for agranulocytosis. In patients with neutropenic fever, surgical intervention may be necessary depending on the source of infection.[15]

Prevention

Prevention of agranulocytosis is dependent upon avoiding certain medications or treatment of underlying conditions. Occasionally, when agranulocytosis is anticipated, such as in the setting of cytotoxic chemotherapy, recombinant G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

See also

References

  1. Dameshek W. (1944). "Leukopenia and Agranulocytosis.". Oxford University Press. 1: 841–52. 
  2. 2.0 2.1 2.2 Andersohn F, Konzen C, Garbe E. (2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs.". Ann Internal Med. 146(9): 657–65. 
  3. Pontikoglou, Charalampos; Papadaki, Helen A. (2010). "Idiosyncratic Drug-Induced Agranulocytosis: The Paradigm of Deferiprone". Hemoglobin. 34 (3): 291–304. ISSN 0363-0269. doi:10.3109/03630269.2010.484791. 
  4. 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. ISSN 0009-2797. doi:10.1016/S0009-2797(97)00017-3. 
  5. Andersohn, Frank; Konzen, Christine; Garbe, Edeltraut (2007). "Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs". Annals of Internal Medicine. 146 (9): 657. ISSN 0003-4819. doi:10.7326/0003-4819-146-9-200705010-00009. 
  6. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. PMID 17470834. doi:10.7326/0003-4819-146-9-200705010-00009. 
  7. 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. 
  8. Strom, Brian L. (1992). "Descriptive Epidemiology of Agranulocytosis". Archives of Internal Medicine. 152 (7): 1475. ISSN 0003-9926. doi:10.1001/archinte.1992.00400190095018. 
  9. 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. ISSN 0028-4793. doi:10.1056/NEJM199307153290303. 
  10. 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. 
  11. 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. 
  12. 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. ISSN 0002-9343. doi:10.1016/S0002-9343(99)80186-7. 
  13. 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. 
  14. 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. ISSN 0003-4819. doi:10.7326/0003-4819-124-5-199603010-00005. 
  15. 15.0 15.1 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. 
  16. 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. ISSN 0007-1048. doi:10.1111/j.1365-2141.2010.08104.x. 
  17. 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. ISSN 0007-1048. doi:10.1111/j.1365-2141.2010.08104.x. 
  18. 18.0 18.1 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. 19.0 19.1 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. 20.0 20.1 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. 
  21. Aapro MS; et al. (2011). "2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors". Eur J Cancer. 47 (1): 8–32. PMID 21095116. 



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