Agranulocytosis: Difference between revisions
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* '''Severe Neutropenia or [[Agranulocytosis]]:''' ANC <500 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. Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection. | 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 (10% vs. 3%; p <0.001). <ref name="PMID17470834">{{cite journal |author=Andersohn F, Konzen C, Garbe E. |title=Systematic review: agranulocytosis induced by nonchemotherapy drugs.|journal=Ann Internal Med.|volume=146(9)|pages=657-65|year=2007|PMID 17470834}}</ref> 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). Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection. | ||
==Pathophysiology== | ==Pathophysiology== | ||
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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]
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, and 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, or severe 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]
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 (10% vs. 3%; p <0.001). [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). 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 one of the three following mechanisms:
- Impaired granulocyte production
- Aplastic anemia
- Hematologic malignancy with bone marrow infiltration
- Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow
- Nutritional deficiencies
- Margination: the process by which free flowing blood cells are signaled to adhere to the endothelial wall and exit circulation.
- Splenic sequestration and destruction
- Adherence to the vascular endothelium
- Accelerated peripheral destruction[3]
Causes
A large number of drugs[4] have been associated with agranulocytosis, including Aubagio immunomodulatory agent with anti-inflammatory properties, antiepileptics, antithyroid drugs (carbimazole, methimazole, and propylthiouracil), antibiotics (penicillin, chloramphenicol and co-trimoxazole), cytotoxic drugs, gold, NSAIDs (indomethacin, naproxen, phenylbutazone, metamizole), mebendazole, allopurinol[5] the antidepressant mirtazapine, and some antipsychotics (the atypical antipsychotic clozapine[6]). Clozapine users in the United States, Canada, and the UK must be nationally registered for monitoring of low WBC and absolute neutrophil counts (ANC).
Although the reaction is generally idiosyncratic rather than proportional, experts recommend that patients using these drugs be told about the symptoms of agranulocytosis-related infection, such as a sore throat and a fever.
The Centers for Disease Control traced outbreaks of agranulocytosis among cocaine users, in the US and Canada between March 2008 and November 2009, to the presence of levamisole in the drug supply. The Drug Enforcement Administration reported that, as of February 2010, 71% of seized cocaine lots coming into the US contained levamisole as a cutting agent.[7] Levamisole is an antihelminthic (i.e. deworming) drug used in animals. The reason for adding levamisole to cocaine is unknown,[8] although it can be due to their similar melting points and solubilities.
Differentiating [Disease] from Other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications, and Prognosis
Natural History
Complications
Prognosis
Diagnosis
Diagnostic Criteria
The diagnosis is made after a complete blood count, a routine blood test. The absolute neutrophil count in this test will be below 500, and can reach 0 cells/mm³. Other kinds of blood cells are typically present in normal numbers.
To formally diagnose agranulocytosis, other pathologies with a similar presentation must be excluded, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplasia and leukemias. This requires a bone marrow examination that shows normocellular (normal amounts and types of cells) blood marrow with underdeveloped promyelocytes. These underdeveloped promyelocytes, if fully matured, would have been the missing granulocytes.
History and Symptoms
Physical Examination
Agranulocytosis may be asymptomatic, or may clinically present with sudden fever, rigors and sore throat. Infection of any organ may be rapidly progressive (e.g., pneumonia, urinary tract infection). Septicemia may also progress rapidly.
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
In patients that have no symptoms of infection, management consists of close monitoring with serial blood counts, withdrawal of the offending agent (e.g., medication), and general advice on the significance of fever.
Transfusion of granulocytes would have been a solution to the problem. However, granulocytes live only ~10 hours in the circulation (for days in spleen or other tissue), which gives a very short-lasting effect. In addition, there are many complications of such a procedure.
Surgery
There are no surgical treatments for agranulocytosis. In patients' with neutropenic fever, surgical intervention may be necessary depending on the source of infection.
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
- ↑ Dameshek W. (1944). "Leukopenia and Agranulocytosis". Oxford University Press. 1: 841–52. Text "NLM ID 39120200R" ignored (help)
- ↑ 2.0 2.1 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)
- ↑ Kumar, Vinay (2007). Robbins Basic Pathology (8 ed.). 441: Elsevier.
- ↑ Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. doi:10.7326/0003-4819-146-9-200705010-00009. PMID 17470834.
- ↑ Elisa Mari; Franco Ricci; Davide Imberti; Massimo Gallerani (June 2011). "Agranulocytosis: an adverse effect of allopurinol treatment". Italian Journal of Medicine. 5 (2): 120–3. doi:10.1016/j.itjm.2011.02.006.
- ↑ Diaz, Jaime (1996). How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall. ISBN 0132815605.
- ↑ U.S. Department of Justice; National Drug Intelligence Center (February 2010). "Colombian Cocaine Producers Increase Use of a Harmful Cutting Agent". National Drug Threat Assessment 2010.
- ↑ "Agranulocytosis associated with cocaine use — four States, March 2008–November 2009". MMWR Morb. Mortal. Wkly. Rep. 58 (49): 1381–5. December 2009. PMID 20019655. Cited in Hsu, Jeremy (18 December 2009). "Majority of U.S. Cocaine Supply Cut with Veterinary Deworming Drug". Popular Science.