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]
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 < 0.5 x 109/L.
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
Classification
The term "agranulocytosis" derives from the Greek: a, meaning without; granulocyte, a particular kind of white blood cell (containing granules in its cytoplasm); and osis, meaning condition [esp. disorder]. Consequently, agranulocytosis is sometimes described as "no granulocytes", but a total absence is not required for diagnosis. However, "-osis" is commonly used in blood disorders to imply cell proliferation (such as in "leukocytosis"), while "-penia" to imply reduced cell numbers (as in "leukopenia"); for these reasons, granulopenia is a more etymologically consistent term, and as such, is sometimes preferred to "agranulocytosis" (which can be misinterpreted as "agranulocyt-osis", meaning proliferation of agranulocytes (i.e. lymphocytes and monocytes). Despite this, "agranulocytosis" remains the most widely used term for the condition.
The terms agranulocytosis, granulocytopenia and neutropenia are sometimes used interchangeably. Agranulocytosis implies a more severe deficiency than granulocytopenia. Neutropenia indicates a deficiency of neutrophils (the most common granulocyte cell) only.
To be precise, neutropenia is the term normally used to describe absolute neutrophil counts (ANCs) of less than 500 cells per microlitre, whereas agranulocytosis is reserved for cases with ANCs of less than 100 cells per microlitre.
The following terms can be used to specify the type of granulocyte referenced:
- Inadequate numbers of neutrophils: neutropenia (most common)
- Inadequate numbers of eosinophils: eosinopenia (uncommon)
- Inadequate numbers of basophils: basopenia (very rare)
In a general sense the pathogenesis of neutropenia can be divided into two categories;
- Inadequate or ineffective formation of granulocytes. This can be due to bone marrow failure such that occurs in aplastic anaemia, several leukaemias and chemotherapeutic agents. There can also be isolated neutropenias where only differentiated granulocyte precursors are affected as in the case of neoplastic proliferation of cytotoxic T cells or NK cells
- Accelerated destruction of neutrophils. Immune-mediated reactions to neutrophils which can be caused by drugs. An enlarged spleen can lead to splenic sequestration and accelerated removal of neutrophils. Utilization of neutrophils can occur in infections[1]
Pathophysiology
Causes
A large number of drugs[2] 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[3] the antidepressant mirtazapine, and some antipsychotics (the atypical antipsychotic clozapine[4]). 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.[5] Levamisole is an antihelminthic (i.e. deworming) drug used in animals. The reason for adding levamisole to cocaine is unknown,[6] 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
- ↑ 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.