Agranulocytosis
Encyclopedia
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia
(lowered white blood cell
count), most commonly of neutrophils causing a neutropenia
in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells. People with this condition are at very high risk of serious infections due to their suppressed immune system
.
In agranulocytosis, the concentration of granulocyte
s (a major class of white blood cells that includes neutrophils, basophils, and eosinophils) drops below 100 cells/mm³ of blood, which is less than 5% of the normal value.
s", 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 should be preferred compared to "agranulocytosis" (which can be misinterpreted as "agranulocyt-osis", meaning proliferation of agranulocytes (ie lymphocytes and monocytes)
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 count
s (ANC) of less than 500 cells per microlitre, whereas agranulocytosis is reserved for cases with ANC of less than 100 cells per microlitre.
The following terms can be used to specify the type of granulocyte referenced:
, 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.
Neutropenia and agranulocytosis are associated with gum diseases, such as gingival bleeding
, saliva increase, halitosis, osteoporosis, and destruction of periodontal ligament.
have been associated with agranulocytosis, including antiepileptics, antithyroid drugs (carbimazole
, methimazole
, and propylthiouracil
), antibiotics (penicillin
, chloramphenicol
and co-trimoxazole
), cytotoxic drugs, gold, NSAIDs (indomethacin, naproxen
, phenylbutazone
, metamizole
), mebendazole
, the antidepressant mirtazapine
, and some antipsychotic
s (the atypical antipsychotic clozapine
). Clozapine users in the US 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 Center for Disease Control recently 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
. Levamisole is an antihelminthic (i.e. deworming) drug used in animals. The reason for adding levamisole to cocaine is unknown, although it can be due to their similar melting points and solubilities.
, 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 leukemia
s. This requires a bone marrow examination that shows normocellular (normal amounts and types of cells) blood marrow with underdeveloped promyelocyte
s. These underdeveloped promyelocytes, if fully matured, would have been the missing granulocytes.
Infection in patients with low white blood cell
counts is usually treated urgently, and usually includes a broad-spectrum penicillin or cephalosporin (piperacillin-tazobactam, ceftazidime
or ticarcillin clavulanate), or meropenem
in combination with gentamicin
or amikacin
.
If the patient remains febrile after 4–5 days and no causative organism for the infection has been identified, antibiotics are, in general, changed to a glycopeptide (e.g., vancomycin
), and subsequently an antifungal agent (e.g., amphotericin B
) is added to the regimen. In agranulocytosis, the use of recombinant G-CSF (filgrastim
) often results in hematologic recovery.
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.
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
(lowered white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
count), most commonly of neutrophils causing a neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells. People with this condition are at very high risk of serious infections due to their suppressed immune system
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
.
In agranulocytosis, the concentration of granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s (a major class of white blood cells that includes neutrophils, basophils, and eosinophils) drops below 100 cells/mm³ of blood, which is less than 5% of the normal value.
Classification
The term "agranulocytosis" derives from the Greek: a, meaning without; granulocyte, a particular kind of cell; osis, from the Greek, meaning condition [esp. disorder]. Consequently, agranulocytosis is sometimes described as "no granulocyteGranulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s", 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 should be preferred compared to "agranulocytosis" (which can be misinterpreted as "agranulocyt-osis", meaning proliferation of agranulocytes (ie lymphocytes and monocytes)
The terms agranulocytosis, granulocytopenia and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
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 count
Absolute neutrophil count
Absolute neutrophil count is a measure of the number of neutrophil granulocytes present in the blood...
s (ANC) of less than 500 cells per microlitre, whereas agranulocytosis is reserved for cases with ANC of less than 100 cells per microlitre.
The following terms can be used to specify the type of granulocyte referenced:
- Inadequate numbers of neutrophils: neutropeniaNeutropeniaNeutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
(most common) - Inadequate numbers of eosinophils: eosinopeniaEosinopeniaEosinopenia is a form of agranulocytosis where the number of eosinophil granulocyte is lower than expected.Leukocytosis with eosinopenia can be a predictor of bacterial infection....
(uncommon) - Inadequate numbers of basophils: basopeniaBasopeniaBasopenia is a form of agranulocytosis associated with a deficiency of basophils.One cause is urticaria.It has been proposed as an indicator of ovulation....
(very rare)
Signs and symptoms
Agranulocytosis may be asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, or may clinically present with sudden fever, rigors and sore throat. Infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
of any organ may be rapidly progressive (e.g., pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
). Septicemia
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
may also progress rapidly.
Neutropenia and agranulocytosis are associated with gum diseases, such as gingival bleeding
Bleeding on probing
250px|right|thumb|Straight [[periodontal probe]] at left, and Nabers probe on the right.Bleeding on probing which is also known as bleeding gums or gingival bleeding is a term used by dentists and dental hygienists when referring to bleeding that is induced by gentle manipulation of the tissue at...
, saliva increase, halitosis, osteoporosis, and destruction of periodontal ligament.
Causes
A large number of drugshave been associated with agranulocytosis, including antiepileptics, antithyroid drugs (carbimazole
Carbimazole
Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents the thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the...
, methimazole
Methimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
, and propylthiouracil
Propylthiouracil
Propylthiouracil or 6-n-Propylthiouracil is a thioamide drug used to treat hyperthyroidism by decreasing the amount of thyroid hormone produced by the thyroid gland...
), antibiotics (penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
and co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
), cytotoxic drugs, gold, NSAIDs (indomethacin, naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, phenylbutazone
Phenylbutazone
Phenylbutazone, often referred to as bute, is a non-steroidal anti-inflammatory drug for the short-term treatment of pain and fever in animals. In the United States, it is no longer approved for human use.-In humans:...
, metamizole
Metamizole
Metamizole sodium or dipyrone is a powerful analgesic and antipyretic. It is marketed under various trade names, including Algozone, Algocalmin, Analgin, Dipirona, Novalgin, Neo-Melubrina and Optalgin. Metamizole was first synthesized by the German company Hoechst AG in 1920, and its mass...
), mebendazole
Mebendazole
Mebendazole or MBZ is a benzimidazole drug developed by Janssen Pharmaceutica and marketed as Vermox, Ovex, Antiox, and Pripsen...
, the antidepressant mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
, and some antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s (the atypical antipsychotic clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
). Clozapine users in the US 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 Center for Disease Control recently traced outbreaks of agranulocytosis among cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
users, in the US and Canada between March 2008 and November 2009, to the presence of levamisole
Levamisole
Levamisole is an anthelminthic and immunomodulator belonging to a class of synthetic imidazothiazole derivatives. It was discovered at Janssen Pharmaceutica in 1966...
in the drug supply. The Drug Enforcement Administration
Drug Enforcement Administration
The Drug Enforcement Administration is a federal law enforcement agency under the United States Department of Justice, tasked with combating drug smuggling and use within the United States...
reported that, as of February 2010, 71% of seized cocaine lots coming into the US contained levamisole as a cutting agent
Cutting agent
A cutting agent is a chemical used to "cut" illicit drugs with something less expensive than the drug itself.-Overview:The classical model of drug cutting A cutting agent is a chemical used to "cut" (dilute) illicit drugs with something less expensive than the drug itself.-Overview:The classical...
. Levamisole is an antihelminthic (i.e. deworming) drug used in animals. The reason for adding levamisole to cocaine is unknown, although it can be due to their similar melting points and solubilities.
Diagnosis
The diagnosis is made after a complete blood countComplete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
, 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
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
, paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
, myelodysplasia and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s. This requires a bone marrow examination that shows normocellular (normal amounts and types of cells) blood marrow with underdeveloped promyelocyte
Promyelocyte
A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte.-External links: - "18. Bone Marrow and Hemopoiesis: bone marrow smear, promyelocyte and erythroblasts " "Bone marrow" "Bone marrow"* - "Bone marrow smear"...
s. These underdeveloped promyelocytes, if fully matured, would have been the missing granulocytes.
Treatment
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.Infection in patients with low white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
counts is usually treated urgently, and usually includes a broad-spectrum penicillin or cephalosporin (piperacillin-tazobactam, ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
or ticarcillin clavulanate), or meropenem
Meropenem
Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
in combination with gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
or amikacin
Amikacin
Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.-Administration:Amikacin may be...
.
If the patient remains febrile after 4–5 days and no causative organism for the infection has been identified, antibiotics are, in general, changed to a glycopeptide (e.g., vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
), and subsequently an antifungal agent (e.g., amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
) is added to the regimen. In agranulocytosis, the use of recombinant G-CSF (filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
) often results in hematologic recovery.
Transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
of granulocytes would have been a solution to the problem. However, granulocytes live only ~10 hours in the circulation (for days in spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
or other tissue), which gives a very short-lasting effect. In addition, there are many complications of such a procedure.