Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells (granulocytes) in the circulating blood. The name granulocyte refers to grain-like bodies within the cell. Granulocytes include basophils, eosinophils, and neutrophils.
Acquired agranulocytosis may be caused by a variety of drugs. However, among the drugs to which a patient may be sensitive are several used in the treatment of cancer (cancer chemotherapeutic agents) and others used as antipsychotic medications (e.g., clozapine). The symptoms of this disorder come about as the result of interference in the production of granulocytes in the bone marrow.
People with acquired agranulocytosis are susceptible to a variety of bacterial infections, usually caused by otherwise benign bacteria found in the body. Not infrequently, painful ulcers also develop in mucous membranes that line the mouth and/or the gastrointestinal tract.
The first symptoms of acquired agranulocytosis are usually those associated with a bacterial infection such as general weakness, chills, fever, and/or extreme exhaustion. Symptoms that are associated with rapidly falling white blood cell levels (granulocytopenia) may include the development of infected ulcers in the mucous membranes that line the mouth, throat, and/or intestinal tract. Some people with these ulcers may experience difficulty swallowing due to irritation and pain.
Granulocytopenia causes a concurrent decrease in the number of neutrophils in the circulating blood (neutropenia). As neutrophil levels decrease, the susceptibility of patients with acquired agranulocytosis to bacterial infections becomes even greater. Fevers and abnormal enlargement of the spleen (splenomegaly) are characteristic features of neutropenia. If neutropenia is not treated, bacterial infections can lead to life-threatening complications such as bacterial shock or bacterial contamination of the blood (sepsis.) (For more information on this disorder, choose “Neutropenia” as your search term in the Rare Disease Database.)
Chronic acquired agranulocytosis generally progresses more slowly than acquired agranulocytosis. Canker sores in the mouth and chronic inflammation of the gums (gingivitis) may be recurring symptoms. Other systemic infections may recur regularly.
Acquired agranulocytosis is almost invariably caused by exposure to drugs and/or chemicals. Any chemical or drug that depresses the activity of the bone marrow may cause agranulocytosis. Some drugs cause this reaction in anyone given large enough doses. Other drugs may cause the reaction in one person but not in another (idiosyncratic). Clinicians do not understand why some people are susceptible to agranulocytosis and others are not.
In some instances, the action of some drugs or chemicals suggests that the immune system is involved. In the case of gold, or anti-thyroid drugs, or quinidine, among others, antibodies are created that appear to break the granulocytes down.
Other drugs that interfere with, or inhibit, granulocyte colony formation may induce agranulocytosis. Drugs with this characteristic include valproic acid, carbamazepine, and the beta-lactam antibiotics.
A complicating factor is that several commonly used anti-cancer drugs are prone to cause agranulocytosis, thus interfering with treatment. The same may be said for several anti-psychotic medications.
A variety of drugs can cause acquired agranulocytosis and neutropenia by destroying special cells in the bone marrow that later mature and become granulocytes (precursors). These drugs include phenytoin, pyrimethamine, methotrexate, and cytarabine. In rare cases of acute acquired agranulocytosis, destructive action of certain white blood cell antibodies (leukocyte isoantibodies) may be induced by certain drugs such as phenylbutazone, gold salts, sulfapyridine, aminopyrine, meralluride, and dipyrine.
Acquired Agranulocytosis is a rare blood disorder that affects males and females in equal numbers. People who are taking certain medications such as cancer drugs, alkylating agents, anti-thyroid drugs, dibenzepin compounds, or other drugs can be at risk for this disorder.
The diagnosis of acquired agranulocytosis is made by combining a thorough history with tests to confirm abnormally low levels of granulocytes in the circulating blood. Regular periodic blood testing is required for individuals who take drugs that place them at high risk for acquired agranulocytosis. In some cases (e.g., people who are taking clozapine), blood tests to monitor granulocyte levels are done on a weekly basis.
Filgrastim (Neupogen) has been designated an orphan drug and approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe, chronic neutropenia; and it has become a standard treatment for acquired agranulocytosis. Filgrastim is one of a class of colony-stimulating factors that does, indeed, stimulate the proliferation and differentiation of neutrophils. It is manufactured by Amgen, Inc., using recombinant DNA technology.
The treatment of acquired agranulocytosis includes the identification and elimination of drugs or other agents that induce this disorder. Antibiotic medications may also be prescribed if there is a positive blood culture for the presence of bacteria or if a significant local infection develops.
Treatment in adults with antibiotics should be limited to about 7-10 days since longer duration carries with it a greater risk of kidney (renal) complications and may set the stage for a new infection. When granulocyte levels return to a near normal range, fever and infections will generally subside.
There is no definitive therapy that can stimulate bone marrow (myeloid) recovery. Corticosteroids are sometimes used to treat shock induced by overwhelming bacterial infection. However, these drugs are not recommended for the treatment of acute agranulocytopenia because they may mask other bacterial infections.
People with abnormally low levels of immune factors in their blood (hypogammaglobulinemia) associated with acquired agranulocytosis are usually treated with infusions of gamma globulin.
Mouth and throat ulcers associated with acquired agranulocytosis can be soothed with gargles of salt (saline) or hydrogen peroxide solutions. Anesthetic lozenges may also help to relieve irritation in the mouth and throat. Mouthwashes that contain the antifungal drug nystatin can be used to treat oral fungal infection (i.e., thrush or candida). A semi-solid or liquid diet may become necessary during episodes of acute oral and gastrointestinal inflammation. (For more information on this disorder, choose "Candidiasis" as your search term in the Rare Disease Database.)
People with chronic granulocytopenia associated with acquired agranulocytosis need to be hospitalized during acute episodes of infection. These affected individuals should be taught to recognize the early symptoms and signs of acute infection and to seek immediate medical attention when necessary. The therapy for chronically affected individuals is similar to that for the acute form of the disease. People with chronic granulocytopenia, who take low-dose oral antibiotics on a rotating basis, must also be monitored for the infections caused by drug-resistant bacteria as well as infections with opportunistic organisms (e.g., fungi, cytomegalovirus). (For more information on this disorder, choose "Opportunistic Infections" as your search term in the Rare Disease Database.)
Acquired agranulocytosis, granulocytosis, granulocytopenia, and other related blood disorders may be helped by new biotechnology drugs including granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF). G-CSF and GM-CSF may stimulate the production and development of immature blood cells that later become granulocytes, ultimately increasing the number of granulocytes in the blood. These treatments are currently under investigation, and more studies are needed to determine the long-term safety and effectiveness of these factors for the treatment of acquired agranulocytosis.
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eMedicine – Agranulocytosis : Article by Ariel Distenfeld, MD
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