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Agranulocytosis, Acquired

Synonyms of Agranulocytosis, Acquired

  • Agranulocytic Angina
  • Granulocytopenia, Primary
  • Neutropenia, Malignant

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders can be similar to those of Acquired Agranulocytosis. Comparisons may be useful for a differential diagnosis:

Chronic Granulomatous Disease is a very rare blood disorder that affects specialized white blood cells (i.e., neutrophils) and is characterized by widespread granular lesions in many areas of the body. People with this disorder have repeated infectious diseases, including abscesses of the liver; respiratory infections and pneumonia; and inflammation of the lymph nodes (suppurative lymphadenitis) and the spinal cord (osteomyelitis). Chronic infections may be evident in the liver, gastrointestinal tract, eyes, and/or brain. (For more information on this disorder, choose "Granulomatous Disease" as your search term in the Rare Disease Database.)

Wegener's Granulomatosis is a rare multisystem disease that is characterized by inflammation and degenerative changes in the blood vessels that serve the lungs and upper respiratory tract. Acute inflammation may also occur in the blood vessels of the kidneys (glomerulonephritis). The symptoms vary greatly among affected individuals, and the disease can be limited to one or more systems of the body. The first symptoms of Wegener's Granulomatosis is usually those of an upper respiratory tract infection including nasal discharge, headache, and coughing accompanied by a mucous discharge. Other early symptoms may include fever, a general feeling of ill health, and weight loss. Symptoms that develop later in the course of the disease may affect the eyes, facial nerves, central nervous system, and/or heart. (For more information on this disorder, choose "Wegener's Granulomatosis" as your search term in the Rare Disease Database.)

Sarcoidosis is a rare disorder that affects many systems of the body. It is characterized by small round lesions (tubercles) of granular material. Symptoms vary depending on the severity of the disease. They may be absent, slight, or severe. Organ function may be impaired by active granulomatous disease or by fibrous changes that are associated with acute inflammation. The initial symptoms may include fever, weight loss, and/or joint pain. Persistent fever is especially common with liver (hepatic) involvement. Enlargement of lymph glands is also common and usually without symptoms. The lungs and the lymph glands between the lungs are frequently affected, and symptoms may include coughing and difficulty breathing. (For more information on this disorder, choose "Sarcoidosis" as your search term in the Rare Disease Database.)

Leukemia is a group of malignant blood diseases affecting the white blood cells (leukocytes). These leukocytes play an important part in the body's defenses against infection. Leukemia can affect both children and adults. Symptoms may include swollen lymph nodes, an enlarged spleen and liver, fevers, weight loss, paleness, fatigue, easy bruising, excessive bleeding, and/or repeated infections. (For more information on this disorder, choose "Leukemia" as your search term in the Rare Disease Database.)

Myelofibrosis-Osteosclerosis is a rare disorder that is characterized by the growth of fibrous tissue in the bone marrow. This will result in anemia, generalized weakness, and fatigue due to low levels of red blood cells. Severe pain in the abdomen, bones, and joints may also occur. (For more information on this disorder, choose "Myelofibrosis" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Treatment
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.)

Investigational Therapies

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.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Agranulocytosis, Acquired

References

TEXTBOOK
Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:909.

Fauci AS, Braunwald E, Isselbacher KJ, et al. Eds. Harrison's Principles of Internal Medicine. 14th ed.McGraw-Hill Companies. New York, NY; 1998:354-55.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:931-34.

REVIEW ARTICLES
Andres E, Kurtz JE, Maloisel F. Non-chemotherapy drug-induced agranulocytosis: experience of the Strasbourg teaching hospital. Clin Lab Haematol. 2002;24:99-106.

Carlsson G, Fasth A. Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original "Kostmann family" and a review. Acta Paediatr. 2001;90:757-64.

Sheng WH, Hung CC, Chen YC et al. Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM. 1999;92:455-61.

Beauchesne MF, Shalansky SJ. Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factor. Pharmacotherpay. 1999;19:299-305.

Guest I, Uetrecht J. Drugs that induce neutropenia/agranulocytosis may target specific components of the stromal cell extracellular matrix. Med Hypotheses. 1999;53:145-51.

JOURNAL ARTICLES
Hagg S, Rosenius S, Spigset O. Long-term combination treatment with clozapine and filgrastim in patients with clozapine-induced agranulocytosis. Int Clin Psychopharmacol. 2003;18:173-74.

Joseph F, Younis N, Bowen-Jones D. Treatment of carbimazole-induced agranulocytosis and sepsis with colony-stimulating factor. Int J Clin Pract. 2003;57:145-46.

Iverson S, Zahid N, Uetrecht JP. Predicting drug-induced agranulocytosis: Characterizing neutrophil-generated metabolites of a model compound, DMP 406, and assessing the relevance of an in vitro apoptosis assay for identifying drugs that may cause agranulocytosis. Chem Biol Interact. 2002;10:175-99.

Andres E, Maloisel F, Kurtz JE, et al. Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med. 2002;13:324-28.

Patel NC, Dorson PG, Bettinger TL. Sudden late onset of clozapine induced agranulocytosis. Ann Pharmacother. 2002;36:1012-15.

Andres E, Kurtz JE, Martin-Hunyadi C, et al. Nonchemotherpay drug-induced agranulocytosis in elderly patients: the effects of granulocyte colony-stimulating factor. Am J Med. 2002;15:460-64.

FROM THE INTERNET
eMedicine - Agranulocytosis : Article by Ariel Distenfeld, MD
www.emedicine.com/med/topic82.htm

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2007/09/17 00:00:00 GMT+0

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