Acquired agranulocytosis is rare, also known as agranulosis or granulopenia, a drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells (granulocytes) in the circulating blood. Agranulocytosis is a condition in which the absolute neutrophil count (ANC) is less than 100 neutrophils per microlitre of 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.
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, granulocytopenia is a more etymologically consistent term, and as such, is sometimes referred to “agranulocytosis” (which can be misinterpreted as “agranulocytosis”, 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 associated with aplastic anemia, leukemia, or 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
- The accelerated destruction of neutrophils. Immune-mediated reactions to neutrophils 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[8]
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, 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 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.
The following are the medications commonly involved with agranulocytosis:
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Cancer chemotherapies
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Analgesic and anti-inflammatory (gold, naproxen, and penicillamine)
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Anti-arrhythmics (quinidine, procainamide)
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Anti-hypertensives (captopril, enalapril, nifedipine)
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Anti-depressants/psychotropics (clozapine, amitriptyline, dosulepin, mianserin)
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Anti-malarials (pyrimethamine, dapsone, sulfadoxine, chloroquine)
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Anticonvulsants (phenytoin, sodium valproate, carbamazepine)[rx]
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Antibiotics (sulphonamides, penicillin, cephalosporins)[rx]
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Miscellaneous (cimetidine, ranitidine, chloropropamide, zidovudine)[rx]
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Bacterial (typhoid fever, shigella enteritis, brucellosis, tularemia, tuberculosis)
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Rickettsial (rickettsialpox, human granulocytic anaplasmosis, Rocky Mountain spotted fever)
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Parasitic (kala-azar, malaria)
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Viral (human immune deficiency, Epstein-Barr virus, cytomegalovirus, hepatitis viruses, human herpesvirus 6)
Autoimmune conditions such as lupus, rheumatoid arthritis, and bone marrow diseases like myelodysplastic and leukemias are also associated with agranulocytosis.
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 every week.
A history of a new medication used or a change in medication, recent exposure to chemical or physical agents, or recent viral or bacterial infection is usually associated with agranulocytosis. A history of autoimmune disease or a strong family history of recurrent infection usually beginning from early childhood may be present. The initial symptoms are often malaise, fever, and chills, or infections, which usually present in the form of ulcers, necrotizing lesions of the gingiva, the floor of the mouth, buccal mucosa, pharynx, or other sites within the oral cavity.[rx] Pharyngitis, with difficulty in swallowing and multiple skin abscesses, could be another presentation of the disease. As the onset of agranulocytosis can be abrupt, sepsis can be the presentation. On examination, a fever usually more than 40 degrees Celcius, tachycardia, tachypnea, and hypotension are usually present.
The diagnosis of agranulocytosis requires a high degree of suspicion based on signs and symptoms, medication use, recent exposure to chemical agents, and infections. A complete blood count (CBC) with the differential count is used in the initial workup. An absolute neutrophil count (ANC) of less than 100 neutrophils per microlitre of blood is necessary to diagnose the condition. The peripheral blood smear should assess neutrophil morphology. A Wright-stained peripheral smear will show a marked decrease and absence of neutrophils. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), coagulation studies (prothrombin time, partial thromboplastin time, D-dimer), lactate dehydrogenase (LDH), antinuclear antibody (ANA), rheumatoid factor (RF), liver function tests (LFT), renal function tests (RFT), and urine analysis can be used in patients with relevant history. If the patient is febrile, cultures of the blood, urine, sputum and other suspected sites of infection should be taken. No imaging technique is used to diagnose agranulocytosis, but a chest X-ray (CXR) can be used for the initial workup. Further, bone marrow aspiration and biopsy can be used after an initial abnormal blood smear.
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 a 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 granulocytopenia 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.)
Agranulocytosis is a serious condition, and prompt treatment for it should be initiated. Once agranulocytosis is documented, any suspected offending medications or agents should be removed regardless of whether the patient is symptomatic or not. If it is due to drugs or offending agents, it usually resolves after one to three weeks after the offending agent is stopped. Meanwhile, general care like oral hygiene to prevent infection of the mucosa and teeth, control of oral and gingival lesion pain with anesthetic gel, and gargles are helpful. Stool softeners can be used in case of constipation. Skin infection and abrasion should be treated promptly.
Hematopoietic growth factors are used to accelerate the production, maturation, migration, and cytotoxicity of the neutrophils.[rx] Filgrastim, a granulocyte colony-stimulating factor (G-CSF),[rx] sargramostim, a granulocyte-macrophage colony-stimulating factor, and pegfilgrastim (a long-acting filgrastim) are the agents used to treat agranulocytosis.
In case of infection, start specific antibiotic therapy with third-generation cephalosporins or equivalent. Cefepime,[rx] carbapenems,[rx] (e.g., meropenem, imipenem-cilastatin), or piperacillin-tazobactam can be used. In suspected cases of resistant bacteria, vancomycin or linezolid can be used in methicillin-resistant Staphylococcus aureus (MRSA). Linezolid or daptomycin can be used in cases of vancomycin-resistant enterococcus. Carbapenems can be used in the case of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria. If the patient’s fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval, consider adding empiric antifungal coverage with amphotericin B (preferably lipid formulation), a broad-spectrum azole (e.g., voriconazole), or an echinocandin (e.g., caspofungin).
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
Agranulocytosis treatment includes:
- Granulocyte colony-stimulating factor (G-CSF): Your provider may recommend injections of a drug to help your body produce white blood cells, specifically neutrophils, faster. Your provider may prescribe filgrastim (Neupogen®), pegfilgrastim (Neulasta®), or lenograstim (Granocyte®).
- Immunosuppressant drugs: If an autoimmune disorder causes agranulocytosis, your provider may recommend medicines such as prednisone. These medications suppress (calm down) the immune system.
- Bone marrow transplant: If other treatments aren’t effective, you may need a bone marrow transplant. During this procedure, you receive bone marrow from a donor so you can produce more white blood cells.
- Preventing infection: People with agranulocytosis should be careful to avoid infection. Wash your hands often, avoid crowds and wear a face-covering in public.
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