eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Agranulocytosis

Author: Ariel Distenfeld, MD, Clinical Professor, Department of Medicine, New York University School of Medicine
Contributor Information and Disclosures

Updated: Dec 11, 2008

Introduction

Background

Agranulocytosis is characterized by a greatly decreased number of circulating neutrophils. Severe neutropenia is the term usually applied to patients with fewer than 500 neutrophils per microliter (μL) (including bands). Agranulocytosis usually refers to patients with fewer than 100 neutrophils/μL.^1,2,3,4

The reduced number of neutrophils makes patients extremely vulnerable to infection.^1,5 Cardinal symptoms include fever, sepsis, and other manifestations of infection. Causes can include drugs, chemicals, infective agents, ionizing radiation, immune mechanisms, and heritable genetic aberrations.

This article is limited to discussing agranulocytosis (absolute neutrophil count [ANC] of <100/µL).The transient neutropenia associated with cancer chemotherapy is not included in this discussion, nor is agranulocytosis occurring as part of general marrow-failure syndromes (eg, aplastic anemia, pancytopenia).

Pathophysiology

Agranulocytosis may be broadly divided into 2 groups: hereditary disease due to genetic mutations and acquired disease.

Hereditary disease due to genetic mutations

Many hereditary disorders are due to mutations in the gene encoding neutrophil elastase, or ELA2. Several alleles are involved. The most common mutations are intronic substitutions that inactivate a splice site in intron 4. Genes other than ELA2 are also involved.

The table below summarizes the genetic conditions; these are uncommon conditions. A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect.

Genetic Conditions in Agranulocytosis⁶

Open table in new window

Source: Modified from Berliner et al, 2004.⁶

AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome.

Acquired disease

Acquired agranulocytic disease may be due to drugs, chemicals, autoimmunity, infectious agents, or other causes.

Bone marrow and peripheral blood are the organ systems affected. Agranulocytosis is characterized by inadequate production of neutrophils, excessive destruction of neutrophils, or both. The resulting infections tend to involve the oral cavity, mucous membranes, and skin. Systemic life-threatening sepsis may ensue. The most common infecting organisms are staphylococci, streptococci, gram-negative organisms, and anaerobes. Fungi are also commonly involved as secondary infective agents.

The occurrence of infection depends on the degree and duration of neutropenia. When the ANC is persistently fewer than 100/µL for longer than 3-4 weeks, the incidence of infection approaches 100%.

Frequency

United States

The exact frequency of agranulocytosis is unknown.

International

The estimated frequency of agranulocytosis is 1.0-3.4 cases per million population per year.

Mortality/Morbidity

• If agranulocytosis is untreated, the risk of dying is high. Death results from uncontrolled sepsis.
• If the condition can be reversed with treatment, the risk of dying is low. Antibiotic and antifungal medications can cure the infection if the ANC rises.
• Morbidity is entirely due to infections that complicate agranulocytosis. The infections may be superficial, involving mainly the oral mucosa, gums, skin, and sinuses, or they may be systemic, with life-threatening septicemia.

Race

Agranulocytosis has no racial predilection.

Sex

Agranulocytosis occurs slightly more frequently in women than in men, possibly because of their increased rate of medication usage. Whether this higher frequency is related to the increased incidence of autoimmune disease in women is unknown.

Age

• Agranulocytosis occurs in all age groups.
• The congenital forms are most common in childhood.
• Acquired agranulocytosis is most common in the elderly population.⁷

Clinical

History

• Patients with agranulocytosis usually present with the following:
  • Sudden onset of malaise
  • Sudden onset of fever, possibly with chills and prostration
  • Stomatitis and periodontitis accompanied by pain
  • Pharyngitis, with difficulty in swallowing
• If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may become life threatening.
• The most commonly involved organisms are from endogenous flora.
  • Staphylococcus aureus organisms are found in cases of skin infections.
  • Gram-negative organisms are observed in infections of the urinary and gastrointestinal tracts, particularly Escherichia coli and Pseudomonas species. Candida albicans infections may also occur.
  • Mixed flora may be found in the oral cavity.
• Patients often report a history of a new drug being used or a recent change in medication. However, the offending medication may no longer be in use; therefore, the inquiry should extend back for some time.
• Occupational or accidental exposure to chemicals or physical agents (eg, ionizing radiation) may have occurred.^8,9
• The patient may have experienced a recent viral infection, although such infections are rarely associated with severe neutropenia. Certain bacterial infections may also precede agranulocytosis.
• A history of periodically recurring infections is suggestive of cyclic neutropenia.
• A history of autoimmune diseases may be associated with antineutrophil antibodies. Such antibodies may also be the only manifestation of autoimmune disease. A number of test methods are available, but none is widely used.
• Primary immune neutropenia is uncommon.
• Secondary immune neutropenia may be associated with systemic lupus erythematosus, rheumatoid arthritis, and Felty syndrome.^10,11,12
• A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect.

Physical

• Fever may be present (temperature often 40 º C or higher).
• Rapid pulse and respiration may be evident.
• Hypotension and signs of septic shock if infection has been present
• Painful aphthous ulcers may be found in the oral cavity.
• Swollen and tender gums may be present.
• Usually, purulent discharge is not present, because not enough neutrophils exist to form pus.
• Skin infections are associated with painful swelling, but erythema and suppuration are usually absent.

Causes

• The most common cause of agranulocytosis is exposure to drugs or chemicals. About one half of patients have a history of medication or chemical exposure. The patient's history must be carefully taken to elicit this information.
  • Any chemical or drug that can depress the bone marrow and cause hypoplasia or aplasia is capable of causing agranulocytosis. Some drugs do this to everyone if they are administered in large enough doses. Other agents seem to cause idiosyncratic reactions that affect only certain susceptible individuals.
  • The mechanisms that cause neutropenia are not completely understood. In many cases, neutropenia occurs after prolonged exposure, resulting in decreased neutrophil production by hypoplastic bone marrow. In other cases, repeated but intermittent exposure is needed. This suggests an immune mechanism, although this idea has not been proven.
  • A drug may act as a hapten and induce antibody formation. This mechanism operates in cases due to gold, aminopyrine, and antithyroid drugs. The antibodies destroy the granulocytes and may not require the continued presence of the drug for their action. As an alternative, the drug may form immune complexes that attach to the neutrophils. This mechanism operates with quinidine.
  • Another mechanism is direct inhibition of myelopoiesis. Valproic acid, carbamazepine, and beta-lactam antibiotics act by this mechanism. In bone marrow cultures, these agents inhibit granulocyte colony formation in a dose-related fashion.
  • Direct damage to the bone-marrow microenvironment or myeloid precursors plays a role in most other cases.
• Many drugs associated with agranulocytosis have been reported to the US Food and Drug Administration (FDA) under its adverse reactions reporting requirement. Many agents are also reported to a registry maintained by the American Medical Association (AMA). The reported drugs were used alone, in combination with another drug known to be potentially toxic, or with another drug without known toxicity. Several drugs are salient because of their high frequency of association with agranulocytosis. They include the following:
  • Phenothiazine
  • Antithyroid drugs (thiouracil and propylthiouracil)
  • Aminopyrine
  • Phenylbutazone
  • Chloramphenicol
  • Sulfonamides
• Drugs reported to be associated with agranulocytosis include the following:
  • Analgesics
    • Acetaminophen
    • Aminopyrine
    • Dipyrone
  • Cardiovascular drugs
    • Captopril
    • Hydralazine
    • Methyldopa
    • Pindolol
    • Procainamide
    • Propranolol
    • Quinidine
  • Antibiotics
    • Cephalosporins
    • Clindamycin
    • Chloramphenicol
    • Doxycycline
    • Gentamicin
    • Griseofulvin
    • Isoniazid
    • Metronidazole
    • Nitrofurantoin
    • Penicillins
    • Rifampin
    • Streptomycin
    • Sulfonamides
    • Vancomycin
  • Diuretics
    • Acetazolamide
    • Bumetanide
    • Chlorothiazide
    • Hydrochlorothiazide
    • Chlorthalidone
    • Methazolamide
    • Spironolactone
  • Anticonvulsants
    • Carbamazepine
    • Mephenytoin
    • Phenytoin
    • Primidone
    • Trimethadione
  • Hypoglycemic agents
    • Chlorpropamide
    • Tolbutamide
  • Antihistamines
    • Brompheniramine
    • Cimetidine
    • Tripelennamine
    • Ranitidine
    • Thenalidine
  • Phenothiazines
    • Chlorpromazine
    • Clozapine
    • Desipramine
    • Prochlorperazine
    • Promazine
    • Thioridazine
    • Trifluoperazine
    • Trimeprazine
  • Anti-inflammatory drugs
    • Fenoprofen
    • Gold salts
    • Ibuprofen
    • Indomethacin
    • Phenylbutazone
  • Neuropharmacologic agents
    • Chlordiazepoxide
    • Clozapine
    • Desipramine
    • Meprobamate
    • Metoclopramide
    • Prochlorperazine
    • Promazine
  • Antimalarials
    • Amodiaquine
    • Dapsone
    • Hydroxychloroquine
    • Pyrimethamine
    • Quinine
  • Miscellaneous drugs
    • Allopurinol
    • Colchicine
    • D-Penicillamine
    • Ethanol
    • Levamisole
    • Levodopa
  • Antithyroid agents
    • Carbimazole
    • Methylthiouracil
    • Propylthiouracil
• Viral infections often lead to mild or moderate neutropenia. Agranulocytosis is uncommon but may occur. The most common organisms are Epstein-Barr virus, hepatitis B virus, yellow fever virus, cytomegalovirus, and influenza.
• Many overwhelming infections, both viral and bacterial, may cause severe neutropenia.
• Autoimmune neutropenia is the neutrophil analogue of autoimmune hemolytic anemia and of idiopathic thrombocytopenic neutropenia. It should be considered in the absence of any of the common causes. Antineutrophil antibodies have been demonstrated in these patients.
• Cyclic neutropenia is characterized by periodic bouts of agranulocytosis associated with infection.
  • Cyclic neutropenia has a periodicity of about 21 days (range, 12-35 d).
  • Granulocyte precursors disappear from the marrow before each neutrophil nadir in the cycle because of accelerated apoptosis of myeloid progenitor cells.¹³
  • Some cases may be genetically determined with an autosomal recessive inheritance. Other cases may be due to an autosomal dominant inheritance.
• Several uncommon causes of severe neutropenia include Kostmann syndrome, chronic severe neutropenia, and myelokathexis.
  • Kostmann syndrome (severe congenital neutropenia) is most often caused by a recessive inheritance and found in remote, isolated populations with a high degree of consanguinity. Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the G-CSF receptor. A risk of conversion to MDS/AML with monosomy 7 exists after treatment with G-CSF.
  • Chronic severe neutropenia has an underlying unknown cause.
  • Myelokathexis occurs in early infancy and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors.

• Search for CME/CE on This Topic »

• Granulocytopenia (Hematology)
• Kostmann Disease (Pediatrics: General Medicine)
• White Blood Cell Function (Pediatrics: General Medicine)
• Neutropenia (Hematology)

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